Compositions of orally dispersible tablets containing combinations of high- and low-dose therapeutic agents

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention aims at pharmaceutical compositions containing a number of microparticles with taste masking, containing high-/low-dose therapeutic agents, at dosage forms containing the above pharmaceutical compositions (such as orally dispersible tablets), and at methods for producing these pharmaceutical compositions and dosage forms.

EFFECT: dosage forms containing the pharmaceutical compositions according to the invention represent the improved homogenous mixtures of the high-dose and low-dose therapeutic agents, which enable controlling the release rate of the therapeutic agent from particles by various ways, as well as flexible correction of dosages when administering the combinations of the therapeutic agents, eg in pain management.

31 cl, 4 dwg, 12 tbl, 8 ex

 

CROSS-REFERENCE TO RELATED APPLICATIONS

In this application claimed priority to US provisional applications 61/174780 and 61/174788, filed may 1, 2009.

PRIOR art

The pain from moderate to severe can be treated effectively opioid analgesics, such as hydrocodone. However, as many opioids are addictive, the risk of abuse can be minimised by combining opioid with non-opioid analgesic, such as acetaminophen, aspirin, ibuprofen and so on, thus making possible the effective control of the pain at lower doses of opioid analgesics. Other medical conditions, such as diabetes (hyperglycemia), cardiovascular disease and schizophrenia, are also effectively treated with drug combinations. However, the need to introduce various dosage forms can cause problems, such as problems with patient compliance with regimens or dosing errors in the introduction.

One approach to the prevention of these problems is the integration of different drugs in a single dosage form to reduce the number of different dosage forms, subject to the introduction, and the assurance that the combination of drugs administered in the correct relative amounts. For example, Vicodin® is a tablet � immediate-release (IR), contains 5 mg of hydrocodone bitartrate and 500 mg acetaminophen, is used to control severe pain. However, it is difficult to reproducibly obtain a homogeneous mixture of hydrocodone and acetaminophen with a desired mass ratio of 1:100 (e.g. content uniformity with RSD (relative standard deviation) of 6% or less, as required by regulatory authorities worldwide). Thus, there is a need for uniform and reproducible ways of combining high-dose drugs and low doses of the drug in one dosage form.

The two most widely used types of oral dosage forms are tablets and capsules. However, such dosage forms have some drawbacks. For example, an estimated 50% of the population have problems swallowing tablets (see Seager, Journal of Pharmacol. and Pharm. 50, pages 375-382, 1998). It is especially difficult to swallow tablets or capsules for the elderly or children, or to treat drug patients who are unable or unwilling to swallow tablets or capsules. In addition, conventional tablets or capsules usually must be administered with water, which is not always possible or convenient. This leads to poor compliance or even non-compliance with treatment regimens, which as a result has a negative impact on perfomance�of treatment. Dosage forms in the form of orally disintegrating tablets (ODT) were implemented to address issues such as ODT rapidly dissolve or disintegrate in the oral cavity, and the resulting slurry or suspension of the drug is easier to be swallowed by the patient. Such dosage forms are also more convenient as they do not require the introduction of water.

Since the ODT dosage form disintegrates in the oral cavity of the patient, disintegrating ODT should be palatable. For example, if one or more medicines to ODT have a bitter taste, the particles containing a drug, and components ODT should be taste masked, for example by coating particles containing a drug, a polymeric membrane to prevent the release of the drug in the oral cavity. However, the main drawback of masking the taste is more of the slow dissolution of drug(s) means(STV) from microparticles with effectively masked the taste. What is more bitter the medicine, the thicker must be kusamakura coating, and consequently the slower the drug release from the particles with masked taste, containing a drug. Thus, the process of effective mA�of kiravani taste particles, containing a drug, leads to a significantly slower drug release, with concomitant slower systemic absorption of the drug in the gastrointestinal tract.

