Misuse protected dosage form for oxidation sensitive opioids

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to thermoformed pharmaceutical dosage form having a minimum tensile strength of 300 N; the above dosage form contains an opioid, a free physiologically acceptable carboxylic acid in an amount from 0.1 to 5.0 wt %, at total weight of the pharmaceutical dosage form and polyalkylene oxide having a minimum average molecular weight Mm of 500,000 g/mole. Carboxylic acid is specified in a group consisting of maleic acid, fumaric acid, glutaric acid, malonic acid and citric acid. The opioid is specified in a group consisting of oxymorphone, oxycodone, hydromorphone and their physiologically acceptable salts. The pharmaceutical dosage form can be packaged.

EFFECT: pharmaceutical dosage for according to the invention is characterised by the improved storage stability.

14 cl, 11 tbl, 9 ex

 

The invention relates to a pharmaceutical dosage form, which contains an opioid with improved storage stability.

Many pharmacologically active compounds have the potential for abuse and therefore, preferably provided in a form protected from usage of pharmaceutical dosage forms. Well known examples of these pharmacologically active compounds are opioids.

The perpetrators are known to traditional crushed pills that contain opioids, to destroy the "microencapsulation", which provides a delayed release, and then swallow the powder obtained by mouth, or pull it through the nose, rectal, or applied by injection.

Have developed various concepts to prevent drug abuse. One of the concepts is based on the mechanical properties of pharmaceutical dosage forms, in particular on the increase of the tensile strength (fracture resistance). The main advantage of such pharmaceutical dosage forms is that, in grinding, in particular grinding into powder, through traditional means, such as grinding in a mortar or destruction with a hammer, is impossible, or at least things�idents difficult.

Such pharmaceutical dosage forms are useful to prevent from abuse of drugs, in particular pharmacologically active compound contained therein, as they can not be crushed into powder in the traditional media and, thus, cannot be applied in powder form, for example, through the nose. The mechanical properties, particularly high tensile strength of these pharmaceutical dosage forms protects them from usage. In the context of such protected from usage of pharmaceutical dosage forms can be referenced, for example, in WO 2005/016313, WO 2005/016314, WO 2005/063214, WO 2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, WO 2006/082097, WO 2006/082099 and WO 2008/107149.

A problem in the manufacture of pharmaceutical dosage forms that contain opioids, such as Oxymorphone, hydromorphone, and oxycodone, is their sensitivity to oxidative damage and degradation. Oxidation can be caused by molecular oxygen or radicals or peroxides formed compounds that come into contact with said sensitive to oxidation of opioids. Pharmaceutical excipients such as, for example, polyethylene glycols, may cause or catalyze the oxidative destruction, for example during the process of manufacturing pharmaceutical dosage forms. In addition, molecular oxygen can form these radicals or peroxides.

Typically, the decomposition was monitored in standard tests on the storage stability, for example, under the forced conditions of storage, such as 40°C/75% relative humidity. Under these conditions, the destruction and decay is faster than in the surrounding environment. State authorities, who claim the drug, such as SNMR (Committee for medical products intended for humans) and FDA (Management on control over foodstuff and medicines), and international unions on harmonization, such as the ICH (international conference on harmonization), set the standard limits of stability during storage, which must be met in order to obtain the approval of pharmaceutical dosage forms.

Certain problems arise when sensitive to oxidation opioid should be exposed to elevated temperatures during the manufacturing process, such as hot melt extrusion, film coating, and the like. Under these conditions, opioids become more sensitive to oxidation. For example, some known processes for the manufacture of pharmaceutical dosage forms having an increased limit strength�STI tear, is necessary, to pharmaceutical composition containing the active ingredient, was subjected to a pressure of a certain value at a certain elevated temperature for a certain period of time. Depending on the components of the pharmaceutical compositions and their amounts, temperature, pressure and time may be different within certain limits. However, if minimum requirements are not met, the tensile strength of the obtained pharmaceutical dosage forms is too low.

In consequence of this, some traditional methods of making pharmaceutical dosage forms, in particular pharmaceutical dosage forms having an increased breaking strength, require relatively stringent conditions of production and, thus, is not applicable for the fabrication of sensitive to oxidation of opioids. In particular, the gap chain of pharmaceutical excipients, such as polyethylene during extrusion hot melt, leads to the risk of formation of free radicals and thus to a further increase in oxidative stress.

Lower dosages are sensitive to the oxidation of opioids often show a higher percentage of oxidation time�of osenia and decomposition, the higher their dosage. Thus, if to take into account the storage stability, pharmaceutical formulations containing lower dosages are sensitive to the oxidation of opioids, require special attention.

The action mechanisms of oxidation and chemical interactions on the stability of polymeric systems for amorphous Δ9-tetrahydrocannabinol (neopod) obtained by the hot melt method described in M. Munjal etc., J. Pharm. Sciences, 95 (11), 2006, 2473-85. The study showed a very unstable drug complex nature of interactions, including the compatibility of the filler and medicines, the use of oxidation inhibitors, cross-linking in polymer matrices, the pH of the microenvironment and the humidity.

K. S. WatermaH, etc., Pharm. Develop. Tech. 7 (1), 2002, 1-32 makes a review of stabilization of pharmaceuticals to oxidative destruction. Recommended different ways to reduce oxidation. The authors conclude that in the end, each medicine represents a unique situation.

WO 2008/107149 discloses a dosage form for oral administration having high tensile strength, which may contain redox stabilizers, such accomplishable agents, for example, EDTA.

WO 2008/086804 relates to compositions with controlled release containing a composition of a matrix comprising a) polymer or mixture of polymers, b) the current (active) substance and optionally C) one or more pharmaceutically acceptable excipients that do not contain alcohol, which causes a rapid release of the dose and has excellent properties in preventing drug abuse. Preferably, the composition is resistant to extraction and/or selection is in the current solution (active substance from the composition from the fragmentation, melting and/or extraction with ethyl alcohol, with the result that the composition is resistant to abuse drugs. As an aromatic substance can be present citric acid. Example 2 relates to compositions containing 7 mass. % citric acid.

WO 2008/148798 discloses a layered composition with a prolonged release for prolonged action and method, which provides a prolonged action, for example, the drug once a day should provide optimal absorption of the active substance in the gastrointestinal tract, from stomach to rectum.

There was no General concept of successful suppression of oxidative�about the destruction of sensitive to oxidation of drugs in pharmaceutical dosage forms. Comprehensive individual mechanisms of oxidation, which are suitable for a particular drug, as well as the many possible factors which influence the processes of oxidation, require extensive research for each case, which will be taken into consideration the specific circumstances.

In addition, it is known that other components of pharmaceutical dosage forms also may exhibit stability problems when they are subjected to severe conditions specified at the time of production. For example, polyethylene oxide with high molecular weight has a tendency to decompose when exposed to the hot melt extrusion. Thus, the destruction of the polymer can result in uncontrolled release profile, in particular when the active ingredient is enclosed in a matrix of polyethylene oxide, and this may be another cause oxidative destruction of an active ingredient radicals. When adding suitable fillers to stabilize the polyethylene oxide with high molecular mass, such as DDDa-tocopherol, should be taken into account that these fillers in turn can have a negative impact on the stability of other components of pharmaceutical dosage forms, for example, pharmacologically and�tive connection.

The object of the present invention is to provide a protected from usage of pharmaceutical dosage forms containing opioids, particularly sensitive to oxidation opioids, which have advantages over the pharmaceutical dosage forms of the prior art. Pharmaceutical dosage forms should have improved storage stability, so that they could contain sensitive oxidation of opioids, even at relatively low doses. In addition, it must be possible to prepare pharmaceutical dosage forms using traditional methods traditional conditions such as high temperature and pressure (for example, in the case of thermoforming by means of hot melt extrusion).

This problem was solved by the object of the claims.

The invention relates to a thermo-moulded pharmaceutical dosage form having a tensile strength amounting to at least 300 N and comprising, an opioid (A),

- a free physiologically acceptable acid (B) in an amount of from 0.001 to 5.0 wt. %, based on the total weight of the pharmaceutical dosage form, and

- polyalkyloxy (C) having a mass-average molecular mass Mm, component, at least 200 000 g/mol.

It has surprisingly been found that certain derivatives morphinan, such as Oxymorphone, oxidative decomposed to N-oxides (e.g., Oxymorphone-N-oxide, N-oxides, usually often considered toxic and possibly carcinogenic) after manufacture and storage of appropriate dosage forms and that the education of these M-oxides and other decomposition products can be suppressed by the presence of a suitable amount of acid (b) In the pharmaceutical dosage form in accordance with the invention.

If not tied to any theory, the stabilizing effect of the acid (V) may be correlated with the value of the ionization constant is sensitive to the oxidation of opioids. The value of the ionization constant of Oxymorphone is 8.3. Traditional formulations of Oxymorphone that are protected from usage due to their high tensile strength, but which do not demonstrate a desirable shelf life, have the pH factor, which accounts for about 7.5, when they are dissolved in water. Under these conditions a significant amount of Oxymorphone is present as the free base (i.e., protonated), which may be more sensitive to oxidation than the (protonated) in the form of salt. In addition, this concept is supported by� the fact, in the absence of acid (In), dosage form tend to have a yellowish, beige color, while the presence of acid (In) leads to more white, for example, colorless tablets. Thus, the presence of acid (B) can reduce the pH within the dosage form, thus improving drug resistance to oxidative damage.

It has surprisingly been found that pharmaceutical excipients, which are traditionally used to improve drug resistance to oxidative damage, in particular certain antioxidants, such as α-tocopherol, can be reactive and worsening rather than improving drug resistance to oxidative damage.

In addition, there are experimental data that unexpectedly acid (B) is capable of stabilizing polyalkyleneglycol high molecular mass destruction, such as polyalkylene (C) having a mass-average molecular mass Mmconstituting at least 200000 g/mol.

Pharmaceutical dosage form in accordance with the invention thermoforming, preferably by extrusion, although other methods of thermoforming may also be used for clicks�release pharmaceutical dosage form in accordance with the invention, such as extrusion at elevated temperature or heating of tablets that were produced using traditional pressing in the first step and then heated above the softening temperature of the polymer in the tablet in the second stage, to form hard tablets. In this respect, thermoforming means forming, or molding mass after applying heat. In a preferred embodiment the pharmaceutical dosage form thermoforming using hot melt extrusion.

Preferably, the pharmaceutical dosage form is a monolithic mass. The pharmaceutical dosage form preferably is prepared using hot melt extrusion. Molten extruded billet is preferably cut into monoliths, which are then preferably formed into tablets. In this respect, the term "tablets" should preferably be understood as a form of medication, which is made by pressing powder or granules (pressing) but rather as formed extrudates.

Pharmaceutical dosage form in accordance with the invention contain, as component (A), opioid (A), preferably sensitive to oxidation opioid (A), most preferably Oxymorphone or oxyco�it. For purposes of description, the term opioid (A) also includes the free base and their physiologically acceptable salts.

According to the ATC index, opioids are divided into alkaloids of opium are of natural origin, derived fenilpiperidina, derivatives of diphenylpropylamine derivatives benzomorphan, oripavine derivatives, derivatives morphinan and others. Examples of alkaloids of natural origin opium are morphine, opium, hydromorphone, Nicomorphine, oxycodone, Dihydrocodeine, diamorphine, papaveretum and codeine. The following opioids (A) represent, for example, Ethylmorphine, hydrocodone, Oxymorphone, and their physiologically acceptable derivatives or compounds, preferably salts thereof and the solvates, preferably their hydrochloride, physiologically acceptable enantiomers, stereoisomers, diastereomers and racemate and their physiologically acceptable derivatives, preferably simple simple ethers, esters or amides.

In addition, preferred opioids (A) include N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (1R,2R,4S)-2-(dimethylamino)methyl-4-(p-forbindelse)-1-(m-methoxyphenyl)cyclohexanol, (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol, (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentane-3-ol, (1RS,3RS,6RS)-6-dimethyl�aminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, preferably as racemate, 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl 2-(4-isobutyl-phenyl)propionate, 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl 2-(6-methoxy-naphthalen-2-yl)propionate, 3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-(4-isobutyl-phenyl)propionate, 3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-(6-methoxy-naphthalen-2-yl)propionate, (RR-SS)-2-acetoxy-4-trifluoromethyl-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-hydroxy-4-trifluoromethyl-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-4-chloro-2-hydroxy-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-hydroxy-4-methyl-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-hydroxy-4-methoxy-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-hydroxy-5-nitro-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2',4'-debtor-3-hydroxy-biphenyl-4-carboxylic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, 1,1-(3-dimethylamino-3-phenylenedimethylene)-6-fluoro-1,3,4,9-tetrahydropyrido[3,4-b]indole, in particular its hemitite; 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylen]-1,3,4,9-tetrahydropyrido[3,4-b]indole, in private�ti its salt of citric acid; and 1,1-[3-dimethylamino-3-(2-thienyl)pentamethylen]-1,3,4,9-tetrahydropyrido[3,4-b]-6-fluoro-indole, in particular its hemitite, and corresponding stereoisomeric compounds, in each case, their respective derivatives, physiologically acceptable enantiomers, stereoisomers, diastereomers and racemate and their physiologically acceptable derivatives, for example, ethers, esters or amides, and in each case physiologically acceptable compounds, in particular their salts and solvates, such as hydrochloride.

Preferred opioids (A) have the General formula (I)

where

R1represents-H, -HE or-OC1-6-alkyl;

R2represents-H or-C1-6-alkyl;

R3represents-H or-HE, and R4represents-H; or R3and

R4together represent =O; and

--- represents an optional double bond;

or their physiologically acceptable salts.

Particularly preferred opioids (A) include Oxymorphone, oxycodone, hydromorphone and their physiologically acceptable salts.

The content of opioid (A) in the pharmaceutical dosage form is not limited.

Preferably, its content is in the range from 0.01 to 80 mass%, more preferably 0.1 to 50 wt.%, even more preferably 1-25 wt.%, based General� mass of pharmaceutical dosage forms. In a preferred embodiment, the content of opioid (A) is in the range of from 7±6 wt.%, more preferably 7±5 wt.%, still more preferably 5±4 wt.%, 7±4 wt.% or 9±4 wt.%, most preferably 5±3 wt.%, 7±3 wt.% or 9±3 wt.%, and in particular 5±2 wt.%, 7±2 wt.% or 9±2 wt.%, based on the total weight of the pharmaceutical dosage form. In another preferred embodiment, the content of opioid (A) is in the range of from 11±10 wt.%, more preferably 11±9 wt.%, still more preferably 9±6 wt.%, 11±6 wt.%, 13±6 wt.% or 15±6 wt.%, most preferably 11±4 wt.%, 13±4 wt.% or 15±4 wt.%, and in particular 11±2 wt.%, 13±2 wt.% or 15±2 wt.%, based on the total weight of the pharmaceutical dosage form. In an additional preferred embodiment of the invention, the content of opioid (A) is in the range of from 20±6 wt.%, more preferably 20±5 wt. %, still more preferably 20±4 wt.%, most preferably 20±3 wt.%, and in particular 20±2 wt.%, based on the total weight of the pharmaceutical dosage form.

Preferably, the total amount of opioid (A), which is contained in the pharmaceutical dosage form is in the range of from 0.01 to 200 mg, more preferably 0.1 to 190 mg, still more preferably 1.0 to 180 mg, and even more prefer�till then 1.5 to 160 mg, most preferably 2.0 to 100 mg and in particular 2.5 to 80 mg.

