Medical form and method for delivery of habit-forming medical substances

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, and deals with medical form and method for delivery of medical substances, in particular, dependence habit-forming medical substances, which are characterised by stability to solvent extraction, compression, crushing and milling.

EFFECT: ensuring initial fast release of medicinal substance with following continuous period of controlled release of medicinal substance.

42 cl, 9 ex, 34 tbl, 22 dwg

 

Technical field of invention

The present invention relates to compositions for oral administration. The present invention preferably include at least one providing resistance to based compositions for drug delivery, with the ability to cause dependence, related to methods of producing such dosage forms and methods of treatment of a patient in need thereof, comprising administration to the patient of the compositions according to this invention.

Background of the invention

Dependence on prescribed drugs has become a public health problem in many communities. One common class of drugs that cause dependence, is the class of opioids. Opioids are a major class of analgesics used for pain management of moderate to severe degree in the United States, due to their efficiency, ease of titration and favourable balance of risks and benefits.

One of the effects of administration of opioids is the ability of such drugs in some individuals to change the mood and feelings so that appeared desirable sense of "well-being", disconnected from therapeutic effects of mitigation. This effect mood changes some is that individuals consider very pleasant, and this may be due to the fact that some consumers have a high risk of the use of illegal drugs and addiction to the use of opioids.

The U.S. has identified three main models of opioid dependence. One model involves individuals, the use of which the medicinal substance begins in terms of medical treatment and who initially receive drug through medical authorities. Another model involves individuals, the use of which medicinal substances begins with experimental or "recreational" drug substance and becomes more intensive application of medicinal substances. Finally, there are the consumers, who are beginning to use medicinal substances obtained from medical institutions or through the way of recreational drugs, but later switched to oral opioids through an organized program of addiction treatment.

Dependence on opioids, administered by mouth, is significant. However, it turns out that another significant problem for opioid dependence is opioid dependence on medicinal substances, administered by parenteral administration, in particular by injection. It is known that the rapid injection of Joigny agonists leads to the calling warming rush of blood to the skin and excitement. Condition, an alternative known as "pleasure", "satisfaction" or "excitement", as a rule, lasts for only 45 seconds, but addicts have found it very enjoyable. Dependent individuals extracted solid dosage forms of opioids, and then injected them to achieve this status. It is also known that opioids cause addiction by nasal administration, where the potential addictive drug is crushed and pulverized and inhale through the nose.

Some of the current pharmacological methods to prevent extraction of oral opioids include one or more opioid antagonists, mixed opioid agonists-antagonists and other negative action of medicinal substances with therapeutic opioid agonist. In most of the proposed systems, the dose of opioid antagonist is not orally active, however, it would be desirable to block for dependent persons, the effects of medicinal substances-agonist or mixed medicinal substance agonist-antagonist, when the medicinal substance is dissolved to obtain agonist (or mixed medicinal substance agonist-antagonist), and then injected parenteral opioid. However, in these cases, doctors may fear that the Nene is improper release of causing negative effects of drug substances can be harmful, and some of them are not willing to prescribe opioids, made in conjunction with causing the negative action of medicinal substances.

For example, the lack of approaches with the inclusion of an opioid antagonist to opioid drug to prevent addiction is that opioid antagonists themselves have side effects that may be adverse. For example, nalorfin causes unpleasant reactions, such as anxiety, irrational feelings, hallucinations, respiratory depression, and miosis. In the case of naloxone described fainting, though infrequently, and in patients after surgery when high doses have revealed pulmonary edema and ventricular fibrillation. Described that naltrexone can cause liver cell damage when the doses already five times or less greater than therapeutic doses. Described that nalmefene, although it is usually well tolerated, in some individuals may cause nausea, vomiting and tachycardia. Small doses of any of these opioid antagonists can also force a withdrawal syndrome in dependent on opioids individuals, even in low doses, an effect that can be extremely dangerous, depending on where the dependent individual takes the drug.

Similarly, opioids, many other classes of drugs also causes the ut dependence, although the nature and effects according to somewhat different.

In WO 2005/079760 (Euroceltique) described extruded melt compositions with controlled release of a variety of particles containing a neutral copolymer of poly(acrylate, methacrylate) and the active ingredient. Indicates that the compositions have koutsokoumnis properties, so they are more resistant to compression.

US 2003/0118641 (Boehringer Ingelheim) relates to a method of reducing capacity in the dependency relationship of oral dosage forms of opioid extractable commonly available household solvents, with the specified method comprises combining a therapeutically effective amount of an opioid compound, the matrix polymer and the ion-exchange resin. Preferred are ion-exchange resins, which exhibit the properties of a strong acid.

WO 00/041481 (Knoll) refers to the forms of drugs containing the active substance with high solubility in the matrix based on acrylate polymers.

Publication of patent application U.S. No. 2006/0002860 (Bartholomaus et al.) refers to resistant to compression of the compositions of medicinal substances suitable in the case of addictive drugs.

Despite the fact that there are many compositions, compositions and methods aimed Rotel dependence on medicinal substances, all compositions, compositions and methods are limitations to a greater or lesser extent. Thus, there is a need to provide new and/or improved formulations, compositions and methods of preventing dependence on medicinal substances that have the potential to cause dependency.

This information about the level of equipment provided for the transmission of some information, which, as suggested by the applicant, may be related to the present invention. Not implied assumptions, and should not be construed that any one of the preceding information constitutes prior art to the present invention.

The invention

Certain preferred embodiments of the present invention relate to pharmaceutical forms and methods of delivery of drugs, particularly addictive drugs, characterized by resistance to solvent extraction, compression, crushing or grinding, and provides the initial release of medicinal substance with subsequent prolonged period of supervised release of medicinal substance.

One illustrative variant implementation of the present invention is to prevent the dependence of the composition of medicinal substances, with the holding subjected to melting a mixture of: a) at least one caller dependence of medicinal substance, b) at least one simple cellulose ether or a complex of cellulose ether and (c) at least one alkylalkoxysilane polymer, alcacaltro polymer or combinations thereof. In this embodiment, the amount of medicinal substance, which is extracted from the composition 40% aqueous ethanol within one hour at 37°C, is less than or equal to double the amount of medicinal substance, which is extracted in 0.01 N hydrochloric acid within one hour at 37°C, and the composition of medicinal substances adapted so that it was suitable for oral administration to a human 3, 2 or 1 time per day.

Another illustrative variant implementation of the present invention relates to monolithic oral pharmaceutical composition with delayed release containing subjected to melting a mixture of: (a) effective for analgesia amount of at least one of the calling dependence of medicinal substance, (b) at least one simple cellulose ether or a complex of cellulose ether and (c) at least one alkylalkoxysilane polymer, alcacaltro polymer or combinations thereof. In this embodiment, the amount of medicinal substance, which is extracted from the composition 40% aqueous ethanol within one h is sa at 37°C, is less than or equal to double the amount of medicinal substance, which is extracted in 0.01 N hydrochloric acid within one hour at 37°C; and a medicinal composition of matter adapted for slow release, so it was suitable for oral administration to a human 3, 2 or 1 time per day.

Another illustrative variant implementation of the present invention relates to oral pharmaceutical composition with delayed release of drug substance, characterized by at least two of the following characteristics: (a) the amount of medicinal substance, which is extracted from the composition 40% aqueous ethanol within one hour at 37°C, is less than or equal to double the amount of medicinal substance, which is extracted in 0.01 N hydrochloric acid within one hour at 37°C, (b) the composition does not collapse under the force of 150 Newtons, preferably 300 Newtons, more preferably 450 Newtons, more preferably 500 Newton, as determined using the Vickers hardness "Pharma Test PTB 501", and (c) the composition releases at least 15% of one drug and not more than 45% of one medicinal substance within the first hour of testing dissolutionin vitroand preferably alsoin vivo.

Another and lucratively option of implementing the present invention relates to unground extruded melt composition of medicinal substance, containing the medicinal substance with the potential to cause drug dependency.

Illustrative variant implementation of the present invention also relates to a monolithic, unground, not consisting of many particles, extruded melt composition of medicinal substance containing a medicinal substance with the potential to cause drug dependency, having a diameter of approximately at least 5.1 mm to about 10 mm and a length of from about 5.1 mm to about 30 mm

Another illustrative variant implementation of the present invention relates to a method for producing stable to addiction dosage pharmaceutical composition of matter comprising extruding a melt of a composition containing at least one therapeutic agent, including additional direct shaping of the extrudate dosage forms without intermediate grinding stage or the stage of the formation of many particles.

Another illustrative variant implementation of the present invention relates to a monolithic, unground, extruded melt composition of medicinal substance containing a medicinal substance with the potential to cause drug dependency, where a monolithic composition has essentially a profile in which osvobojdenie medicinal substance, similar to crushed form a monolithic composition, where a monolithic composition is crushed when from about 20,000 rpm to about 50000 rpm in a machine for grinding coffee for about 60 seconds c device for grinding with stainless steel blades, a motor of about 150 watts, and capacity for approximately 90 ml (i.e. approximately 3 ounces) of coffee beans.

Another illustrative variant implementation of the present invention is to prevent the dependence of the composition of medicinal substance containing subjected to melting a mixture of: a) at least one calling the dependence of the drug, b) at least one modifying the speed pharmaceutically acceptable polymer, copolymer, or combinations thereof. In this embodiment, the amount of medicinal substance, which is extracted from the composition 40% aqueous ethanol within one hour at 37°C, is less than or equal to double the amount of medicinal substance, which is extracted in 0.01 N hydrochloric acid within one hour at 37°C; and a medicinal composition of matter adapted to ensure that it was suitable for oral administration to a human 3, 2 or 1 time per day.

Another illustrative variant of implementation of the present invented the I refers to preventing the dependence of the composition of medicinal substance, containing subjected to melting a mixture of: a) at least one caller dependence of medicinal substance, where the specified medicinal substance is a hydrocodone (or pharmaceutically acceptable salt, such as of hydrocodone bitartrate pentahedra), (b) at least one simple cellulose ether or a complex of cellulose ether and (c) at least one acrylic polymer, methacrylic polymer, or combinations thereof. In this embodiment, the pharmaceutical composition of matter adapted to ensure that it was suitable for oral administration to a human 3, 2 or 1 time per day, and approximately ninety percent of the hydrocodone is releasedin vitrofor about 4-6 hours, when it is adapted for the introduction of 3 times a day, for about 6-10 hours, when it is adapted for the introduction of 2 times a day, and within about 16-22 hours, when it is adapted for the introduction of 1 time per day.

Another illustrative variant implementation of the present invention also relates to preventing dependence of the composition of medicinal substance containing subjected to melting a mixture of: a) at least one opioid and b) at least one modifying the speed pharmaceutically acceptable polymer, copolymer, or combinations thereof. In this embodiment, about what westline quantity of medicinal substance, which is extracted from the composition 40% aqueous ethanol within one hour at 37°C ranged from approximately 70% to 110% of the amount of drug that is extracted in 0.01 N hydrochloric acid within one hour at 37°C; and a medicinal composition of matter adapted to ensure that it was suitable for oral administration to a human 3, 2 or 1 times per day. This and other embodiments of have the desired pharmacokinetic profiles.

In another illustrative embodiment, the present invention relates to a method of treating pain in a patient is a human, comprising oral administration to the patient is a man songs by one of the above embodiments.

These and other aims, advantages and characteristics of this invention will become apparent to experts in this field when reading the detailed description of the methods according to this invention and compositions used in them, as described in more detail below.

Brief description of drawings

The figure 1 presents the rate of dissolution of various dosage forms of medicinal substance 1-6 in 0.01 N hydrochloric acid.

The figure 2 presents the rate of dissolution of various dosage forms of medicinal substance 1-6 20% aqueous solution of ethanol.

In the figure 3 ol dstanley the rate of dissolution of various dosage forms of medicinal substance 7-9 hydrocodone in 0.01 N hydrochloric acid.

The figure 4 presents the rate of dissolution of various dosage forms of medicinal substance 7-9 acetaminophen (APAP; also known as paracetamol) in 0.01 N hydrochloric acid.

The figure 5 presents the rate of dissolution of various dosage forms of medicinal substance 7-9 hydrocodone is a 40% aqueous solution of ethanol.

The figure 6 presents the rate of dissolution of various dosage forms of medicinal substance 7-9 acetaminophen (APAP) in 40% aqueous solution of ethanol.

The figure 7 presents the power measuring transducer and illustrative holder with tablet having a tablet that is used to measure the strength of the tablets.

The figure 8 shows the cylinder with a wedge-shaped tip with certain illustrative dimensions suitable for holding "Pharma Test PTB 501" for measuring the hardness of the tablets.

In figure 9 (A) presents the chemical structure of acetaminophen (APAP), (B) presents the half-life, Cmax, Tmaxand AUC for some embodiments the compositions of this invention (30) after the introduction of the oral dose of this composition (30) males dwarf pigs (Goettingen), (C) presents the average (±SEM) concentrations of acetaminophen in plasma after administration of the oral dose of a variant of implementation of the composition in this image the structure (30) in male dwarf pigs (Goettingen).

In figure 10 (A) presents the half-life, Cmax, Tmaxand AUC for some embodiments the compositions of this invention (form 26, 27, 28, 29, 30), control 1 and control 2 males dwarf pigs (Goettingen) and control 1 person, (B) presents the average (±SEM) concentrations of acetaminophen in plasma after administration of oral doses of certain embodiments of the compositions of this invention (form 26, 27, 28, 29, 30), control 1 and control 2 males dwarf pigs (Goettingen) and composition of control 1 in humans.

The figure 11 presents the mean values (±SEM) concentrations of acetaminophen in plasma after administration of oral doses of some embodiments of the composition according to this invention (forms 26, 27, 28, 29 and 30), control 1 and control 2 males dwarf pigs (Goettingen) and composition of control 1 in humans.

In figure 12 (A) presents the half-life, Cmax, Tmaxand AUC for some embodiments the compositions of this invention (forms 26, 27, 28 and 29), control 1 and control 2 males dwarf pigs (Goettingen) and composition of control 1; (B) presents the average (±SEM) concentrations of acetaminophen in plasma after administration of oral doses of some embodiments of the composition according to this invention (forms 26, 27, 28 and 29), control 1 and control 2 males calico who's pigs (Goettingen) and composition of control 1.

In figure 13 (A) presents the chemical structure of hydrocodone; (B) presents the half-life, Cmax, Tmaxand AUC after administration of oral doses of some embodiments of the composition according to this invention (forms 26, 27, 28 and 29), control 1 and control 2 males dwarf pigs (Goettingen) and composition of control 1; (C) presents the average (±SEM) concentrations of hydrocodone in plasma after administration of oral doses of some embodiments of the composition according to this invention (forms 26, 27, 28 and 29), control 1 and control 2 males dwarf pigs (Goettingen) and composition of control 1.

The figure 14 shows the rate of dissolution of various dosage forms of medicinal substance 32-37 about hydrocodone in 20% aqueous solution of ethanol.

The figure 15 shows the rate of dissolution of various dosage forms of medicinal substance 32-37 about hydrocodone in 0.01 N hydrochloric acid.

In the figure 16 presents the dissolution rate of the dosage form of a medicinal substance 31 relative to the hydrocodone in 0.01 N hydrochloric acid immediately after production and after storage for 1 month at 25°C/60%relative humidity, at 40°C/relative humidity of 75% and at 60°C in dry conditions, respectively.

Figure 17 presents the speed of the process is possible a pharmaceutical form of medicinal substance 31 relative to acetaminophen (APAP) in 0.01 N hydrochloric acid immediately after production and after storage for 1 month at 25°C/60%relative humidity, at 40°C/relative humidity of 75% and at 60°C in dry conditions, respectively.

Figure 18 presents the rate of dissolution of various dosage forms of medicinal substance 32, 34 and 36 relative to acetaminophen (APAP) in 0.01 N hydrochloric acid + 5% NaCl.

The figure 19 shows the rate of dissolution of various dosage forms of medicinal substance 32, 34 and 36 relative to acetaminophen (APAP) in 0.05 M phosphate buffer pH of 6.78.

The figure 20 shows the rate of dissolution of various dosage forms of medicinal substance 32, 34 and 36 relative to acetaminophen (APAP) in 0.01 N HCl and 0.09% NaCl.

Figure 21 presents the rate of dissolution of various dosage forms of medicinal substance 32, 34 and 36 relative to acetaminophen (APAP) in 0.01 N HCl.

On Fig presents the rate of dissolution of various dosage forms of medicinal substance 38-40 about hydrocodone in 0.01 N HCl.

On Fig presents the rate of dissolution of various dosage forms of medicinal substance 38-40 relative to acetaminophen (APAP) in 0.01 N HCl.

On Fig presents the rate of dissolution of various dosage forms of medicinal substance 38-40 regarding hydrocodone is a 40% aqueous solution of ethanol.

On Fig presents the rate of dissolution of various dosage forms of medicinal substance 38-40 is otnositelno acetaminophen (APAP) in 40% aqueous solution of ethanol.

On Fig presents the profiles of the average concentration of acetaminophen-time to form 45 and control 1.

On Fig A and B show the concentration profile of hydrocodone-time a separate entity to form 45 and control 1, respectively.

On Fig A and B presents the profile of the concentration of acetaminophen-time a separate entity to form 45 and control 1, respectively.

In Fig. 30 A and B presents the profile of the average concentration of hydrocodone-time during period 1 and 2 respectively to form 45 and control 1.

In Fig. 31 A and B presents the profile of the average concentration of acetaminophen-time through periods 1 and 2 respectively to form 45 and control 1.

In Fig. 32 A and B presents the average concentrations of hydrocodone and acetaminophen to form 45in vitrocontrolin vitro1, the concentration control 1in vivoandin vitro-in vivothe predicted concentration for the form 45.

In Fig. 33 A and B presents the profiles of the average values of the dissolution of hydrocodone and acetaminophenin vitrofor form 45 and control 1.

Detailed description of the invention

This invention is not limited to specific methods, protocols, animal studies and described reagents, which may vary. Also it should be understood that as used in this document terminology is intended only to describe a particular Varian is s implementation and is not intended to limit the scope of the present invention, which may be limited only by the attached claims.

It should be noted that, as used herein and in the appended claims, the singular includes reference to the plural, unless the context clearly indicates otherwise. Thus, for example, reference to "a compound" includes a number of such compounds and their equivalents, known to specialists in this field, etc. are Also the singular, the terms "one or more" and "at least one" may be used herein interchangeably. It should also be noted that the terms "comprising", "including" and "having" can be used interchangeably.

If not specified differently, all technical and scientific terms used herein have the same meaning as generally understood by the experts in the field to which this invention relates. Although you can use any methods and materials similar or equivalent to the methods and materials described herein, when the practice or testing of the present invention, the preferred methods and materials are described herein. All publications mentioned herein are incorporated herein as references for the purposes of describing and presenting imicheskih substances, animals, instruments, statistical analysis and methods, which are described in the publications which might be used for this invention. Nothing in this document should not be interpreted as the assumption that the present invention does not give the right to date this publication earlier on the basis of previous inventions.

Trade names used in this description as a convenient shorthand for well-known materials. As understood by a person skilled in the field, the following brand names indicate, these substances are:

EUDRAGIT®Polymers formed from esters of acrylic and methacrylic acid

METHOCEL®: Methyl - or methoxycinnamate

KOLLICOAT®: Graft copolymers of polyvinyl alcohol-polyethylene glycol

PLASDONE®: a Polymer or copolymer of polyvinylpyrrolidone

LAUROGLYCOL®: ester of laurate propylene glycol

SPAN®: esters sorbitan and fatty acids

CREMOPHOR®: Polyethoxysiloxane castor oil

POLOXAMER®Copolymers of polyoxyethylene and polyoxypropylene or polyoxyethylene and polypropylenglycol

TWEEN®: esters polyethoxyethanol sorbitan

KLUCEL®: Hydroxypropylcellulose

KOLLIDON®: Homo - and copolymers of polyvinylpyrrolidone

XYLITOL®: (2,3,4,5)Tetrahydroxyphenyl

ISOMALT®: Equimolar to notice 6-0-α-D-glucopyranoside-D-sorbitol (1,6-GPS) and 1-0-α-D-glucopyranoside-D-mannitol-dihydrate (1,1-GPM-dihydrate)

POLYOX®: water-Soluble resin on the basis of polyethylene oxide

XYLIT®: (2,3,4,5)Tetrahydroxyphenyl

PLUROL OLEIQUE®: Oleic esters of polyglycerol

LUTROL®Block copolymers of polyoxyethylene and polyoxypropylene or polyoxyethylene and polypropylenglycol

ETHOCEL®: Ethylcellulose

PRIMOJEL®: Sodium starch glycolate

The present invention relates to improved solid substance or solid solution, oral dosage compositions, which provides slow release ofin vivopharmaceutically active compounds ("drugs"), which have properties, providing the ability to cause dependence, or for which it has been shown that they often cause dependence, as well as their salts, esters, prodrugs and other pharmaceutically acceptable equivalents.