In some cases, a slower drug release is a particular problem ODT dosage forms that are intended to be bioequivalent to the reference dosage form with immediate release (IR), for example bioequivalent to the conventional tablet or effervescent tablet on the basis of IR dosage forms with a Tmaxless than an hour and the rapid onset of action. For such products, ODT, biosimilar products are immediate-release, it is important that cusomisable layer is not substantially reduced the rate of release of the drug. For ODT compositions containing combinations of two or more drugs (e.g. the composition of high-dose/low-dose drugs) this problem is particularly acute, since different drug components of the combination ODT may require different levels of masking of taste, depending on the degree of bitterness of medicines (i.e. medicines with low levels of bitterness may require little or no required musk�El of taste, while for very bitter drugs can require substantial kusamakura layers). As a further complication, kusamakura layers reduce the rate of release of poorly soluble drugs to a greater extent than the more soluble drugs. In some cases it may be more desirable the ODT composition containing particles of a low-dose drug with masked taste in combination with the particles of high-dose drugs that have coating sustained release.

In addition, ODT must rapidly disintegrate upon contact with saliva in the oral cavity, while also providing sufficient tablet hardness and strength sufficient to withstand the friction in the process of packing, storage, transportation, distribution and end use, and to provide acceptable organoleptic properties (such as being pleasant to the taste, as described above, and to provide a smooth (non-granular) taste and acceptable pharmacokinetic properties (i.e., rapid onset of action, the Gusto, the characteristics of the AUC that is similar to the reference medicinal products). Is often quite difficult to achieve all these properties, as sufficient for masking of taste more than soluble and/or more bitter Leka�governmental funds may require thicker kusamakura layers, what can make it challenging to obtain the desired rapid release of the drug.

Thus, the production of clinically effective pharmaceutical compositions containing at least high-dose and low-dose medicament, in particular in the form of an ODT, is quite complex and requires coordination of many different and often competing requirements.

A BRIEF SUMMARY of the INVENTION

In one embodiment of the present invention is directed to. pharmaceutical composition comprising a plurality of microparticles having a coating with modified release, containing high-dose/low-dose drug where microparticles containing the drug, include:

(a) a core containing a high-dose drug;

(b) a first coating containing a low-dose drug, located on top of the kernel; and

(C) a second coating, located on top of the core, the coating with modified release (e.g. kusamakura coating, or coated with a slow release for attaining taste masking and/or properties of prolonged/sustained release) containing water-insoluble polymer.

In another embodiment of the present invention is directed to pharmaceutical.�Oia, comprising a plurality of microparticles with masked taste, containing a non-opioid analgesic drug/opioid analgesic drug, where microparticles containing a drug include:

(a) a core containing a high-dose drug, such as non-opioid analgesic drug;

(b) a layer containing a low-dose drug such as an opioid analgesic drug, located on top of a kernel, containing high-dose drug; and

(b) at least one layer of the coating with modified release (e.g. layer kusamakura coating, or the coating layer delayed release) located on top of the core with high-dose drug, and the nucleus, containing high-dose/low-dose drug where at least one layer kusamakura coatings or coatings with delayed release contains a water-insoluble polymer or a combination of water-insoluble polymer with one or more water soluble polymer, enteric polymer or glucocortoids the blowing agent.

In yet another embodiment of the present invention is directed to a pharmaceutical composition containing mn�types of microparticles, containing high-dose/low-dose drug in combination with microparticles containing high-dose drug, where microparticles containing a drug include:

(a) a core containing a high-dose drug;

(b) perhaps encapsulating cover located over a core containing high-dose drug;

(b) a coating layer with a slow release, located on top of a kernel, containing high-dose drug;

(g) a layer of a low-dose medicines are located on top of the coating layer delayed release;

(e) a sealing cover located on top of a layer of a low-dose drug; and

(e) cusomisable layer located on top of the sealing cover;

where the coating layer delayed release contains a water-insoluble polymer, possibly in combination with one or more water-soluble or enteric polymer; thus providing taste masking and/or sustained release properties of the microparticles containing high-dose drug; and cusomisable layer located on top of microparticles containing a low-dose drug contains insoluble in water� polymer, possibly in combination with glucocortoids polymer or glucocortoids the blowing agent.

In yet another embodiment of the present invention is directed to a pharmaceutical composition containing numerous coated with modified release microparticles containing high-dose/low-dose drug where microparticles containing a drug include:

(a) a core containing a high-dose drug;

(b) perhaps encapsulating cover located over a core containing high-dose drug;

(b) a layer kusamakura coating situated on top of a layer of the sealing cover;

(g) a layer of a low-dose medicines are located on top of the layer kusamakura coatings;

(e) a sealing cover located on top of a layer of a low-dose drug; and

(e) flavouring layer located on top of the sealer.