In a preferred embodiment, opioid (A) is contained in the pharmaceutical dosage form in the amount of 7.5±5 mg, 10±5 mg, 20±5 mg, 30±5 mg, 40±5 mg, 50±5 mg, 60±5 mg, 70±5 mg, 80±5 mg, 90±5 mg, 100±5 mg, 110±5 mg, 120±5 mg, 130±5, 140±5 mg, 150±5 mg, or 160±5 mg. In another preferred embodiment, opioid (A) is contained in the pharmaceutical dosage form in an amount of 5±2.5 mg, 7.5±2.5 mg, 10±2.5 mg, 15±2.5 mg, 20±2.5 mg, 25±2.5 mg, 30±2.5 mg, 35±2.5 mg, 40±2.5 mg, 45±2.5 mg, 50±2.5 mg, 55±2.5 mg, 60±2.5 mg, 65±2.5 mg, 70±2.5 mg, 75±2.5 mg, 80±2.5 mg, 85±2.5 mg, 90±2.5 mg, 95±2.5 mg, 100±2.5 mg, 105±2.5 mg, 110±2.5 mg, 115±2.5 mg, 120±2.5 mg, 125±2.5 mg, 130±2.5 mg, 135±2.5 mg, 140±2.5 mg, 145±2.5 mg, 150±2.5 mg, 155±2.5 mg, or 160±2.5 mg.

In a particularly preferred embodiment, opioid (a) is Oxymorphone, preferably its HCI salt, and the pharmaceutical dosage form is suitable for use twice a day. In this embodiment, opioid (A) is preferably contained in the pharmaceutical dosage form in an amount of from 5 to 40 mg. In another, particularly preferred embodiment, opioid (a) is Oxymorphone, preferably its HCI salt, and the pharmaceutical dosage form is suitable for the application of one �once a day. In this embodiment, opioid (A) is preferably contained in the pharmaceutical dosage form in an amount of from 10 to 80 mg.

In another particularly preferred embodiment, opioid (a) is oxycodone, preferably its HCI salt, and the pharmaceutical dosage form is suitable for use twice a day. In this embodiment, opioid (A) is preferably contained in the pharmaceutical dosage form in an amount of from 5 to 80 mg. In another particularly preferred embodiment, opioid (a) is oxycodone, preferably its HCI salt, and the pharmaceutical dosage form is suitable for use once a day. In this embodiment, opioid (A) is preferably contained in the pharmaceutical dosage form in an amount of from 10 to 320 mg.

In still another particularly preferred embodiment, opioid (a) is hydromorphone, preferably its HCI salt, and the pharmaceutical dosage form is suitable for use twice a day. In this embodiment, opioid (A) is preferably contained in the pharmaceutical dosage form in an amount of from 2 to 52 mg. In each�m particularly preferred embodiment, opioid (a) is hydromorphone, preferably its HCI salt, and the pharmaceutical dosage form is suitable for use once a day. In this embodiment, opioid (A) is preferably contained in the pharmaceutical dosage form in an amount of from 4 to 104 mg.

Pharmaceutical dosage form in accordance with the invention has excellent storage stability. Preferably, after storage for 4 weeks at 40°C and 75% relative humidity, the content of opioid (A) is at least of 98.0 %, more preferably at least 98,5%, even more preferably at least 99,0%, and even more preferably at least 99.2 percent, most preferably at least 99.4% of and in particular, at least 99.6% of its original content before storage. Suitable methods of measuring the concentration of the opioid (A) in the pharmaceutical dosage form are known to those skilled in the art. In this connection we may refer to the European Pharmacopoeia or the Pharmacopoeia of the United States, in particular on the analysis of HPLC with reversed phase. Preferably, the pharmaceutical dosage form is stored in a closed, preferably sealed containers, preferably as described in the experimental section, it is most preferable Snab�enny oxygen scavenger, in particular oxygen scavenger that is effective even at low relative humidity.

Pharmaceutical dosage form in accordance with the invention contains, as component (B), a free physiologically acceptable acid in an amount of from 0.001 to 5.0 wt. %, based on the total weight of the pharmaceutical dosage form. Acid (C) may be organic or inorganic, liquid or solid. Solid acids are preferred, in particular crystalline organic or inorganic acid.

Acid (C) is free. This means that the acid functional groups of the acid (B) are not all together comprise salts of the opioid (A). If

opioid (A) is present as an acid salt, e.g. as hydrochloride, pharmaceutical dosage form in accordance with the invention preferably contains as component (B) another excellent chemically acid, which is present as a constituent salts of the opioid (A). In other words, monocolore, which form a salt with the opioid (A), cannot be considered as free acids (B) in the meaning of the present invention. When the acid (B) has more than one acidic functional group (e.g., phosphoric acid), the acid (B) may be present in the composition�returns the salt of the opioid (A), provided that at least one of the acidic functional groups of the acid (B) not involved in the formation of salt, that is is free. It is preferred that all, without exception, the acid functional group of the acid (B) were not involved in the formation of salts of the opioid (A). It is also possible that the free acid (V) and the acid forms a salt with the opioid (A), are the same. In these circumstances, the acid (B) is preferably present in molar excess compared with the opioid (A).

In a preferred embodiment, the acid (B) contains at least one acidic functional group (e.g., -CO2H, -SO3H, -RO3N2HE and the like) having the value of the ionization constant, which is in the range of 2.00±1,50, more preferably of 2.00±1,25, even more preferably of 2.00±1.00 and more preferably 2,00±0,75, most preferably of 2.00±0.50 and in particular 2,00±0,25. In another preferred embodiment, the acid (B) contains at least one acid functional group having the value of the ionization constant, which is in the range of 2.25±1,50, more preferably 2.25 to±1,25, even more preferably 2.25 to±1.00 and more preferably 2.25 to±0,75, most preferably 2,2±0.50 and in particular 2,25±0,25. In another preferred embodiment, the acid (B) contains at least one acid functional group having the value of the ionization constant, which is in the range of 2.50±1,50, more preferably from 2.50±1,25, even more preferably from 2.50±1.00 and even more preferably from 2.50±0,75, most preferably from 2.50±0.50 and in particular 2,50±0,25. In another preferred embodiment, the acid (B) contains at least one acid functional group having the value of the ionization constant, which is in the range of 2.75±1,50, more preferably of 2.75±1,25, even more preferably of 2.75±1.00 and more preferably of 2.75±0,75, most preferably of 2.75±0.50 and in particular of 2.75±0,25. In another preferred embodiment, the acid (B) contains at least one acid functional group having the value of the ionization constant, which is in the range of 3.00±1,50, more preferably 3,00±1,25, even more preferably of 3.00±1.00 and more preferably 3,00±0,75, it is most preferable to 3.00±0.50 and in particular 3,00±0,25. In still another preferred embodiment of the invention, the acid (B) contains at least one acid functional group having the value of the ionization constant, which is in the range of 3.25±1,50, �more preferably 3,25±1,25, even more preferably 3,25±1.00 and more preferably 3,25±0,75, it is most preferable to 3.25±0.50 and in particular 3,25±0,25.

In yet another preferred embodiment, the acid (B) contains at least one acid functional group having the value of the ionization constant, which is in the range of 4.50±1,50, more preferably 4,50±1,25, even more preferably of 4.50±1.00 and more preferably 4,50±0,75, most preferably of 4.50±0.50 and in particular 4,50±0,25. In yet another preferred embodiment, the acid (B) contains at least one acid functional group having the value of the ionization constant, which is in the range of 4.75±1,50, more preferably 4,75±1,25, even more preferably of 4.75±1.00 and more preferably 4,75±0,75, most preferably of 4.75±0.50 and in particular 4,75±0,25. In yet another preferred embodiment, the acid (B) contains at least one acid functional group having the value of the ionization constant, which is in the range of 5.00±1,50, more preferably 5,00±1,25, even more preferably of 5.00±1.00 and more preferably 5,00±0,75, most preferably of 5.00±0.50 and in particular 5,00±0,25.

Preferably, the acid (B) is an organic carboxylic or sulfonic to�slotow, in particular carboxylic acid. Multicurrency acid and/or hydroxy-carboxylic acids in particular are preferred.

In case multicurrency acid partial salt should also be considered as multicurrency acid, for example, incomplete sodium, potassium or ammonium salts. For example, citric acid is multicurrency acid having three carboxyl groups. Because there is at least one protonated carboxyl group (for example, sodium dihydrogen citrate or Dunadry hydrogen citrate), salt should be treated as multicarinata acid. Preferably, however, all carboxyl groups multichromosomal acids were protonated.

Preferably, the acid (B) has a low molecular weight, i.e., is not polymerized. Typically, the molecular weight of the acid (B) is below 500 g/mol.

Examples of acids include saturated and unsaturated monocarboxylic acids, saturated and unsaturated bicarbonate acids, tricarboxylic acids, α-hydroxy acids and β-hydroxy acids, monocarboxylic acids, α-hydroxy acids and β-hydroxy acids bicarbonic acids, α-hydroxy acids and β-hydroxy acids and tricarboxylic acids, keto-acids, α-keto-acids, β-keto-acids, polycarboxylic acid�t, polyhydroxyalkanoic acids, polyhydroxyalkanoic acids, polyhydroxyalkanoic acids.

Preferably, the acid (B) selected from the group consisting of benzolsulfonat acid, citric acid, α-glucoheptonate acid, D-gluconic acid, glycolic acid, lactic acid, malic acid, malonic acid, mandelic acid, propane acid, succinic acid, tartaric acid (d, I, or dI), toluensulfonate acid, valeric acid, palmitic acid, amoeba acid, sabotinova acid, stearic acid, lauric acid, acetic acid, adipic acid, glutaric acid, 4-chlorobenzenesulfonic acid, etanislao acid, Atlanterra acid, fumaric acid, galactosemia acid (murinova acid), D-glucuronic acid, 2-oxo-glutaric acid, glycerophosphoric acid, hippuric acid, stinova acid (atanassova acid, lactobionic acid, maleic acid, maleic acid, 1,5-naphthalene-disulfonate acid, 2-naphthalene-sulfonic acid, iwalewa acid, terephthalic acid, titanova acid, choline acid, n-dodecyl sulfate, 3-hydroxy-2-naftalina acid, 1-hydroxy-2-naftalina acid, oleic acid, undecanoate acid, ascorbic acid, (+) - camphor acid, d-�aparadhamula acid, dichlorooxine acid, econsultancy acid, formic acid, methanesulfonic acid, nicotinic acid, orotic acid, oxalic acid, picric acid, L-pyroglutamyl acid, saccharin, salicylic acid, gentisic acid and/or 4-acetamidobenzoic acid.

The content of acid (B) is in the range from 0.001 to 5.0 wt.%, preferably from 0.005 to 2.5 wt.%, more preferably 0.01 to 2.0 mass%, even more preferably 0.05 to 1.5 mass%, most preferably 0.1 to 1.0 wt.% and in particular 0.2 to 0.9 mass%, based on the total weight of the pharmaceutical dosage form.

Preferably, the acid (B) is multichromosomal acid. More preferably, multicurrency acid selected from the group consisting of citric acid, maleic acid and fumaric acid.

Citric acid in particular is preferred.

Multicarinata acid, preferably citric acid, may be present in its anhydrous form or as a solvate and hydrate, respectively, e.g., as a monohydrate.

In a preferred embodiment, the acid content (B), preferably citric acid, is within 0.2±0.18 wt.%, more preferably 0,2±0,15 wt.%, even more preferably 0,2±0.12 wt.%, and even more preferably 0.2 to±0,09 �ACC.%, most preferably 0,2±0.06 mass%, and in particular 0,2±0,03 wt.%, based on the total weight of the pharmaceutical dosage form.

In another preferred embodiment, the acid content (B), preferably citric acid, is within 0.3±0.18 wt.%, more preferably 0,3±0,15 wt.%, even more preferably 0,3±0.12 wt.%, and even more preferably of 0.3±0.09 wt.%, most preferably of 0.3±0.06 mass%, and in particular of 0.3±0.03 wt.%, based on the total weight of the pharmaceutical dosage form.

In still another preferred embodiment of the invention, the acid content (B), preferably citric acid, is within 0.4±0.18 wt.%, more preferably of 0.4±0.15 mass%, even more preferably of 0.4±0.12 wt.%, and even more preferably of 0.4±0.09 wt.%, most preferably of 0.4±0.06 mass%, in particular 0,4±0,03 wt.%, based on the total weight of the pharmaceutical dosage form.

In yet another preferred embodiment, the acid content (B), preferably citric acid, is within 0.5±0.18 wt.%, more preferably 0,5±0,15 wt.%, even more preferably 0,5±0.12 wt.%, and even more preferably 0,5±0.09 wt.%, most preferably 0,5±0.06 mass%, and in particular of 0.5±0.03 wt.%, based on the total weight of the pharmaceutical l�drug form.

In yet another preferred embodiment, the acid content (B), preferably citric acid, is in the range of 0.6±0.18 wt.%, more preferably 0,6±0,15 wt.%, even more preferably of 0.6±0.12 wt.%, and even more preferably of 0.6±0.09 wt.%, most preferably of 0.6±0.06 mass%, and in particular of 0.6±0.03 wt.%, based on the total weight of the pharmaceutical dosage form.

In yet another preferred embodiment, the acid content (B), preferably citric acid, is in the range of 0.7±0.18 wt.%, more preferably of 0.7±0.15 mass%, even more preferably of 0.7±0.12 wt.%, and even more preferably of 0.7±0.09 wt.%, most preferably of 0.7±0.06 mass%, in particular 0,7±0,03 wt.%, based on the total weight of the pharmaceutical dosage form.

In yet another preferred embodiment, the acid content (B), preferably citric acid, is in the range of 0.8±0.18 wt.%, more preferably 0,8±0,15 wt.%, even more preferably of 0.8±0.12 wt.%, and even more preferably of 0.8±0.09 wt.%, most preferably of 0.8±0.06 mass%, and in particular of 0.8±0.03 wt.%, based on the total weight of the pharmaceutical dosage form.

In yet another preferred embodiment, the acid content (b), predpochtitel�but citric acid, is in the range of 0.85±0.18 wt.%, more preferably of 0.85±0.15 mass%, even more preferably of 0.85±0.12 wt.%, and even more preferably of 0.85±0.09 wt.%, most preferably of 0.85±0.06 mass%, and in particular of 0.85±0.03 wt.%, based on the total weight of the pharmaceutical dosage form.

In still another preferred embodiment of the invention, the acid content (B), preferably citric acid, is in the range of 0.9±0.18 wt.%, more preferably of 0.9±0.15 mass%, even more preferably of 0.9±0.12 wt.%, and even more preferably of 0.9±0.09 wt.%, it is most preferable to 0.9±0.06 mass%, in particular 0,9±0,03 wt.%, based on the total weight of the pharmaceutical dosage form.

In an additional preferred embodiment, the acid content (B), preferably citric acid, is in the range of 1.0±0.18 wt.%, more preferably of 1.0±0.15 mass%, even more preferably of 1.0±0.12 wt.%, and even more preferably of 1.0±0.09 wt.%, most preferably of 1.0±0.06 mass%, in particular 1,0±0,03 wt.%, based on the total weight of the pharmaceutical dosage form.

Pharmaceutical dosage form in accordance with the invention comprises, as component (C), polyalkylene (C) having a mass-average molecular mass Mm, which is at least 200000 g/mol�, preferably, at least 500000 g/mol, more preferably at least 750000 g/mol, even more preferably at least 1000000 g/mol, most preferably at least 2000000 g/mol and in particular is in the range from 500,000 to 15000000 g/mol.

Preferably, polyalkylene selected from the group consisting of polyethylenoxide, polyethylene oxide and polypropyleneoxide, their copolymers and mixtures.

Polyalkyloxy (C) may include only polyalkylene having a certain average molecular weight, or a mixture of (impurity) of various polymers such as a mixture of two, three, four or five polymers, e.g., polymers of the same chemical nature but different average molecular weight, polymers of different chemical nature but same average molecular weight, or polymers of different chemical nature and different molecular mass.

For purposes of description pag has a molecular weight of up to 20000 g/mol, while polyalkylene has a molecular weight greater than 20,000 g/mol. In a preferred embodiment, the average mass as a result of all molecular masses of all polyalkyleneglycol contained in the pharmaceutical dosage form is at least 200000 g/mol. In affect�, polyalkylene glycols, if any, is preferably not taken into account when determining the mass-average molecular weight of polyalkylene (C).