The term "AUC" refers to the area under the curve of the dependence of concentration on time, calculated using the trapezoid rule, and the Clast/k, where Clast is the last observed concentration and k is a calculated rate constant of excretion.

The term "AUCt" refers to the area under the curve of the dependence of concentration on time for the last observed concentration, calculated using the trapezoid rule.

The term "Cmax" refers to the concentration is tion in plasma specified caller dependence of the medicinal substance in T maxexpressed in ng/ml and μg/ml, respectively, which causes oral composition according to this invention. Unless specifically stated otherwise, Cmaxrefers to the total maximum observed concentration.

The term "Cmin" refers to the minimum observed concentration in a certain interval dosing, for example in the interval dosing twelve hours for a track marked as suitable for dosing every 12 hours or if necessary, the dosage form according to this invention, the input for continuous dosing intervals of 5 doses.

The term "ng·h/ml/mg" refers to the amount of a substance, measured in nanograms, multiplied by the number of hours per millilitre of blood, divided by the number of milligrams calling dependence of medicinal substance, administered to an animal or person.

As used herein, the expression "increasing the rate of release" refers to the dissolution rate, which mainly increases over time, so that the medicinal substance is dissolved in the liquid used in the environment with speed, which mainly increases with time and is not constant or does not decrease to depletion of approximately 80% of the drug substance dosage form.

In about the nom preferred embodiment, this invention relates to dosage forms, which inhibit the extraction of the composition of the medicinal substance in the usual solvents, such as, but not limited to, distilled water ethanol. The composition prevents dependence due to limits on the ability of individuals to extract the drug from the composition (either intentionally or unintentionally), so that the opioid is not easy to concentrate for parenteral administration. It also provides stability to the dependence of the composition cannot easily be crushed into smaller particles or in the form of powder, which can easily cause addiction when inhaled through the nose. This provides stability to the composition does not require the inclusion of an opioid antagonist (although opioid antagonist can be added to the drug to prevent additional dependencies). Without regard to any particular theory, I believe that the inclusion of alkylsilanes, such as (but not limited to) hydroxymethylcellulose and preferably hydroxypropylmethylcellulose, leads to the stability of the composition to extraction in alcohol, in particular 20% or 40% aqueous solution of ethanol. Alkylsalicylate preferably has at least 12% by substitution of alkyl Deputy, more preferably at least 16% by substitution of alkyl substituent and most preferably at IU is greater as 19% substitution of the alkyl substituent. Alkyl substitution of the cellulose less than about 40% and more preferably less than about 30% is preferred in the context of this invention. In addition, preferably alkyl substituent represents a C1-C6more preferably C1C2or C4and most preferably C3and it can be straight or branched, when the alkyl substituent contains 3 or more carbon atoms.

In another preferred embodiment, the dosage form are not necessarily resistant to cutting, grinding, pulverizing, etc. Convenient indicator of this aspect of this invention is "strength", as determined by the device for testing hardness "Pharma Test PTB 501". The composition according to this invention preferably has a strength of at least 150 Newtons (150 N). More preferably the composition according to this invention has a strength of at least 300 N, more preferably at least 450 N and more preferably at least 600 N.

Strength in accordance with the present invention can be determined using tablets with a diameter of 10 mm and thickness 5 mm in accordance with the method of determining the strength of the tablets published in the European Pharmacopoeia 1997, page 143, 144, method no. 2.9.8. The preferred device, sportwave to measure strength, is a device for testing materials "Zwick Z 2.5", Fmax= 2.5 kN, maximum movement 1150 mm with installation comprising a column and measuring the tip clearance less than 100 mm and the test speed 0,1800 mm/min Measurement can be made using injection piston with twisted pair insert and cylinder (diameter 10 mm), force transducer (Fmax= 1 kN, diameter = 8 mm, class from 0.5 to 10 N, class 1 from 2 H to ISO 7500-1, the total force Zwick Fmax= 1,45 kN). The optional device can be obtained from Zwick GmbH & Co. KG, Ulm, Germany.

To obtain the compositions of this invention can use any suitable method. In a preferred embodiment, the composition is preferably subjected to melting and more preferably the extrusion melting, and then in any case immediately shape without crushing or grinding the composition. Notwithstanding the foregoing, assume that the tablet composition, which immediately gave the form, can optionally be coated with additive to facilitate ingestion, such as, but not limited to, gelatin coating. Without regard to any particular theory, I believe that the direct shaping to prevent unwanted strongly protruding elements on the composition without premiato the Noah grinding stage leads to the most high strength compositions. In addition, embodiments of the compositions of this invention do not necessarily provide additional strength by using at least two subjected to melting of polymers. Without regard to a particular theory, I believe that the second subjected to melting the polymer preferably communicates with the first subjected to melting of the polymer, so that mainly bring to the junction temperature of the glass composition as a whole during the formation of tablets.

In one embodiment, the composition can be used the polymer or copolymer, or combinations thereof to create subjected to melting and more preferably extruded melt, directly molded composition. It is also possible to use polymers that are pharmacologically inactive and provide an enteric coating or the profile of a delayed release composition. In one embodiment, suitable polymers/copolymers include poly(meth)acrylate, such as Eudragit L or S-type, which are pharmacologically inactive.

EUDRAGIT® is a trading name of some preferred polymers that are suitable for use in this invention and which is formed from esters of acrylic and methacrylic acid. Properties of EUDRAGIT polymers, mainly the m to determine the functional groups included in the monomers of the polymers EUDRAGIT. Separate classes EUDRAGIT® differ in their value neutral, alkaline and acidic groups and, thus, their physico-chemical properties. You can use ammonium-alkyl methacrylate copolymers or methacrylate copolymers having the following formula:

According to 2007 US Pharmacopoeia Eudragit determined according to USP 30 / NF 25

Methacrylic acid copolymer, type a NF = Eudragit L-100

Methacrylic acid copolymer type B NF = Eudragit S-100

Methacrylic acid copolymer, type C NF = Eudragit L-100-55 (contains a small amount of detergent)

Ammonium methacrylate copolymer, type a NF = Eudragit RL-100 (granules)

Ammonium methacrylate copolymer, type a NF = Eudragit RL-PO (powder)

Ammonium methacrylate copolymer type B NF = Eudragit RS-100 (granules)

Ammonium methacrylate copolymer type B NF = Eudragit RS-PO (powder)

The polyacrylate dispersion 30 per cent of Ph. Eur. = Eudragit NE30D (= 30% aqueous dispersion)

The main bottled methacrylate copolymer Ph. Eur. = Eudragit E-100

where the functional group has a group of Quaternary ammonium (trimethylammoniumchloride), or R = COOCH2CH2N+(CH3)SCr [commercially available as EUDRAGIT® (RL or RS)], or a functional group is carbonophobia, or R = COOH [commercially available as EUDRAGIT® (L)]. When the functional group is a carboxylic acid group, the polymer is EUDRAGIT® (L) is stable in the stomach and dissolve in the intestine. Thus, compositions using EUDRAGIT® (L) will be resistant to gastric juice and will release the active substance in the intestine. When the functional group is trimethylammoniumchloride group, polymers EUDRAGIT® (RL or RS) are insoluble, permeable, dispersible and pH-independent. Thus, these polymers EUDRAGIT® (RL or RS) can be used for slow release of the drug substance in compositions with delayed release. EUDRAGIT® is sold in various forms such as a solid form (EUDRAGIT® L100/ S100/ L-100-55, EUDRAGIT® E PO, EUDRAGIT® RL PO, Eudragit RS PO), granules (EUDRAGIT® E 100, EUDRAGIT® RL 100/RS 100), dispersion (L 30 D-55/FS 30D 30%, EUDRAGIT® NE 30 D/40 D 30%/40% of the content of the polymer, EUDRAGIT® RL 30 D and RS 30 D 30%) and organic solutions (EUDRAGIT® L12.5, EUDRAGIT® E12.5, EUDRAGIT® RL 12.5/RS 12.5 - 12.5 percent organic solution).

When using at least two subjected to melting of the polymer, preferably one is a derivative of cellulose, more preferably derived hydroxyethylcellulose and not necessarily hydroxypropylmethylcellulose, and, independently, the other polymer is preferably a (m is t)acrylate polymer (such as any suitable polymer Eudragit). Among the (meth)acrylate polymers, polymers preferred in the context of this invention, are Eudragit L and Eudragit RS. One preferred polymer in the context of this invention is Eudragit RL. The Eudragit polymers can be used in combination, with a mixture of Eudragit RS and RL are preferred.

Persons who (albeit unintentionally) drink substantial amounts of alcoholic beverages when taking prescribed drugs, can significantly change the composition of gastric juice in the stomach, and in extreme cases of gastric juices can contain up to 40% alcohol. Mainly embodiments of preventing dependence of the compositions of this invention optionally contain subjected to melting a mixture of at least one of the calling dependence of medicinal substance, at least one simple cellulose ether or a complex of cellulose ether and at least one (meth)acrylic polymer, where the amount of medicinal substance, which is extracted from the composition 20% aqueous solution of ethanol, and 40% aqueous solution of ethanol, or both, within one hour at 37°C, is less than or equal to double the amount of medicinal substance, which is extracted in 0.01 N hydrochloric acid within one h is sa at 37°C or at 25°C or at both these temperatures. Resistance to extraction, 40% ethanol is predominant in those cases where an individual purposefully trying to extract addictive drug substance from the drug containing addictive drug.

Protocols for the extraction of 20% or 40% aqueous solution of ethanol or 0.01 N hydrochloric acid, respectively, are given in the experimental section, below. In more preferred embodiments, the implementation of a number of medicinal substance, which is extracted from the composition 20% or 40% aqueous solution of ethanol is less than or equal to 1.5 times the amount of medicinal substance, which is extracted in 0.01 H hydrochloric acid within one hour. In other preferred embodiments, the implementation of a number of medicinal substance, which is extracted from the composition 20% or 40% aqueous solution of ethanol is less than or equal to the amount of medicinal substance, which is extracted in 0.01 N hydrochloric acid within one hour. In other preferred embodiments, the implementation of a number of medicinal substance, which is extracted from the composition 20% or 40% aqueous solution of ethanol is less than or equal to 0.9 times the amount of medicinal substance, is which is extracted in 0.01 N hydrochloric acid within one hour.

Also the present invention relates to compositions with delayed release of at least one of the calling dependence of the medicinal substance, which prevents the extraction of the drug substance from the composition when the extraction is carried out by solvent extraction using widely available household solvents for extraction, such as isopropyl alcohol, distilled alcohols, examples of which is vodka, white vinegar, water and an aqueous solution of ethanol (for example, 20% ethanol). While the composition is substantially resistant to solvent extraction, it nevertheless provides the proper release of drug substance in aqueous solutions, such as gastric fluid. This composition when crushing or grinding also ensures the proper release of drug substance in aqueous solutions, such as gastric fluid. Well, in some preferred embodiments of this invention, the number of the calling dependence of drug substance released from being put in 3 ounces of one, or two, or three, or more than three household solvents listed above (i.e. at time 0 hours, 1 hour, not more than 15% higher than the number released at the same time swallowing the conventional people, or from more than 1 hours to about 4 hours it is not more than 15% higher than the number released at the same time if swallowed an ordinary person, or both of these options.

Illustrative preferred compositions according to this invention contain the following.

Simple cellulose ethers and esters of cellulose, which can be used separately or in combination in this invention have a preferred molecular weight in the range from 50,000 to 1250000 daltons. Ethers of cellulose are preferably selected from alkylsilanes, hydroxyethylcellulose, hydroxyethylmethylcellulose or their mixtures, such as ethylcellulose, methylcellulose, hydroxypropylcellulose (NF), hydroxyethyl cellulose (NF) and hypromellose (USP) or their combination. Suitable ethers of cellulose are, but are not limited to, acetate cellulose (NF), cellulose acetate butyrate, cellulose acetate propionate, phthalate of hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate phthalate and mixtures thereof. Most preferably it is possible to use nonionic polymers, such as hypromellose.

The number of groups of the substituents on the elements anhydroglucose in cellulose can be described by the average number of groups of the substituents attached to the ring, the concept of the local specialists in the field of chemistry of cellulose as "degree of substitution" (D.S.). If you replaced all three available positions on each element, D. S. denote as 3, if on average two out of every rings react, D. S. denote as 2, and so on

In preferred embodiments, the implementation of a simple cellulose ether has a degree of substitution by alkyl of from 1.3 to 2.0 and molar substitution hydroxyalkyl up to 0.85.

In preferred embodiments, the implementation of a replacement alkyl represents methyl. In addition, the preferred alternative hydroxyalkyl is a hydroxypropyl. These types of polymers with different degrees of substitution of methoxy substitutions, hydroxypropoxy summarized in the pharmacopoeias, such as USP, entitled "hypromellose".

Methyl cellulose is available under the trade name METHOCEL A. METHOCEL has A D. S. bromide (or methoxyl) from 1.64 to 1.92. These types of polymers are listed in the pharmacopoeias, such as USP, entitled "methyl cellulose".

Especially preferred simple cellulose ether is a hypromellose. The hypromellose available under the trade name METHOCEL E (D. S. for bromide is approximately 1,9, a molar substitution of hydroxypropyl approximately 0,23), METHOCEL F (D. S. for bromide is approximately 1.8, the molar substitution of hydroxypropyl approximately 0,13) and METHOCEL K (D S. for bromide is approximately 1.4, the molar substitution of hydroxypropyl approximately 0,21). METHOCEL F and METHOCEL K are preferred hydroxypropylmethylcellulose for use in the present invention.

Suitable acrylic polymer includes homopolymers and copolymers (this term includes polymers having more than two different repetitive elements)containing the monomers of acrylic acid, and/or alkhakalaki acid and/or alkyl(ALK)acrylate. As used herein, the term "alkyl(ALK)acrylate" refers to either the corresponding acrylate or alkalisation complex ether, which is usually formed from the corresponding acrylic or alkalinovh acids, respectively. In other words, the term "alkyl(ALK)acrylate" refers to either alkylalkoxysilane or alkylacrylate. Preferably the alkyl(ALK)acrylate is a (C1-C22)alkyl(C1-C10)ALK)acrylate. Examples of C1-C22the alkyl groups of the alkyl(ALK)acrylates include methyl, ethyl, n-propyl, n-butyl, isobutyl, tert-butyl, isopropyl, pentyl, hexyl, cyclohexyl, 2-ethylhexyl, heptyl, octyl, nonyl, decyl, Isodecyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, Needell, eicosyl, behenyl and their isomers. The alkyl group may be straight or once evennou. Preferably (C1-C22)alkyl group is a (C1-C6)alkyl group, as defined above, more preferably a (C1-C4)alkyl group, as defined above. Examples of C1-10talkgroup alkyl(ALK)acrylates include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclohexyl, 2-ethylhexyl, heptyl, octyl, nonyl, decyl and isomers. Talkgroup can be straight or branched. Preferably (C1-C10)altgraph is a (C1-C6)altgroup, as defined above, more preferably a (C1-C4)altgroup, as defined above.

Preferably the alkyl(ALK)acrylate is a (C1-C4)alkyl(C1-C4)ALK)acrylate, most preferably (C1-C4)alkyl(meth)acrylate. It will be understood that the term (C1-C4)alkyl(meth)acrylate refers to either (C1-C4)alkylacrylate, or (C1-C4)alkylmethacrylamide. Examples (C1-C4)alkyl(meth)acrylate include methyl methacrylate (MMA), ethyl methacrylate (EMA), n-propyl methacrylate (PMA), isopropylmyristate (IPMA), n-butylmethacrylate (BMA), isobutyronitrile (IBMA), tert-butylmethacrylate (TBMA), methyl acrylate (MA), acrylate (EA), n-propylacetate (PA), n-butyl acrylate (BA), isopropylacetate (IPA), isobutyryl the t (IBA), and combinations thereof.

Preferably the monomer alkhakalaki acid is a (C1-C10)altacelow acid. Examples (C1-C10)alkalinovh acids include methacrylic acid, ethacrylate acid, n-propeciabuy acid, izopropilovyi acid, n-botaksilau acid, isobutyryloxy acid, tert-botaksilau acid, pentakalos acid, hexabromo acid, heptachlor acid and their isomers. Preferably (C1-C10)Alcarria acid is a (C1-C4)altacelow acid, most preferably methacrylic acid.

In certain embodiments of the implementation of the alkyl group may be substituted by aryl groups. As used herein, "alkyl" group refers to an unbranched, branched or cyclic, saturated or unsaturated aliphatic hydrocarbons. Alkyl group has 1 to 16 carbon atoms and may be unsubstituted or substituted by one or more groups selected from halogen, hydroxy, alkoxy, carbonyl, amido, alkylamino, dialkylamino, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl. Group "hydroxy" refers to the group-OH. Group "alkoxy" refers to-O-alkyl group, where alkyl is as defined above. Group "thio" refers to the group-SH. the group "thioalkyl" refers to the group-SR, where R is an alkyl, as defined above. Group "amino" refers to the group-NH2. Group "alkylamino" refers to the group-other, where R is an alkyl, as defined above. Group "dialkylamino" refers to the group-NRR', where all R and R' are as defined above. Group "amido" refers to the-CONH2. Group "alkylamino" refers to the group-CONHR, where R is an alkyl, as defined above. Group "dialkylamino" refers to the group-CONRR', where R and R' are alkyl as defined above. The band "nitro" refers to a group of NO2. Group "carboxyl" refers to a group COOH.

In certain embodiments of the implementation of the alkyl group may be substituted by aryl groups. As used herein, "aryl" includes both carbocyclic and heterocyclic aromatic rings, as monocyclic and condensed polycyclic, where the aromatic ring may be a 5 - or 6-membered ring. Representative monocyclic aryl groups include, but are not limited to, phenyl, furanyl, pyrrolyl, thienyl, pyridinyl, pyrimidinyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolin etc. Condensed polycyclic aryl groups are aromatic groups, which include 5 - or 6-membered Aro eticheskoe or heteroaromatic ring, as one or more rings in the system of condensed rings. Representative kondensirovannye polycyclic aryl groups include naphthalene, anthracene, indolizine, indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, benzthiazole, purine, quinoline, isoquinoline, cinnoline, phthalazine, hinzelin, enoxaparin, 1,8-naphthiridine, pteridine, carbazole, acridine, fenesin, phenothiazines, phenoxazin and azulene. Also, as used herein, the aryl group includes arylalkyl group. In addition, as used herein, "arylalkyl" refers to groups such as benzyl, where the aromatic group is linked to the alkyl group.

Preferably the acrylic polymer is an acrylic copolymer. Preferably, the acrylic copolymer contains the monomer formed from the alkyl(ALK)acrylate and/or acrylic acid, and/or alkhakalaki acid, as defined herein above. Most preferably, the acrylic copolymer contains the monomer formed from the alkyl(ALK)acrylate, i.e. copolymerizate alkylacrylate and alkylalkoxysilane monomers as defined herein above. Especially preferred acrylic copolymers include (C1-C4)alkylacrylate monomer and copolymerizing (C1-C4)alkyl(C1-C4)and akrilaty comonomer, in particular copolymers formed from methyl methacrylate and copolymerizing of co monomer of methyl acrylate and/or ethyl acrylate and/or n-butyl acrylate.

Preferably (meth)acrylic polymer is an ionic (meth)acrylic polymer, in particular cationic methacrylic polymer. Ionic (meth)acrylic polymer produced by copolymerization of (meth)acrylic monomers having ionic groups to the neutral (meth)acrylic monomers. Ionic groups preferably represent groups of Quaternary ammonium.