In yet another embodiment of the present invention is directed to ODT dosage form containing a combination of one of the pharmaceutical compositions of the present invention, bistrotdepierrerue microbeads and possibly a second set of particles containing high-dose drug, comprising a core, sod�rashee high-dose drug covered with a layer of the coating with modified release.

In yet another embodiment of the present invention is directed to a method of manufacturing the pharmaceutical compositions disclosed in the present description of the invention, including:

(1) obtaining cores containing high-dose drug;

(2) coating the cores with stage (1) containing high-dose drug layer of a low-dose of the drug, thus obtaining microparticles containing high-dose/low-dose drug; and

(3) coating the cores with stage (1) containing high-dose drug, and/or microparticles from step (2) containing high-dose/low-dose drug with a covering layer containing water-insoluble polymer, with the formation thereby of microparticles sustained release and taste masked, containing high-dose/low-dose drug.

In yet another embodiment of the present invention is directed to a method of manufacturing a pharmaceutical composition ODT, as disclosed in the present description of the invention, further comprising:

(1) manufacture bistrotdepierrerue microbeads containing a sugar alcohol, a saccharide or a mixture thereof with an average particle size of not more than 30 μm and superathletes;

(2) manufacture�pressure of the mixture, comprising microparticles containing high-dose/low-dose drug with microparticles containing high-dose drug, and bistrotdepierrerue microbeads

(3) compressing the mixture in orally disintegrating tablets. In yet another embodiment of the present invention is directed to a method of treating a patient susceptible to the disease or condition, comprising administering to a patient in need, a therapeutically effective amount of the compositions of the present invention containing high-dose drug and low-dose drug.

BRIEF DESCRIPTION of GRAPHIC MATERIALS

Fig.1 shows a schematic representation of one embodiment of a microparticle having a coating with modified release, comprising a core containing a high-dose drug and microparticles with masked taste, containing a low-dose/high-dose drug. The cross section of the combination of high-dose/low-dose medicines. The combination of ODT high-dose/low-dose medicines contains bistrotdepierrerue microbeads, microparticles high-dose/low-dose drugs with masked taste and microparticles are high-dose medicines� taste masked or delayed release

Fig.2 shows the profiles based plasma concentrations of acetaminophen from tablets of hydrocodone bitartrate/acetaminophen, observed in a pilot of the Republic of Kazakhstan (pharmacokinetic) study.

Fig.3 shows the profiles based on the concentration in plasma from time to of hydrocodone bitartrate tablets of the hydrocodone bitartrate/acetaminophen, observed in a pilot of the study.

Fig.4 shows the profiles based plasma concentrations of acetaminophen from acetaminophen ODT compared to Panadol®, observed in a pilot of the study.

DETAILED description of the INVENTION

All the documents cited in this description of the invention incorporated by reference in their entirety for all purposes. Citation of any document is not to be construed as an admission that it constitutes prior art against the present invention.

The present invention is directed to pharmaceutical compositions containing a lot of with a coverage modified release microparticles containing high-dose/low-dose drug, as described in this description of the invention. The compositions of the present invention provide an oral dosage form containing a combination of high-dose lekarstvennoj� medium/low doses of the drug, satisfying one or more of the following:

microparticles having kusamakura coating and/or coated with a slow release, where a low-dose drug layer is applied to microparticles containing high-dose drug, where the homogeneity of the mixture meet the requirements of USP;

microparticles with effectively masked the taste, regardless of differences in solubility and bitterness high-dose and low-dose drugs;

in some embodiments also contain bistrotdepierrerue pellets to provide the ODT dosage form that rapidly disintegrates after contact with saliva in the oral cavity and forms a smooth, easy-to-swallow suspension containing particles of the drug with taste masked;

- drug particles with an average particle diameter of not more than about 400 μm to provide a smooth taste that leaves no aftertaste (i.e. minor or minimal drug release from non-granular or Nesmelova taste) until swallowing;

provides rapid, essentially complete release of the dose of the particles of the drug immediate-release and taste masked after entry into the stomach, t�Kim, the increase in the probability to be bioequivalent to the corresponding(s) reference(s) dosage(s) product(s) with immediate-release or providing targeted release profile of high-dose medicines suitable for dosing once or twice a day; and

- getting a solid tablet of drugs that demonstrate acceptable hardness and friability of tablets, suitable for packaging in HDPE (high density polyethylene) bottles and/or transport without packaging or packaged tablets for commercial distribution, and end use.