Preferably, the content of polyalkylated (C) is in the range from 20 to 99 mass%, more preferably, cables 25-95 wt.%, even more preferably 30-90 wt.%, and even more preferably 30-85 wt.%, most preferably 30-80 wt.% in particular 30-75 wt.%, based on the total weight of the pharmaceutical dosage form. In a preferred embodiment, the content of polyalkylated is at least 20 mass%, more preferably at least 25 wt.%, even more preferably, at least 30 wt.%, and even more preferably at least 35 wt.% and in particular at least 40 wt.%.

In a preferred embodiment, the full contents of polyalkylated (C) is in the range of 25±20 wt.%, more preferably 25±15 wt.%, most preferably 25±10 wt.%, and in particular 25±5 wt.%. In another preferred embodiment, the full contents of polyalkylated (C) is in the range of 35±20 wt.%, more preferably 35±15 wt.%, most preferably 35±10 wt.%, and in particular 35±5 wt.%. In still another preferred embodiment, the implementation of�of bretania the full content of polyalkylated (C) is in the range of 45±20 wt.%, more preferably 45±15 wt.%, most preferably 45±10 wt.%, and in particular 45±5 wt.%. In yet another preferred embodiment, the full contents of polyalkylated (C) is in the range of 55±20 wt.%, more preferably 55±15 wt.%, most preferably 55±10 wt.%, and in particular 55±5 wt.%. In an additional preferred embodiment, the full contents of polyalkylated (C) is in the range of 65±20 wt.%, more preferably 65±15 wt.%, most preferably 65±10 wt.%, and in particular 65±5 wt.%. In still an additional preferred embodiment of the invention, the full contents of polyalkylated (C) is in the range of 75±20 wt.%, more preferably 75±15 wt.%, most preferably 75±10 wt.%, and in particular 75±5 wt.%. In still an additional preferred embodiment of the invention, the full contents of polyalkylated (C) is in the range of 80±15 wt.%, more preferably 80±10 wt.%, and most preferably 80±5 mass%.

In a preferred embodiment, polyalkylene (C) homogeneously distributed in the pharmaceutical dosage form in accordance with the invention. Preferably, polyalkylene (C) forms the matrix which contain the opioid (A). Especially in the preferred�ohms embodiment, opioid (a) and polyalkylene (C) directly homogeneously distributed in the pharmaceutical dosage form, what pharmaceutical dosage form does not contain any segments where either opioid (A) is present in the absence of polyalkylated (C), or polyalkyloxy (C) is present in the absence of opioid (A).

When the pharmaceutical dosage form is film-coated, polyalkyloxy (C) is preferably homogeneously distributed in the core of the pharmaceutical dosage form, i.e. membranous sheath preferably contains no polyalkylated (C). Nevertheless, membranous sheath, as such may of course contain one or more polymers, which however, preferably differ from polyalkyleneglycol (C), which is contained in the core.

Polyalkyloxy (C) can be combined with one or more different polymers selected from the group consisting of polyalkylene, preferably polyethylenoxide, polyethylene oxide, polypropyleneoxide; polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyvinylpyrrolidone, poly(ALK)acrylate, poly(hydroxy fatty acids), such as, for example, poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (Biopol®), poly(hydroxyvalerenic acid); polycaprolactone, polyvinyl alcohol, polyesteramide, polyethylene succinate, Polyglactin, polyglycolide, polyurethane, polyamide, polylactide, poliac�tal (for example, polysaccharides optionally with modified side chains), polylactide/glycolide, Polyglactin, polyglycolide, paleontology ether, polyanhydride, block copolymers of polyethylene glycol and polybutylene terephthalate (Polyactive®), polyanhydride (Polifeprosan), copolymers, block copolymers, and mixtures of at least two of the stated polymers, or other polymers with the above characteristics.

Preferably, the molecular weight dispersity Mm/Mhpolyalkylated (C) is in the range of 2.5±2,0, more preferably of 2.5±1.5 m, even more preferably of 2.5±1.0, and even more preferably 2,5±0,8, most preferably 2,5±0,6, and in particular 2,5±0,4.

Polyalkyloxy (C) preferably at a temperature of 25°C has a viscosity that is 30-17 600 SP, more preferably 55-17600 SP, even more preferably 600-17600 JV and most preferably 4500-17600 SP, measured in 5 wt.% aqueous solution using a model RVF Brookfield viscometer (spindle number 2 / rotational speed 2 rpm); which is 400-4000 JV, more preferably 400-800 JV or 2000-4000 SP, measured in 2 wt.% the combined solution, using the aforementioned viscometer (spindle number 1 or 3 / rotational speed 10 rpm); or which is 1650-10000 JV, more preferably 1650-5 SP 500, 5500-7500 JV or 7500-10000 JV, pristerene 1 wt.% aqueous solution, using the aforementioned viscometer (spindle number 2 / rotational speed 2 rpm).

In a preferred embodiment of the invention in accordance with the invention, polyalkylene (C) having a weight average molecular weight that is at least 200000 g/mol, combine at least one further polymer, preferably but not necessarily also having a weight average molecular mass (Mm), which is at least 200000 g/mol, selected from the group consisting of polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, poly(hydroxy fatty acids), polycaprolactone, polyvinyl alcohol, polyesteramide, poliatilenaksidna, polylactones, Paul eagle and IDA red, polyurethane, polyvinylpyrrolidone, polyamide, polylactide, polylactide/glycolide, polylactide, Paul eagle and IDA red, paleontologico ether, polyanhydride, block copolymers of polyethylene glycol and polybutylene terephthalate, polyanhydride, Polyacetal, of cellulose esters, cellulose ethers and their copolymers. Esters of cellulose and cellulose ethers in particular are preferred, for example, methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose of hydroxypropylmethylcellulose�, carboxymethylcellulose and the like.

In a preferred embodiment of the invention, the additional polymer is neither polyalkyleneglycol, no pag. However, the pharmaceutical dosage form may contain the pag, for example, as a plasticizer, but then, the pharmaceutical dosage form preferably is trekhkomponentnoi mixture of polymers: polyalkyloxy (C) + additional polymer + plasticizer.

In a particularly preferred embodiment of the invention, the additional polymer is a hydrophilic ester of cellulose or a simple ester of cellulose, preferably hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) or hydroxyethyl cellulose (HEC), preferably having an average viscosity is preferably measured using a capillary viscometer or a rotational viscometer), which are 1000-150000 MPa∙s, more preferably 3000-150000. In a preferred embodiment, the average viscosity is in the range of 110,000±50000 MPa s, more preferably of 110,000±40000 MPa∙s, even more preferably of 110,000±30000 MPa∙s, most preferably of 110,000±20000 MPa∙s, and in particular 100000±10000 MPa∙S.

In a preferred embodiment of osushestvlyaetsya the ratio of the specific gravity of the specified polyalkylated (C) and specified additional polymer is in the range from 20:1 to 1:20, more preferably 10:1 to 1:10, even more preferably 7:1-1:5, and still more preferably 5:1-1:1, most preferably 4:1-1,5:1 and in particular 3:1-2:1. In a preferred embodiment of the invention, the ratio of the specific gravity of the specified polyalkylated (C) and specified additional polymer is in the range from 10:1 to 5:1, more preferably 8:1 to 5:1, most preferably 7:1 to 5:1.

Preferably, the said additional polymer is 0.5-25 wt.%, more preferably 1.0 to 20 mass%, even more preferably 2.0 to 22.5 wt.%, and even more preferably of 3.0 to 20 wt.% and most preferably 4.0 to 17.5 wt.% and in particular 5.0 to 15 wt.%, based on the total weight of the pharmaceutical dosage form.

In a preferred embodiment the additional polymer is an ester of cellulose or a simple cellulose ether, preferably HPMC, the content of which is in the range of 10±8 wt.%, more preferably 10±6 wt.%, yet more preferably 10±5 wt.%, and still more preferably 10±4 wt.%, most preferably 10±3 wt.%, and in particular 10±2 wt.%, based on the total weight of the pharmaceutical dosage form.

In another preferred embodiment the additional polymer is an ester Zell�vines or simple cellulose ether, preferably HPMC, the content of which is in the range of 14±8 wt.%, more preferably 14±6 wt.%, even more preferably 14±5 mass%, and even more preferably 14±4 wt.%, most preferably 14±3 wt.%, and in particular 14±2 wt.%, based on the total weight of the pharmaceutical dosage form.

All polymers are preferably used as powders. They can be soluble in water.

In addition to the opioid (A), acid (In) and polyalkylated (C) pharmaceutical dosage form in accordance with the invention may contain additional components, such as traditional pharmaceutical excipients.

Preferably, the pharmaceutical dosage form comprises an antioxidant. Suitable antioxidants include ascorbic acid, α-tocopherol (vitamin E), trouble soothing, butyl hydroxytoluene, salts of ascorbic acid (vitamin C), ascorbyl palmitate, monothioglycerol, coniferious benzoate, nordihydroguaiaretic acid, esters of Gallic acid, phosphoric acid, and their derivatives such as vitamin E succinate or vitamin E palmitate and/or sodium bisulfite, more preferably the stabilizer (OSH) or trouble soothing (.) and/or α-tocopherol.

Preferably, the content of the antioxidant is in the range from 0.001 to 5.0 wt.%, Bo�it is preferably from 0.002 to 2.5 mass%, more preferably 0.003 to 1.5 mass%, even more preferably of 0.005 to 1.0 mass%, and even more preferably 0.01 to 0.5 mass%, most preferably 0.05 to 0.4 wt.% and in particular 0.1 to 0.3 wt.%, based on the total weight of the pharmaceutical dosage form.

In a particularly preferred antioxidant is an α-tocopherol. Unexpectedly it was found that α-tocopherol stabilizes polyalkyloxy and simultaneously destabilizes certain opioids, such as Oxymorphone. Thus, in a preferred embodiment of the invention, the content of α-tocopherol balanced between sufficient stability polyalkylated with one hand and a sufficient stability of the opioid (A), on the other hand.

In a preferred embodiment, the content of α-tocopherol is in the range of 0.2±0.18 wt.%, more preferably 0,2±0,15 wt.%, even more preferably 0,2±0.12 wt.%, and even more preferably of 0.2±0.09 wt.%, most preferably 0,2±0.06 mass%, and in particular 0,2±0,03 wt.%, based on the total weight of the pharmaceutical dosage form.

In a preferred embodiment of the invention, the ratio of the specific gravity of the acid (B), preferably citric acid, and an antioxidant, preferably α-tocopherol is in the range of from 10:1 to 1:10, more preferably 8:1-1:8 even more preferably 6:1-1:6, and even more preferably 5:1-1:4, most preferably 4:1-1:3, and in particular 3:1-1:2.

Pharmaceutical dosage form in accordance with the invention can also contain natural, semisynthetic or synthetic wax. Preferred are waxes with a softening temperature that is at least 50°C, more preferably 60°C. particularly preferred are Carnauba wax and beeswax, in particular Carnauba wax.

Preferably, the release profile of the opioid (A) is retardirovannah release matrix type. Preferably opioid (A) is enclosed in a matrix containing polyalkylene, the matrix controls the release of the opioid (A) from the pharmaceutical dosage form.

As additional matrix materials can be used physiologically acceptable materials which are known to those skilled in the art. As a hydrophilic matrix materials preferably used polymers, particularly preferably cellulose ethers, esters of cellulose and/or acrylic resin. As matrix materials often preferably used ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxymethylcellulose, hydrociat�cellulose, poly(meth)acrylic acid and/or their derivatives such as their salts, amides or esters. The matrix materials made of hydrophobic materials such as hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or corresponding esters or ethers or mixtures thereof, are also preferred. In particular as hydrophobic materials preferably used are mono - or dichloride12-C30fatty acids and/or C12-C30fatty alcohols and/or waxes or mixtures thereof. Also as materials of the matrix it is possible to use mixtures of the aforementioned hydrophilic and hydrophobic materials.

Preferably, the ratio of the specific gravity of polyalkylated to the opioid (A) is at least 0.5:1, more preferably at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1 or at least 9:1; even more preferably, at least 10:1 or at least 15:1, and even more preferably at least 20:1, most preferably at least 30:1 Yves particular, at least 40:1. In a preferred embodiment, the ratio of the specific gravity of polyalkylated to the opioid (A) is within the limits of�Oh from 3:1 to 50:1, more preferably 3:1-40:1 Yves particular 3:1 to 30:1.

Pharmaceutical dosage form in accordance with the invention preferably contains a plasticizer. The plasticizer improves the ability of polyalkylated to handle. The preferred plasticizer is a pag, such as polyethylene glycol, triacetin, fatty acids, esters of fatty acids, waxes and/or microcrystalline waxes. Particularly preferred plasticizers are polyethylene glycols, such as PEG.

Preferably, the content of the plasticizer is in the range from 0.1 to 25 mass%, more preferably 0.5 to 22.5 mass%, even more preferably 1.0 to 20 mass%, and even more preferably 2.5 to 17.5 wt.%, most preferably 5.0 to 15 wt.,% and in particular 7.5 to 12.5 mass%, based on the total weight of the pharmaceutical dosage form.

In a preferred embodiment the plasticizer is a pag, the content is, his efforts are in the range of 10±8 wt.%, more preferably 10±6 wt.%, yet more preferably 10±5 wt.%, and still more preferably 10±4 wt.%, most preferably 10±3 wt.%, and in particular 10±2 wt.%, based on the total weight of the pharmaceutical dosage form.

In another preferred embodiment, the image�etenia plasticizer is a pag, the content of which is in the range of 15±8 wt.%, more preferably 15±6 wt.%, still more preferably 15±5 wt.%, and still more preferably 15±4 wt.%, most preferably 15±3 wt.%, and in particular 15±2 wt.%, based on the total weight of the pharmaceutical dosage form.

In a preferred embodiment, the ratio of the specific gravity of polyalkylated to the pag is in the range of 4.2±2:1, more preferably 4,2±1,5:1, even more preferably of 4.2±1:1, and even more preferably 4,2±0,5:1, most preferably 4,2±0,2:1, and in particular 4,2±0,1:1. This ratio satisfies the requirements of a relatively high content of polyalkylated and good ability to resist extrusion.

When the dosage form is made from parts that are obtained by cutting the extrudate billet, the mass of the parts determines the mass of the resulting dosage form. A marked change in mass of these parts leads to a corresponding deviation of the mass of the dosage form from a given mass. The change in mass of the parts is strongly dependent on the surface characteristics of the extrudate billet. The blank with a completely smooth surface allows to obtain parts, showing a small change in mass. On the contrary, wavy or ribbed surface of the workpiece �riodic to what parts show a more significant change in mass, thus increasing the number of marriage.

It was unexpectedly found that the characteristics of the workpiece surface of the extrudate can depend on polyalkylated: the ratio of the mass of the polyalkylene glycol.