(Meth)acrylic polymers, mainly, are insoluble in water, but can be swelling and are permeable in aqueous solutions and digestive fluids. The molar ratio of cationic groups and a neutral (meth)acrylic esters provides control of the permeability of water in the composition. In preferred embodiments, the implementation of the (meth)acrylic polymer is a copolymer or mixture of copolymers, where the molar ratio of cationic groups and a neutral (meth)acrylic esters is in the range on the average from about 1:20 to 1:35. The ratio can be adjusted by selecting the appropriate commercially available cationic (meth)acrylic polymer or a blend of cationic (meth)acrylic polymer with a suitable amount of the Central (meth)acrylic polymer.

Suitable (meth)acrylic polymers are commercially available from Rohm Pharma under the trade name Eudragit, preferably Eudragit RL and Eudragit RS. Eudragit RL and Eudragit RS are copolymers of acrylic and methacrylic esters with a low content of Quaternary ammonium groups, with the molar ratio of the ammonium groups and the remaining neutral (meth)acrylic esters is 1:20 in Eudragit RL and 1:40 in Eudragit RS. The average molecular weight is approximately 150000.

In addition to the (meth)acrylic polymers, for more pharmaceutically acceptable polymers can be included in the compositions of this invention in order correction properties of the composition and/or simplify its manufacture. These polymers can be selected from the group consisting of:

the homopolymers of N-vinylation, especially polyvinylpyrrolidone (PVP),

copolymers of N-vinylacetate and one or more comonomers, copolymerizing with them, with comonomers selected from nitrogen-containing monomers and oxygen-containing monomers, especially a copolymer of N-vinylpyrrolidone and vinylcarbazole, while preferable examples are a copolymer of N-vinylpyrrolidone and vinyl acetate or a copolymer of N-vinylpyrrolidone and finalproject;

graft copolymers of polyvinyl alcohol-polyethylene glycol (available, for example, as Kollicoat® IR from BASF AG, Ludwigshafn, Germany);

high-molecular oxides polyalkylene, such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and of propylene oxide;

polyacrylamides;

polymers of vinyl acetate, such as copolymers of vinyl acetate and crotonic acid, partially hydrolyzable polyvinyl acetate (also referred to as saponified "polyvinyl alcohol");

polyvinyl alcohol;

poly(hydroxy acids)such as poly(lactic acid), poly(glycolic acid), poly(3-hydroxybutyrate) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate); or a mixture of one or more of them.

Imply that "addictive drug" means any biologically effective ingredient, the dissemination of which is subject to regulatory restrictions. Addictive drugs, which usually can be made in the context of this invention, include, but are not limited to, pseudoephedrine, antidepressants, strong stimulants, nutritional drugs, steroids and non-steroidal anti-inflammatory drugs. In the category of strong stimulants methamphetamine is one drug that has recently received attention as a calling dependence of the medicinal substance. Also at present there are some of which which are concerned about having the ability to induce drug dependence atropine, giostsiamina, phenobarbital, scopolamine, etc. Another great class associated with addiction of drugs is a class of analgesics, especially opition.

The term "opioid" refers to substance, such as agonist, antagonist or mixed agonist-antagonist, which reacts with one or more receptor sites associated endogenous opioid peptides such as enkephalins, endorphins and dynorphin. Opioids include, but are not limited to, Alfentanil, allylprodine, Alphaprodine, Anileridine, benzylmorphine, Bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, Dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, Dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, Ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, Ketobemidone, levallorphan, levophenacylmorphan, Levorphanol, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, mirfin, nalbufin Narain, Nicomorphine, norpipanone, opium, oxycodone, Oxymorphone, populetum, pentazocine, phenadoxone, phenazocine, phenomorphan, Phenoperidine, piminodine, propiram, propoksifen, Sufentanil, Tilidine and tramadol and salt and mix.

In some preferred the variants of implementation of the composition according to this invention includes at least one additional drug. In more preferred embodiments, the implementation of additional medicinal substance can be selected, but not limited to, from the group consisting of non-steroidal analgesics, and further optionally selected from the group consisting of acetaminophen, aspirin, fentanyl, ibuprofen, indomethacin, Ketorolac, naproxen, fenatsetina, piroxicam, sufentanyl, sulindaka and interferon alpha. Especially preferred are combinations of drugs sold in the society at present as combinations fixed dose under the control of suitable national or regional organizations, such as (as an example) the U.S. Food and Drug Administration. Such medicinal substances include, but are not limited to, the combination with a fixed dose of hydrocodone and acetaminophen, or a combination (with a fixed dose of hydrocodone and ibuprofen.

Addictive drug substance(a) is preferably dispersed in the matrix, which is preferably formed by a simple cellulose ether or a complex ester of cellulose and one acrylic or methacrylic polymer and other optional ingredients of the composition. Also it is understood that this description includes systems having small particles, typically with a diameter less than 1 μm, lekarstvennoj the substance in the matrix phase. These systems preferably do not contain significant quantities of the active opioid ingredient in their crystalline or microcrystalline state, as shown by thermal analysis (DSC) or rentgendifraktsionnym analysis (WAXS). At least 98% (by weight) of the total amount of drug is preferably presented in the amorphous state. If not defiant according to the active drug, such as acetaminophen, is additionally in the composition in accordance with the present invention, this additional active drug substance(s) may be in a crystalline state, immersed in the composition.

When the variance of the components is such that the system is chemically and physically uniform or essentially completely homogeneous or consists of a single thermodynamic phase, this dispersion is called a "solid solution". Solid solutions related to the dependence of the active substances are preferred.

Also the composition may contain one or more additives selected from alcohols, sugars or their derivatives, maltodextrins, pharmaceutically acceptable surfactants, regulators fluidity, disintegrity agents, fillers and lubricants. Examples of prigodin the x sugar alcohols are mannitol, sorbitol, xylitol; suitable derivatives of the sugar alcohol include, but are not limited to, isomaltose, hydrogenated condensed palatinose and other derivatives that are either similar or not similar to them.

Pharmaceutically acceptable surfactants are preferably a pharmaceutically acceptable non-ionic surfactant. The inclusion of surfactants is particularly preferred in the case of matrices, containing the poorly soluble in water active ingredients, and/or to give a composition wettability. Surfactant can make instant emulsification of the active ingredient released from the dosage form, and to prevent precipitation of the active ingredient in the aqueous fluids of the gastrointestinal tract.

Some preferred additives include alkyl ethers of polyoxyethylene, for example lauric simple ether of polyoxyethylene (3), cetyl simple ether of polyoxyethylene (5), stearyl simple ether of polyoxyethylene (2), stearyl simple ether of polyoxyethylene (5); alcylaryl ethers of polyoxyethylene, for example nonylphenoxy simple ether of polyoxyethylene (2), nonylphenoxy simple ether of polyoxyethylene (3), nonylphenoxy simple ether of polyoxyethylene (4) is whether octylphenoxy simple ether of polyoxyethylene (3); esters of fatty acids and of polyethylene glycol, such as monolaurate PEG-200, dilaurate PEG-200, dilaurate PEG-300, dilaurate PEG-400, distearate PEG-300 or dioleate PEG-300; complex monetary fatty acids and alkalophiles, for example mono - and dilaurate propylene glycol (Lauroglycol®); esters of fatty acids and sucrose, for example, sucrose monostearate, distearate sucrose, monolaurate sucrose or dilaurate sucrose, complex mono-and diesters of fatty acids and sorbitan, such as monolaurate sorbitan (Span® 20), monooleate sorbitan, monopalmitate sorbitan (Span® 40) stearate sorbitan, polyoxyethylenated derivatives of castor oil, such as polyoxyethyleneglycol triricinolein, or polyoxyl-35-castor oil (Cremophor® EL; BASF Corp.), or polyoxyethyleneglycol oxystearate, such as peg-40-hydrogenated castor oil (Cremophor® RH 40) or polyethylene glycol-60-hydrogenated castor oil (Cremophor® RH 60); or block copolymers of ethylene oxide and propylene oxide, also known as block copolymers of polyoxyethylene and polyoxypropylene or polyoxyethylene and polypropylenglycol, such as Pluronic® F68, Pluronic® F127, Poloxamer® 124, Poloxamer® 188, Poloxamer® 237, Poloxamer® 388, or Poloxamer® 407 (BASF Wyandotte Corp.); or complex monetary fatty acid polyoxyethylene (20) sorbitan, such as polyoxyethylene (20) sorbitan monooleate (Tween® 80), polyoxyethylene (20) is orbitone the monostearate (Tween® 60), of polyoxyethylene (20) sorbitan monopalmitate (Tween® 40), polyoxyethylene (20) sorbitan monolaurate (Tween® 20), etc. as well as mixtures of two, three, four, five or more of them.

In the melt can include various other additives such as a fluidity regulators, such as colloidal silicon dioxide; lubricants, fillers, dezintegriruetsja substances, plasticizers, stabilizers such as antioxidants, light stabilizers, acceptors radicals or stabilizers against microbial attack.

The compositions of this invention can be obtained by any suitable process of melting, such as the use of a heated press, and they are preferably produced by extruding a melt. In order to achieve a homogeneous distribution and a sufficient degree of dispersion of drug substance containing the medicinal substance, the melt can be kept in the heated barrel of the device for extruding the melt for a sufficient time. Melting occurs at the transition in liquid or kauchukopodobnoe state, with the possible homogeneous immersion of one component to another. Melting generally involves heating above the softening point of simple ether/complex cellulose ether or (meth)acrylic polymer. The melt can be obtained in various ways.

As a rule, the temperature p is Alenia is in the range from 70 to 250°C, preferably from 80 to 180°C, most preferably from 100 to 140°C.

When the melting process includes extruding the melt, the melting and/or mixing may occur in the device, usually used for this purpose. Particularly suitable are the extruder or kneading machine. Suitable extruders include single screw extruders, extruders coupled with augers and mnogochasovye extruders, preferably twin-screw extruders, which can be co-rotating or in the opposite direction to rotate and equipped with optional discs for mixing. It will be clear that the working temperature will be determined by the type of the extruder or the type of configuration of the extruder. Part of the energy required for melting, mixing and dissolution of the components in the extruder may be provided by heating elements. However, friction and shear stress of the material in the extruder can also result in mixture with substantial amounts of energy and contribute to the formation of a homogeneous melt of the components.

In another embodiment, this invention relates to an oral dosage form, delayed release, characterized in that it has at least two of the following characteristics: (a) the amount of medicinal substance, which extragere the descendants of the composition of an ethanol solvent, for example, 40% or 20% aqueous solution of ethanol or both of them, within one hour at 37°C. with shaking or without it, is less than or equal to double the amount of medicinal substance, which is extracted in 0.01 N hydrochloric acid within one hour at 37°C, (b) the dosage form is resistant to compression and does not collapse under the force of 300 Newtons, preferably 600 Newtons, more preferably 1200 Newtons, as measured by a hardness tester "Pharma Test PTB 501", and (c) dosage form releases at least 15%, more preferably 18% and optional 24% of the drug substance, but not more than 45%, more preferably 38% or optional 34% of the drug substance within 30 minutes, the first hour or the first two hours of testing dissolutionin vitroand also optionalin vivo(i.e. in the digestive tract of the animal or human). Without regard to any particular theory, I believe that the high initial rate of release of drug substance from the composition reaches, providing high load medicinal substance in the composition. Load the drug for one active ingredient, such as acetaminophen, in some embodiments, the implementation of the compositions of this invention may comprise more than rough is about 60%, 70%, 75%, 80%, 85% by mass. Load medicinal substance for acetaminophen may be limited to 80%.

The preferred implementation of this dosage form is a monolithic form or in solid solution. The term "monolithic" is formed from roots meaning "single" and "stone". Monolithic form or solid substance preferably have at least one dimension that is more than 5 mm monolithic versions of implementation of this invention addictive drug substance preferably is a single element of a solid substance or a single solid solution. Monolithic solid or solid solution may not necessarily be covered with other materials or combined with them. These other materials preferably do not contain a significant number of the calling dependence of medicinal substances, and these materials are preferably essentially no effect on the rate of dissolution or dispersion of the calling dependence of medicinal substancein vivoorin vitro. Speed of release ofin vitroand/orin vivocalling addiction drug or substance-related addiction of drugs after about the first hour preferably are essentially constant over minicamera approximately 6, 8, 10, 12, or 16 hours. Thus, embodiments of this invention provide a single-phase composition of medicinal substances, which can be adapted for quick release calling the dependence of the medicinal substance (s) in order to enable the rapid achievement of therapeutic levels of drug substances in the blood of the patient or animal and to maintain in order to provide therapeutic amounts over a period of at least about 8, 12 or 24 hours. In addition, the composition of the medicinal substance is preferably suitable for repeated introduction of a person or an animal once, twice or three times a day.

Mostly preferred embodiments of the dosage form according to this invention release essentially the full number of the calling dependence of medicinal substances in dosage form. For example, the dosage form according to this invention may be adapted for delivery to more than 90% and preferably 95% of the drug substance during testing dissolutionin vitrofor approximately 16 and optional 12 or 9 hours. The total concentration in the blood, or AUC, impossible to know based on the time during which the composition is released 90% of the drug substances is a, however, as a rule, higher AUC in mg calling the dependence of the medicinal substance can be achieved when the composition of the medicinal substance releases essentially all or all of the addictive drug in the gastrointestinal tract are able to absorb the medicinal substance in the blood system of the patient (or animal).

In another preferred embodiment, this invention relates to a method for producing resistant based pharmaceutical composition of medicinal substance, comprising extruding a melt of a composition containing at least one therapeutic substance, further comprising a direct validation of the extrudate dosage forms without intermediate grinding stage. Product extruding the melt preferably contains a derivative of cellulose and preferably also contains a polymer Eudragit. Preferred polymers include Eudragit Eudragit L or Eudragit RS or both of them, and especially preferred is Eudragit RL or a combination of Eudragit RL and Eudragit RS.

The melt may vary from pasty to viscous. Before allowing the melt to solidify, the melt is optional, you can give almost any desired shape. Conveniently, the shaping of the extrudate optional can be performed by means of the CMV calender, preferably by means of two counter-rotating rollers with mutually matching grooves on their surface. A wide range of tablet forms can be obtained from the use of rollers with different shapes of the recesses. Alternative extrudate can be cut into fragments, either before ("hot tapping"), or after hardening ("cold cutting"), or used in the stamping process. The melting process involving heated press, also not necessarily can be calendered.

The resulting composition optionally may be coated with materials that do not contain significant quantities of medicinal substances with the potential to cause drug dependence. For example, a monolithic dosage form, containing addictive drug substance can be coated with a colored coating that swallowed additive or another layer of pharmaceutically acceptable materials. The layer of material deposited on a monolithic form, preferably does not significantly alter the rate of release of active ingredient from the dosage form.

In order to facilitate the introduction of such dosage forms mammals, it is preferable to giving a dosage form appropriate form. Large tablets, which can be conveniently propose is s, thus, preferably are elongated and not round in shape.

Film coating on the dosage form further intended to facilitate swallowing. Also film coating improves the taste and provides a pleasing appearance. If desirable, the film coating may be an enteric coating. Film coating typically comprises a polymeric film-forming material such as hypromellose, hydroxypropylcellulose and acrylate or methacrylate copolymers. In addition to the film-forming polymer, the film coating may further contain a plasticizer, such as polyethylene glycol, a surfactant such as Tween®, and optional pigment, for example titanium dioxide or iron oxides. Film coating may also contain talc as an anti-adhesive means. Usually film coating is less than about 5% by weight of the dosage form.

In one embodiment, the present invention relates to preventing the dependence of the composition of medicinal substance containing subjected to melting a mixture of a) at least calling the dependence of the medicinal substance, (b) at least one simple cellulose ether or a complex of cellulose ether and (c) at least one alkalark the crylate polymer, alcacaltro polymer or a combination of both. In this embodiment, the amount of medicinal substance, which is extracted from the composition 40% aqueous ethanol within one hour at 37°C, is less than or equal to double the amount of medicinal substance, which is extracted in 0.01 N hydrochloric acid within one hour at 37°C; and a medicinal composition of matter adapted to ensure that it was suitable for oral administration to a human 3, 2 or 1 time per day.

Preferably in this embodiment, a simple cellulose ether has a degree of substitution by alkyl of from 1.3 to 2.0 and molar substitution hydroxyalkyl up to 0.85. More preferably, the substituting alkyl represents methyl. Most preferably the replacement hydroxyalkyl is a hydroxypropyl. In another aspect of this variant implementation preferably a simple cellulose ether is a hypromellose.

In another aspect of this variant implementation alkylalkoxysilane or ELECRICITY polymer has Monomeric elements (C1-C22)alkyl(C1-C10)ALK)acrylate or (C1-C10)alkalidata. More preferably ELECRICITY polymer is an acrylic polymer or a methacrylic polymer. B is more preferably ELECRICITY polymer is an ionic acrylic polymer or ion methacrylic polymer. More preferably ELECRICITY polymer is a cationic acrylic polymer or cationic methacrylic polymer. Most preferably ELECRICITY polymer is a copolymer of esters of acrylic polymer and a methacrylic polymer containing Quaternary ammonium group. In the most preferred embodiment, ELECRICITY polymer is a copolymer or mixture of copolymers, where the molar ratio of cationic groups and neutral esters is in the range on the average from about 1:20 to 1:35.

In another aspect of this variant implementation of the addictive drug is selected from the group consisting of atropine, giostsiamina, phenobarbital and scopolamine, their salts, esters, prodrugs and mixtures. In another aspect of the addictive drug is an analgesic, and in another aspect of the addictive drug is an opioid. Opioid may be selected from the group consisting of Alfentanil, allylprodine, Alphaprodine, Anileridine, benzylmorphine, Bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, Dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dim is teliamura, dioxaphetyl of butyrate, Dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, Ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, Ketobemidone, levallorphan, levophenacylmorphan, Levorphanol, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbufina, narceine, Nicomorphine, norpipanone, opium, oxycodone, Oxymorphone, populetum, pentazocine, phenadoxone, phenazocine, phenomorphan, Phenoperidine, piminodine, propiram, propoxyphene, Sufentanil, Tilidine and tramadol and their salts, esters, prodrugs and mixtures. In another aspect of the addictive drug is selected from pseudoephedrine, antidepressants, strong stimulants, nutritional drugs, steroids and non-steroidal anti-inflammatory drugs, their salts, esters, salts, prodrugs, and mixtures. Preferably a strong stimulator is a methamphetamine or amphetamine. The above composition also optionally contain at least one additional drug. In one aspect, the additional drug is selected from the group consisting of non-steroidal neopytnyh analgesics, and optionally further selected from the group consisting of acetaminophen, aspirin is, fentanyl, ibuprofen, indomethacin, Ketorolac, naproxen, fenatsetina, piroxicam, sufentanyl, sulindac and interferon alpha.

In these compositions addictive drug substance is preferably dispersed in the composition in a state of solid solution. In one aspect, these compositions can optionally contain at least one additive is independently selected from the group consisting of surfactants, regulators fluidity, dezintegriruetsja agents, fillers, lubricants, effervescent agents, dyes, food additives and combinations thereof. In one embodiment of this invention, between 11% and 47% calling dependence drug substance is released in 0.01 N hydrochloric acid for two hours at 37°C. In another embodiment, less than 20% of the calling dependency drug substance is released in 40% aqueous ethanol within one hour at 37°C.

In another embodiment, the present invention relates to monolithic oral pharmaceutical composition with delayed release. This composition of medicinal substance contains subjected to melting a mixture of: (a) effective for analgesia amount of at least one of the calling dependency drug vexes the VA, b) at least one simple cellulose ether or a complex of cellulose ether and (c) at least one alkylalkoxysilane polymer, alcacaltro polymer or combinations thereof. In this composition, the amount of medicinal substance, which is extracted from the composition 40% aqueous ethanol within one hour at 37°C, is less than or equal to double the amount of medicinal substance, which is extracted in 0.01 N hydrochloric acid within one hour at 37°C; and a medicinal composition of matter adapted for slow release, so it was suitable for oral administration to a human 3, 2 or 1 times per day. In addition, in this embodiment, preferably a simple cellulose ether has a degree of substitution by alkyl of from 1.3 to 2.0 and molar substitution hydroxyalkyl up to 0.85. In another aspect replacement alkyl represents methyl. In another aspect of the alternate hydroxyalkyl is a hydroxypropyl. Preferably a simple cellulose ether is a hypromellose.