The term "medicament", "active" or "active pharmaceutical ingredient" when used in this description of the invention includes pharmaceutically acceptable and therapeutically effective compound, its pharmaceutically acceptable salts, stereoisomers and mixtures of stereoisomers, solvates (including hydrates), polymorphs, and/or their esters. At the mention of drugs in the descriptions of various embodiments of the invention, this reference covers essential medicine, its pharmaceutically acceptable salts, stereoisomers and mixtures of stereoisomers, solvates (including hydrates), polymorphs, and/or esters, unless otherwise indicated.

The terms "layer" or "coating" when used in this description of the invention, are synonymous. For example, the terms sealing layer, a layer of the drug and so on are synonymous with the sealant coating, the drug coating and so on�.

The terms "orally disintegrating tablet" or "ODT" refer to the tablet, which disintegrates rapidly in the oral cavity of a patient after administration, without the need chewable. The speed of the falling may vary, but it is higher than the falling speed of conventional solid dosage forms (e.g. tablets or capsules) that are intended to be swallowed immediately after administration, or chewing solid dosage forms. Orally disintegrating compositions of the present invention may contain pharmaceutically acceptable ingredients which swell, dissolve or otherwise facilitate the disintegration or dissolution of the ODT composition. Such ingredients may include pharmaceutical disintegrant, such as polyplasdone, water-soluble sugar alcohol such as mannitol, saccharide, such as lactose, or a mixture thereof, water-soluble binder, such as povidone, fusible solid substance (for example a hydrophobic wax such as polyethylene glycol, glycerinated, stearic acid, hydrogenated castor oil, and so forth), which can release the drug when entering the stomach. Orally disintegrating compositions of the present invention may be in the form of a pill, minitablets, single-dose capsules or sachets, or suhag� powder for recovery.

The term "about" when used in this description of the invention in relation to a numerical value includes "exactly". For example, "about 60 seconds" includes exactly 60 seconds, and values close to 60 seconds (for example, 50 seconds, 55 seconds, 59 seconds, 61 sec, 65 seconds 70 seconds, and so on).

Unless otherwise indicated, the number of different coatings or layers described in this description of the invention (the"coating weight") is expressed as a percentage of the increase in the mass of particles or granules that provide a dry coating relative to the initial mass of particles or granules before coating. Thus, the coating mass of 10% applies to the dry coating that increases the weight of the particles by 10%.

When used in this description of the invention the term "immediate release" or IR refers to the release of more than or equal to about 50%, or more than about 75%, or more than about 90%, or more than about 95% of the drug within about 2 hours, more particularly within about one hour after administration of the dosage form.

The term "essentially splits" means the falling level corresponding to the disintegration of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or about 100%-nomu decay�Oia ODT compositions.

When used in this description of the invention, the term " coating "modified release" includes coverage that suspend the release, slow release, extend release, prevent release, and/or otherwise prolong the drug release relative to compositions that do not have such coatings, which release a drug relatively quickly (i.e. composition "immediate-release"). The term "controlled release" encompasses "sustained release", "prolonged release", "delayed release" and "timed, pulsatile release". The term coverage "lag time" refers to the specific type of coverage "with adjustable release", where the coating with time delay delaying the release of the drug after injection. The term "controlled release" is also used interchangeably with "modified release". The term "particle with controlled release" refers to a particle having one or more properties of the controlled release, as described in this description of the invention. The term "particle with adjustable release" also refers to a particle containing a drug �the case, covered by one or more coatings with controlled release, as described in this specification.