Preferred compositions of X1-X32pharmaceutical dosage forms in accordance with the invention are summarized in the tables below:

mass. %X1X2X3X4
opioid (A) (eg. hydrochloride of Oxymorphone)1,50±1,251,50±1,001,50±0,751,50±0,50
acid (In) (eg. citric acid)0,5±0,300,5±0,250,5±0,200,5±0,15
Polyalkyloxy (C)77±2277±2077±1577±10
the ester or ether of cellulose (eg. HPMC) 12±1012±7,512±512±2,5
plasticizer (eg. PEG)10±7,510±510±2,510±1,0
an antioxidant (eg. α-tocopherol)0,2±0,120,2±0,10,2±0,050,2±0,03
wt.%X5X6X7X8
opioid (A) (eg. hydrochloride of Oxymorphone)2,33±1,252,33±1,002,33±0,752,33±0,50
acid (In) (eg. citric acid)0,85±0,600,85±0,500,85±0,250,85±0,15
Polyalkyloxy (C)70±2570±2070±1570±10
the ester or ether of cellulose (eg. HPMC) 10±9,510±7,510±510±2,5
plasticizer (eg. PEG)16,6±7,516,6±516,6±2,516,6±1,0
an antioxidant (eg. α-tocopherol)0,2±0,120,2±0,10,2±0,050,2±0,03
wt.%X9X10X11X12
opioid (A) (eg. hydrochloride of Oxymorphone)3,50±1,253,50±1,003,50±0,753,50±0,50
acid (In) (eg. citric acid)0,85±0,600,85±0,500,85±0,250,85±0,15
Polyalkyloxy (C)69±3069±2069±1569±10
the ester or ether of cellulose (eg. G�YAC) 10±9,510±7,510±510±2,5
plasticizer (eg. PEG)16,4±7,516,4±516,4±2,516,4±1,0
an antioxidant (eg. α-tocopherol)0,2±0,120,2±0,10,2±0,050,2±0,03
wt.%X13X14X15X16
opioid (A) (eg. hydrochloride of Oxymorphone)4,65±1,254,65±1,004,65±0,754,65±0,50
acid (In) (eg. citric acid)0,85±0,600,85±0,500,85±0,250,85±0,15
Polyalkyloxy (C)68±3068±2068±1568±10
ester, or just� cellulose ether (e.g. HPMC)10±9,510±7,510±510±2,5
plasticizer (eg. PEG)16,2±7,516,2±516,2±2,516,2±1,0
an antioxidant (eg. α-tocopherol)0,2±0,120,2±0,10,2±0,050,2±0,03
wt.%X17X18Xl9X20
opioid (A) (eg. hydrochloride of Oxymorphone)6,98±1,256,98±1,006,98±0,756,98±0,50
acid (In) (eg. citric acid)0,85±0,600,85±0,500,85±0,250,85±0,15
Polyalkyloxy (C)66±3066±2066±1566±10
complex e�Ira or a simple ester of cellulose (eg. HPMC)10±9,510±7,510±510±2,5
plasticizer (eg. PEG)15,8±7,515,8±515,8±2,515,8±1,0
an antioxidant (eg. α-tocopherol)0,2±0,120,2±0,10,2±0,050,2±0,03
mass. %X21X22X23X24
opioid (A) (eg. hydrochloride of Oxymorphone)9,30±1,259,30±1,009,30±0,759,30±0,50
acid (In) (eg. citric acid)0,85±0,600,85±0,500,85±0,250,85±0,15
Polyalkyloxy (C)64±3064±2064±1564±10
ester and�and simple cellulose ether (e.g. HPMC)10±9,510±7,510±510±2,5
plasticizer (eg. PEG)15,3±7,515,3±515,3±2,515,3±1,0
an antioxidant (eg. α-tocopherol)0,2±0,120,2±0,10,2±0,050,2±0,03
wt.%X25X26X27X28
opioid (A) (eg. hydrochloride of Oxymorphone)13,95±1,2513,95±1,0013,95±0,7513,95±0,50
acid (In) (eg. citric acid)0,8±50,600,85±0,500,85±0,250,85±0,15
Polyalkyloxy (C)60±3060±2060±1560±10
complex airily simple cellulose ether (e.g. HPMC)10±9,510±7,510±510±2,5
plasticizer (eg. PEG)13,9±7,513,9±513,9±2,513,9±1,0
an antioxidant (eg. α-tocopherol)0,2±0,120,2±0,10,2±0,050,2±0,03
wt.%X29X30X31X32
opioid (A) (eg. hydrochloride of Oxymorphone)18,60±1,2518,60±1,0018,60±0,7518,60±0,50
acid (In) (eg. citric acid)0,85±0,600,85±0,500,85±0,250,85±0,15
Polyalkyloxy (C)57±3057±2057±1557±10
complex airily simple cellulose ether (e.g. HPMC)10±9,510±7,510±510±2,5
plasticizer (eg. PEG)13,6±7,513,6±513,6±2,513,6±1,0
an antioxidant (eg. α-tocopherol)0,2±0,120,2±0,10,2±0,050,2±0,03

In a preferred embodiment the pharmaceutical dosage form has a total mass which is in the range of 100±75 mg, more preferably 100±50 mg, most preferably 100±25 mg. In another preferred embodiment the pharmaceutical dosage form has a total weight which is within 200±75 mg, more preferably 200±50 mg, most preferably 200±25 mg. In another preferred embodiment the pharmaceutical dosage form has a total mass which is in the range of 250±75 mg, more preferably 250±50 mg, most preferably 250±25 mg. In yet another preferred embodiment the pharmaceutical dosage form has a total weight, to�area is in the range of 300±75 mg, more preferably 300±50 mg, most preferably 300±25 mg. In another preferred embodiment the pharmaceutical dosage form has a total mass which is in the range of 400±75 mg, more preferably 400±50 mg, most preferably 400±25 mg.

In a preferred embodiment the pharmaceutical dosage form has a total mass which is in the range of 500±250 mg, more preferably 500±200 mg, most preferably 500±150 mg. In another preferred embodiment the pharmaceutical dosage form has a total mass which is in the range of 750±250 mg, more preferably 750±200 mg, most preferably 750±150 mg. In another preferred embodiment the pharmaceutical dosage form has a total mass which is in the range of 1000±250 mg, more preferably 1000±200 mg, most preferably 1000±150 mg. In yet another preferred embodiment the pharmaceutical dosage form has a total mass which is in the range of 1250±250 mg, more preferably 1250±200 mg, most preferably 1250±150 mg.

In a preferred embodiment the pharmaceutical dosage form in accordance with image�Itanium has a bulk density, which is in the range of 1.19±0.30 g/cm3more preferably 1,19±0.25 g/cm3even more preferably 1,19±0.20 g/cm3and even more preferably of 1.19±0.15 g/cm3, most preferably 1,19±0.10 g/cm3and , in particular, 1,19±0,05 g/cm3. Preferably, the bulk density of pharmaceutical dosage forms in accordance with the invention is 1,1710,02 g/cm3, 1,19±0.02 g/cm3or 1.21±0.02 g/cm3. Methods of measuring the density of the dosage form known to those skilled in the art. Bulk density of the dosage form may be determined, for example, using the mercury injection method or the helium picnometry, as described in the European Pharmacopoeia

Preferably, the pharmaceutical dosage form in accordance with the invention is suitable for oral administration. Nevertheless, it is also possible to apply pharmaceutical dosage form by various routes of administration and, thus, an alternative pharmaceutical dosage form may be suitable for buccal of payasyougo, rectal or vaginal application. Implants are also possible.

In a preferred embodiment the pharmaceutical dosage form in accordance with the invention is�tsya suitable to receive once daily. In another preferred embodiment the pharmaceutical dosage form in accordance with the invention is suitable for receiving two times a day. In yet another preferred embodiment the pharmaceutical dosage form in accordance with the invention is suitable for receiving three times a day.

For purposes of description, "twice daily" means equal or nearly equal intervals, approximately every 12 hours, or different time intervals, e.g., 8 and 16 hours, or 10 and 14 hours between meals.

For purposes of description, "three times daily" means equal or nearly equal time intervals, i.e., approximately every 8 hours, or different time intervals, e.g., 6, 6, and 12 hours; or 7, 7 and 10 hours between individual methods.

Preferably, the pharmaceutical dosage form in accordance with the invention determines, at least partially delayed or prolonged release of the opioid (A).

Controlled or sustained-release means in accordance with the invention preferably to mean a release profile in which the opioid (A) is released over a relatively long period with reduced frequency of consumption for the expanded thera�political action. Preferably, the term "sustained-release" is in accordance with the European Directive concerning the nomenclature of the release profile of pharmaceutical dosage forms (SNMR - Committee on medical products intended for humans). It is in particular achieved by oral administration. The expression "at least partially delayed or prolonged release" covers in accordance with the invention, any pharmaceutical dosage form, which guarantee the modified release opioids (A) that are contained in them. Pharmaceutical dosage forms preferably include pharmaceutical dosage forms coated with coating or without it, which are made with the use of certain excipients, certain processes or a combination of two possible options, to purposefully change the rate of release or the location of the release.

In the case of pharmaceutical dosage forms in accordance with the invention, the time profile of the release form controlled release can be modified, for example, as follows; extended release, re-release action, sustained-release and slow-released�E.

For purposes of description of the "controlled release" preferably means a product in which the release of active compound over time is controlled by the type and composition of the formulations. For purposes of description of the "extended release" preferably means a product in which the release of active compound is delayed by a defined time delay, after which the release is free. For purposes of description the re-release of the action" preferably means a product in which the first portion of active compound is released from the start, followed by at least one of the next portion of active compound which is released subsequently. For purposes of description "sustained-release" preferably means a product in which the rate of release of active compound from preparative form after the application has been reduced over time, in order to maintain therapeutic activity, to reduce toxic effects, or for some other therapeutic purpose. For purposes of description "sustained release" preferably means a method of preparation of the drug so that it is released into the body continuously, over a long period of time, such �by Braz, reducing the frequency of administration. For additional details can be referred to, for example, K. N. Bauer, Lehrbuch der PharmazeutischeH Technologie, 6th edition, WVG Stuttgart, 1999; and European Pharmacopoeia.

Pharmaceutical dosage form in accordance with the invention may include one or more of the opioid (A) at least partially in the additional form of controlled release, where the controlled release can be achieved using conventional materials and processes known to those skilled in the art, for example, the conclusion of the active substance in a matrix controlled release, or applying one or more coatings, controlled release. The release of active substances, however, needs to be controlled so that the addition of materials, delayed release maintains the required tensile strength. Controlled release pharmaceutical dosage forms in accordance with the invention preferably is achieved by the conclusion of the matter in the matrix. Preferably, polyalkylene (C) serves as the matrix. Auxiliary substances act as matrix materials, controlled release. The matrix materials can, for example, be hydrophilic, the fabric forming the gel,�which a release emanates mainly by diffusion, or hydrophobic materials from which the release occurs mainly by diffusion from the pores in the matrix.

Preferably, the release profile is substantially controlled by the matrix, preferably by inclusion of the opioid (A) matrix containing polyalkylene (C) and optional additional materials of the matrix. Preferably, the release profile is not osmotic. Preferably, the release kinetics is not of order zero.

Preferably, under physiological conditions the pharmaceutical dosage form in accordance with the invention after 30 minutes releases the opioid (A) in an amount of 0.1-75 %, after 240 minutes in the amount of 0.5-95 %, after 480 minutes in an amount of 1.0 to 100% and after 720 minutes in an amount of 2.5-100%. The following preferred release profiles R1-R6summarized in the table below [all data in wt. % released opioid (A)]:

timeR1R2R3R4R5R6
60 min0-300-50 0-5015-2520-3020-50
120 min0-400-750-7525-4035-5040-75
240 min3-553-9510-9540-7055-7560-95
480 min10-6510-100The 35-10060-9080-9580-100
720 min20-7520-10055-10070-10090-10090-100
960 min30-8830-10070-100>8095-100
1440 min50-10050-100>90
2160 min>80>80

The following preferred release profiles R1-R6summarized in the table below [all data in wt.% released opioid (A)]:

timeR7R8R9R10R11R12
30 min17.5±7.517.5±6.517.5±5.517.5±4.517.5±3.517.5±2.5
60 min27.0±8.027.0±7.027.0±6.027.0±5.027.0±4.027.0±3.0
120 min41.5±9.541.5±8.541.5±7.541.5±6.5 41.5±5.541.5±4.5
timeR7R8R9R10R11R12
240 min64.5±12.564.5±11.564.5±10.564.5±9.564.5±8.564.5±7.5
480 min88.0±12.088.0±11.088.0±10.088.0±9.088.0±8.088,0±7.0
720 min96.0±9.096.0±8.096.0±7.096,0±6.096.0±5.096.0±4.0
840 min97.5±7.597.5±6.597.5±5.597.5±4.597.5±3.597.5±2.5

Preferably, the release profile of pharmaceutical dosage forms in accordance with this image�Itanium is stable after storage, preferably, after storage at elevated temperature, for example at 37°C, for 3 months in sealed containers. In this regard, "stable" means that when comparing the initial release profile the release profile after storage, at any given time release profiles differ from each other not more than 20 %, more preferably not more than 15 %, even more preferably not more than 10 %, and still more preferably not more than 7.5 %, most preferably not more than 5.0% and in particular not more than 2.5 %.

Preferably, the in vitro pharmaceutical dosage form releases the opioid (A) initially contained in the pharmaceutical dosage form, after 0.5 h in an amount of 1.0 to 35 wt.%, after 1 h in the amount of 5.0 to 45 wt.%, after 2 h in an amount of 10-60 mass%, after 4 h, at least in an amount of 15 mass%, after 6 hours, at least 20 wt.%, after 8 h, at least in the amount of 25 wt.% after 12 h, at least in an amount of 30 mass%.

Suitable conditions in vitro are known to those skilled in the art. In this respect can be mentioned, for example, the European Pharmacopoeia. Preferably, the release profile is measured under the following conditions: the device with the blade, provided with a load of 50 rpm.� minute 37±5°C, 900 ml reproducible intestinal fluid with a pH value amounting to 6.8 (phosphate buffer) or pH value, amounting to 4.5. In a preferred embodiment of the invention, the rotation speed of the blades is increased to 100 rpm.

In a preferred embodiment, after preferably oral administration of the pharmaceutical dosage form in accordance with the invention, in vivo the average value of the peak level in plasma (Cmax) is achieved on average after tmaxthat is 4.0±2.5 h, more preferably after tmaxthat is 4.0±2.0 h, still more preferably after tmaxthat is 4.0±1.5 h, most preferably after tmaxwhich is of 4.0±1.0 h and in particular after tmaxthat is 4.0±0.5 h. In another preferred embodiment, after preferably oral administration of the pharmaceutical dosage form in accordance with the invention, in vivo the average value of the peak level in plasma (Cmax) is achieved on average after tmaxthat is 5.0±2.5 h, more preferably after tmaxthat is 5.0±2.0 h, still more preferably after tmaxthat is 5.0±1.5 h, �the ideal preferably after t maxthat is 5.0±1.0 h and in particular after tmaxthat is 5.0±0.5 h. In still another preferred embodiment, after preferably oral administration of the pharmaceutical dosage form in accordance with the invention, in vivo the average value of the peak level in plasma (Cmax) is achieved on average after tmaxthat is 6.0±2.5 h, more preferably after tmaxthat is 6.0±2.0 h, still more preferably after tmaxthat is 6.0±1.5 h, most preferably after tmaxthat is 6.0±1.0 h and in particular after tmaxthat is 6.0±0.5 h.

In a preferred embodiment, the average value for t1/2after preferably oral administration of the pharmaceutical dosage form in accordance with the invention in vivo is 4.0±2.5 h, more preferably of 4.0±2.0 h, still more preferably of 4.0±1.5 h, most preferably of 4.0±1.0 h and in particular of 4.0±0.5 h. In another preferred embodiment, the average value for t1/2after preferably oral administration of the pharmaceutical dosage form in accordance with the invention in vivo is preferably 5.0 to±2.5 h, more pre�occhialino 5,0±2,0 h, even more preferably of 5.0±1.5 h, most preferably of 5.0±1.0 h and in particular of 5.0±0.5 h. In still another preferred embodiment of the invention the average value for t1/2after preferably oral administration of the pharmaceutical dosage form in accordance with the invention in vivo is preferably of 6.0±2.5 h, more preferably of 6.0±2.0 h, still more preferably of 6.0±1.5 h, most preferably of 6.0±1.0 h and in particular of 6.0±0.5 h.

Preferably, the pharmaceutical dosage form in accordance with the invention comprises a coating, preferably a film sheath. Suitable coating materials known to those skilled in the art. Suitable coating materials are commercially available, e.g. under the trademarks é® and Eudragit®.

Examples of suitable materials include esters of cellulose and cellulose ethers such as methylcellulose (MC), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC), ethylcellulose (EC), acetated cellulose (APC), hydroxypropylmethyl cellulose phthalate (HPMCP); poly(meth)acrylates, such as copolymers of aminoalkylsilane, copolymers of an acrylate and methylmethacrylate, copolymers of methacrylic acid and metalmetal�Lata, copolymers of methacrylic acid and methylmethacrylate; miniprimer, such as polyvinylpyrrolidone, polyvinylacetate, polyvinyl alcohol, polyvinyl acetate; and natural film-forming materials, such as shellac.