In another aspect of this variant implementation ELECRICITY polymer is an acrylic polymer or a methacrylic polymer. Preferably ELECRICITY polymer is an ionic acrylic polymer or ionic meta is relevy polymer. More preferably ELECRICITY polymer is a cationic acrylic polymer or cationic methacrylic polymer. Most preferably ELECRICITY polymer is a copolymer of esters of acrylic polymer and a methacrylic polymer containing Quaternary ammonium group. Also more preferably an acrylic polymer or a methacrylic polymer is a copolymer or mixture of copolymers, where the molar ratio of cationic groups and neutral esters is in the range on the average from about 1:20 to 1:35.

In one aspect of this variant implementation of the addictive drug is selected from the group consisting of atropine, giostsiamina, phenobarbital and scopolamine, their salts, esters, prodrugs and mixtures. Preferably addictive drug is an analgesic. More preferably addictive drug is an opioid. Most preferably, the opioid is a hydrocodone, its salts and esters. As also described above, an opioid selected from the group consisting of Alfentanil, allylprodine, Alphaprodine, Anileridine, benzylmorphine, Bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, d is xtranormal, dezocine, diampromide, Dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl of butyrate, Dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, Ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, Ketobemidone, levallorphan, levophenacylmorphan, Levorphanol, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbufina, narceine, Nicomorphine, norpipanone, opium, oxycodone, Oxymorphone, populetum, pentazocine, phenadoxone, phenazocine, phenomorphan, Phenoperidine, piminodine, propiram, propoxyphene, Sufentanil, Tilidine and tramadol and their salts, esters, prodrugs and mixtures. In addition, addictive drug substance is selected from pseudoephedrine, antidepressants, strong stimulants, nutritional drugs and non-steroidal anti-inflammatory drugs, their salts, esters, salts, prodrugs, and mixtures. Preferably a strong stimulator is a methamphetamine or amphetamine. Another variant of implementation of the composition is at least one additional drug substance. In this embodiment, the additional active pharmaceutical ingredient selected from the group consisting of asteroids the x neopytnyh analgesics, and optionally further selected from the group consisting of acetaminophen, aspirin, fentanyl, ibuprofen, indomethacin, Ketorolac, naproxen, fenatsetina, piroxicam, sufentanyl, sulindac and interferon alpha. Preferably addictive drug substance is dispersed in the composition in a state of solid solution. In one embodiment, the composition further comprises at least one additive is independently selected from the group consisting of surfactants, regulators fluidity, dezintegriruetsja agents, fillers, lubricants, effervescent agents, colorants, flavorings. In one aspect of this case for between 11% and 47% calling dependence drug substance is released in 0.01 N hydrochloric acid for two hours at 37°C. In another aspect, the dosage form provides a composition, where less than 20% of the calling dependency drug substance is released in 40% aqueous ethanol within one hour at 37°C.

Another variant of implementation of the present invention relates to oral dosage compositions with delayed release of medicinal substance, characterized by at least two of the following characteristics: (a) the amount of medicinal substance, which of extras is delegated composition of 40% aqueous ethanol within one hour at 37°C, is less than or equal to double the amount of medicinal substance, which is extracted in 0.01 N hydrochloric acid within one hour at 37°C, (b) the composition does not collapse under the force of 150 Newtons, preferably 300 Newtons, more preferably 450 Newtons, more preferably 500 Newton, as determined by the hardness tester "Pharma Test PTB 501", and (c) the composition releases at least 15% of one drug and not more than 45% of one medicinal substance in the first hour of testing dissolutionin vitroand preferably alsoin vivo. Preferably in this embodiment, the composition cannot be inhaled through nasal injection, which means that when processed in a coffee mill (as defined above) within 60 seconds, the material is either inconvenient for inhalation, or does not release the addictive drug is more than 40% faster, more preferably less than 30 percent faster and more preferably less than about 20 percent faster than in the case of ingestion of water, or 20% aqueous solution of ethanol or 40% aqueous solution of ethanol or both of these options. Also preferably, the medicinal substance is an opioid, amphetamine or methamphetamine. More PR is doctitle composition comprises preventing the dependence of the composition of the medicinal substance, obtained via subjected to melting of the mixture of a) at least one caller dependence of medicinal substance, (b) at least one simple cellulose ether or a complex of cellulose ether and (c) at least one alkylalkoxysilane polymer, alcacaltro polymer or combinations thereof. In this composition, the amount of medicinal substance, which is extracted from the composition 40% aqueous ethanol within one hour at 37°C, is less than or equal to double the amount of medicinal substance, which is extracted in 0.01 N hydrochloric acid within one hour at 37°C; and a medicinal composition of matter adapted to ensure that it was suitable for oral administration to a human 3, 2 or 1 times per day. In this embodiment, preferably a simple cellulose ether has a degree of substitution by alkyl of from 1.3 to 2.0 and molar substitution hydroxyalkyl up to 0.85. More preferably, the substituting alkyl represents methyl. More preferably the replacement hydroxyalkyl is a hydroxypropyl. Most preferably a simple cellulose ether is a hypromellose. Also in this embodiment, alkylalkoxysilane or ELECRICITY polymer has Monomeric elements (C1-C22 )alkyl(C1-C10)ALK)acrylate or (C1-C10)alkalidata. Preferably ELECRICITY polymer is an acrylic polymer or a methacrylic polymer. More preferably ELECRICITY polymer is an ionic acrylic polymer or ion methacrylic polymer. More preferably ELECRICITY polymer is a cationic acrylic polymer or cationic methacrylic polymer. Most preferably ELECRICITY polymer is a copolymer of esters of acrylic polymer and a methacrylic polymer containing Quaternary ammonium group. In this most preferred embodiment, furthermore, ELECRICITY polymer is a copolymer or mixture of copolymers, where the molar ratio of cationic groups and neutral esters is in the range on the average from about 1:20 to 1:35.

Another variant of implementation of the present invention relates to unground extruded melt composition of medicinal substance containing a medicinal substance with the potential to cause drug dependence. In this preferred embodiment, the composition cannot be inhaled via nasal administration. Also preferably, the medicinal substance represents the t of an opioid, amphetamine or methamphetamine. Most preferably the composition directly give the dosage form obtained from the melt extrudate without intermediate grinding stage. Also more preferably, the composition directly give the dosage form obtained from the melt extrudate without an intermediate stage of the formation of many particles. Most preferably the composition directly give the dosage form obtained from the melt extrudate through a process of cylindromyia.

Another variant of implementation of the present invention relates to monolithic unground not consisting of many particles extruded melt composition of medicinal substance containing a medicinal substance with the potential to cause drug dependency, having a diameter of approximately at least 5.1 mm to about 10 mm and a length of from about 5.1 mm to about 30 mm In this embodiment, preferably the composition directly give the dosage form obtained from the melt extrudate without intermediate grinding stage. In addition, preferably the composition directly give the dosage form obtained from the melt extrudate without an intermediate stage of the formation of many particles. In the above variations is tah the most preferred compositions directly give the dosage form obtained from the melt extrudate through a process of cylindromyia. Also, as described above, preferably the composition comprises preventing the dependence of the medicinal substance, obtained by subjected to melting of the mixture of a) at least one caller dependence of medicinal substance, (b) at least one simple cellulose ether or a complex of cellulose ether and (c) at least one alkylalkoxysilane polymer, alcacaltro polymer or combinations thereof. In this embodiment, the amount of medicinal substance, which is extracted from the composition 40% aqueous ethanol within one hour at 37°C, is less than or equal to double the amount of medicinal substance, which is extracted in 0.01 N hydrochloric acid within one hour at 37°C; and a medicinal composition of matter adapted to ensure that it was suitable for oral administration to a human 3, 2 or 1 times per day. Preferably in this embodiment, a simple cellulose ether has a degree of substitution by alkyl of from 1.3 to 2.0 and molar substitution hydroxyalkyl up to 0.85. Also preferably, the substituting alkyl represents methyl. More preferably the replacement hydroxyalkyl is a hydroxypropyl. Most preferably a simple cellulose ether is a hypromellose. Also is this the embodiment, alkylalkoxysilane or ELECRICITY polymer has Monomeric elements (C 1-C22)alkyl(C1-C10)ALK)acrylate or (C1-C10)alkalidata. Preferably ELECRICITY polymer is an acrylic polymer or a methacrylic polymer. More preferably ELECRICITY polymer is an ionic acrylic polymer or ion methacrylic polymer. Most preferably ELECRICITY polymer is a cationic acrylic polymer or cationic methacrylic polymer. In this most preferred embodiment, ELECRICITY polymer is a copolymer of esters of acrylic polymer and a methacrylic polymer containing Quaternary ammonium group. Also preferably in this embodiment, ELECRICITY polymer is a copolymer or mixture of copolymers, where the molar ratio of cationic groups and neutral esters is in the range on the average from about 1:20 to 1:35.

The present invention relates to another variant implementation, describing prevent the dependence of the composition of the medicinal substance, formed by a process comprising extruding a melt of a composition having at least one medicinal substance, and direct giving extrudate dosage forms without intermediate grinding stage is whether the stage of the formation of many particles. In this embodiment, preferably the medicinal substance contains preventing drug dependence substance having: a) at least one addictive drug, b) at least one simple cellulose ether or ester of cellulose and (c) at least one alkylalkoxysilane polymer ELECRICITY polymer or a combination of both. In this composition, the amount of medicinal substance, which is extracted from the composition 40% aqueous ethanol within one hour at 37°C. is less than or equal to double the amount of medicinal substance, which is extracted in 0.01 N hydrochloric acid within one hour at 37°C; and a medicinal composition of matter adapted to ensure that it was suitable for oral administration to a human 3, 2 or 1 times per day. For this arrangement a simple cellulose ether has a degree of substitution by alkyl of from 1.3 to 2.0 and molar substitution hydroxyalkyl up to 0.85. Preferably, the substituting alkyl represents methyl. More preferably the replacement hydroxyalkyl is a hydroxypropyl.

Most preferably a simple cellulose ether is a hypromellose. Also in this embodiment, alkylalkoxysilane or ELECRICITY polymer region is AET Monomeric elements (C 1-C22)alkyl(C1-C10)ALK)acrylate or (C1-C10)alkalidata. More preferably ELECRICITY polymer is an acrylic polymer or a methacrylic polymer. Also more preferably ELECRICITY polymer is an ionic acrylic polymer or ion methacrylic polymer. More preferably ELECRICITY polymer is a cationic acrylic polymer or cationic methacrylic polymer. And most preferably ELECRICITY polymer is a copolymer of esters of acrylic polymer and a methacrylic polymer containing Quaternary ammonium group. In this preferred embodiment, ELECRICITY polymer is a copolymer or mixture of copolymers, where the molar ratio of cationic groups and neutral esters is in the range on the average from about 1:20 to 1:35.

Another variant of implementation of the present invention relates to a method for obtaining resistant based pharmaceutical composition of medicinal substance, comprising extruding a melt of a composition containing at least one therapeutic drug substance, including additional direct giving extrudate dosage forms without intermediate grinding stage and the stage and the formation of many particles. This process is preferably obtained by melt extrudate contains a derivative of cellulose. More preferably it is derived cellulose contains commercially available polymer Eudragit. More preferably obtained by melt extrudate contains Eudragit® L or Eudragit® RS, or both of them. Most preferably obtained by melt extrudate contains Eudragit® RL or mixtures containing as Eudragit® RS and Eudragit® RL.

In another embodiment, obtained by melt extrudate contains preventing drug dependence substance having: a) at least one addictive drug, b) at least one simple cellulose ether or ester of cellulose and (c) at least one alkylalkoxysilane polymer ELECRICITY polymer or a combination of both. In this embodiment, the amount of medicinal substance, which is extracted from the composition 40% aqueous ethanol within one hour at 37°C, is less than or equal to double the amount of medicinal substance, which is extracted in 0.01 N hydrochloric acid within one hour at 37°C; and a medicinal composition of matter adapted to ensure that it was suitable for oral administration to a human 3, 2 or 1 times per day. Preferably in this embodiment, simple is th the cellulose ether has a degree of substitution by alkyl of from 1.3 to 2.0 and molar substitution hydroxyalkyl up to 0.85. More preferably, the substituting alkyl represents methyl. More preferably the replacement hydroxyalkyl is a hydroxypropyl. Most preferably a simple cellulose ether is a hypromellose. As also described above, in this embodiment, alkylalkoxysilane or ELECRICITY polymer has Monomeric elements (C1-C22)alkyl(C1-C10)ALK)acrylate or (C1-C10)alkalidata. Preferably ELECRICITY polymer is an acrylic polymer or a methacrylic polymer. More preferably ELECRICITY polymer is an ionic acrylic polymer or ion methacrylic polymer. And most preferably ELECRICITY polymer is a cationic acrylic polymer or cationic methacrylic polymer. In this most preferred embodiment, ELECRICITY polymer is a copolymer of esters of acrylic polymer and a methacrylic polymer containing Quaternary ammonium group. Also in this preferred embodiment, ELECRICITY polymer is a copolymer or mixture of copolymers, where the molar ratio of cationic groups and neutral esters is in the range in average approx the tion from 1:20 to 1:35.

Another variant of implementation of the present invention relates to monolithic unground extruded melt composition of medicinal substance containing a medicinal substance with the potential to cause drug dependency, where a monolithic composition has essentially the release profile of drug substances, similar to crushed form a monolithic composition, where a monolithic composition is crushed when from about 20,000 rpm to about 50000 rpm in a machine for grinding coffee for about 60 seconds. Preferably in this embodiment, obtained by melt extrudate contains preventing drug dependence substance having: a) at least one addictive drug, b) at least one simple cellulose ether or ester of cellulose and (c) at least one alkylalkoxysilane polymer ELECRICITY polymer or a combination of both. In this composition, the amount of medicinal substance, which is extracted from the composition 40% aqueous ethanol within one hour at 37°C, is less than or equal to double the amount of medicinal substance, which is extracted in 0.01 N hydrochloric acid within one hour at 37°C; and the composition of the medicinal substance adapter the van, so it was suitable for oral administration to a human 3, 2 or 1 times per day. Preferably a simple cellulose ether has a degree of substitution by alkyl of from 1.3 to 2.0 and molar substitution hydroxyalkyl up to 0.85. More preferably, the substituting alkyl represents methyl. Also more preferably, the replacement hydroxyalkyl is a hydroxypropyl. Most preferably a simple cellulose ether is a hypromellose. Moreover, in this embodiment, alkylalkoxysilane or ELECRICITY polymer has Monomeric elements (C1-C22)alkyl(C1-C10)ALK)acrylate or (C1-C10)alkalidata. Preferably ELECRICITY polymer is an acrylic polymer or a methacrylic polymer. More preferably ELECRICITY polymer is an ionic acrylic polymer or ion methacrylic polymer. More preferably ELECRICITY polymer is a cationic acrylic polymer or cationic methacrylic polymer. Most preferably ELECRICITY polymer is a copolymer of esters of acrylic polymer and a methacrylic polymer containing Quaternary ammonium group. In this most preferred embodiment, ELECRICITY poly the EP is a copolymer or mixture of copolymers, where the molar ratio of cationic groups and neutral esters is in the range on the average from about 1:20 to 1:35. In addition, in some preferred embodiments, the implementation of the pharmaceutical composition of the substance does not contain more than 0.5% of genotoxic compounds formed from the calling dependence of drug or other active pharmaceutical ingredient included in the composition. For example, it was found that the polyethylene oxide oxidizes some opioids with the formation of N-oxide derivative, which may be genotoxic. Thus, in embodiments of this invention, including the oxide, polyethylene or other polymers or substances that cause significant oxidation of opioids, other addiction of drugs, or oxidizable not associated with the dependence of medicinal substances, the composition of this invention preferably contains sufficient amounts of antioxidants to prevent the accumulation of potentially genotoxic derivatives, preferably less than 1%, more preferably less than 0.5%, more preferably less than 0.3%, more preferably less than 0.1% and most preferably less than 0.05% by weight of genotoxic compounds, of the total mass of drug substance in which the song.

Another variant of implementation of the present invention is to prevent the dependence of the composition of medicinal substance containing subjected to melting a mixture of a) at least one caller dependence of medicinal substance, (b) at least one modifying the speed pharmaceutically acceptable polymer, copolymer, or a combination of both. In this embodiment, the amount of medicinal substance, which is extracted from the composition 40% aqueous ethanol within one hour at 37°C, is less than or equal to double the amount of medicinal substance, which is extracted in 0.01 N hydrochloric acid within one hour at 37°C; and a medicinal composition of matter adapted to ensure that it was suitable for oral administration to a human 3, 2 or 1 times per day. Preferably modifies the speed of the polymer is a polymer of simple cellulose ether or a complex ester of cellulose. In another embodiment, changing the speed of a polymer selected from the group consisting of homopolymers, copolymers or combinations of monomers N-vinylation, nitrogen-containing monomers oxygen-containing monomers, vinyl alcohol, ethylene glycol, alkalisation, ethylene oxide, propylene oxide, acrylamide, vinyl acetate, hydroxy acids. In other variations is the implementation of changing the speed of the polymer represents a hydrogen-peroxide polymer is polyvinylpyrrolidone. In another preferred embodiment, altering the speed of the copolymer, or a combination of them contain at least one alkylalkoxysilane polymer ELECRICITY polymer or a combination of both. More preferably simple cellulose ether has a degree of substitution by alkyl of from 1.3 to 2.0 and molar substitution hydroxyalkyl up to 0.85. Also more preferably, the substituting alkyl represents methyl. More preferably the replacement hydroxyalkyl is a hydroxypropyl. Most preferably a simple cellulose ether is a hypromellose. In another embodiment, alkylalkoxysilane or ELECRICITY polymer has Monomeric elements (C1-C22)alkyl(C1-C10)ALK)acrylate or (C1-C10)alkalidata. More preferably ELECRICITY polymer is an acrylic polymer or a methacrylic polymer. More preferably ELECRICITY polymer is an ionic acrylic polymer or ion methacrylic polymer. Most preferably ELECRICITY polymer is a cationic acrylic polymer or cationic methacrylic polymer. In addition, in the preferred embodiment, ELECRICITY polymer is a copolymer complex ester is an acrylic polymer and a methacrylic polymer, the group containing Quaternary ammonium. In this most preferred embodiment, ELECRICITY polymer is a copolymer or mixture of copolymers, where the molar ratio of cationic groups and neutral esters is in the range on the average from about 1:20 to 1:35. Changing the speed of the polymers may be suitable for the formation of pharmaceutically acceptable matrix polymer for sustained release.

Another variant of implementation of the present invention is to prevent the dependence of the composition of medicinal substance containing subjected to melting a mixture of a) at least one caller dependence of medicinal substance, where the specified medicinal substance is a hydrocodone; (b) at least one modifying the viscosity of the substance, and (c) at least one polymer, copolymer for slow release or combinations thereof. In this embodiment, more than 30% of the hydrocodone is extracted from the composition within about one hour at 37°C in 0.01 N hydrochloric acid; and the composition of medicinal substances adapted so that it was suitable for oral administration to a human 3, 2 or 1 times per day. In this embodiment, changing the viscosity of the substances represent farm is citiesi acceptable polymers, which can be used to modify the viscosity or temperature of the glass transition in polymer melt, which is used for compositions with delayed release. In one preferred embodiment, altering the viscosity of the substance is a simple cellulose ether or ester of cellulose. In another preferred embodiment, the polymer, copolymer for slow release or a combination of them contain at least one alkylalkoxysilane polymer ELECRICITY polymer or a combination of both. Also preferably in this embodiment, a simple cellulose ether has a degree of substitution by alkyl of from 1.3 to 2.0 and molar substitution hydroxyalkyl up to 0.85. In a more preferred embodiment, the substituting alkyl represents methyl. In another preferred embodiment, the replacement hydroxyalkyl is a hydroxypropyl. Most preferably a simple cellulose ether is a hypromellose. Also in another embodiment of this invention alkylalkoxysilane or ELECRICITY polymer has Monomeric elements (C1-C22)alkyl(C1-C10)ALK)acrylate or (C1-C10)alkalidata. Preferably ELECRICITY polymer is the Oh acrylic polymer or a methacrylic polymer. Preferably ELECRICITY polymer is an ionic acrylic polymer or ion methacrylic polymer. More preferably ELECRICITY polymer is a cationic acrylic polymer or cationic methacrylic polymer. Most preferably ELECRICITY polymer is a copolymer of esters of acrylic and methacrylic polymer containing Quaternary ammonium group. In this most preferred embodiment, ELECRICITY polymer is a copolymer or mixture of copolymers, where the molar ratio of cationic groups and neutral esters is in the range on the average from about 1:20 to 1:35.