The term "substantially masks the taste" in relation to kusamakura layer of IR particles (if present) refers to the ability kusamakura layer to substantially preclude the release of the drug with a bitter taste in the mouth of the patient. Cusomisable layer, which "substantially masks" the taste of the drug, usually releases less than about 10% of the drug in the patient's mouth, in other embodiments less than about 5%, less than about 1%, less than about 0.5%, less than about 0.1%, less than about 0.05%, less than about 0.03% and less than about 0.01% of the medicine. Kusamakura properties kusamakura layer compositions of the present invention can be measured in vivo (e.g., using conventional organoleptic test techniques known in the art) or in vitro (e.g., using tests for dissolution, as described in this description of the invention). Specialist it is obvious that the magnitude of release of the drug associated with kusamakura layer, which "substantially masks" the taste of the drug, are not limited to ranges, clearly disclosed in this description of�of bretania, and can vary depending on other factors, such as the perceived bitterness of the drug and the presence of other flavouring agents in the composition.

The term "substantially modifies the release" in relation to a layer, refers to the ability of this layer to provide the properties of modified release, that is, to delay the release, slow release, extend release, prevent release, and/or otherwise prolong the drug release compared to compositions lacking such coverage, which release a drug relatively quickly (i.e. compositions "immediate-release"), as described in this specification.

When used in this description of the invention, the term "sustained release" (SR) refers to the property of slow release of the drug from the core particles containing a drug, without significant time delay. The term "coating sustained release or SR coating" refers to coating, showing the properties of sustained release. The term "particle with a slow release" refers to a particle containing a drug, showing the properties of slow-released�me. In one embodiment the coating contains a slow release water insoluble polymer and possibly water-soluble polymer. The SR coating may contain a plasticizer or other ingredients that have no adverse effects on such properties of the coating as a "slow release".

When used in this description of the invention the term "timed pulsatile release" (TPR) refers to the property of modified release drug after a predetermined time delay. The term "coating with timed pulsatile release" or "TPR coating" refers to coating, showing the properties of a timed pulse release. The term "particle with a timed pulsatile release" refers to a particle containing a drug, showing the properties of a timed pulse release. In some embodiments, the time delay from at least about 2 to about 10 hours is achieved by coating the particles, for example, a combination of at least one water-insoluble polymer and at least one enteric polymer (e.g. a combination of ethyl cellulose and phthalate hypromellose). Pokr�Thiais possible TPR may contain a plasticizer or other ingredients, which do not adversely affect the properties of the coating "timed pulsed release".

The term "having a coating with modified release microparticles containing a drug" refers mainly to the microparticles containing a drug (such as crystals, granules, pellets, manufactured by controlled spheronization or particles/granules covered with a layer of the drug), is covered by one or more functional polymers to achieve effective taste masking and/or extended/sustained release. As for the microparticles containing high-dose/low-dose drug, this term refers to microparticles having a coating with modified release, containing high-dose/low-dose drug, as described in this specification.

The terms "profile based plasma concentration from time", "Relish", "AUC", "Tmax"and "half life" have their generally accepted meanings as defined in "Guidelines for the production:

Bioequivalence" FDA (Management on control over products and medicines of the USA).

Unless otherwise indicated, all percentages and ratios are calculated by weight in the calculation� on the weight of the whole composition.

The term "positioned atop" means that the second substance is applied over the first substance, where the second substance may be or may not be in direct physical contact with the first substance. Thus, it is possible, but not necessary, to between the first and second substances located intermediate substance.

Therapy with combination of medicines is increasingly useful in treating diseases or conditions, which are mainly treated by introducing two or more drugs. For example, treatment of pain is benefiting from the introduction of low doses of opioid analgesics combination with relatively high doses of non-opioid analgesics (for example NSAID (non-steroidal anti-inflammatory drug)) that are effective in treating pain from moderate to strong, in addition to reducing the number of potentially forming addictive administered opioid drugs. For other indications (e.g. diabetes), the combination of medicines may interact synergistically with the development of more significant clinical benefits in comparison with any drug, introduced separately. However, the need to enter multiple dosage forms, each of which contains one drug can lead to the same� problems as poor patient compliance with treatment regimens, errors during the correct doses of each drug, and so on. In such situations, it is advantageous to prepare a single dosage form by combining two (or more) of the drug, thereby providing the possibility of introducing a single dosage form, and not two (or more) dosage forms. However, the production of such combined pharmaceutical compositions when one of the drugs present in relatively high concentrations compared with one or more other drugs can be difficult; in practice it is difficult to obtain a homogeneous mixture of high-dose drugs and low doses of the drug, so that the high-dose drug, and a low-dose drug have been reproducibly achieved in their respective proper dosages.