In a particularly preferred embodiment, the coating is soluble in water. In a preferred embodiment the coating based on polyvinyl alcohol such as polyvinyl alcohol, a partially, and may further contain a polyethylene glycol, such as macrogol 3350, and/or dyes. In another preferred embodiment the coating is based on methylcellulose, preferably hypromellose type 2910 having a viscosity of equal to 3-15 MPa∙S.

Coating of pharmaceutical dosage forms may increase its storage stability.

The coating can be resistant to gastric juice and dissolved as a function of pH of the release. Using this coverage, it is possible to ensure that the pharmaceutical dosage form in accordance with the invention passes through the stomach undissolved and the active compound is released only in the intestine. The coating, which is resistant to gastric juice, preferably dissolves at pH, to�oroe lies within 5 and 7.5. Appropriate materials and methods for the delayed release of the active compounds and to the use of coatings which are resistant to gastric juice, are known to those skilled in the art, for example from "Coated Pharmaceutical dosage forms - Fundamentals, Manufacturing Techniques, Biopharmaceutical Aspects, Test Methods and Raw Materials" by Kurt H. Bauer, K. Lehmann, HermanH P. Osterwald, Rothgang, Gerhart, 1st edition, 1998, Medpharm Scientific Publishers.

In a preferred embodiment the pharmaceutical dosage form in accordance with the invention contains no substances which irritate the nasal passages and/or pharynx, i.e. substances which, when applied through the nasal passages and/or throat cause a physical reaction which is either so unpleasant for the patient that he or she is unwilling or unable to continue taking, for example burning, or physiologically counteract the application of a suitable active compounds, for example due to increased nasal secretion or sneezing. The following examples of substances which irritate the nasal passages and/or throat, are the ones that cause burning, itching, an urge to sneeze, increased formation of secretions or at least a combination of two of these stimuli. Appropriate substances and the quantities that are traditionally used are known to those skilled in this about�Asti equipment. Some of the substances which irritate the nasal passages and/or pharynx, respectively, based on one or more constituents or one or more vegetable components of the freshly prepared medicines. The corresponding freshly prepared active substances known as such to the person skilled in the art, and described, for example, in "Pharmazeutische Biologie - DrogeH und ihre Inhaltsstoffe" by Prof. Dr. Hildebert Wagner, 2nd, revised edition, Gustav Fischer Verlag, Stuttgart-new York, 1982, page 82 et seq. An appropriate description is thereby incorporated by reference and considered part of the Scriptures of the invention.

In addition, the pharmaceutical dosage form in accordance with the invention preferably contains no antagonists of the opioid (A), preferably contains no antagonists psychotropic substances, in particular does not contain opioid antagonists (A). Antagonists suitable for a given opioid (A), are known to those skilled in the art, and may be present or also in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of their salts or solvates. Pharmaceutical dosage form in accordance with the invention preferably does not contain antagonist�, selected from among the group comprising naloxone, naltrexone, nalmefene, nalid, naloxone, nalorphine or Malutin, in each case optionally in the form of corresponding physiologically acceptable compounds, in particular in the form of base, salt or solvate; and contains neuroleptics, for example, joints, wybranego from the group including haloperidol, promethazine, fluphenazine, perphenazine, levomepromazine, thioridazine, perazine, chlorpromazine, chlorprothixene, zuclopentixol, flupentixol, prothipendyl, zotepine, benperidol, pipamperone, melperone and bromperidol.

Pharmaceutical dosage form in accordance with the invention furthermore preferably contains no emetic. Emetics are known to those skilled in the art, and may be present or also in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of their salts or solvates. Pharmaceutical dosage form in accordance with the invention preferably contains no emetic based on one or more components of the root of Ipecacuanha (meadowsweet), for example, based on the constituent emetine, such as, for example, described in "Pharmazeutische Biologie - DrogeH und ihre Inhaltsstoffe" prof�sorom by Prof. Dr. Hildebert Wagner, 2nd, revised edition, Gustav Fischer Verlag, Stuttgart-new York, 1982. The corresponding literature description is thereby incorporated by reference and deemed a part of this description of the invention. Pharmaceutical dosage form in accordance with the invention preferably also contains apomorphine as an emetic.

Finally, the pharmaceutical dosage form in accordance with the invention preferably also contains bitter substances. Examples of bitter substances and their amounts, effective to use, can be found at US-2003/0064099 A1 corresponding to the description of which should be considered a description of the present application, and thus is included here as a reference. Examples of bitter substances are aromatic oils such as peppermint oil, eucalyptus oil, oil of bitter almonds, menthol, fruit aroma substances, aromatics of lemon, orange, lime, grapefruit or mixtures thereof and/or denatonium benzoate.

Pharmaceutical dosage form in accordance with the invention accordingly preferably contains no substances which irritate the nasal passages and/or pharynx, nor antagonists of the opioid (A), no vomit funds, nor bitter substances.

Pharmaceutical dosage form in accordance with the invention is preferably�tsya suitable for oral administration.

Typically, a pharmaceutical dosage form in accordance with the invention is presented in the form of tablets. Preferably, the pharmaceutical dosage form not represented in the form of a film, and consists of many particles.

Pharmaceutical dosage form in accordance with the invention preferably is protected from usage. Preferably, the protection usage is achieved on the basis of the mechanical characteristics of pharmaceutical dosage forms to prevent fragmentation or at least substantially to hinder it. In accordance with the invention, the term fragmentation refers to the grinding into a powder pharmaceutical dosage form with conventional means commonly available to the attacker, such as for example a pestle and mortar, a hammer, a hammer or other traditional tools used to grind to powder by the force. Thus, protection from usage, preferably means that the grinding into a powder pharmaceutical dosage form with conventional means is prevented or at least substantially impeded.

Preferably, the mechanical characteristics of the pharmaceutical dosage form according to the invention, in particular the tensile strength, significantly depend on the presence and spatial distribution of polyalkylated (C), though his mere presence is usually not satisfactory, in order to achieve these characteristics. Useful mechanical characteristics of pharmaceutical dosage forms in accordance with the invention cannot be achieved automatically, by simple technological treatment of opioid (A) acid (b), polyalkyleneglycol (C) and optional additional fillers using traditional methods, suitable for the manufacture of pharmaceutical dosage forms. In fact, typically, for the manufacture it is necessary to choose a suitable machine, and must accommodate the critical process parameters, in particular pressure/force, temperature and time. Thus, even if you use conventional devices, the protocols of the process usually needs to adapt in order to meet the required criteria.

Pharmaceutical dosage form in accordance with the invention has a tensile strength that is at least 300 N, preferably at least 400 N, more preferably at least 500 N, preferably at least 750 N, and even more preferably, at least 1000 N, most preferably at least 1250 Niamh particular at least 1500 N.

"Tensile strength" (resistance to fracture) pharmaceutical dosage forms known to the person skilled in the art. In this respect can be mentioned, for example, W. A. Ritschel, Die Tablette, 2. Auflage, Editio Cantor Verlag Aulendorf, 2002; H Liebermann, etc., Pharmaceutical dosage forms: Tablets, vol. 2, Informa Healthcare; 2 edition, 1990; and Encyclopedia of Pharmaceutical Technology, Informa Healthcare; 1 edition.

For purposes of description, the tensile strength is preferably defined as the amount of force that is necessary to granulate the pharmaceutical dosage form (= destructive force). For this reason, for purposes of description of the pharmaceutical dosage form preferably does not show the desired tensile strength, if it collapses, that is, breaks at least into two separate parts, which are separated from each other. In another preferred embodiment of the invention, however, the pharmaceutical dosage form is considered to be destroyed if the power is reduced by 25 % (limit value) of the high strength, temperature during measurement (see below).

Pharmaceutical dosage forms in accordance with the invention differs from conventional pharmaceutical dosage forms by the fact that due to�e their tensile strength, they cannot be crushed into powder by the use of force in the traditional media, such as for example a pestle and mortar, a hammer, a hammer or other traditional means used for pulverization, in particular devices developed for this purpose (pill crusher). In this regard, "grinding into powder" means crushing into small particles that will immediately release the pharmacologically active compound (A) in a suitable medium. Preventing grinding into powder eliminates oral or parenteral administration, in particular the use intravenously or through the nose.

Traditional tablets typically have a tensile strength substantially below 200 N in any direction stretching. The tensile strength of traditional round tablets may be installed in accordance with the following empirical formula: tensile strength [N] = 10 × Tablet Diameter [in mm]. Thus, in accordance with the empirical formula, round tablet having a tensile strength amounting to at least 300 N, would have a diameter of at least 30 mm). Thus, this pill should not be swallowed. The above empirical formula is preferably not applied to the pharmaceutical Lekarstvo�m forms of the invention, are not traditional, but rather special.

In addition, the current value of the chewing force of approximately 220 N (see, e.g., R. A. Proeschel, etc., J Dent Res, 2002, 81 (7), 464-468). This means that the traditional tablet having a tensile strength substantially below 200 N, can be fragmented after chewing, while the pharmaceutical dosage form in accordance with the invention.

Moreover, when using the acceleration of gravity is approximately 9.81 m/s2, 300 N correspond to the force of gravity is greater than 30 kg, i.e. the pharmaceutical dosage form in accordance with the invention can preferably withstand a weight of more than 30 kg and not be crushed into powder.

Ways to measure the tensile strength of the pharmaceutical dosage form known to those skilled in the art. Suitable devices are commercially available.

For example, the tensile strength (fracture resistance) may be determined in accordance with the European Pharmacopoeia 5.0, 2.9.8 or 6.0, 2.09.08 "Resistance to Crushing of Tablets". The test is designed to determine, under defined conditions, the resistance to the destruction of the tablets installed with the help of the force necessary to destroy� by their fragmentation. The apparatus consists of 2 clamping devices placed against each other, one of which is moving in the other direction. Flat surface clamping device perpendicular to the direction of movement. Grinding the surface of clamping devices are planar and are more than the area of contact with the tablet. The apparatus precalibration, using the system with an accuracy of 1 Newton. The tablet is placed between the clamping devices, taking into account, where applicable, the shape, the measuring mark and the inscription; for each measurement, the tablet features the same way relative to the direction of application of force (and direction of stretching, in which the tensile strength must be installed). The measurement is performed on 10 tablets, taking into account that all the fragments of the tablets were removed before each new measurement. The results are expressed as the average, minimum and maximum values of the established forces, all expressed in Newtons.

A similar description of the tensile strength (breaking stress) can be found in the Pharmacopoeia of the United States. Alternatively, the tensile strength may be determined in accordance with the method described in it, where it is alleged that the tensile strength represents the strength needed to lead t�bledu in disrepair (i.e., to destroy) in a particular plane. Tablets, usually placed between the two clamping devices, one of which moves to apply to the tablet a force sufficient to cause destruction. For a traditional, round (round cross section) of the pills, the load goes through their diameter (sometimes referred to as diametrically load), and fracture occurs in the plane. Destructive force tablets is commonly called hardness in the pharmaceutical literature; however, the use of this term is misleading. In materials science, the term hardness refers to the resistance of a surface to penetration or indentation, using small samples. The term ultimate strength in compression is also often used to describe the resistance of tablets to the application of compressive loads. Although this term describes the true nature of the test more accurately than the hardness, it is understood that the pills actually break up out during testing that often occurs.

Alternatively, the tensile strength (fracture resistance) may be determined in accordance with WO 2005/016313, WO 2005/016314, and WO 2006/082099 that can be regarded as a modification of the method described in the European Pharmacopoeia. The apparatus used for the measurement, preferably �is installation for testing materials "Zwick Z 2.5", Fmax= 2.5 kN with a maximum displacement of 1150 mm, which is adjusted via one support and one spindle with a clearance behind of 100 mm and a test speed that is set between the values of 0.1 and 800 mm/min testControl software. The measurement is performed using a pneumatic piston with tabs and screwing the cylinder (diameter 10 mm), a force sensor, Fmax. 1 kN, diameter = 8 mm, class 0.5 from 10 N, class 1 from 2 N to ISO 7500-1, with evidence of M about the manufacturer's test according to DIN (German standards Institute) 55350-18 (total power Zwick Fmax= The 1.45 kN) (all apparatus from the company Zwick GmbH & Co. KG, Ulm, Germany) with the index number BTC-FR 2.5 TONS. D09 to install for test, index number BTC-LC 0050N. R01 for force sensor, index number IN 70000 S06 for centering the device.

In a preferred embodiment, the tensile strength is determined using an apparatus to test the tensile strength, for example, Sotax®, type T or type NT1 (Allschwil, Switzerland). Both types, Sotax® NT and Sotax® HT1 can measure the tensile strength in accordance with two different principles of measurement: at a constant speed (where the clamping device of the test apparatus is moving at a constant speed, settable from 5 to 200 mm/min) or constant force (g�e clamping device test machine increases force, regulated sequentially from 5-100 H/C). In any case, both principles of measurement are appropriate for measuring the tensile strength of the pharmaceutical dosage form in accordance with the invention. Preferably, the tensile strength is set at a constant speed, preferably at a constant speed, which is 120 mm/minute.

In a preferred embodiment the pharmaceutical dosage form is considered destroyed if it is broken, at least two separate parts.

Pharmaceutical dosage form in accordance with the invention preferably shows a mechanical strength in a wide temperature range, and in addition to the tensile strength (resistance to fracture) optionally also sufficient hardness, impact resistance, impact elasticity, tensile strength and/or modulus of elasticity, optionally also at low temperatures (e.g. below -24°C, below -40°C or in liquid nitrogen), effectively making it impossible to grind it to a powder directly by chewing, grinding in a mortar, crushed, etc. Thus, preferably, the relatively high tensile strength of the pharmaceutical dosage form in accordance with the invention supports�I even at low or very low temperatures, for example, when the pharmaceutical dosage form is first cooled to increase its brittleness, for example to temperatures below -25°C, below -40°C or even in liquid nitrogen.

Pharmaceutical dosage form in accordance with the invention is characterized by a certain level of tensile strength. This does not mean that the pharmaceutical dosage form must also demonstrate a certain level of hardness. The hardness and tensile strength are different physical characteristics. Therefore, protection against usage of pharmaceutical dosage forms is not necessarily dependent on the hardness of pharmaceutical dosage forms. For example, due to its tensile strength, impact resistance, modulus of elasticity and tensile strength, respectively, of the pharmaceutical dosage form may preferably be deformed, for example, plastically, being subject to external force, for example using a hammer, but it cannot be crushed into powder, that is, to be crushed on a large number of fragments. In other words, the pharmaceutical dosage form in accordance with the invention is characterized by a certain level of tensile strength, but also not necessarily differs certain level stable�of the form.

Therefore, the value of the description, a pharmaceutical dosage form, which is deformed by being subjected to a force in a direction of stretching, but not destroyed (plastic deformation, or flow) should preferably be considered as having desirable tensile strength in accordance to the direction of stretching.

In a particularly preferred embodiment of implementation, the invention relates to protected usage of pharmaceutical dosage form having a tensile strength amounting to at least 300 N, and thus thermoforming using the hot melt extrusion, specified in the pharmaceutical dosage form contains

- opioid (A) is selected from the group consisting of Oxymorphone, oxycodone, meperidine, and their physiologically acceptable salts;

- a free physiologically acceptable multicurrency acid (B), preferably citric acid, where the acid content (B) is in the range from 0.001 to 5.0 wt.%, based on the total weight of the pharmaceutical dosage form;

- antioxidant, where the content of the antioxidant, preferably α-tocopherol is in the range of from 0.001 to 5.0 wt. %, based on the total weight of the pharmaceutical dosage form; and

- polyalkyloxy (C) having among�non-mass molecular mass Mm, component, at least 200 000 g/mol;

where

- opioid (A) is enclosed in a matrix containing polyalkylene (C) where the specified matrix controls the release of the opioid (A) from the pharmaceutical dosage form; and

- after storage for 4 weeks at 40°C and 75% relative humidity, the content of opioid (A) is at least of 98.0% of its original content before storage.