Another variant of implementation of the present invention is to prevent the dependence of the composition of medicinal substance containing subjected to melting a mixture of a) at least one caller dependence of medicinal substance, where the specified medicinal substance is a hydrocodone or hydrocodone of the bitartrate pentahedra, b) at least one simple cellulose ether or a complex of cellulose ether and (c) at least one acrylic polymer, methacrylic polymer, or a combination of both. In this embodiment, the pharmaceutical composition of matter adapted to whom it was suitable for oral administration to a human 3, 2 or 1 time per day, and approximately ninety percent of the hydrocodone is releasedin vitrofor about 4-6 hours, when it is adapted for the introduction of 3 times a day, for about 6-10 hours, when it is adapted for the introduction of 2 times a day, and within about 16-22 hours, when it is adapted for the introduction of 1 times a day. In one aspect of this invention, more than 30% of the hydrocodone is extracted from the composition within about one hour at 37°C in 0.01 N hydrochloric acid. In another aspect of the composition is less than 30% of the hydrocodone is extracted from the composition within about one hour at 37°C in 0.01 N hydrochloric acid.

Another variant of implementation of the present invention is to prevent the dependence of the composition of medicinal substance containing subjected to melting a mixture of a) at least one caller dependence of medicinal substance, where the specified medicinal substance is an opioid; and (b) at least one modifying the speed pharmaceutically acceptable polymer, copolymer, or combinations thereof. In this embodiment, the amount of medicinal substance, which is extracted from the composition 40% aqueous ethanol within one hour at 37°C ranged from approximately 70% to 110% of the number of medicinal substances which is extracted in 0.01 N hydrochloric acid within one hour at 37°C; and a medicinal composition of matter adapted to ensure that it was suitable for oral administration to a human 3, 2 or 1 times per day. Also, in another aspect, the amount of medicinal substance, which is extracted from the composition 40% aqueous ethanol within one hour at 37°C is from about 70% to about 100% of the amount of drug that is extracted in 0.01 N hydrochloric acid within one hour at 37°C. In another aspect, the amount of medicinal substance, which is extracted from the composition 40% aqueous ethanol within one hour at 37°C is approximately 70% to approximately 90% of the amount of drug that is extracted in 0.01 N hydrochloric acid within one hour at 37°C. In another preferred aspect, the amount of medicinal substance, which is extracted from the composition 40% aqueous ethanol within one hour at 37°C is from about 75% to about 90% of the amount of drug that is extracted in 0.01 N hydrochloric acid within one hour at 37°C. Preferably, in this embodiment, addictive, in addition to the public the substance further contains a non-analgesic. Non-analgesic may also be a non-steroidal analgesic, and he further optionally selected from the group consisting of acetaminophen, aspirin, fentanyl, ibuprofen, indomethacin, Ketorolac, naproxen, fenatsetina, piroxicam, sufentanyl, sulindac and interferon alpha. In another embodiment, non-analgesic preferably is a acetaminophen or ibuprofen. In addition, in this embodiment, most preferably an opioid is a hydrocodone, or its salts or esters.

The composition according to this invention preferably is adapted to provide two-phase speed of release of the calling dependence of medicinal substance when it is exposed to suitable aquatic environmentin vitroin the device USP Type II. Each phase of two-phase speed of release ofin vitromore preferably has a zero order or decreasing for at least about 4 hours, when the composition is adapted so that it was suitable for administration to a person every 8 hours (i.e. 3 times per day), for at least about 7 hours, when the composition is adapted so that it was suitable for administration to a person every 12 hours (i.e. 2 times a day), and during at least 16 hours when HDMI is tion adapted, so it was suitable for administration to a human every 24 hours (i.e. 1 time per day).

The composition according to this invention preferably releases at least 30 to 45% of the opioid for approximately 1 hourin vitroin particular when the composition is adapted so that it was suitable for administration to a person every 12 hours (i.e. 2 times per day). Similarly, the composition preferably releases at least 90% of opioid composition for from about 6 hours to about 9 or about 10 hours, asin vitroin the device USP Type II Apparatus, andin vivo(in relation to mean value) with the introduction of the healthy population of North Americans or Western Europeans, in particular, when the composition is adapted so that it was suitable or intended for the introduction of man every 12 hours if necessary. However, when the composition is adapted so that it was suitable or intended for administration to a human every 24 hours, if necessary, then the composition is preferably releases at least 90% of the opioid from the composition for from about 15 hours to about 20 hoursin vitro(device USP Type II) or, on average, under the supervision ofin vivoafter the introduction of the healthy population of North Americans or Western Europeans, in particular when the composition ADAP is arowana, so it was suitable or intended for administration to a human every 24 hours, if necessary.

The composition according to this invention preferably provides a relatively complete delivery of the calling dependence of the medicinal substance. In the embodiment, the composition according to this invention releases at least 95% of the opioid in a period of approximately 6 hours or 7 hours to about 9 hours, or 10 hours after placing the device in a USP Type II. The composition according to this invention does not necessarily deliver at least 99% of the opioid less than about 12 hours and do not necessarily within from about 10 hours to about 11 hours.

The composition of this invention also preferably provides a relatively rapid onset of analgesia, which is preferred for the treatment of moderate to moderately severe pain in humans. Thus, the composition is preferably adapted to provide AUC calling dependence of medicinal substances from about 0.22 to about 0.51 in the first hour after administration, from about 1,07 to approximately 1,76 during the second hour after administration, from about to 2.06 to approximately is 3.08 during the third hour after injection of approximately 3.12 to approximately of 4.44 for even artego hours after administration, where AUC is defined as the average value observed in the group of at least 15 healthy North Americans or Western Europeans. AUC values measured in ng·h/ml plasma/mg of hydrocodone. Values /mg of hydrocodone do not take into account the mass of salt and hydration, and they relate only to the group of hydrocodone, compared with 15 mg of hydrocodone bitartrate of pentahedra equal to the remaining 9.08 mg free hydrocodone. The concentration of hydrocodone after 1 h ranges from approximately 0.70 to approximately 1,21 ng/ml plasma/mg of hydrocodone. The concentration of hydrocodone after 2 h is between about 0.91 and about 1,30 ng/ml plasma/mg of hydrocodone. The concentration of hydrocodone after 3 h is from about 0.99 to about of 1.35 ng/ml plasma/mg of hydrocodone. The concentration of hydrocodone after 4 h ranges from approximately 1,07 to approximately USD 1.43 ng/ml plasma/mg of hydrocodone.

The composition according to this invention may contain hydrocodone, and if it does, it is preferably adapted to provide an average profile in plasma in normal group of at least 10 healthy living in North America or Western Europe persons, characterized by Cmaxfor hydrocodone of between about 0.4 ng/ml/mg and about 1.9 ng/ml/mg, more preferably between approximately 0.6 ng/ml/mg and bring the flax of 1.4 ng/ml/mg, optional between approximately 0.6 ng/ml/mg and about 1.0 ng/ml/mg after a single dose suitable for the treatment of moderate to moderately severe pain for about 12 hours. When the composition according to this invention contains hydrocodone, the composition preferably also leads to the profile in the plasma, characterized by a Cminfor hydrocodone of between about 0.6 ng/ml/mg and about 1.4 ng/ml/mg after a single dose suitable for the treatment of moderate to moderately severe pain for about 12 hours. Moreover, the composition according to this invention in the variants of implementation, including hydrocodone, can lead to the desired effect of hydrocodone on blood plasma of the patient. For example, the composition according to this invention may be adapted to provide from the minimum AUC for hydrocodone of approximately 7,0 ng·h/ml/mg, or optionally about 9.1 ng·h/ml/mg, up to a maximum AUC for hydrocodone about 19.9 ng·h/ml/mg, or optional approximately 26.2 ng·h/ml/mg)

In another embodiment, the present invention also relates to a method of treating pain in a patient is a human, comprising oral administration to the patient is a person of the composition described in any of the above embodiments, the implementation or the examples below.

Shadowseeker will serve to further illustrate this invention without its limitations. In these examples, "UpM" or "rpm" refers to revolutions per minute, and "h" refers to the number of hours. The term "hydrocodone" in the examples of various compositions refers to of hydrocodone bitartrate pentahedra, which was used as the starting material in all the following examples of the composition.

EXAMPLE I: Dissolution in HCl and an aqueous solution of ethanol

Below is a description of an illustrative method of the study the dissolution rate of some songs in HCl and 20% aqueous solution of ethanol. Similar methods can be used to study the dissolution rate of 40% aqueous solution of ethanol.

(i) Description of method: solution in 0.01 N HCl

Device: a device for dissolving a USP Dissolution Apparatus II (paddle)

Rotation speed: 50 rpm

Medium: 0.01 N HCl

The volume of medium: 900 ml

Temperature: 37°C

Time sampling: 1 / 2 / 3 / 4 / 6 / 8 hours

Sample size: 10 ml (without replacement volume)

Obtaining samples used in the form in which was

Completion of analysis: UV detection wavelength 280 nm

(ii) Description of method: Dissolve in 20 or 40% aqueous solution of ethanol

Device: a Device for dissolving a USP Dissolution Apparatus II (paddle)

Rotation speed: 50 rpm

Wednesday: 20 or 40% aqueous solution of ethanol

The volume of medium: 500 ml

Temperature:37°C

Time sampling: 15 / 30 / 45 / 60 / 90 / 120 / 180 / 240 / 360 / 420 / 480 minutes

Sample size: 10 ml (without replacement volume)

Obtaining samples: dilution 1+1 20% or 40% aqueous solution of ethanol

Completion of analysis: UV detection wavelength 280 nm

EXAMPLE II

Various compositions of certain compounds described in the following sections.

(i) the Composition of some of the investigated compounds 1-6 are summarized in table 1. The compositions do not contain a medicinal substance that causes addiction; they are presented as a test experiment.

Table 1
The composition of the investigated compounds
No. songForm 1Form 2Form 3Form 4Form 5Form 6
MedicationTablet extrudate acetaminophen, 500 mg
Track55% acetaminophen
44% Eudragit RL-PO
1% Colloidal silicon dioxide
55% acetaminophen
22% Eudragit RL-PO
22% Eudragit RS-PO
1% Colloidal silicon dioxide
55% AC is taminophen
22% Eudragit RL-PO
22% Methocel K100M
1% Colloidal silicon dioxide
55% acetaminophen
44% Eudragit RS-PO
1% Colloidal silicon dioxide
55% acetaminophen
11% Eudragit RL-PO
11% Methocel K100M
22% Klucel EF*
1% Colloidal silicon dioxide
55% acetaminophen
22% Eudragit RL-PO
22% Klucel EF*
1% Colloidal silicon dioxide
The planned mass mg833 mg833 mg833 mg833 mg833 mg833 mg
*Klucel EF: hydroxypropylcellulose

In the embodiment of this invention, crushed, consisting of many particles or poroshkovaya the mixture of ingredients can be served in rotating in the same direction twin screw extruder. In one preferred embodiment, a homogeneous powder mixture of ingredients was applied in rotating in the same direction twin screw extruder (screw diameter 18 mm). The extrusion was carried out at 134°C (the melting temperature in the transient Department head extruder) during the rotation of the screw with a speed of 114 rpm and deletion of 1.5 kg per hour. Received the extrudate is slightly dirty color and the extrudate filing is whether the calender with the formation of elongated tablets weighing approximately 910 mg. Tablets were cooled to room temperature, i.e. approximately 25°C.

The nature of the dissolution of the tablets was tested in 0.01 N HCl and 20% aqueous solution of ethanol in accordance with the above Protocol.

In 0.01 N hydrochloric acid (figure 1) form 1 showed the most rapid release of active ingredient from the release of approximately 95% of the active ingredient after 8 hours (it should be noted that the values for 6 and 8 hours showed high variability). Forms 2 and 6 showed a rapid initial release of approximately 20% of the active ingredient within the first 2 hours, followed by a more slow, almost linear release the other 25% of the active ingredient within the next 6 hours. The total interest amount of the released active ingredient for forms 2 and 6 were 47% and 44%, respectively. Forms 3 and 5 showed almost linear release of 33% and 36% of active ingredient, respectively, after 8 hours. Most slow release of the active ingredient was identified for the form 4 (Eudragit RS-PO as a single component matrix), while only 13% of drug substance is released after 8 hours.

The release profiles in 20% aqueous solution of ethanol are presented in figure 2. Forms 1, 2 and 4 were dissolved quickly and you who were sabodala full amount of the active ingredient within the first 45 minutes. Adding Klucel EF to the matrix in the form of 6 led to a slower, but nevertheless the full release of the active ingredient after approximately 7 hours. Two containing Methocel K 100M extrudate (forms 3 and 5) showed the slowest release of the active ingredient. After 8 hours in 20% aqueous solution of ethanol form 3 was released 42% of the drug substance; form 5 was released 46%.

(ii) the Composition of some other of the investigated forms 7-9 are summarized in table 2:

Table 2
No. songForm 7The form 8Form 9
Track60% acetaminophen
8,0% Eudragit RL-PO
8,0% Methocel K 100
6,0% Methocel K 100M
17,2% Kollidon 17PF
1.8% of the hydrocodone
1% Colloidal silicon dioxide
60% acetaminophen
12.8% of Eudragit RL-PO
6,0% Methocel K 100
6,0% Methocel K 100M
12,6% xylitol
1.8% of the hydrocodone
1% Colloidal silicon dioxide
60% acetaminophen
8,0% Eudragit RL-PO
6,0% Methocel K100
6,0% Methocel K100M
17,2% Isomasil F
1.8% of the hydrocodone
1% Colloidal silicon dioxide
The planned mass mg833,33 833,33

The nature of the dissolution of the tablets was tested in 0.01 N HCl and 40% aqueous solution of ethanol in accordance with the above Protocol.

In addition, as shown in table 3, below, and figure 3, the rate of dissolution of hydrocodone in 0.1 N HCl was measured in various dosage forms, 7, 8 and 9, for about 480 minutes.

Table 3
Drug releaseForm 7The form 8Form 9
The time of test (min)The average value in %The average value in %The average value in %
0000
30232125
60303236
120424450
180515460
240586267
300646874
360697379
420747882
480787886

Also, as shown in table 4, below, and in figure 4, the rate of dissolution of acetaminophen (APAP) in 0.1 N HCl was measured in various dosage forms, 7, 8 and 9, for about 480 minutes.

Table 4
Drug releaseForm 7The form 8Form 9
The time of test (min)The average value in % The average value in %The average value in %
0000
30778
60111112
120161619
180212125
240252529
300292934
360323238
420353541
480383645

As shown in table 5, neither is e, on figure 5, the rate of dissolution of hydrocodone is a 40% aqueous solution of ethanol was measured in various dosage forms, 7, 8 and 9, for about 480 minutes.

Table 5
Drug releaseForm 7The form 8Form 9
The time of test (min)The average value in %The average value in %The average value in %
0000
30161316
60222225
120333137
180403947
24047 4754
300535161
360585666
420636071
480676475

As shown in table 6, below, and in figure 6, the rate of dissolution of acetaminophen (APAP) in 40% aqueous solution of ethanol was measured in various dosage forms, 7, 8 and 9, for about 480 minutes.

Table 6
Drug releaseForm 7The form 8Form 9
The time of test (min)The average value in %The average value in %The average value in %
000
3010911
60161518
120232327
180303036
240363643
300414150
360454656
420505062
480545467

The release profiles of drug substances, as shown in tables 3-6, various dosage forms 7, 8 and 9 mainly shows that hydrocodone slowly released a 40% aqueous solution of ethanol (AP is sustained fashion 10% less drug substance is released after 8 hours, than 0.01 N HCl). In addition, drug release APAP in these compositions is faster in the 40% aqueous solution of ethanol than in 0.01 N HCl.

(iii) composition of the form 31 is presented in table 7:

Table 7
No. songForm 31
ARAR/hydrocodone 15/500 mg
Tablet extrudate SR
Track60% acetaminophen
a 12.5% Eudragit RL-PO
6,0% Methocel K100
6,0% Methocel K100M
12,8% xylitol
1.8% of the hydrocodone
The planned mass mg833,33

As shown in table 8, below, and in figure 16, the rate of dissolution of hydrocodone in 0.01 N HCl was measured in the dosage form 31 for about 480 minutes immediately after production and after storage for 1 month at 25°C/60%relative humidity, at 40°C/relative humidity of 75% and at 60°C in dry conditions, respectively.

As shown in table 8, below, and in figure 16, the rate of dissolution of hydrocodone in 0.01 N HCl was measured in various dosage forms 31-34 for about 480 minutes.

Table 8
Drug releaseForm 31Form 31,
1 month
at 25°C/60%relative humidity
Form 31,
1 month
at 40°C/ relative humidity 75%
Form 31,
1 month
at 60°C in dry conditions
The time of test (min)The average value in %The average value in %The average value in %The average value in %
00000
3021212020
6032302926
12044434240
180545251 49
24062605856
30068666462
36073717067
42078767472
48078807875

As shown in table 9, below, and in figure 17, the rate of dissolution of acetaminophen in 0.01 N HCl was measured in the dosage form 31 for about 480 minutes immediately after production and after storage for 1 month at 25°C/60%relative humidity, at 40°C/relative humidity of 75% and at 60°C in dry conditions, respectively.

Table 9
Drug releaseForm 31 Form 31,
1 month
at 25°C/60%relative humidity
Form 31,
1 month
at 40°C/ relative humidity 75%
Form 31,
1 month
at 60°C in dry conditions
The time of test (min)The average value in %The average value in %The average value in %The average value in %
0000
307666
6011101010
12016161616
18021212121
24025252 25
30029292929
36032323232
42035353535
48038383838

(iv) the Composition of some other studied forms, 32-37, presented in table 10:

Table 10
No. songForm 32Form 33Form 34Form 35Form 36Form 37
MedicationTablet extrudate acetaminophen, 500 mg
Track60% acetaminophen
13% Eudragit RL-PO
13% Methocel K100M
13% Kluce EF
1% Colloidal silicon dioxide
60% acetaminophen
13% Eudragit RL-PO
13% Methocel K100M
13% Kollidon VA84
1% Colloidal silicon dioxide
60% acetaminophen
6.5% of Eudragit RL-PO
6.5% of Eudragit RS-PO
20% Klucel EF
1% Colloidal silicon dioxide
60% acetaminophen
6.5% of Eudragit RL-PO
6.5% of Eudragit RS-PO
13% Methocel K100M
13% Kollidon VA84
1% Colloidal silicon dioxide
60% acetaminophen
13% Eudragit RL-PO
13% Methocel K100M
13% Polyox
1% Colloidal silicon dioxide
60% acetaminophen
13% Eudragit RL-PO
13% Kollidon VA84
13% Klucel EF
1% Colloidal silicon dioxide
The planned mass mg833 mg833 mg833 mg833 mg833 mg833 mg

The nature of the dissolution of the tablets was tested in 0.01 N HCl and 20% aqueous solution of ethanol in accordance with the Protocol described above.

As shown in table 11, below, and figure 14, the rate of dissolution of hydrocodone in 20% aqueous solution of ethanol was measured in various dosage forms, 32-37, for about 480 minutes.

Table 11
Drug releaseForm 32Form 33Form 34Form 35Form 36Form 37
The time of test (min)The average value in %The average value in %The average value in %The average value in %The average value in %The average value in %
0000000
155575611
3078137818
4591017/td> 91025
60111122111232
90141430141646
120161738161858
180202254202377
240252566242891
3603233873036102
4803840983742102

As shown in table 12, below, and figure 15, the rate of dissolution of hydrocodone in 0.01 N HCl was measured in various dosage forms, 32-37, for about 480 minutes.