The present invention is directed to pharmaceutical compositions comprising a plurality of microparticles containing high-dose/low-dose drug with a masked taste, each of which contains both the high-dose drug (or drugs) and a low-dose drug (or drugs). The core of the microparticles containing you�okumoto/low-dose drug with a masked taste, contains high-dose drug and low-dose drug is presented in the layer of a low-dose medicines, located on top of a kernel, containing high-dose drug.

Suitable compositions of the core particles include high-dose of the drug itself (for example formed by recrystallization or precipitation of high-dose of the drug from solution, or by grinding and sieving of high-dose drugs, and so on, to obtain particles containing high-dose drug with desired particle size and distribution particle size). Alternatively, the core may contain granules containing particles of high-dose drug in combination with one or more pharmaceutically acceptable excipients (e.g. lactose, mannitol, microcrystalline cellulose and so on), and possibly a binder, obtained by wet or dry granulation. In other embodiments the core may contain extruded and spheronization particles containing high-dose medicament (for example in combination with suitable pharmaceutically acceptable excipients, as described in this description of the invention), or �alley high-dose medicines are prepared by controlled spheronization in Granurex VEC-35 or VEC-40 from Vector Corpoation and these pellets are coated with polymers or mixtures of polymers, providing a target release profiles of the medicinal product, suitable for dosing once or twice a day. In other embodiments, the core contains granules coated with a drug, that is, an inert core (e.g., sugar spheres, microcrystalline cellulose, mannitol-microcrystalline cellulose, silicon dioxide and so on), covered with a layer of high-dose medication and possibly a binder. In other embodiments the core may contain a high-dose drug in combination with a pharmaceutically acceptable excipient, pressed into "minitablets" with the particle diameter in the range of about 2-5 mm. In a particular embodiment the core contains particles high-dose drugs. In many embodiments the core has an average particle size less than about 500 microns, or less than about 400 microns, or less than about 300 microns, or less than about 200 microns.

Any pharmaceutically acceptable combination of high-dose/low-dose drug which is effective in the treatment of disease States or conditions, including, for example, cardiovascular disease, diabetes, pain from moderate to severe, gastrointestinal disorders, and so forth, can be selected according to specific embodiments of the present invented�I to create pharmaceutical compositions contains one or more aggregates which have a coating with modified release microparticles containing high-dose/low-dose drug, demonstrating desirable release profiles of the drug in vitro/in vivo.

Any pharmaceutically acceptable polymeric binder which is compatible with high-dose drug and/or other components of the composition, can be used in the manufacture of cores containing high-dose medicament (e.g. binder used in forming the granules, forming the granules covered with a layer of medicines, and so on.). Suitable polymeric binders include, for example, polymers selected from the group consisting of hydroxypropyl cellulose, povidone, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyethylene oxides, polysaccharides, gum Arabic, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethyl cellulose, gelatin, glucose syrup (liquid glucose), guar gum, hydroxypropylmethylcellulose, methylcellulose, pectin, PEG (peg), povidone, gelatinized starch and so on.

A core containing a high-dose drug CPE�PTS can be directly covered with a layer of low doses of the drug, or can be first coated with a sealing layer. Suitable sealing layers contain water-soluble hydrophilic polymer. Non-limiting examples of suitable hydrophilic polymers include hydrophilic hydroxypropyl cellulose (e.g. Klucel® LF), hydroxypropyl methylcellulose or hypromellose (for example é® Clear or Pharmacoat™ 603), copolymer of vinylpyrrolidone-vinyl acetate copolymer (such as Kollidon® VA 64 from BASF) and ethylcellulose, such as ethylcellulose low viscosity. In many embodiments, especially when a core containing a high-dose drug, is a particles are high-dose medicines for the compositions of the present invention does not require sealing layer, which is deposited directly on the core.

The sealing layer may be applied with a coating weight from about 1% to about 10%, for example about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10%, including all ranges and subranges between these values.