Pharmaceutical dosage form in accordance with the invention can be manufactured in various ways, especially preferred of which are explained in more detail below. Some suitable methods were already described in the prior art. In this respect can be mentioned, for example, WO 2005/016313, WO 2005/016314, WO 2005/063214, WO 2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, WO 2006/082097 and WO 2006/082099.

The present invention also relates to pharmaceutical dosage forms, may be obtained by any of the methods described below.

Typically, the method of manufacturing a pharmaceutical dosage form in accordance with the invention preferably comprises the following steps:

(a) mixing all components;

(b) optionally pre-forming the mixture obtained in step (a), preferably with application of heat and/or force to the mixture obtained in step (a), �while the magnitude of the applied heating is preferably not sufficient to heat polyalkyloxy (C) up to its softening temperature;

(c) hardening the mixture by applying heat and force, it is possible to apply heat during and/or before use of force and the magnitude of the applied heat is sufficient to heat polyalkyloxy (C), at least up to its softening temperature;

(d) optionally separation of the hardened mix;

(e) optionally forming a pharmaceutical dosage form; and

(f) optionally providing a film of the shell.

Heat can be used directly, for example, by contact or by means of a hot gas such as hot air, or by using ultrasound. Power can be applied, and/or the pharmaceutical dosage form may be molded, for example, by means of direct tableting or by a suitable extruder, in particular with the aid of a screw extruder with two screws (twin screw extruder) or by using the extruder with a planetary gear.

The final shape of the pharmaceutical dosage forms may either be provided during the hardening of the mixture, when used to heat and power (stage (C) or in a subsequent stage (stage (e)). In both cases, the mixture of all components is preferably in the PLA�appealing condition, that is, preferably, molding is carried out at a temperature at least above the softening temperature of polyalkylated (C). However, extrusion at lower temperatures, for example, at ambient temperature, is also possible and may be preferable.

Molding can be carried out for example using a tablet press comprising a mold and punches the appropriate form.

Particularly preferred method of making a pharmaceutical dosage form of the invention includes a hot melt extrusion. In this method, the pharmaceutical dosage form in accordance with the invention is manufactured by thermoforming using an extruder, preferably without any significant subsequent discoloration of the extrudate. Unexpectedly it was found that the acid (B) is able to inhibit discoloration. In the absence of acid (B), the extrudate tends to be painted from beige to yellowish, while in the presence of acid (In) extrudates are essentially colorless, i.e. white.

This method is characterized in that

(a) all components are mixed,

(b) the resulting mixture is heated in the extruder at least up to the softening temperature of polyalkylated (C) and extruded through the outlet of the extruder with application�m force

c) the still plastic extrudate is separated into pieces and formed into the pharmaceutical dosage form or

(d) the cooled and optionally re-heated split the extrudate is formed into the pharmaceutical dosage form.

The mixing of components in accordance with the stage of the method (a) can also occur in the extruder.

Components can also be mixed in a mixer known to the person skilled in the art. The mixer may be, for example, roller mixer, a mixer with a shaking mechanism, mixer with shear effort or with a mixer with effort.

Before mixed with the other components, polyalkyloxy (C) is preferably mixed in accordance with the invention with an antioxidant, preferably α-tocopherol. This can occur by mixing these two components, polyalkylated (C) and an antioxidant, preferably by dissolving or suspending an antioxidant in a highly volatile solvent and then the solution or suspension is homogeneously mixed with polyalkyleneglycol (C) and then the solvent is removed by drying, preferably in an inert gas atmosphere.

Preferably the molten mixture, which was heated in the extruder at least up to the softening temperature of polyalkylene�sid (C), extruded from the extruder into the mold, at least one hole.

Method in accordance with the invention requires the use of suitable extruders, preferably a screw extruder. Screw extruders, which are equipped with two augers (screw extruder), in particular are preferred.

The extrusion is preferably carried out so that the stretching of the workpiece by the extrusion amounted to no more than 30%, that is when you have to use a mold with a hole having a diameter, for example 6 mm, the extruded billet must have a diameter not greater than 8 mm. More preferably, the stretching of the workpiece is not more than 25%, even more preferably no more than 20%, most preferably no more than 15% and in particular not more than 10%.

Preferably, the extrusion is carried out in the absence of water, i.e., do not add any water. However, traces of water (e.g. caused by atmospheric humidity) may be present.

The extruder preferably comprises at least two temperature zones, with heating of the mixture at least up to the softening temperature of polyalkylated (C), which occurs in the first zone, the bottom zone of the feed, and optionally mixing zone. The throughput of the mixture is preferably a composition, comprising�ing from 1.0 kg up to 15.0 kg/hour. In a preferred embodiment, the bandwidth ranges from 1.0 to 3.5 kg/hour. In another preferred embodiment, the bandwidth is from 4.0 to 15.0 kg/h.

In a preferred embodiment, the pressure in the mold is in the range from 25 to 100 bar. The pressure in the mold may be controlled by the size of the mold, the temperature and speed of extrusion.

The size of the mold or the size of the hole are chosen at random. The mold or the hole can be round, oblong or oval in cross section, round cross-section preferably has a diameter of 0.1 mm to 15 mm, and an oblong cross-section preferably has a maximum longitudinal dimension of 21 mm and in the transverse direction, the size of which is 10 mm. Preferably, the mold or the hole has a circular cross-section. The casing of the extruder used in accordance with the invention, can be heated or chilled. The corresponding temperature control, i.e. heating or cooling, is arranged in such a way that the mixture, which will ekstradiroval, showed at least an average temperature (product temperature) corresponding to temperatureresistance of polyalkylated (C) and is not increased above the temperature, in which may be damaged opioid (A). Preferably, the suitable temperature of the mixture to be ekstradiroval, brought to a temperature below 180°C, preferably below 150°C, but at least up to the softening temperature of polyalkylated (C). The typical extrusion temperature is 120°C and 130°C.

In a preferred embodiment the torque of the extruder is in the range from 30 to 95%. Torque of the extruder may be controlled by the size of the mold, temperature and speed of extrusion.

After extrusion of the molten mixture and optional cooling of the extruded billet or extruded billets, the extrudate is preferably divided into parts. The specified separation may preferably be accomplished by cutting the extrudates by means of automatic or rotary cutters, hydro-mechanical cutters, wires, blades or with the help of laser cutters.

Preferably, the intermediate or final storage of the optional razdeleng extrudates or finished pharmaceutical dosage forms in accordance with the invention is carried out in a free oxygen from the atmosphere that can be achieved, for example, by using oxygen absorbers.

Split the extrudate can be �progress-formed into tablets to give the final shape of the pharmaceutical dosage form.

The use of force in the extruder the mixture which, at least, given the plasticity is regulated by means of controlling the speed of rotation of the corresponding device in the extruder and its size, as well as through selection of the size of the outlet so that the pressure required for extruding the plastic mixture can be fed into the extruder, preferably directly prior to extrusion. The extrusion parameters, which, for each particular composition needed to provide a pharmaceutical dosage form with desired mechanical properties can be set in a simple preliminary test.

For example, but not limited to, extrusion may be performed using a twin-screw extruder, type ZSE18 or ZSE27 (company Leistritz, Nuremberg, Germany), the diameters of the screws are 18 or 27 mm. Can be used augers having eccentric ends. Can be used heated mold with a round hole having a diameter of 7, 8, or 9 mm. extrusion Parameters may be adjusted e.g. to the following values: rotational speed of the screws: 120 rpm; the speed of loading of 2 kg/h for a ZSE 18 or 8 kg/h for ZSE27; product temperature: up to molds, 125°C and after the mold at 135°C; and the shell temperature: 110°C.

Preferably, the extrusion is carried out at �amoxi twin-screw extruders or extruders with planetary mechanisms the twin-screw extruder (rotating in one direction or rotating in the opposite direction) are particularly preferred.

Pharmaceutical dosage form in accordance with the invention is preferably produced by thermoforming with the assistance of the extruder without any noticeable discoloration of the extrudates.

A method of manufacturing a pharmaceutical dosage form in accordance with the invention preferably is carried out continuously. Preferably, the method comprises extruding a homogeneous mixture of all components. Is particularly preferred if the thus obtained intermediate product, for example, the workpiece obtained by extrusion, demonstrates homogeneous characteristics. In particular, it is desirable to uniform density, uniform distribution of the active compounds, homogeneous mechanical characteristics, uniform porosity, uniform in appearance, the surface, etc. Only under these conditions can be ensured uniformity pharmacological characteristics, such as stability of the release profile and the amount of deviation should be maintained low.

An additional aspect of the invention relates to a package containing a pharmaceutical dosage form in accordance with the invention and an oxygen absorber. Suitable packing containers include blister packs and bottles, such as glass vials or bottles, made of thermoplastic polymers.

Suitable oxygen scavengers are known to those skilled in the art. The oxygen scavenger may be any filter known in the prior art, which is used to clear the oxygen. Can be used both organic and inorganic oxygen scavengers.

In one embodiment, the oxygen scavenger is any metal complex, which shows an oxygen-absorbing action. Examples include complexes containing one or more aluminum alloys, aluminum ferrosilicon, antimony, beryllium, silicide of calcium, cerium, cobalt, gallium, hafnium, iron, magnesium, Nickel catalyst, selenium, silicon, silver, strontium, titanium, zinc and/or zirconium.

In yet another embodiment, as oxygen absorbers can be used one or more elements of Group 1A of the periodic table and their alloys and compounds. Examples of elements of Group 1A include cesium, lithium, potassium, sodium. The following examples of inorganic oxygen scavengers include one or more of compounds such as sodium azide (NaNs), sodium sulfite (Na2SO3), hydras�n, and hydroxylamine.

In one embodiment, the oxygen scavenger is an organic compound. Examples include one or more of compounds such as polyterpenes, in primary forms, ascorbic acid, aminopolycarboxylate acid, cyclohexandion, tetramethylpiperidine, and heterocyclic compound with N-substituted amino groups.

Oxygen absorbers and their use in packaging pharmaceutical products are known to those skilled in the art. In a preferred embodiment, the oxygen scavenger is selected from the group consisting of a metal-catalyzed oxidizable organic polymers and antioxidants. Especially preferred are those oxygen absorbers that are able to demonstrate performance characteristics in dry environment, which corresponds to a relative humidity of below 60 %, preferably below 30% relative humidity, and that combined with desiccant. Examples of commercially available oxygen scavengers that meet these requirements include Pharmakeep® KD10 and KD20.

Unexpectedly it was found that the storage stability of a pharmaceutical dosage form can be increased by maintaining the low oxygen content of the air environment in the limit� packaging. How to package pharmaceutical dosage forms and the application of suitable oxygen scavengers are known to those skilled in the art. In this regard a reference can be made, for example, D. A. Dean, Pharmaceutical Packaging Technology, Taylor&Francis, 1st ed.; F. A. Paine, etc., Packaging Pharmaceutical and Healthcare Products, Springer, 1st ed.; and O. G. Piringer, etc., Plastic Packaging: Interactions with Food and Pharmaceuticals, Wiley-VCH, 2nd ed.

As for packing, round bottles, made of polyolefin, preferably of HDPE (high density polyethylene), are preferred. The wall thickness of the bottles is preferably at least 0.25 mm, more preferably at least 0.5 mm, otherwise the bottle may be deformed.

As to cover packaging, the package is preferably sealed by electromagnetic induction or thermostatically aluminum foil.

Unexpectedly it was found that by selecting the appropriate form of packaging and the type of sealing, low blood pressure, which is created by the action of oxygen absorber (a vacuum of approximately 20000 PA = 2 N/cm2) can be adjusted without causing deformation of the package. Sealing by electromagnetic induction (for example, 3 seconds of exposure energy) is preferred. When sealed and�aminievo foil 75 ml bottle having a hole diameter of 1 inch, a vacuum of 20 000 PA by oxygen absorber, results in a force of approximately 10 N, corresponding to the force exerted by pressure of weight of 1 kg.

The mechanical strength of the sealing can be checked either by inserting an appropriate number of oxygen absorber in the bottle, sealing and waiting over a sufficient period of time, say 2 days, that oxygen is absorbed and a vacuum is established in approximately 20000 PA. Alternatively, the vial can be sealed without any oxygen absorber inside, and all in 1 kg can be put on aluminum foil, thus simulating the effect.

An additional aspect of the invention relates to the use of opioid (A) for the manufacture of pharmaceutical dosage forms as described above, for the treatment of pain.

An additional aspect of the invention relates to the use of pharmaceutical dosage forms as described above, to prevent or discourage the abuse of opioid (A), which is contained there.

An additional aspect of the invention relates to the use of pharmaceutical dosage forms as described above, to prevent or inhibit accidental overdose of the opioid (A), which contains�I was there.

In this regard, the invention also relates to the use of opioid (A), as described above, and/or polyalkylated (C), as described above, for the manufacture of pharmaceutical dosage forms in accordance with the invention for the prophylaxis and/or treatment of the disease, thereby preventing an overdose of the opioid (A), in particular due to the fragmentation of the pharmaceutical dosage form by mechanical action.

Furthermore, the invention relates to a method of prevention and/or treatment of the disease, which contains the reception of the pharmaceutical dosage form in accordance with the invention, thereby preventing an overdose of the opioid (A), in particular due to the fragmentation of the pharmaceutical dosage form by mechanical action. Preferably, the mechanical action is chosen from the group consisting of chewing, grinding in a mortar, fragmentation, and use of machines in order to grind into powder traditional pharmaceuticals dosage forms.

The following examples further illustrate the invention, but should not be construed as limiting its scope.

Example 1

Tablets were manufactured using hot melt extrusion of homogeneous mixtures of different composition in the following, the same extrusion conditions:

type e�of struder: extruder Leistritz ZSE18PH 40D with augers with high shear forces and the mold diameter, components 9 mm

capacity: 1.0 kg/h

rotation speed: 100 rpm / minute

the temperature of the working cylinder: 100°C

the temperature of the extrudate: 120°C

the extrudate was cut into pieces by 325 mg, containing approximately 5 mg of the hydrochloride of Oxymorphone.

The individual components of the extruded mixtures, as well as the total amount of degradation products before and after storage under accelerated storage conditions are summarized in the table below:

td align="center"> 76,4
etc.Components (mass, %)additional ingredient (mass. %)the products of decomposition (mass. %)
(A)PEOPEGHPMCmesh.oNo1oNo2Σ1Σ2
A11,576,910,010,01,5/0,06 0,580,411,93
And21,577,510,010,01,0/0,090,490,581,81
And31,578,010,010,00,5/0,080,360,56Of 1.64
And41,578,310,010,00,2/0,080,260,631,51
And51,578,510,010,00,0/0,07 0,170,811,69
B11,576,910,010,01,5/0,060,580,411,93
B21,540,010,046,91,5/0,090,550,64Of 1.76
In31,550,010,036,91,5/0,000,520,29Of 1.64
In41,550,036,910,01,5/ 0,110,760,361,74
C11,576,910,010,01,5/0,060,580,411,93
With21,576,9/10,01,510,00 Lutrol® F680,050,530,651,83
With31,550,010,010,01,526,90 mannitol0,080,820,392,72
With41,576,9/10,01,5 10,00 Carnauba wax0,120,530,391,03
D11,576,910,010,01,5/0,060,580,411,93
D21,576,810,010,01,50,10 fumaric acid0,050,480,521,70
D31,576,810,010,01,50,10 Na-EDTA0,070,510,481,77
D41,576,810,0 10,01,5Of 0.10 citric acid0,070,480,371,45
E11,576,910,010,01,5/0,060,580,411,93
E21,576,810,010,01,5Of 0.10 citric acid0,070,480,371,45
E31,576,710,010,01,5To 0.20 citric acid0,000,400,201,13
E41,510,010,01,50,50 citric acid0,000,060,120,17

(A): hydrochloride of Oxymorphone

PEO: polyethylene oxide Mm7 million g/mol

PEG: polyethylene glycol 6000

HPMC: polymer 100000 PA*s

α-current.: α-tocopherol

oNo: Oxymorphone-N-oxide (mixture)

S: the sum of all impurities

1: after extrusion, before storage

2: after storage, the bottles of yellow glass, plastic cover, 4 weeks, 40°C, 75% relative humidity

The decomposition products were analyzed using HPLC-UV. Peak elution for Oxymorphone-N-oxide could not be sufficiently under the zero line is separated from a peak of unknown product decomposition (called the "UK 0.83"). Thus, both peaks were pooled together. As a result of comparison examples A1And5it becomes apparent that the content of Oxymorphone-N-oxide prior to storage (oNo1) does not change significantly, if the content of the antioxidant α-tocopherol reduced from 1,5 wt. % to 1.0 mass. %, 0.5 mass. %, 0.2 wt. % and even to 0% by weight. Thus, after storage (oNo2) the content of Oxymorphone-N-oxide is proportional to the content of α. This is unexpected because Oxymorphone-N-oxide is an oxidation product, and one would expect that anti-oxidants normally inhibit rather than support the formation of oxidation products.