Table 12
Drug releaseForm 32Form 33Form 34Form 35Form 36Form 37
The time of test (min)The average value in %The average value in %The average value in %The average value in %The average value in %The average value in %
0000000
15445446
30665679
457877911
6089981013
90111211111316
120131413131519
1801618 17171924
240192220202328
360252925263034
480293530313640

Based on the above experiments, it was visually observed that a 20% aqueous solution of ethanol (i) tablet form 32 was dissolved very slowly, (ii) the pill form 33 partially formed gel-like coating, while the remaining part has not changed, (iii) the pill form 34 form a small core tablet at the bottom of the blade, (iv) tablets form 35 had essentially unaltered core tablets with others small transparent crystals, (v) the pill form 36 was approximately 80% unchanged tablets after 8 h and (vi) to form 37, tablet 3, 4, 6 were dissolved in 5 h, ableto 5 was dissolved in 6 h, tablet 2 was dissolved in 7 hours and a small number of tablets 1 remained after 8 o'clock in Addition, based on the above experiments, it was visually observed that in 0.01 N HCl (i) form 32 was approximately 90% unchanged tablets tablets after 8 h, with the formation of lumps, (ii) form 33 had 90% unchanged tablets after 8 h, with the formation of lumps, (iii) form 34 had 90% unchanged tablets after 8 h, with the formation of lumps, (iv) form 35 was approximately 90% unchanged tablets through 8 h, with the formation of lumps, (v) form 36 was approximately 80% unchanged tablets after 8 h and the outer layers of the tablets were very rough and flocculation (vi) form 37 was essentially unchanged after 8 hours Typical test results, based on the above experiments, provided the results of Flexural strength and fracture toughness, as shown in tables 13 and 14 below:

td align="center"> > 500
Table 13
Bending strengthForm 32Form 33Form 34Form 35Form 36Form 37
The average value (N)> 500> 500> 500431> 500

Table 14
Tensile fractureForm 32Form 33Form 34Form 35Form 36Form 37
The average value (N)> 500431> 500418> 500484

(v) dissolve tablets forms 32, 34 and 36 were tested in 0.01 N HCl + 5% NaCl, 0,05 M phosphate buffer, pH of 6.78/50 rpm, 0.01 N HCl + 0.9% NaCl/50 Rev/min and 0.01 N HCl/200 rpm in accordance with the protocols, essentially the same as the above described protocols.

In addition, as shown in table 15, below, and figure 18, the rate of dissolution of acetaminophen in 0.01 N HCl + 5% NaCl was measured in various dosage forms 32, 34 and 36 for about 480 minutes.

Table 15
Drug releaseForm 32Form 34Form 36
The time of test (min)The average value in %The average value in %The average value in %
0000
15435
30657
45769
608711
9010914
120121116
180151320
240181523
360221829
480252134

In addition, as shown in table 16, below, and figure 19, the rate of dissolution of acetaminophen in 0.05 M phosphate buffer, pH of 6.78/50 rpm was measured in various dosage forms, 32, 34 and 36, for about 480 minutes.

Table 16
Drug releaseForm 32Form 34Form 36
The time of test (min)The average value in %The average value in %The average value in %
0000
15556
30 778
459911
60101012
90121315
120151518
180181922
240212225
360262731
480303138

As shown in table 17, below, and in figure 20, the rate of dissolution of acetaminophen in 0.01 N HCl + 0.9% NaCl/50 rpm was measured in various dosage forms, 32, 34 and 36, for about 480 minutes.

the table 17
Drug releaseForm 32Form 34Form 36
The time of test (min)The average value in %The average value in %The average value in %
0000
15454
30656
45777
60888
90111111
120131313
1801616 16
240201920
360252425
480302829

As shown in table 18, below, and figure 21, the rate of dissolution of acetaminophen in 0.01 N HCl/200 rpm was measured in various dosage forms, 32, 34 and 36, for about 480 minutes.

8
Table 18
Drug releaseForm 32Form 34Form 36
The time of test (min)The average value in %The average value in %The average value in %
0000
15588
30119
45101311
60121413
90151717
120182020
180242525
240293031
360404142
480515254

(vi) the Composition of some other studied forms 38-40 presented in table 19.

Table 19
No. SongForm 38 Form 39Form 40
MedicationTablet extrudate acetaminophen, 500 mg
Track60% acetaminophen
8,0% Eudragit RL-PO
6,0% Methocel K 100
6,0% Methocel K 100M
17,2% Kollidon 17PF
1.8% of the hydrocodone
1% Colloidal silicon dioxide
60% acetaminophen
12.8% of Eudragit RL-PO
6,0% Methocel K 100
6,0% Methocel K 100M
12,6% Xylitol
1.8% of the hydrocodone
1% Colloidal silicon dioxide
60% acetaminophen
8,0% Eudragit RL-PO
6,0% Methocel K100
6,0% Methocel K100M
17,2% Isomail F
1.8% of the hydrocodone
1% Colloidal silicon dioxide
The planned mass mg833,33833,33833,33

Dissolve tablets forms 38, 39 and 40 were tested in 0.01 N HCl and 40% aqueous solution of ethanol in accordance with the protocols given above.

As shown in table 20, below, and figure 22, the rate of dissolution of hydrocodone in 0.01 N HCl was measured in various dosage forms, 38, 39 and 40, for about 480 minutes.

Table 20
Drug release Form 38Form 39Form 40
The time of test (min)The average value in %The average value in %The average value in %
0000
30162125
60233236
120354450
180445460
240526267
300586874
360657379
42071 7882
480757886

As shown in table 21, below, and figure 23, the rate of dissolution of acetaminophen (APAP) in 0.01 N HCl was measured in various dosage forms, 38, 39 and 40, for about 480 minutes.

Table 21
Drug releaseForm 38Form 39Form 40
The time of test (min)The average value in %The average value in %The average value in %
0000
30878
60121112
120201619
180262125
240332629
300392934
360443238
420503541
480563646

As shown in table 22, below, and figure 24, the rate of dissolution of hydrocodone is a 40% aqueous solution of ethanol was measured in various dosage forms, 38, 39 and 40, for about 480 minutes.

Table 22
Drug releaseForm 38Form 39Form 40
The time of test (min)The average value in %Average the e value in % The average value in %
0000
30151316
60222225
120323137
180413947
240484754
300555161
360625666
420676071
480726475

As shown in table 23, below, and figure 25, the MSE of the ity of dissolution of acetaminophen (APAP) in 40% aqueous solution of ethanol was measured in various dosage forms, 38, 39 and 40, for about 480 minutes.

Table 23
Drug releaseForm 38Form 39Form 40
The time of test (min)The average value in %The average value in %The average value in %
0000
3010911
60161518
120252327
180333035
240403643
30046 4150
360524656
420585062
480635467

EXAMPLE III

The method of determination of strength tablets

Oblong tablet having a diameter of from about 5.1 mm to about 10 mm and a length of from about 5.1 mm to about 30 mm, placed exactly in the holder for tablets, so that the seam was located at the top (away from the wedge), i.e. strength was measured across the weld. The cylinder in the form of a wedge pushing perpendicular to the long side of the tablet, as shown in figure 7, and move to tablet with constant speed to the destruction of the tablets. Record the force required to break the tablet. The maximum applicable force of 500 Newtons.

Used for this measurement device is a device for testing hardness "Pharma Test PTB 501", Fmax= 500 N, the displacement max. 40 mm, the speed of the translational motion of ~ 3 mm/s Measurement was performed using a cylinder (diameter 14 mm) with a wedge-shaped tip with the size of the AMI, presented in figure 8 (a device from Pharma Test Apparatebau, Hainburg, Germany).

The following compositions of some of the investigated forms, 10-18, are illustrative for different dosage forms having different strength.

I. Tablets with strength of more than 150 N:

Form 10Form 11
80% of the acetaminophen
8,0% Eudragit RL-PO
6,0% Methocel K 100
6,0% Methocel K 100M
17,2% Xylitol
1.8% of the hydrocodone
1% Colloidal silicon dioxide
60% acetaminophen
8,0% Eudragit RL-PO
6,0% Methocel K100
6,0% Methocel K100M
17,2% Isomail F
1.8% of the hydrocodone
1% Colloidal silicon dioxide

The strength of the form 10 is approximately 190 N, while the strength of the form 11 is approximately 250 N.

II. Tablets with strength of more than 300 H:

Form 12Form 13
60% acetaminophen
10.1% of Eudragit RL-PO
5% Methocel K 100
5% Methocel K 100M
10,1% Klucel EF
5% Plurol Oleique CC
1.8% of the hydrocodone
1% Colloidal silicon dioxide
60% acetaminophen
11,4% Klucel EF
11.4% of Eudragit RL-PO
11.4% of Methocel K100
3% Lutrol F68
1.8% of the hydrocodone
1% Colloidal silicon dioxide

The strength of the form 12 is approximately 339 N, is as the strength of the form 13 is approximately 410 N.

III. Tablets with strength of more than 450 H:

Form 14Form 15
60% acetaminophen
19,2% Kollidon VA64
9,0% Eudragit RL-PO
9,0% Methocel K 100
1.8% of the hydrocodone
1% Colloidal silicon dioxide
60% acetaminophen
12.8% of Eudragit RL-PO
6,0% Methocel K100
6,0% Methocel K100M
12.5% xylitol
1.8% of the hydrocodone
1% Colloidal silicon dioxide

The strength of the form 14 is approximately 454 N, while the strength of the form 15 is approximately 484 N.

IV. Tablets with strength of more than 500 N:

Form 16Form 17Form 18
80% of the acetaminophen
12.6% of Eudragit RL-PO
6,0% Methocel K 100
6,0% Methocel K100M
12,6% Klucel EF
1.8% of the hydrocodone
1% Colloidal silicon dioxide
60% acetaminophen
18.5% of Eudragit RL-PO
18,6% Methocel K100
1.8% of the hydrocodone
1% Colloidal silicon dioxide
60% acetaminophen
18.5% of Eudragit RL-PO
18,6% Methocel K100
1.8% of the hydrocodone
1% Colloidal silicon dioxide

The strength of the forms 16, 17 and 18 is more than 500 N.

EXAMPLE IV

The following compositions of some of the investigated forms, 19-22 illustrate various medicinal is of the form, have specific release profiles of hydrocodone, where less than 30% of the hydrocodone is released after 1 h in 0.01 N HCl at 37°C.

Tablets that release less than 30% of the hydrocodone after 1 h in 0.01 N HCl at 37°C

In illustrative embodiments, the implementation presents a profile of release for different dosage forms in the form of unmodified and subjected to crushing of tablets in 40% aqueous solution of ethanol and 0.01 N HCl. As presented below in the following examples, in one preferred embodiment, unmodified tablets drug release during the first hour in 40% aqueous ethanol is less than or equal to double the number released in 0.01 N HCl. In a more preferred embodiment, unmodified tablets drug release during the first hour in 40% aqueous ethanol is less than or equal to 1.5 times the amount released in 0.01 N HCl. In the most preferred embodiment, unmodified tablets drug release during the first hour in 40% aqueous ethanol is less than or equal to 0.90 on the number released in 0.01 N HCl.

In another preferred embodiment, subjected to crushing of tablets, the drug release is the first substance in the first hour in 40% aqueous ethanol is less than or equal to triple the amount, released in 0.01 N HCl. In this embodiment, the full release is after 3 or more hours in a 40% aqueous solution of alcohol. In a more preferred embodiment, subjected to crushing of tablets, the drug release during the first hour in 40% aqueous ethanol is less than or equal to 2.5 times the amount released in 0.01 N HCl. In this embodiment, the full release is after about 8 hours or more in 40% aqueous solution of alcohol. In the most preferred embodiment, subjected to crushing of tablets, the drug release during the first hour in 40% aqueous ethanol is less than or equal to double the number released in 0.01 N HCl. In this embodiment, the full release is after 8 or more hours in a 40% aqueous solution of alcohol.

Unmodified tablets

a.) release after 1 h in 40% ethanol at 37°C, less than or equal to the double release in 0.01 N HCl, to form 19, as shown in table 24:

Table 24
Form 19The release of drug substance, hydrocodone/td> In 0.01 N HClIn 40% EtOH
The time of test (min)The average value in %The average value in %
60% acetaminophen
19,2% Kollidon VA64
9% Eudragit RL-PO
9% Methocel K 100
1.8% of the hydrocodone
1% Colloidal silicon dioxide
0
30
60
120
180
240
300
360
420
480
0
18
22
32
40
46
52
57
62
66
0
24
44
64
79
89
97
101
103
103

b.) release after 1 h in 40% ethanol at 37°C, less than or equal to 1.5 times the release in 0.01 N HCl, to form 20, as shown in table 25:

Table 25
Form 20The release of drug substance, hydrocodoneIn 0.01 N HClIn 40% EtOH
The time of test (min)The average value in %The average mn is an increase in %
60% acetaminophen
12.6% of Eudragit RL-PO
12.3% of Methocel K100
6% Methocel K100M
6,3% Klucel EF
1.8% of the hydrocodone
1% Colloidal silicon dioxide
0
30
60
120
180
240
300
360
420
480
0
15
21
30
37
43
46
52
57
60
0
16
20
28
36
41
48
53
58
62

2. Subjected to crushing tablets

a.) release after 1 h in 40% ethanol at 37°C, less than or equal to the triple release in 0.01 N HCl, to form 21, as shown in table 26:

Table 26
Form 21The release of drug substance, hydrocodoneIn 0.01 N HClIn 40% EtOH
The time of test (min)The average value in %The average value in %
60% acetaminophen
11,4% Klucel EF
11.4% of Eudragit RL-PO
11.4% of Methocel K100
3% Lutrol F68
1.8% of the hydrocodone
1% Colloidal silicon dioxide
0
30
60 120
180
240
300
360
420
480
0
16
22
32
42
50
58
65
71
76
0
63
64
83
91
98
100
101
101
101

b.) release after 1 h in 40% ethanol at 37°C, less than or equal to 2.5-fold release in 0.01 N HCl, to form 22, as shown in table 27:

Table 27
Form 22The release of drug substance, hydrocodoneIn 0.01 N HClIn 40% EtOH
The time of test (min)The average value in %The average value in %

60% acetaminophen
10.1% of Eudragit RL-PO
6% Methocel K100
6% Methocel K100M
10,1% Klucel EF
5% Plurol Oleique CC
1.8% of the hydrocodone
1% Colloidal silicon dioxide
0
30
60
120
180
240
300
360
420
480
0
18
23
32
40
47
53
59
65
69
0
45
52
61
68
75
80
84
88
91

POR THE MEASURES V

The following compositions of some of the investigated forms, 23-25 illustrate various dosage forms that have specific release profiles of hydrocodone, where more than 30% of the hydrocodone is released after 1 h in 0.01 N HCl at 37°C.

Tablets that release more than 30% of the hydrocodone after 1 h in 0.01 N HCl at 37°C

In illustrative embodiments, the implementation presents a profile of release for different dosage forms in the form of unmodified and subjected to crushing of tablets in 40% aqueous solution of ethanol and 0.01 N HCl. As shown in the following examples, in one preferred embodiment, unmodified tablets drug release during the first hour in 40% aqueous ethanol is less than or equal to 1.5 times the amount released in 0.01 N HCl. In a more preferred embodiment, unmodified tablets drug release during the first hour in 40% aqueous ethanol is less than or equal to 0.90 on the number released in 0.01 N HCl.

In another preferred embodiment, subjected to crushing of tablets, the drug release during the first hour in 40% aqueous ethanol is less than or equal to double the number released is 0.01 N HCl.

1. Unmodified tablets

a.) release after 1 h in 40% ethanol at 37°C, less than or equal to 1.5 times the release in 0.01 N HCl, to form 23, as shown in table 28.

Table 28
Form 23The release of drug substance, hydrocodoneIn 0.01 N HClIn 40% EtOH
The time of test (min)The average value in %The average value in %
76% acetaminophen
11.2% of Eudragit RL-PO
10,0% Methocel K100
1.8% of the hydrocodone
1% Colloidal silicon dioxide
0
30
60
120
180
240
300
360
420
480
0
24
34
48
58
66
72
77
82
88
0
24
39
61
78
90
99
103
105
105

b.) release after 1 h in 40% ethanol at 37°C, less than or equal to 0.9 times the release in 0.01 N HCl, to form 24, as shown in table 29.

Table 29
Form 24The release of drug substance, hydrocodoneIn 0.01 N HClIn 40% EtOH
The time of test (min)The average value in %The average value in %
60% acetaminophen
8,0% Eudragit RL-PO
6,0% Methocel K100
6,0% Methocel K100M
17,2% Isomatt F
1.8% of the hydrocodone
1% Colloidal silicon dioxide
0
30
60
120
180
240
300
360
420
480
0
25
36
50
60
67
74
79
82
86
0
16
25
37
47
54
61
66
71
75

2. Subjected to crushing tablets

a.) release after 1 h in 40% ethanol at 37°C, less than or equal to the double release in 0.01 N HCl, to form 25, as shown in table 30:

td align="left">
Table 30
Form 25The release of drug substance, hydrocodoneIn 0.01 N HClIn 40% EtOH
The time of test (min)The average value in %The average value in %
60% acetaminophen
12.6% of Eudragit RL-PO
6% Methocel K100
6% Methocel K100M
12,6% xylitol
1.8% of the hydrocodone
1% Colloidal silicon dioxide
0
30
60
120
180
240
300
360
420
480
0
21
32
44
54
62
68
73
78
78
0
45
52
62
70
75
80
84
87
89

EXAMPLE VI

Pharmacokinetic analysis of compositions (forms 26, 27, 28 and 29)

A series of test studies were performed in order to evaluate the biological equivalence of the compositions according to this invention (forms 26 to 29), compared with the composition of control 1, which is similar to the composition described in example 4, Cruz et al. (publication of the patent application U.S. No. 2005/0158382). Shows a comparison of the PK profile of four embodiments of this invention, a single composition of the capsule and the composition of control 1 after oral dose in male dwarf pigs, as also shown in figures 12 and 13. PK profiles of these compositions are also compared to the PK profile of the composition of control 1 of ALZA when dosing in humans with normal function of the PE the Yeni. Data for humans receive in a separate study.

Six male dwarf pigs Gottingen (11-15 kg; Ellegard, Denmark)used in these studies, randomly administered orally, the dose of the compositions mentioned below. Animals were subjected to fasting overnight prior to dosing, but were given water without restrictions and food, mainly through twelve hours after dosing. Dwarf pigs were kept individually in pens in the research process. For oral administration tablets used bloodwater, then gave 50 ml of water. Before the introduction of the doses from each animal was given a sample of blood. Form 26-29 presented below in table 31:

Table 31
No. songForm 26Form 27Form 28Form 29Control 2Control 1
Track
60% acetaminophen
11,4% Klucel EF
11.4% of Eudragit RL-PO
11.4% of Methocel K100
3% Lutrol F68
1.8% of the hydrocodone
1% Colloidal silicon dioxide
60% acetaminophen
13.6% of Eudragit RL-PO
13,6% Methocel CM
10% propylene glycol
1.8% of the hydrocodone
1% Colloidal silicon dioxide
60% acetaminophen
10.1% of Eudragit RL-PO
6% Methocel K100
6% Methocel K100M
10,1% Klucel EF
5% Plurol Oleique CC
1.8% of the hydrocodone
1% Colloidal silicon dioxide
60% acetaminophen
12.6% of Eudragit RL-PO
6% Methocel K100
6% Methocel K100M
12,6% xylitol
1.8% of the hydrocodone
1% Colloidal silicon dioxide
Hydrocodone 15 mg
Acetaminophen
500 mg
MMID D0500008
The planned mass mg833,33833,33833,33833,33838,3equals 967.4

Blood samples with potassium-ETDA was obtained from each animal approximately 0, 0,5, 1,0, 1,5, 2, 3, 4, 6, 8, 12, 24, 32, 48 and 72 hours after administration of a drug. After collection the samples were centrifuged at approximately 4°C. the resulting plasma samples were analyzed in relation to acetaminophen, hydrocodone, and hydromorphone using the method of liquid chromatography - mass spectrometry.

The results of the observations

Profiles in which the time of acetaminophen in plasma can be evaluated for all compositions, hydrocodone was subjected to detection only after the dosage forms 27 and 28. Signs of sedation were observed in all animals after dosing.