In some embodiments it is envisaged that the compositions of the present invention disintegrate in the oral cavity of the patient after administration (e.g. ODT dosage form, as described in this description �of Soberania). In such embodiments, when high-dose drug and/or low doses, the drug has an unpleasant to the senses properties (for example bitter taste), taste cores containing high-dose drug, and/or the layer containing a low-dose drug mask to protect the patient from feeling the taste of high-dose and/or low doses of the drug, for example, by coating a nucleus containing high-dose drug, and/or the layer containing a low-dose drug kusamakura layer. For example, the compositions of the present invention can include one cusomisable layer, as described in this description of the invention, located between a core containing high-dose drug, and the layer containing a low-dose drug, one cusomisable layer, as described in this description of the invention, located on top of a layer containing a low-dose drug, or two kusamakura layer is located between a core containing high-dose drug, and the layer containing a low-dose drug, and the top layer containing a low-dose drug. Cusomisable layer can be applied�orestano on the core, containing high-dose drug, and/or on the layer containing a low-dose drug or a core containing a high-dose drug, and/or a layer containing a low-dose drug can first be covered with a sealing layer (for example, as described in this description of the invention), for example, to minimize or prevent static charge and/or friction of the particles, followed by application kusamakura polymer coating. When the compositions of the present invention contain two or more kusamakura layer, kusamakura layers may be independently selected from any of the compositions kusamakura layer described in this specification.

Suitable kusamakura layers may contain water-insoluble polymer or a combination of water-insoluble polymer and glucocerebrosidase of the blowing agent (for example glucocerebroside and pharmaceutically acceptable organic, or inorganic polymeric substances).

Cusomisable layer may be deposited on a core containing a high-dose drug, and/or on the layer containing a low-dose drug, by any suitable method, for example, by coating in a fluidized bed or by means of coacervation. For example, taste�asterousia polymer coating may be deposited on the core weight (after coating and drying) of from about 3% to about 50%, including about 3%, about 5%, about 7%, about 10%, about 12%, about 15%, about 17%, about 20%, about 22%, about 25%, about 27%, about 30%, about 35%, about 40%, about 45% or about 50%, including all ranges and subranges between these values.

Non-limiting examples of suitable water-insoluble polymers include ethylcellulose, cellulose acetate, triacetylcellulose, cellulose acetate butyrate, polyvinyl acetate, neutral copolymers methylacrylate acid-methyl methacrylate (for example Eudragit RL, RS, and NE30D, and so on), and mixtures thereof. In one embodiment of the water-insoluble polymer contains ethylcellulose. In another embodiment of the water-insoluble polymer contains ethylcellulose with an average viscosity of 10 CP (1 PA·s) (for example Ethocel Standard 10 Premium), or about 100 CPS (Ethocel Standard 100 Premium) in a 5% solution in a mixture of 80/20 toluene/ethanol, measured at 25°C. by Ubbelohde viscometer.

As described in this description of the invention, in some embodiments cusomisable(s) layer(s) independently contain(at) a combination of the water-insoluble polymer (as described in this description of the invention) and glucocerebrosidase the blowing agent. The blowing agents include polymeric and polimernye pharmaceutically acceptable glucocerebroside substances. Non-limiting examples polimernyh glucocortoid then�educational include pharmaceutically acceptable inorganic substances, such as calcium carbonate, magnesium carbonate, calcium phosphate, hydroxide, iron (III) phosphate, iron (III), magnesium hydroxide, magnesium phosphate and so on; pharmaceutically acceptable polimernye organic substances such as saccharide calcium, calcium succinate, calcium tartrate, magnesium citrate, acetate of iron(III) and so on; pharmaceutically acceptable glucocerebroside polymers comprising maltrin, copolymers of aminoalkylsilanes, commercially available under the trademark Eudragit® (type E100 or EPO), polyvinylacetal diethylaminoacetate, e.g., AEA®, commercially available from Sankyo Company Limited, Tokyo (Japan) and the like; and mixtures thereof. In one embodiment glucocortoids polymer is a terpolymer based dimethylaminoethylmethacrylate, butylmethacrylate and methyl methacrylate. In another embodiment, the terpolymer has an average molecular weight of 150,000 and a ratio of monomers is 1:2:1 of methyl methacrylate, N,N-dimethylaminoethylmethacrylate and butylmethacrylate, and mixtures thereof.