However, the complete exclusion of the antioxidant (α-tocopherol) has its drawbacks. Through measurements of viscosity can be demonstrated that the polyethylene oxide with high molecular weight decomposed after extrusion and/or storage in the absence of the antioxidant. Unexpectedly it was found that approximately 0.2 masses. % α-tocopherol is sufficient to stabilize the poly (ethylene oxide); a higher content of α-tocopherol does not lead to higher viscosity of polyalkylated and, thus, does not prevent more clearly PEO from decomposition. Thus, the content of the antioxidant (α-tocopherol) is preferably balanced so that on the one hand, the polyethylene oxide with high molecular weight was sufficiently stable, and on the other hand, was kept at a low level of undesirable formation of Oxymorphone-N-oxide during storage.

Furthermore, when comparing examples B1-B4and examples of C1-C4it becomes clear that partial replacement of polyethylene oxide with high molecular weight or Deputy�and poliatilenglikola alternative plasticizer does not significantly reduce the content of undesirable Oxymorphone-N-oxide. This is unexpected, since one would expect that the polyethylene oxide and polyethylene glycol are potential carriers of peroxide, and that their reduction would lead to a reduction of oxidative processes, such as oxidation of Oxymorphone to Oxymorphone-N-oxide.

Furthermore, when comparing examples D1-D5and E1-E4becomes obvious that the addition of physiologically acceptable acids, in particular citric acid, decreases the formation of Oxymorphone-N-oxide. This is more obvious when the amount of acid increased. At the concentration of 0.1 mass%, the acid is comparatively weak, but at a concentration of 0.2 wt.% the acid is stronger and, moreover, is enhanced when the concentration of citric acid increases. Not only the quantity of Oxymorphone-N-oxide is reduced, but also the total amount of decomposition products, in particular those having a high time of incubation HPLC.

Example 2

The pills were produced in analogy with PR (A1B1, C1, D1and E1above were Packed in different packaging materials and stored at 40°C and 75% RH. humidity. The degradation products before and after storage under accelerated storage conditions are summarized in the table below:

Before storageclosed HDPE, sealed with aluminum foilopen a bottle yellow glassclosed bottle yellow glass + oxygen scavengerclosed bottle yellow glass + silica gelclosed bottle yellow glass + argon
4 weeks8 weeks4 weeks8 weeks4 weeks8 weeks4 weeks8 weeks4 weeks8 weeks
323,64 Mg324,05 mg325,57 mg323,56 mg337,25 mg325,23 mg322,65 mg321,27 mg322,69 mg324,62 mg324,30 mg
the content of Oxymorphone 96,30%92,90%89,40%93,70%88,50%96,70%94,80%94,60%92,50%94,60%92,50%
the purity of Oxymorphone99,18%97,70%96,70%Of 98.03%94,50%99,10%98,62%98,59%97,98%98,36%To 98.04%
the content of α-tocopherol91,69%91,51%90,89%93,51%79,94%94,52%93,62%90,56%88,23%93,51%92,18%
Oxymorphone-N-oxide0,09%Of 0.64%1,16%0,19%0,53% 0,03%0,04%0,15%0,24%0,17%0,30%
UK 0.830,00%0,00%0,00%0,36%Of 2.15%0,06%0,08%0,32%0,77%0,00%0,00%
The amount of Oxymorphone-N-oxide and UK 0.83Of 10.09%Of 0.64%1,16%0,55%2,63%0,09%0,12%0,37%1,01%0,17%0,30%
OSN. neizvesten.With 0.13%0,38%0,43%Of 0.45%Of 2.15%0,16%0,18%0,32%0,77%0,46%0,34%
The amount of impurities Σ0,73%2,22%3,21%1,88%5,44%0,82%0,95%1,33%1,94%1,55%1,88%
The HDPE bottles had a volume of 75 ml. oxygen Scavenger was Pharmakeep® KD20 (Mitsubishi, Japan).

Unexpectedly it was found that the inclusion of an oxygen scavenger into the packaging leads to additional stabilization of the dosage form, so that the formation of decomposition products was limited to extremely low values.

Example 3:

Tablets were manufactured as described in example 1, packaged in HDPE bottles with a volume of 75 ml with oxygen absorber and desiccant (Pharmakeep 20 KD), sealed using electromagnetic induction and covered by a plastic cover.

The individual components of the extruded mixtures, the total amount of degradation products before and after storage under accelerated storage conditions are summarized in the table below:

PR.components (m�SS. %)decomposition products (wt.%)
(A)PEOPEGHPMCα-current.Citric acidoNo1oNo2oNo3Σ1Σ2Σ3
F11,573,810,014,00,20,5NdndNdndnd0,05
F21,577,810,010,00,20,5NdndNdnd0,050,10

(A): hydrochloride of Oxymorphone

PEO: polyethylene oxide Mm7 m�n g/mol

PEG: polyethylene glycol 6000

HPMC: polymer 100000 PA*s

α-current.: α-tocopherol

oNo: Oxymorphone-N-oxide (mixture)

S: the sum of all impurities

1: after extrusion, before storage

2: after storage, HDPE bottles, plastic cover sealed with the help of electromagnetic induction, an oxygen absorber, 4 weeks, 40°C, 75% Rel. Humidity

3: after storage, HDPE bottles, sealed with the help of electromagnetic induction, plastic cover, an oxygen absorber, 8 weeks, 40°C, 75% Rel. humidity

The results show that the purity of the product is very high after manufacturing and that the product shows stability during storage for 8 weeks at accelerated degradation conditions comprising a temperature of 40°C/75% RH. moisture.

Example 4:

Tablets were manufactured as described in example 1, but were cut to pieces by 215 mg, which contained 5 mg or 40 mg of the hydrochloride of Oxymorphone, after forming the tablets were coated with approximately 6.5 mg each traditional film coating é II containing polyvinyl alcohol as film-forming filler, Packed in HDPE bottles with a volume of 75 ml with oxygen absorber and desiccant (Pharmakeep 20 KD), sealed using electromagnetic induction and covered by a plastic cover.

Separate� components extruded mixtures the total number of degradation products before and after storage under accelerated storage conditions are summarized in the table below:

etc.constituents (wt. %)decomposition products (wt.%)
(A)PEOPEGHPMCα-current.Citric acidoNo1oNo2Σ1Σ2
G12,3370,016,6310,00,20,84ndndNdNd
G218,656,813.56 MHz10,00,20,84ndnd 0,050,05

(A): hydrochloride of Oxymorphone

PEO: polyethylene oxide Mm7 million g/mol

PEG: polyethylene glycol 6000

HPMC: polymer 100000 PA*s

α-current.: α-tocopherol

oNo: Oxymorphone-N-oxide (mixture)

S: the sum of all impurities

1: after extrusion, before storage

2: after storage, HDPE bottles, sealed with the help of electromagnetic induction, plastic cover, an oxygen absorber, 1 month, 40°C, 75% Rel. humidity

Example 5:

The most preferred dosage form in accordance with example 3 is also suitable for the stabilization of oxycodone. This can be demonstrated for formulations containing 80 mg of oxycodone hydrochloride, manufactured in analogy to example 1, but in this case, the extrudate was cut into pieces 400 mg:

etc.constituents (wt. %)The products of decomposition (mass. %)
(A)PEOPEGHPMCα-current.Citric acidoNo1 oNo2Σ1Σ2
H12054,315100,20,50,060,070,220,13

And oxycodone

PEO: polyethylene oxide Mm 7 million g/mol

PEG: polyethylene glycol 6000

HPMC: polymer 100000 PA*s

α-current.: α-tocopherol

oNo: oxycodone-N-oxide (impurity D+E)

1: after extrusion, before storage

2: after storage, the bottles of yellow glass, plastic cover, an oxygen absorber desiccant (Pharmakeep 20KD), 1 month, 40°C, 75% Rel. humidity

Example 6:

In a single dose (40 mg of the hydrochloride of Oxymorphone, the tablets of example 4), randomized, three-way crossover study with 1 week between doses patients did not eat food the night before, and the meal was carried out after 4 and 10 hours after administration. Within ±1 hour after administration of the drug did not drink water. All the pills washed down with 240 ml of water (example T).

Samples for pharmacokinetics were taken before taking Oxymorphone and 6-Oh-Oxymorphone and 48 hours after administration.

B�ekvivalentnosti compared with Opana ER® (reference R). The results summarized in the tables below:

TreatmentAverageODKB
Cmax[PG/ml]T214798946%
R2671116344%
PCT [PG*h/ml]T386951383636%
R381711465238%
ACC [PG*h/ml]T425751583637%
R412961524237%
Point Estimate T/RLower limit 90% ClThe upper limit of the 90% Cl
Cmax 79,3771,69Of 87.87
PCT101,9895,17109,29
ACC102,2495,48109,48

Cl = confidence interval

It becomes apparent that the dosage forms in accordance with the invention, having an increased tensile strength, be bioequivalent in comparison with conventional dosage forms (Opana ER®).

Example 7:

Tablets were manufactured under identical conditions of hot melt extrusion of two homogeneous components h and mixtures h:

I1I2
Hydrochloride of Oxymorphone [%]11,111,1
PEO [%]68,263,2
PEG [%]10,015,0
HPMC ShiH Etsu [%]10,0/td> 10,0
α-tocopherol [%]0,20,2
Citric acid, anhydrous [%]0,50,5
Weight pills [mg]360360
PAOLAAbout 6,82:14,21 :1

in the following, the same extrusion conditions:

the type of extruder: Extruder Leistritz type Micro 27GL 40D with augers with

average shear effort and the mold, component 8 mm in diameter

throughput: 10 kg/h

rotation speed: 120 Rev / minute

manufacturing time: 30 minutes

the temperature of the hot zone of heating: 100°C

the temperature of the mold: 130°C.

The extrudate was cut into pieces by 360 mg, containing approximately 40 mg of the hydrochloride of Oxymorphone.

100 parts were weighed separately and found the standard deviation of the mass. The part with the song I1(PEO:LEG = about 6,82:1) showed a standard deviation of 2.3 %, while the part with the song I2(PEO:PEG = 4,21:1) showed a standard deviation of only 1.6 %.

From these comparative studies, which show an unexpected result�, it becomes apparent that the ability to handle extenderbase mass can be improved by adjusting the ratio of PEO to the PEG.

Example 8:

In order to determine whether multicurrency acid in addition to citric acid, also inhibit the formation of Oxymorphone-N-oxide, tablets were manufactured as described in example 1, containing maleic acid or fumaric acid. For comparison were also made tablets containing inorganic salt NaH2PO4. The samples were stored in open dishes at 40°C and 75% RH. humidity for 4 weeks.

The individual components of the extruded mixtures as well as the total amount of degradation products before and after storage under accelerated storage conditions are summarized in the table below:

etc.constituents (wt. %)additional ingredient (mass. %)the products of decomposition (mass. %)
(A)PAPEGHPMCα-current.oNo1oNo2 Σ1Σ2
J11,576,010,010,01,5Maleic acid 1,0 %Ndnd0,200,22
J21,576,010,010,01,5Fumaric acid 1,0 %Ndnd0,170,30
J31,576,010,010,01,5NaH2PO41,0%*Nd0,180,060,75

(A): hydrochloride of Oxymorphone

PEO: polyethylene oxide Mm7 million g/mol

PEG: polyethylene glycol 6000

HPMC: polymer 100000 PA*s

α-current.: α-tocopherol

*Na 2PO4: applied in the form of 1.3 % dihydrate

OMO: Oxymorphone-N-oxide (mixture)

Σ: sum of all impurities; maleic acid, fumaric acid and related compounds after deducting from the amount of impurities

1: after extrusion, before storage

2: after storage, outdoor meals, 4 weeks, 40°C, 75% Rel. humidity

In the case of maleic and fumaric acid, these compounds, and in the case of maleic acid and other related compounds were detected during the study of purity as impurities (approximately 40%). Their values were subtracted from the total number of impurities.

In the comparison examples J1and J2-A1and B1becomes obvious that the presence of maleic and fumaric acid fully protects Oxymorphone against oxidation to N-oxides and to a large extent against another decomposition, despite the fact that the samples were stored in open containers, and not in closed vials. These results are comparable with results obtained with citric acid (example 1, D4and E2-E4). Samples containing NaH2PO4(J3) demonstrated protection against formation of N-oxides and other decomposition when they were compared to preparative forms, not containing any acidic compounds (A1and B1), but to a lesser with�class than multicurrency acid, such as citric, maleic and fumaric acid.

Example 9:

To establish whether the presence of citric acid to protect sensitive oxidation of opioids, except Oxymorphone, against N-oxidation, tablets containing the hydrochloride of oxycodone were manufactured as described in example 1.

For comparison were also made tablets containing a smaller amount of α-tocopherol. The samples were stored in open dishes at 40°C and 75% RH. humidity for 4 weeks.

The individual components of the extruded mixtures, as well as the total amount of degradation products before and after storage under accelerated storage conditions are summarized in the table below:

0,23
etc.constituents (wt. %)additional ingredient (mass. %)the products of decomposition (mass. %)
(A)PAPEGHPMCα-current.oNo1oNo2Σ1Σ2
1,577,010,010,01,5/0,050,580,311,63
K21,578,310,010,00,2/0,050,280,580,69
K31,576,010,010,01,5Citric acid 1,0ndNd0,190,22
K41,577,310,010,00,2Citric acid 1,0ndNd0,18

(A): oxycodone hydrochloride

PEO: polyethylene oxide Mm 7 million g/mol

PEG: polyethylene glycol 6000

HPMC: polymer 100000 PA*s

α-current.: α-tocopherol

oNo: oxycodone-N-oxide

Σ: sum of all impurities

1: after extrusion, before storage

2: after storage, outdoor cookware, 4 weeks, 40°C, 75% Rel. humidity

These results demonstrate that citric acid fully protects oxycodone against oxidation to N-oxides and to a large extent against another decomposition, despite the fact that the samples were stored in open containers, and not in closed vials. Reducing the amount of α-tocopherol resulted in a decrease of the decomposition in the case when the formulations did not contain citric acid. These results are comparable with results obtained for Oxymorphone.

1. Tub pharmaceutical dosage form having a tensile strength amounting to at least 300 N and comprising
- opioid (A),
- a free physiologically acceptable multicurrency acid (B) in an amount which is from 0.1 to 5.0 wt.%, based on the total weight of the pharmaceutical dosage forms,
- polyalkyloxy (C) having a mass-average molecular mass Mmconstituting at least 500000 g/mol.

2. Pharmaceutical drug f�PMA in accordance with p 1, where multicurrency acid selected from the group consisting of maleic acid, fumaric acid, glutaric acid, malonic acid and citric acid.

3. Pharmaceutical dosage form in accordance with claim 1, wherein the content of acid (In) is in the range from 0.2 to 2.5 wt.%, based on the total weight of the pharmaceutical dosage form.