Profile of acetaminophen

The half-life, revealed in the case of compositions of the form 26 (5,8 h) and form 27 (5,9 h)was similar. To form identified 27 t1/2(half-life) was 4.9 hours At the same time for the composition forms 29 and control 1 and control 2 showed similar half-life average of 3.5 hours, 3.6 hours and 3.5 hours, respectively, and, thus, it is shorter than in the other three compositions. Compared to control 1 in humans, the half-life of three forms (26, 27 and 28) was significantly longer, however, the composition forms 29, control 2 and control 1 had a shorter half-life.

As shown in figures 12 and 13, the highest value of Cmaxthe dwarf pigs were observed for the composition of control 1. Cmaxidentified two miniature pigs for the composition of control 1 was 3 times higher than Cmaxobserved in humans. Cmaxthe dwarf pigs for forms 26, 27, 28 and 29; compositions of control 2 and control 1 were approximately 2-3 times higher than that observed in the case of the composition of control 1 in humans.

AUC dwarf pigs for forms 26, 27, 28 and 29; compositions of control 2 and control 1 were approximately 4 times higher than the AUC, abrudaime in the case of man. The highest AUC values in dwarf pigs was observed in the case of the form 29. AUC (± sem) for form 27 was 87567 (± 4504) ng·h/ml, to form 28 it was 98100 (± 9759) ng·h/ml, to form 26 it was 101433 (± 13053) ng·h/ml, and for form 29 it was 120000 (± 4450) ng·h/ml

All animals acetaminophen in plasma was determined 48 hours after a dose. A similar effect was observed in humans, except that one of the subject of the level of acetaminophen in plasma was quantitatively determined up to 60 h after a dose.

Profile of hydrocodone and hydromorphone

Hydrocodone was quantitatively determined in all human samples up to 36 hours after a dose. At the same time, the dwarf pigs hydrocodone was not detected above the LOQ level (1.2 ng/ml) in plasma, with the exception of two animals that were injected with three different compositions (form 27 and 28 and control 2).

In the case of form 28 the level of hydrocodone, it was possible to quantify up to 8 hours after administration of doses in animals, while in the case of form 27 other animal level of hydrocodone can be quantified up to 3 hours after a dose. In the case of the composition of control 2 level hydrocodone was observed only between 2 h and 4 h after dose. Only one animal had shown levels of hydrocodone for two different compositions is s, form 27 and composition of control 2, different day.

Was not identified hydromorphone in plasma samples of both man and dwarf pigs. These observations suggest species-specific metabolism of hydrocodone compared to man. Observed fluctuations in the plasma levels of acetaminophen and hydrocodone animals separately.

EXAMPLE VII

Pharmacokinetic analysis form 30

Six male dwarf pigs Gottingen (11 - 15 kg; Ellegard, Denmark)used in these studies were administered oral dose forms 30, see table 32. Animals were subjected to fasting overnight prior to dosing, but were given water without restrictions and food, mainly through twelve hours after dosing. In studies of dwarf pigs were kept individually in pens. For oral administration tablets used bloodwater, then gave 50 ml of water. Before the introduction of the dose were collected blood samples from each animal. Blood samples with potassium-ETDA was obtained from each animal approximately 0, 0,5, 1,0, 1,5, 2, 3, 4, 6, 8, 12, 24, 32, 48 and 72 hours after administration of a drug. After collection the samples were centrifuged at approximately 4°C. the resulting plasma samples were analyzed in relation to the acetaminophen using the method of liquid chromatography - mass spectrometry, as pok is shown in figure 9.

Table 32
Track60% acetaminophen
11% Eudragit RL
11% Methocel CM
12% Klucel EF
5% Cromophor EL
1% Colloidal silicon dioxide
The planned mass mg833,3

The results of the observations

Profiles acetominaphen in plasma were determined for all animals.

The apparent end of the half-life (t1/2), identified for the form 30, was $ 5.2 hours it Was found that Cmax is 7025 ng/ml and AUC 106000 ng·h/ml

Comparison of pharmacokinetic parameters obtained for the form 30 in dwarf pigs, the composition of control 1 and control 2 are presented in figures 10 and 11.

EXAMPLE VIII

Some illustrative prevent the dependence of the composition produced based on the combination of inhibiting substances and polymers that are insoluble or poorly soluble in ethanol. Below in table 32 composition reduce the dependence provided associated with the dependence of drug substances (e.g., opioids), making the extraction of the calling dependence of medicinal substances more difficult. This is achieved by maintaining the properties of a controlled release composition even after fractional is to be placed and/or grinding of the dosage form, and they preferably do not depend on the environment. In the following examples and related options for implementation after crushing or grinding machine for grinding coffee (as defined above) the rate of release of the medicinal substance is preferably increased to a much higher speed, for example, it is less than 40% faster, more preferably less than about 30 percent faster and more preferably less than about 20 percent faster than in the case of the unmodified composition in 0.01 N HCl or 20% or 40% aqueous solution of ethanol, especially as defined in the period of time from 1 to 4 hours after placing in the aquatic environment or household solvent.

In some illustrative preferred embodiments of implementation of the components prevents dependence compositions include the following components.

1. Eudragit RS or RL (ammonium methacrylate copolymer type B or type A) in accordance with the pharmacopoeias, such as USP/NF or Pharm. Eur.

2. The polymer category I-III (low solubility in EtOH, further defined below).

Although you can use any suitable ratio of the masses of certain preferred ratios include Eudragit RS, RL)/polymer (I-III) from 0.6 to 1.4:1, more preferably from 0.8 to 1.2:1 and not necessarily about the part 1:1.

(a) the Composition of some of the compositions (% by weight) according to this invention as define:

1. Active pharmaceutical ingredient: up to 70%.

2. Polymer A: Eudragit RS, RL): 20-80% (sum of A+B).

Polymer B: Polymer categories I-III from the list below.

3. Other excipients: 0-25%.

(b) shaping: in some embodiments, implementation of the preferred method of shaping the tablet is calendering, however, also possible to use any suitable method, including, but not limited to, direct the shaping of molten polymers (for example, injection molding extrusion). Grinding and pelleting, on the other hand, are not the preferred alternatives for the shape of the tablets, as they have a tendency to the formation of tablets, more amenable to compression (crushing or grinding), so essentially violate the profile of a controlled release composition under the influence of household solvent (as defined in the present description) or other aqueous solution.

(c) Certain polymers are used in a variety of compositions, based on the following categories: category I corresponds to the most preferred polymers; category II corresponds to the preferred polymers; category III corresponds to an additional polymers suitable in the context of this and the finding; and category IV corresponds to the polymers, which can also be used, but as additional excipients.

Some preferred compositions were based on solubility in aqueous solution of ethanol and thermoplastic properties of polymers that may be necessary for use as the primary polymer in the extrusion process by melting. Among them, nonionic polymers were preferred.

(d) solubility in aqueous solution of ethanol was based on the following criteria:

CategorySolubility
I:<3% of the mass in H2O/EtOH (80/20)
II:3% of the mass. - 6% of the mass. a 20% aqueous solution of ethanol
III:6 wt% to 10 wt%. a 20% aqueous solution of ethanol
IV:>10% of the mass. a 20% aqueous solution of ethanol

In the most preferred embodiment, preferred polymers must be thermoplastic with a solubility of less than 6% of the mass. a 20% aqueous solution of ethanol.

Some illustrative prevent the dependence of the composition of the lead is received in the following table 33:

Table 33
PolymerCategorySubstitutionObservations
Hydroxypropylcellulose (Klucel®)
HF, MF, JF,
LF, EF differ in viscosity
IV
IV
IV
IV
IV
Molecular substitution: 3,0Soluble in water; soluble in EtOH
HydroxypropylcelluloseII or IIIL-HPCneuroplasticity hydroxypropylcellulose (HPC) with a low substitution
Methylcellulose (Methocel® A)IA:
-OMe of 27.5-31.5 per cent
Significantly less soluble in EtOH than HPC
The methylcelluloseIV-OMe 40-47%
HydroxyethylcelluloseIII or IISoluble in water, weak thermoplastic properties
Carboxylic cellulose-Na III or IISoluble in water, weak thermoplastic properties
Ethylcellulose (Ethocel®)IV
III or II
Standard: -OEt to 48.0-49.5 per cent; medium: -OEt 45-47%Wednesday: leads to the formation of gels
Sodium starch glycolate (Primojel)®III or IIPoorly soluble in EtOH, insoluble in water
StarchIII or IIContains starch from corn, rice, potatoes and wheat
GelatinIII or IISwells; soluble in hot water
TragakantIII or IISoluble in water at 15-40%, forms gels
Polyox
The polyethylene oxide NF
I or IISoluble in EtOH at > 45°C, very good thermoplastic properties
Polyvinylpyrrolidone (PVP, Kollidon®)
Povidone USP (= a homopolymer PVP)
Copovidone Ph. Eur. (= copolymer of PVP with vinylacetate)
IV
Polyethylene glycol (PEG)IV
Polypropyleneglycol (PPG)IV
Eudragit
Methacrylic acid copolymer, type A, NF (Eudragii® L100)
Methacrylic acid copolymer, type B, NF (Eudragit® S100)
Methacrylic acid copolymer, type C, NF (Eudragit® L100-55)
A 30% dispersion of a polyacrylate 30 Ph. Eur. = Eudragit NE30D
(= 30% aqueous dispersion)
The main bottled copolymer of methacrylate Ph. Eur. = Eudragit E-100
IVL (methacrylic acid Copolymer, type a), S (methacrylic acid Copolymer, type B), E (poly(butyl)methacrylate NE30D
dispersion of poly(acrylate-methacrylate)
Soluble in EtOH
GuarIII or II
PectinIII or II
Aginova acid/Na-alginateIII or IIGood thermoplastic properties
Gum ArabicIII or II
Phthalate of hydroxypropylmethylcellulose
The phthalate-free hypromellose NF
II or IIIHPMCPThermoplastic, ion
Hydroxypropylmethylcellulose acetate phthalateII or IIIAQOATThermoplastic, ion
ChitosanII or III
Carboximetilkrahmal sodiumIIISodium starch glycolateNeuroplasticity poorly soluble in EtOH
The polyvinyl acetateIIIPVACThermoplastic, soluble in EtOH
The cellulose acetate
Cellulo the s acetate butyrate
Cellulose acetate propionate
I-IIThermoplastic, non-ionic, insoluble in tO

EXAMPLE IX

The relative bioavailability of the composition form 45 compared with the control 1 person

The aim of this study was to compare the relative bioavailability of the test composition, form 45 and control for comparison 1.

Form 45 produced as a composition tablets for clinical trials in humans, as shown below: homogeneous powder mixture containing 1.8 kg of acetaminophen, 54,0 g of hydrocodone bitartrate of pentahedra, 378,0 g Eudragit® RL, of 180.0 g of Methocel® K100, of 180.0 g of Methocel® K100M, 378,0 g of xylitol and 29.9 g of colloidal silicon dioxide (type: Aerosil® 200), was filed in the co-rotating twin screw extruder with 6 cylinders (screw diameter 18 mm) with a feed rate of 1.5 kg/h of the speed of rotation of the screw was about 94/min, and the melting point was 140°C. the White homogeneous melt emerging from the extruder in the region of the head, immediately attached form an oblong tablets through a calender having two rotating in the opposite direction of the roller. After cooling at room temperature with tablets filmed roughness in container device for mixing under strong shaking in order to remove the seams on the ablett, formed by calandrinia. End tablets had an average weight of tablets 833 mg in accordance with the content of drug substance is 500 mg (acetaminophen) and 15 mg (of hydrocodone bitartrate pentahedra) in each tablet.

The study was performed with the following parameters.

The open cross-sectional study with a single dose, after fasting, with two periods spent 16 people with the following schema:

form 45: 1 tablet, 15 mg of hydrocodone bitartrate/acetaminophen 500mg;

control 1: 1 tablet, 15 mg of hydrocodone bitartrate/acetaminophen 500mg.

The sampling of blood was performed through 0, 0,25, 0,5, 0,75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours after dosing on 1 day of the study.

As is shown in Fig. 26 and 27, and the following table 34 shows the preliminary pharmacokinetic parameters for form 45 vs. control 1.

As a form 45 and the control 1 have similar values of Cmaxand AUC for hydrocodone. However, acetaminophen Cmaxapproximately 61% lower and AUCtapproximately 23% less. As a form 45 and the control 1 have similar AUCfor acetaminophen. For acetaminophen apparent t1/2for form 45 approximately in 2 times more, while Tmaxis less variable.

Without regard to any specific theory is th, the value of t1/2can be based on the slow release form 45 and the value of tmaxcan be based on the fact that the form 45 is not mushy.

Table 34
SchemePharmacokinetic parameters
Hydrocodone
tmax
(h)
Withmax
(ng/ml)
AUCt
(ng·h/ml)
AUCinf
(ng·h/ml)
t1/2
(h)
CL/F
(l/h)
Form 454,8
(33%)
13,4
(22%)
225
(22%)
229
(21%)
6,8
(16%)
41,5
(23%)
Control 16,8
(36%)
13,6
(25%)
225
(25%)
229
(24%)
5,5
(14%)
41,7
(22%)
Acetaminophen
tmax
(h)
Withmax
(ág/ml)
AUCt
(µg·h/ml)
AUCinf
(µg·h/ml)
t1/2
(h)
CL/F
(l/h)
Form 453,4
(37%)
0,83
(28%)
18,6
(29%)
25,3
(48%)
11,0
(71%)
24,2
(45%)
Control 12,3
(120%)
2,12
(24%)
24,1
(23%)
24,3
(23%)
5,8
(17%)
21,8
(27%)

For the study in example IX additional pharmacokinetic details presented on Fig-33. On Fig presents the average concentration profiles of hydrocodone is the time to form 45 and control 1. In Fig. 27 presents the average concentration profiles of acetaminophen-time to form 45 and control 1. In Fig. 28 A and B show the concentration profile of hydrocodone-time at an individual subject to forms 45 and control 1, respectively. In Fig. 29 A and B presents the profile of the concentration of acetaminophen-time at an individual subject to forms 5 and control 1, respectively. In Fig. 30 A and B presents the profile of the average concentration of hydrocodone-time for periods 1 and 2 respectively to form 45 and control 1. In Fig. 31 A and B presents the profile of the average concentration of acetaminophen-time for periods 1 and 2 respectively to form 45 and control 1. In Fig. 32 A and B presents the average concentrations of hydrocodone and acetaminophenin vitrofor form 45,in vitrofor control 1, the concentration control 1in vivoand predicting concentrations ofin vitro-in vivofor form 45. In Fig. 33 A and B presents the profiles of the average solubility of hydrocodone and acetaminophenin vitrofor form 45 and control 1. In Fig. 26 presents the average concentration profiles of hydrocodone is the time to form 45 and control 1.

The above detailed description and accompanying examples are merely illustrative and are not intended to limit the scope of this invention, which is defined only by the attached claims and their equivalents. Various changes and modifications of the described embodiments will be apparent to experts in this field, and they are part of the present invention. Such changes and modifications, including, but not limited to, changes and modifications relating to the chemical structures, replacement, derivatives, intermediates, synthesis, compositions and/or methods applied shall I to this invention, can be performed without deviating from the essence and scope.

1. Solid, oral pharmaceutical composition with delayed release containing subjected to melting a mixture of:
(a) effective for analgesia amount of at least one of the calling addiction drugs
b) at least one simple cellulose ether or a complex ester of cellulose, and
c) at least one alkylalkoxysilane polymer, alcacaltro polymer or combinations thereof,
where the amount of medicinal substance, which is extracted in vitro composition of 40% aqueous ethanol within one hour at 37°C is less than or equal to double the amount of medicinal substance, which is extracted in 0.01 N hydrochloric acid within one hour at 37°C;
where the medicinal composition of matter adapted for slow release, so it was suitable for oral administration to a human 3, 2 or 1 times a day,
where the pharmaceutical composition directly give the dosage form obtained from the melt extrudate without intermediate grinding stage and without the intermediate stage of the formation of many particles.

2. The composition according to claim 1, where a simple cellulose ether is a hypromellose.

3. The composition according to claim 1, where a is akrilaty polymer is an acrylic polymer or a methacrylic polymer.

4. The composition according to claim 1, where ELECRICITY polymer is an ionic acrylic polymer or ion methacrylic polymer.

5. The composition according to claim 1, where ELECRICITY polymer is a cationic acrylic polymer or cationic methacrylic polymer.

6. The composition according to claim 1, where ELECRICITY polymer is a copolymer of esters of acrylic polymer and a methacrylic polymer containing Quaternary ammonium group.

7. The composition according to claim 1, where the addictive drug is an analgesic.

8. The composition according to claim 1, where the addictive drug is an opioid.

9. Composition according to any one of claims 7 to 8, optionally containing at least one medicinal substance.

10. The composition according to claim 1, where the addictive drug is dispersed in the composition in a state of solid solution.

11. The composition according to claim 1, where between 11% and 47% calling dependence drug substance is released in vitro in 0.01 N hydrochloric acid for two hours at 37°C.

12. The composition according to claim 1, where less than 20% of the calling dependency drug substance is released in vitro in 20% aqueous ethanol within one hour at 37°C.

13. The composition according to claim 1, where the composition is additionally characterized by the following features:
a) the composition does not collapse under the force of 150 N, preferably 300 N, more preferably 450 N, more preferably 500 N, as measured by a hardness tester "Pharma Test PTB 501", and
b) the composition releases at least 15% of one drug and not more than 45% of one medicinal substance within the first hours when tested in vitro dissolution and preferably also in vivo.

14. The composition according to item 13, where the composition can not be inhaled via nasal administration.

15. The composition according to item 13, where the medicinal substance is an opioid, amphetamine or methamphetamine.

16. The composition according to any one of claims 1 or 13, where alkylalkoxysilane or ELECRICITY polymer has Monomeric elements (C1-C22)alkyl ((C1-C10)ALK) acrylate or (C1-C10)alkalidata.

17. The composition according to any one of claims 1 or 13, where ELECRICITY polymer is a copolymer of esters of acrylic polymer and a methacrylic polymer containing Quaternary ammonium group.

18. The composition according to any one of claims 1 or 13, where ELECRICITY polymer is a copolymer or mixture of copolymers, where the molar ratio of cationic groups and neutral esters is in the range on the average from about 1:20 to 1:35.

19. The composition according to claim 1, where the composition is I essentially has the release profile of drug substances, similar to crushed form a monolithic composition, where a monolithic composition is crushed when from approximately 20,000 rpm./minutes to approximately 50,000.minutes in a machine for grinding coffee for about 60 seconds.

20. The composition according to claim 19, where the composition of the drug substance does not contain more than 0.5% of genotoxic compounds after manufacturing and after a minimum of 6 months of storage at 25°C./60% relative humidity or 40°C/relative humidity 75%, or in both of these cases.

21. The composition according to claim 20, where the composition comprises a polyethylene oxide and antioxidant.

22. The composition according to claim 20, where the genotoxic compound is a N-oxide opioid.

23. The composition according to claim 1, where the composition has a diameter of from about at least 5.1 mm to about 10 mm and a length of from about 5.1 mm to about 30 mm

24. The composition according to item 23, where the composition directly shape of the resulting melting of the extrudate of the dosage form by a process of calendering.

25. A method of obtaining a composition according to claim 1, comprising extruding a melt of a composition containing at least one addictive drug, including additional direct giving of the dosage form the extrudate without intermediate grinding stage or stage of education the centre of the WA particle.

26. Monolithic preventing dependence of the composition of a medicinal substance containing subjected to melting a mixture of:
a) at least one caller dependence of medicinal substance, where the specified medicinal substance is a hydrocodone,
b) at least one simple cellulose ether or a complex ester of cellulose, and
c) at least one acrylic polymer, methacrylic polymer, or combinations thereof,
where the medicinal composition of matter adapted to ensure that it was suitable for oral administration to a human 3, 2 or 1 time per day; and
where approximately 90% of the hydrocodone is released in vitro for about 4-6 hours, when it is adapted for the introduction of 3 times a day, for about 6-10 hours, when it is adapted for the introduction of 2 times per day and for approximately 16-22 hours, when it is adapted for the introduction of 1 times a day, and
where the pharmaceutical composition directly give the dosage form obtained from the melt extrudate without intermediate grinding stage and without the intermediate stage of the formation of many particles.

27. Preventing dependence of the composition of the medicinal substances in claim 20, where more than 30% of the hydrocodone is extracted from the composition within about one hour at 37°C. in 0.01 N chloritoid the same acid.