4. Pharmaceutical dosage form in accordance with claim 1, which contains the pag, where the ratio of the specific gravity of polyalkylated to the pag is in the range of 4.2±2 : 1.

5. Pharmaceutical dosage form in accordance with claim 1, which contains an antioxidant.

6. Pharmaceutical dosage form in accordance with claim 5, where the antioxidant is an α-tocopherol.

7. Pharmaceutical dosage form in accordance with claim 5 or 6, where the content of the antioxidant is in the range from 0.001 to 5.0 wt.% based on the total weight of the pharmaceutical dosage form.

8. Pharmaceutical dosage form in accordance with claim 1 wherein after storage for 4 weeks at 40°C and 75% relative humidity, the content of opioid (A) is at least of 98.0% of its original content before storage.

9. Pharmaceutical dosage form in accordance with claim 1, wherein the opioid (A)is enclosed in a matrix, containing polyalkylene (C), wherein said matrix controls the release of the opioid from a pharmaceutical dosage form.

10. Pharmaceutical dosage form in accordance with claim 1, wherein the opioid (A) is selected from the group consisting of Oxymorphone, oxycodone, meperidine, and their physiologically acceptable salts.

11. Pharmaceutical dosage form in accordance with claim 1, where the ratio of the specific gravity of polyalkylated (C) and opioid (A) is at least 1:1.

12. Pharmaceutical dosage form in accordance with claim 1, which is designed to receive once a day or twice a day.

13. Pharmaceutical dosage form in accordance with claim 1, which has a tensile strength amounting to at least 500 N.

14. Pharmaceutical dosage form according to any one of claims. 1-13 placed in the package containing the oxygen scavenger.



 

Same patents:
Hypotensive means // 2554815

FIELD: medicine.

SUBSTANCE: invention represents a hypotensive means, which contains felodipinum as an active component, as well as target additional components: mesoporous silicon dioxide, lactose, hypromeloza. Realisation of the invention ensures the high technological efficiency of the claimed medical means production with the provision of a prolonged release of an active substance with the application of available components. Felodipinum is included into spherical particles with a highly developed mesoporous structure of silicon oxide.

EFFECT: increase of stability in storage and protection from unfavorable environmental factors.

4 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition in the form of a tablet with an erodible matrix, which contains one or more fumaric acid ethers, as well as a rate-controlling agent, representing hydroxypropylcellulose and a binding agent, representing lactose, with the decomposition of the said degradable matrix providing the controlled release of the said fumaric acid ether (ethers).

EFFECT: provision of the controlled release of fumaric acid ether (ethers).

19 cl, 43 ex, 2 tbl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and represents a sustained release solid therapeutic agent containing a combination of praziquantel with emodepside, polyvinylpyrrolidone and/or a polyvinylpyrrolidone derivative in an amount of 10 to 50 wt %, polyvinylpyrrolidone and/or the polyvinylpyrrolidone derivative is a mixture of one short-chain polyvinylpyrrolidone and one polyvinylpyrrolidone or the polyvinylpyrrolidone derivative with longer chains, and at least one excipient in an amount of 5 to 80 wt %.

EFFECT: sustained release of active substances and no lump formation in the gastrointestinal tract if two or more tablets taken.

4 cl, 7 ex, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to oral pharmaceutical composition in the form of a granulate produced without spheronisation. The composition contains 92-98 wt % of mesalazine or its pharmaceutically acceptable salt, 2-8 wt % of polyvinylpyrrolidone and an ethylcellulose coating, wherein the above coating weight relates to the above mesalazine weight as 0.3-1.5% and the ethylcellulose coating weight makes 0.11-0.15 mg/cm2. The granulate is packed in a sachet, a capsule or a blister. What is also described is a method for preparing a pharmaceutical composition.

EFFECT: ethylcellulose-coated mesalazine granulate combines a high drug load and a desired mesalazine release profile, namely, 5-25% of released mesalazine 15 min later, 30-70% of released mesalazine 90 min later and 75-100% of released mesalazine 240 min later.

10 cl, 1 ex

FIELD: medicine.

SUBSTANCE: establishing the diagnosis of myocardial infarction is immediately followed by prescribing trimetazidine MB, a modified-release cardiocytoprotector trimetazidine in a dose of 35 mg 2 times a day accompanied by enhancing motion activity gradually: degree Ia activity - turning to the sides; degree Ib activity - sitting for 5-10 minutes 2-3 times a day; degree IIa activity - sitting for 20 minutes, sitting meals, changing on a chair; degree IIb activity - walking along the chamber; degree IIIa activity - coming out into the corridor, unlimited sitting; degree IIIb activity - walking along the corridor, going up the stairs one level higher; degree IVa activity - going for a walk; degree IVb activity - taking 1.0-1.5km walk. The next degree is started in accordance with the patient's chronotropic response to physical exercises providing a heart rate gain to age-specific submaximal values.

EFFECT: method enables providing the more effective rehabilitation of the patients by the combined use of physical exercises and drug treatment accompanied by controlling an age-specific chronotropic criterion.

3 ex, 4 tbl, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and represents a controlled-release preparative form of diacerein administered once a day for treating or autoimmune diseases or their complications. The preparative form contains a core, an active layer, a sustained-release film layer and a delayed-release film layer, wherein the active layer is followed by the sustained-release film, and the delayed-release film layer thereafter. The sustained-release film layer contains ethyl cellulose polymer, povidone, triethylacetate and talc; the delayed-release film layer contains Eudragit polymer, triethylacetate and talc.

EFFECT: reducing the negative side action of diacerein.

18 cl, 23 ex, 33 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and represents a controlled-release aceclofenac preparation for oral administration once a day, exhibiting the fast analgesic and anti-inflammatory action, containing a fast-release layer containing aceclofenac, a solubiliser, a water-soluble additive, a disintegrating agent, a vehicle and a fast-acting additive, as well as a sustained-release layer containing aceclofenac, a solubiliser and a release control base consisting of mixture of hydroxypropyl methyl cellulose (HPMC) with a viscosity of 80,000 sP to 120,000 sP and carbomer taken in mass ratio 7:1 to 9:1.

EFFECT: invention provides a sequential and uniform dissolution rate and a controlled release of the active agent.

7 cl, 12 tbl, 11 dwg, 10 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically to pharmaceutical compositions possessing prolonged antiarrhythmic actions and applicable to correct the cardiac arrhythmia, including that of the ischemic origin. What is presented is a pharmaceutical composition with the prolonged antiarrhythmic acitivity containing bis[2-(diethylamino)]-N-(2,6-dimethylphenyl)acetamide L-glutaminate, L-glutamic acid, 2-aminoethane sulpho-acid and excipients.

EFFECT: prolonged antiarrhythmic action and stability of the dosage form (tablets, capsules for oral application or solution for injections).

3 cl, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a pharmaceutical composition in the form of a coated retard tablet characterised by the fact that it contains a nucleus comprising a nucleus containing trimebutine maleate, microcrystalline cellulose, povidone, hypromellose, magnesium stearate, and a coating that represents Opadry II film (series 85) consisting of partially hydrolysed polyvinyl alcohol, macrogol-3550, titanium dioxide E 171 and talc powder with the ingredients of the composition taken in certain relations, mg.

EFFECT: invention provides storage-stability and high clinical effect.

2 cl, 3 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical compositions according to the invention contain at least one dopamine agonist, and a pharmaceutical vehicle comprising a pharmaceutically acceptable permeation enhancer, a pharmaceutically acceptable solubility enhancer, and a pharmaceutically acceptable bioadhesion enhancer. The dosage forms according to the invention have a pharmacological profile, which is described by Tmax to approximately 90 minutes after administering the dosage form, and the plasma medicament concentration of at least 50% Cmax over the period of time from 90 to 360 minutes after achieving Cmax.

EFFECT: improved therapeutic effect as compared to the oral dosage forms of dopamine agonists.

65 cl, 8 dwg, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacology, namely represents an additive for an erythrocyte-rich fluid. The additive is prepared by adding a hemolysis inhibitor and a surfactant into a blood storage solution. The HLB value of the surfactant makes not less than 13; while the oxyethylene group number in a hydrophilic segment of the molecular structure of the surfactant is not less than 20. The hemolysis inhibitor represents an acetic acid derivative in the form of vitamin E.

EFFECT: additive provides the high-efficacy inhibition of hemolysis and the excellent erythrocyte storage characteristic.

7 cl, 6 dwg, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to the field of pharmaceutics and deals with a pharmaceutical composition, which contains feline erythropoietin as an active ingredient, to which two or more polyethyleneglycol molecules with a non-branched chain are attached, with a water-soluble long-chain molecule having the molecular weight, constituting not less than 30 kDa and producing the haemopoietic effect. A haemopoietic medication and a medication for the treatment of anaemia are based on the said composition.

EFFECT: group of inventions provides the haemopoietic effect, which lasts for not less than seven days, when introduced to humans and/or animals.

8 cl, 4 dwg, 2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention represents a drug preparation for Parkinson disease containing micronised L-DOPA (3-hydroxy-L-tyrosine) as an active ingredient, which represent stable particles containing poly(lactic-co-glycolic acid 50/50 (PLGA 50/50), or poly(lactic-co-glycolic acid 75/25 (PLGA 75/25), or poly(lactic-co-glycolic acid 50/50 with carboxyl group (PLGA-COOH 50/50), or lactic acid polymer (PLA) in an amount of 75.0÷79.0 wt %, D-mannitol in an amount of 7.5÷8.0 wt %, as well as either polyvinyl alcohol (PVA) or Tween 80.

EFFECT: treating Parkinson disease more effectively.

2 cl, 4 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine. What is described is a transdermally absorbable formulation prepared by dissolving donepezil in an adherent plaster base, which contains a hydrophobic polymer and an absorption enhancer. The absorption enhancer represents one substance, or two or more substances specified in lauryl alcohol, triethyl citrate, isopropylmyristate, cetyl lactate, oleyl alcohol, sorbitan monooleate, polyethyleneglycol monostearate, lauromacrogol, N-methyl-2-pyrroldone and triacetin.

EFFECT: transdermally absorbable formulation can administer donepezil stably for a relatively long period of time and can provide both blood donepezil increase, and the properties of sustained release of donepezil.

4 cl, 4 dwg, 6 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to bioencapsulation, namely to a method for cephalosporin bioencapsulation, wherein poludan is used as a microcapsule coating. The declared method is characterised by adding a cephalosporin powder 0.060 g and the E472 preparation 0.05 g as a surfactant to 1% aqueous poludan 2 g. The prepared mixture is mixed; after the reaction mixture ingredients are dissolved to prepare a transparent solution, carbinol 1 ml as the first precipitation agent, and acetone 5 ml as the second precipitation agent are added drop by drop very slowly. The prepared microcapsule suspension is filtered in a filter, washed in acetone and dried in a drying cabinet; the method is implemented at 25°C.

EFFECT: simplifying and fastening the process of microencapsulation in poludan and higher weight yield.

3 ex

FIELD: medicine.

SUBSTANCE: therapeutic agent contains an alloy of polyethylene oxide of molecular weight 400 and 1500 as a base and comprises a combination of antiseptic, benzalkonium chloride and metronidazole as therapeutic ingredients. The invention provides preparing the therapeutic agent possessing the antimicrobial, sorption and wound-healing action on local pyoinflammatory processes in soft tissues and mucous membranes, used in surgery, dermatology, obstetrics and gynaecology, otorhinolaryngology.

EFFECT: agent possesses the higher efficacy.

2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and describes a pharmaceutical composition of polymer microparticles with modified release kinetics of poorly soluble drug substances. The composition represents a mixture of polymer microparticles having a size of 1 to 100 mcm and consisting of a composite of a biodegradable and biocompatible polymer of poly-3-oxybutyrate or poly-3-oxybutyrate-with-3-oxyvalerate; an active drug substance having a water-solubility of less than 20 mcg/ml, particularly ivermectin; and an additive substance specified in phospholipids and/or polyethylene glycols, and/or poloxamers. The weight ratio of the additive substance to the polymer in the microparticles of the pharmaceutical composition profiles release kinetics of the active drug substance.

EFFECT: mixture of microparticles of various modifications enables additional variations of release kinetics of the active drug between the linear to degree nature, and a release rate.

18 cl, 3 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely to ophthalmology, and may be used for treating dry age-related macular degeneration (dry ARMD). That is ensured by preparing a biocompatible prolonged release drug delivery system containing bevacizumab from 5 mcg to 20 mcg, and a carrier made of a polymer hyaluronic acid associated with bevacizumab administered into a vitreous body with using a 25-30-measuring syringe. In average, bevacizumab from 14 to 120 ng is released for 24 hours in the period of three to six months. The delivery system has a viscosity of 130,000 cPs to 300,000 cPs at the shear velocity of 0.1/second at 25°C.

EFFECT: using the given inventions enables treating dry ARMD with preventing or delaying wet ARMD.

5 cl, 1 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmacy and medicine, and concerns a composition, a method and a kit which enable a controlled release of octreotide, e.g. octreotide acetate in an individual. The composition contains a preparation containing octreotide basically enclosed in a hydrophilic polymer specified in polyurethane polymers and methacrylate polymers; it is effective for providing octreotide release at a rate of 30 mcg to 800 mcg a day for six months in vivo, wherein the hydrophilic polymer, but not the preparation, additionally contains a releasing substance with molecular weight of at least approximately 1,000 Dalton, wherein the preparation contains octreotide 40 to 120 mg, and the releasing substance is specified in a group consisting of Brij 35 (polyoxyethylene lauryl ester), polyoxyethylene(20)sorbitan trioleate, Tween 20, Tween 80, vitamin E TPGS and mixtures of any of the two or more.The method for reducing GH levels or IGF-1 levels and/or treating an octreotide-sensitive disease involving a subcutaneous implantation of at least one dry implanted device comprising the declared preparation. The kit comprising the declared composition for octreotide controlled release.

EFFECT: group of inventions provides a therapeutically effective amount of octreotide for a long period of time with treating hormonal conditions.

25 cl, 11 ex, 7 tbl, 21 dwg

FIELD: chemistry.

SUBSTANCE: group of inventions relates to compositions of materials, containing basic aminoacid arginine, and their application for coating devices intended for application in the oral cavity, or for manufacturing such devices. One of composition versions contains basic amino acid arginine, in free form or in form of salt, placed in biodegradable polymer, selected from polyacrylates, polymethacrylates or their copolymers. The other composition version contains matrix with pores from 10 to 70 mcm and basic amino acid arginine, located inside said pores, with matrix representing plastic, selected from polyethylene, polymethylmethacrylate, polyurethane, polyethylene terephthalate, polypropylene, polystyrene, polyamides, bioplastic. Also claimed is application of said compositions of material in production of device for application in the oral cavity, as well as device for application in the oral cavity (for instance, toothbrush, tongue scraper, mouthguard, orthodontic correcting device), which has a surface coated with any of said compositions, and methods of delivery of basic amino acid arginine by means of such device into the oral cavity of a subject, requiring it.

EFFECT: application of such devices, manufactured with application of said compositions, ensures release of arginine into the oral cavity within a long period of time.

22 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to immunology, and describes set for preservation of native erythrocytes, applied for detection of antibodies to antigens of erythrocytes, consists of two solutions: water solution for short-term stay of erythrocytes, which contains 9.0-11.0 g/l of glucose, 0.2-0.3 g/l of sodium citrate, 0.01-0.02 g/l of citric acid and 0.95-1.05 g/l of bull serum albumin, and water solution for storing erythrocytes, which includes 0.2-0.4 g/l of adenine, 25.0-35.0 g/l of glucose, 6.0-8.0 g/l of mannitol, 0.2-0.3 g/l of sodium citrate, 0.05 -0.07 g/l of citric acid and 0.95-1.05 g/l of bull serum albumin.

EFFECT: invention ensures preserving ability of antigens of membrane of preserved native erythrocytes to bind with respective clinically significant antibodies for term not less than 2 months.

3 cl, 1 tbl

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