28. Preventing dependence of the composition of the medicinal substances in claim 20, where from about 12% to about 25% of the hydrocodone is extracted from the composition within about one hour at 37°C. in 0.01 N hydrochloric acid.

29. Preventing dependence of the composition of a medicinal substance containing subjected to melting the mixture
a) at least one opioid;
b) at least one modifying the speed pharmaceutically acceptable polymer, copolymer, or combinations thereof;
where the amount of medicinal substance, which is extracted from the composition 40% aqueous ethanol within one hour at 37°C ranged from approximately 70% to 110% of the amount of drug that is extracted in 0.01 N hydrochloric acid within one hour at 37°C; and
where the medicinal composition of matter adapted to ensure that it was suitable for oral administration to a human 3, 2 or 1 time per day
where the pharmaceutical composition directly give the dosage form obtained from the melt extrudate without intermediate grinding stage and without the intermediate stage of the formation of many particles.

30. Preventing dependence of the composition of the medicinal substance in clause 29, where the amount of medicinal substance, which extragere the tsya composition of 40% aqueous ethanol within one hour at 37°C. is from about 70% to about 100% of the amount of drug that is extracted in 0.01 N hydrochloric acid within one hour at 37°C.

31. Preventing dependence of the composition of the medicinal substance in clause 29, where addictive drug substance further comprises a non-analgesic.

32. Preventing dependence of the composition of the medicinal substance in clause 29, where non-analgesic is a acetaminophen or ibuprofen.

33. Preventing dependence of the composition of the medicinal substance in clause 29, where the opioid is a hydrocodone or oxycodone, or pharmaceutically acceptable salts or esters.

34. Preventing dependence of the composition of the medicinal substance in clause 29, where the opioid is a hydrocodone and where the introduction of the patient-person composition leads to the profile in the plasma, characterized by a Cmax for hydrocodone of between 0.4 ng/ml/mg and about 1.9 ng/ml/mg after a single dose.

35. Preventing dependence of the composition of the medicinal substance in clause 29, where the opioid is a hydrocodone and where with the introduction of the patient-the person, the composition leads to a profile in the plasma, characterized by a Cmax for hydrocodone of between about 0.4 ng/ml/mg or optional 0,6 is g/ml/mg and about 1.4 ng/ml/mg after a single dose.

36. Preventing dependence of the composition of the medicinal substance in clause 29, where the opioid is a hydrocodone and where with the introduction of the patient-the person dosage form results from the minimum AUC for hydrocodone of approximately 7,0 ng·h/ml/mg to a maximum AUC for hydrocodone of approximately 26.2 ng·h/ml/mg)

37. Preventing dependence of the composition of the medicinal substance in clause 29, where the rate of release of the composition in vitro has a biphasic release profile, and where each phase speed of release in vitro has zero order or is increasing.

38. Preventing dependence of the composition of the medicinal substance in clause 29, where at least 30-45% of the opioid is released in vitro from the composition within 1 hour

39. Preventing dependence of the composition of the medicinal substance in clause 29, where at least 90% of the opioid is released from the composition within about 6 hours to about 10 hours

40. Preventing dependence of the composition of the medicinal substance in clause 29, where at least 90% of the opioid is released from the composition within about 15 hours to about 20 hours

41. Preventing dependence of the composition of the medicinal substance in clause 29, where AUC is at least one of the following
(a) within one hour from approximately 0.22 to 0.51 ng the h/ml/mg,
b) two hours is of 1.07 to about 1,76 ng·h/ml/mg,
c) three hours is up to 2.06 about is 3.08 ng·h/ml/mg,
a) four hours is from 3,12 to approximately of 4.44 ng·h/ml/mg)

42. A method of treating pain in a patient is a human, comprising oral administration to the patient is a person of the composition according to any one of claims 1 to 41.



 

Same patents:

Organic compounds // 2430921

FIELD: chemistry.

SUBSTANCE: invention relates to an azathiabenzo-azulene derivative of formula I

,

where R3 denotes C1-C6alkyl, R4 denotes OH, R5 denotes halogen and R6 denotes H or halogen, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds, having anti-inflammatory or analgesic action.

EFFECT: obtained compounds and pharmaceutical composition can be used to treat arthritis and arthritis-related conditions, and for relieving inflammation and pain associated with acute inflammation of body parts, primarily joints, as a result of injury or as a result of arthritic conditions or other diseased conditions.

17 cl, 8 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxadiazole derivatives of general formula , where X denotes CH, CH2, CH=CH, CH2CH2, CH2CH=CH or CH2CH2CH2, R1 denotes an unsubstituted or mono- or disubstituted phenyl or pyrrolyl residue or an unsubstituted or mono- or disubstituted phenyl connected through a C1-C3alkyl or a thienyl or indolyl residue, where the said substitutes are selected from a group comprising F, Cl, Br, OCF3, O-C1-C6alkyl or C1-C6alkyl, R2 denotes an unsubstituted or mono- or disubstituted phenyl or thienyl residue or an unsubstituted or mono- or disubstituted phenyl residue connected through a C1-C3alkyl, where the said substitutes are selected from a group comprising F, Cl, and R3 and R4 denote a saturated straight C1-C6alkyl in form of a racemate, diastereomers, mixture of enantiomers and/or diastereomers, or a specific diastereomer, bases and/or salts with physiologically compatible acids. The invention also relates to a method of producing said compounds and a medicinal agent based on said compounds and having affinity to the µ-opioid receptor.

EFFECT: obtaining novel compounds and a medicinal agent based on said compounds, which can be used in medicine to pain killing and for treating depression, enuresis, diarrhoea, skin itching, alcohol and drug abuse, drug induced addiction, aspontaneity or for anxiolyis.

11 cl, 2 tbl, 331 ex

FIELD: medicine.

SUBSTANCE: invention relates to drug form for treatment pain in patients suffering from diarrhea using medications, simultaneously containing opioid analgesic and opioid antagonist, which includes from 10 to 40 mg of oxycodon and/or its pharmaceutically acceptable salt and from 5 to 20 mg of naloxon and/or its pharmaceutically acceptable salt, present in ratio 2:1 by weight.

EFFECT: providing drug form for treatment of pain in patients suffering from diarrhea using medications, simultaneously containing opioid analgesic and opioid antagonist.

9 cl, 51 dwg, 38 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine. What is described is a preparation for percutaneous absorption containing a medical composition for percutaneous absorption in which an active component selected from morphine and its salts, is mixed in such amount which matches with saturation solubility or more, with an excipients keeping an active ingredient, having fluidity at temperature approximately equal to human skin surface temperature, and at least a portion of the active ingredient is found as crystals. The preparation is applied to an intact skin of a back of a white rabbit cut by electric shaver for 72 o'clock; an available dose of the active component in one dose of the preparation makes 10 mg to 400 mg of morphine at the morphine base, and the plasma concentration of the active ingredient 24 hours and 48 hours after the preparation application in the conditions specified above makes in each case at least 40 ng/ml at the morphine base.

EFFECT: preparation for percutaneous absorption is capable to support blood morphine concentration for a log time at an effective level for at least 48 hours.

35 cl, 2 dwg, 6 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 3,4-dihydrobenzoxazine compounds of general formula [1] (where X denotes a nitrogen atom or CR3; R1 denotes a hydrogen atom or a halogen atom; R2 denotes a C1-6alkoxy group which can be substituted with 1-5 identical or different substitutes selected from a halogen atom and a hydroxyl group; and R3 denotes a halogen atom. However, R1 denotes a halogen atom when X denotes CR3). Said compounds are effective when treating diseases where activity of vanilloid receptors subtype 1 (VR1) is involved, e.g. pain.

EFFECT: more efficient use of pharmaceutical compositions based on said compounds, more effective treatment or pain killing.

19 cl, 4 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazoline derivatives of formula (I), where n equals 0 or 1, R1 denotes a saturated branched or straight unsubstituted C1-C4alkyl, saturated unsubstituted C3-C8cycloalkyl or unsubstituted phenyl bonded through a C1-C3alkyl chain, R2 denotes an unsubstituted or halogen atom-monosubstituted phenyl or thiophenyl, or unsubstituted phenyl bonded through a C1-C3alkyl chain, R3 denotes a saturated branched or straight C1-C8alkyl which is not substituted or contains one substitute selected from a group comprising -COO-methyl, thiomethyl or thiobenzyl, or a phenyl which is mono-substituted with a halogen atom and bonded through a C1-C3alkyl chain, R4 denotes a C1-C4alkyl, R5 and R6 independently denote a saturated branched or straight C1-C6alkyl, in form of a racemate, enantiomers, diastereomers, mixture of enantiomers or diastereomers or a separate enantiomer or diastereomer, bases and/or salts with physiologically compatible acids. The invention also relates to a method for synthesis of the compound of formula (I), intermediate compounds of formula B , a medicinal agent based on the compound of formula (I) or formula B and use of compounds of formula (I) or formula B to prepare a medicinal agent.

EFFECT: novel derivatives of imidazoline and substituted aldehyde of formula B, having µ-opiate receptor affinity, are obtained.

16 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (A), where the whole of (A), except X, is denoted as MR36G-NR1R2-S; R1 is a linear or branched (C1-C10)-alkyl; R2 is hydrogen; R3 is a YR group. Y is oxygen, R is a linear or branched (C1-C6)-alkyl, provided that R3 is not O-CH3; X is hydrogen, a -S-R4-W radical or a MR36G-NR1R2-S radical, where R4 is (C1-C8)-alkyl, -(CH2)n-C(O)-NH-, or -(CH2)n-NH-C(O)-, where n is an integer ranging from 1 to 8; and W is naltrindole, as well as pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on said compounds for preparing a medicinal agent for curing pain, as well as use of said compounds to prepare a medicinal agent for curing pain.

EFFECT: more effective use of the compounds.

9 cl, 6 tbl, 4 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof , where D denotes phenyl; n equals 0; A, B and Q denote hydrogen; Z is selected from a group comprising a bond, straight C1-3alkylene; R1 is selected from a group comprising hydrogen, C1-10alkyl, C3-8cycloalkyl, benzyl, a 6-member monocyclic, 9-10-member bicyclic aromatic carbon-containing ring system and a spiro-ring system of formula (V): where X1 and X3 denote O; and where the said alkyl, cycloalkyl or benzyl from the R1 group is optionally substituted with 1-3 substitutes selected from a group comprising C1-3alkyl, cyano, phenyl, wherein the said phenyl is optionally substituted with 1-3 substitutes selected from halogen. The invention also relates to compounds of formulae .

Values of radicals of the said compounds are given in the claim. The invention also relates to a pharmaceutical composition having ORL1 receptor or µ opioid receptor inhibiting properties, containing an effective amount of the disclosed compound, a method of curing pain and a method of modulating pharmacological response from the opioid receptor, including the ORL1 or µ opioid receptor.

EFFECT: improved method.

41 cl, 5 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

, where R1 denotes a lower alkyl; R2 denotes phenyl or a 5- or 6-member heteroaryl containing 1-2 N atoms or 1 N atom and 1 S atom as heteroatoms, which may be unsubstituted or substituted with a substitute selected from halogen or lower alkyl; R3 denotes hydrogen, phenyl or a 5-6-member heteroaryl containing 1-2 N atoms and 1 O atom as heteroatoms, which can be unsubstituted or substituted with a substitute selected from 1-2 halogen atoms, lower alkyl or a S(O)2-lower alkyl group; as well as pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, having metabotropic glutamate receptor mGluR5 antagonist properties, which contains the compound of formula (I) as active component and pharmaceutically acceptable excipients.

EFFECT: possibility of using said derivatives as mGluR5 receptor antagonists.

25 cl, 2 dwg, 1 tbl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a product of oxymorphone hydrochloride exhibiting an analgesic activity and containing less than 10 parts/million of alpha, beta unsaturated ketones by HPLC, also the invention refers to a pharmaceutical formulation containing said product of oxymorphone hydrochloride and to a method of oxymorphone hydrochloride purification involving reduction of a basic substance of oxymorphone hydrochloride in highly acid aqueous and alcohol reaction medium with hydrogen gas at temperature within 60 to 70°C.

EFFECT: there is produced and described improved analgesic oxymorphone hydrochloride containing less than 10 parts/million of alpha, beta unsaturated ketones.

22 cl, 3 ex, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: combined antituberculous drug contains main components in the following proportions (wt %): rifabutin - 4.40-18.5, pyrazinamide - 35.53-56.50, protionamide - 1.52-11.10, pyridoxine hydrochloride - 0.8-1.30. As auxiliary substances, the drug contains colloidal silicon dioxide, gelated starch, potato and/or corn starch, crospovidone, lactose, stearic acid and/or its salts, medium molecular weight polyvinylpyrrolidone, sodium carboxymethyl starch, magnesium hydrosilicate, cellulose microcrystalline, dyes, aromatising agents and/or flavouring additives. The invention also concerns a method for preparing said composition in which each main component passes own stage of wet granulation and drying, then mixed up and tabletted.

EFFECT: combined drug exhibits higher clinical effectiveness in drug-resistant forms of tuberculosis and lower toxicity.

5 cl, 3 tbl

New dosage form // 2431473

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to drugs, and concerns a method for preparing a tabletted pharmaceutical composition. For this purpose, an active pharmaceutical ingredient of formula being a receptor NK1 antagonist, or its pharmaceutically acceptable acid addition salts, and a water-soluble poloxamer are processed together by hot melt extrusion before mixing with the other ingredients.

EFFECT: hot melt extrusion with the single ingredients being the active ingredient of formula I and the water-soluble poloxamer provides producing a microcrystalline solid dispersion which when mixed with the other ingredients enables to prepare a tablet exhibiting the solubility characteristics necessary for drug bioavailability.

14 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: declared invention refers to chemical-pharmaceutical industry, and concerns a method for preparing a solid oral dosage form which contains a poorly soluble and/or poorly mouldable drug substance and a hydrophylic polymer. The method is implemented by using an extruder with an added unstable plasticiser in the form of a liquefied gas or a supercritical fluid, e.g. such as a supercritical carbon dioxide. The unstable plasticiser is added to accelerate material processing.

EFFECT: unstable plasticiser is used to reduce viscosity of the mould mixture, and/or improved solubility of the drug substance.

9 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to a stable trehalose-stabilised formulation of amorphous perindopril erbumine, a method for preparation thereof consisting in the fact that a perindopril erbumine hydrate is dissolved in water or a mixture of water and alcohol; an alkaline stabiliser solution and inert ingredients is added to this solution for producing a granulate, dried in vacuum or in air flow at 40°C and less to be granulated to produce granulate.

EFFECT: formulations have higher stability.

16 cl, 7 dwg, 1 tbl, 13 ex

FIELD: medicine.

SUBSTANCE: medication contains the following components per tablet weight of 350 mg: water-soluble chitosan 25.0; powder of Scutellaria baicalensis roots 15.0; powder of Schizonepeta multifida herb 50.0; powder of ginger root 35.0; powder of Rhodiola rosea root 10.0; powder of herb of Astragalus membranaceus 25.0; powder of root of Maral root 30.0; powder of herb of Phlojodicarpus villosus 40.0; powder of Bacora monnieri herb 20.0; chaga powder - the remaining part.

EFFECT: medication makes it possible to normalise brain functions, improves memory and supports healthy energy exchange between brain neurons, acceleration rate of thinking and quick-wittedness, medication contributes to more efficient brain work, as it eliminates deficit of especially necessary for its cells nutrients.

3 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: application relates to composition for application of sugar coatings by method of spraying directly on core material with obtaining of hard drug form. According to invention, composition includes water and hard component, representing mixture of sugar, binding agent, hydroxyalkylcellulose, water-soluble polymer, therapeutic agent, second polymer, which is water-soluble or dispersible in water and plasticiser. Invention also relates to hard drug form, in particular, tablet for peroral introduction, which has described above coating, and as therapeutic agent, in core material contains conjugated estrogens. Invention also relates to method of said sugar coating application, which includes core obtaining, application of coating composition on core material and in case of necessity application of colour and glossy coatings.

EFFECT: invention ensures obtaining coatings which demonstrate good mechanical strength and elasticity when applied on substrate, thus reducing probability of cracks development; in addition, application of water-soluble system in coating composition makes it possible to minimise application of organic solvents in process of film coating application.

110 cl, 1 dwg, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, and deals with medication for internal application in form of tablets, in composition of which main active substance is mexidol. Pharmaceutical medication in form of tablet contains mexidol, lactose monohydrate, magnesium stearate and sodium carboxylmethylcellulose. Additionally pharmaceutical medication can contain collidone 30 (polyvinylpyrrolidone). Tablets are mainly covered with coating based on film-producing suspension Opadry II white.

EFFECT: elaboration of novel medication.

3 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed are dietary and/or nutriceutic pharmaceutical composition for peroral application which contains S-adenosylmethi-onine-para-toluolsulfonate (SAMe) in combination with inositol and/or ino-sitol-1-phosphate and pharmaceutically acceptable excipients, in which at least one of and pharmaceutically acceptable excipients represents magnesium oxide in concentration from approximately 1.0 to approximately 10.0% of composition weight (versions), method of its obtaining, method of stabilisation of hard food and/or nutriceutic pharmaceutical composition based on SAMe-para-toluolsulfonate by application of inositol and/or inositol-1-phosphate, application of SAMe-para-toluolsulfonate in combination with inositol and/or inositol-1-phosphate for obtaining composition for treatment of depressive states and panic syndromes.

EFFECT: inclusion of magnesium oxide into composition increases SAMe-para-toluolsulfonate stability, inositol reduces SAMe-para-toluolsulfonate hygroscopicity and contributes to its soothing and antidepressant action.

27 cl, 41 tbl, 7 ex

Hard medication // 2426530

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is medication for treating diabetes, which contains part (1) and part (2), where part (1) contains coated particles, in which particles, including pioglitazone or its salt, are covered with lactose or sugar alcohol; and part (2), which contains glimeperide. As special case of combined medication claimed is multi-layered tablet.

EFFECT: increase of pioglitazone solubility in its application in one tablet with glimeperide.

15 cl, 2 tbl, 17 ex

FIELD: food industry.

SUBSTANCE: invention relates to biologically active additives (BAA) production. BAA includes ascorbic acid, potato starch, calcium stearate, stearic acid, aerosil, a flavouring agent (identical to natural or natural) as well as a sweetening agent represented by fructose at the following components ratio, g per tablet weighting 0.57-3.2 g. ascorbic acid - 0.009250-0.0297; potato starch - 0.0285-0.1258; calcium stearate - 0.001-0.0116; stearic acid - 0.001-0.0116; aerosil - 0.002-0.0233; flavouring agent - 0.00114-0.0076; the rest is fructose. Alternatively the BAA sweetening agent may be represented by glucose at the following components ratio, g per tablet weighting 0.57-3.2 g: ascorbic acid - 0.00925-0.03547; potato starch - 0.0285-0.1258; calcium stearate - 0.001-0.0116; stearic acid - 0.001-0.0116; aerosil - 0.002-0.0233; flavouring agent - 0.00114-0.0076; the rest is glucose. Alternatively the BAA sweetening agent may be represented by a combination of sugar and glucose at the following components ratio, g per tablet weighting 2.6-3.2 g: ascorbic acid - 0.023-0.0297; sugar - 0.9045-1.2160, potato starch - 0.0936-0.1258; calcium stearate - 0.01305-0.0175; stearic acid - 0.01305-0.0175; aerosil - 0.0261-0.0351; flavouring agent - 0.00549-0.0076; the rest is glucose.

EFFECT: invention allows to cardinally enhance the tablets mechanical strength, improve their compressibility, ensure stable and long storage life (2 years) of BAA in the form of tablets, reduce the volume of processing deficiency due to tablet stratification in the process of production of BAA tablets.

6 cl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof:

,

where A is a single bond or oxygen; R1 is selected from a group comprising hydrogen; -C(O)OC1-10alkyl and -C(O)OC1-10alkyl-phenyl; and R2 is selected from a group comprising C1-10alkyl, (CH2)n-phenyl, adamantinyl, adamantinyl, C1-10alkyl substituted with C3-10carbocycle, and C3-10carbocycle, where n assumes values from 0 to 4.

EFFECT: novel compounds and salts thereof which can be used in preventing or treating Parkinson's disease are obtained and described.

6 cl, 105 ex, 3 tbl, 2 dwg

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