The ratio of insoluble polymer to glucocerebrosidase the blowing agent is in the range from about 95/5 to about 50/50, including about 90/10, about 85/15, about 80/20, about 75/25, about 70/30, about 65/35, about 60/40, or about 55/45.

Coating mass kusamakura layer containing insoluble in �ode polymer and glucocortoids a blowing agent, is in the range from about 5% to about 30%, or about 5%-25%, about 5%-20%, about 5% -15%, about 5%-10%, about 10% -30%, about 10% -25%, about 10% -20%, about 10% -15%, about 15%-30%, about 50% -25%, about 15%-20%, about 20% -30%, about 20% -25%, or about 25% -30%.

The ratio of insoluble polymer to glucocerebrosidase the polymer is in the range from about 9/1 to about 1/1, including the range from approximately 6/3 to about 2/1. In other embodiments the ratio of water insoluble polymer to glucocerebrosidase the polymer is about 95/5, about 90/10, about 85/15, about 80/20, about 75/25, about 70/30, about 65/35, about 60/40, about 55/45 or about 50/50, including all values, ranges and subranges between these values.

In some embodiments cusomisable layer containing a combination of water-insoluble polymer and glucocerebrosidase polymer, has a weight of coating is from about 10% to about 40 wt.%, including ranges from about 12% to about 30%, from about 15% to about 25% and from about 20% to about 30%. In other embodiments, the coating mass kusamakura layer containing a combination of water-insoluble and glucocerebrosidase polymers is about 10%, about 12.5 percent, or about 13%, about 15%, about 17%, about 18%, about 20%, about 22%, example�about 24%, about 25%, about 27%, about 30%, about 35% or about 40%, including all ranges and subranges between these values.

In various embodiments, it is desirable to provide a covering layer of slow release on the cores containing high-dose drug to modify the release of high-dose drugs. Coated slow release, coated on a core containing high-dose drug, may contain water-insoluble polymer, thereby forming a coating with a slow release (SR); water-insoluble polymer in combination with enteric-coated or water-soluble polymer, thereby forming a coating with a timed pulsatile release (TPR). In other embodiments, the coating contains slow release enteric polymer deposited on the particle-containing high-dose drug, thereby forming a coating with a delayed release (DR).

In some embodiments, the coating slow release provides suitable properties (e.g. prolonged release properties, mechanical properties and coating properties) without the need for plasticizer. For example, ethylcellulose without plasticizer used�comfort coating on the core, containing a drug, by coacervation in a solvent by phase separation, for taste masking, and/or it may be applied, for example, of a suitable solvent to provide sustained release properties. Also coatings containing polyvinyl acetate (PVA), neutral and cationic copolymers of esters of acrylate/methyl acrylate (for example NE30D and EPO), waxes, and so forth, can be applied without plasticizers.

Non-limiting examples of suitable enteric polymers include acatitla cellulose phthalate of hydroxypropylmethylcellulose, acetonuria of hydroxypropylmethylcellulose, polyvinyl acetate phthalate, pH-sensitive copolymers methylacrylate acid/methyl methacrylate (for example Eudragit® L, S and FS polymers), shellac and mixtures thereof. In some embodiments polimernye enteric substances such as polimernye waxes and composition of fatty acids, can be used instead of enteric polymers, provided that they have a pH-sensitive solubility associated with enteric polymers. Such enteric polymers can be used in the form of a solution in a mixture of solvents or in aqueous dispersion. Some commercially-available substances which can be used are copolymers methylacrylate sour�s, sold under the trademark Eudragit (L100, S100, L30D) manufactured by Rohm Pharma, Cellacefate (cellulose acuticauda) from Eastman Chemical Co., Aquateric (water dispersion of cellulose acuticauda) from FMC Corp. and Aqoat (water dispersion of hydroxypropylmethylcellulose of acetolactate) from Shin Etsu K. K.

Coating mass slow release, containing a combination of water-insoluble polymer and enteric polymer is in the range from about 10 to 60%, more specifically from about 30% to 60%, including about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50% or about 55%, including all ranges and subranges between these values. The ratio of insoluble polymer to enteric polymer may vary from about 10:1 to 1:2, more specifically from about 2:1 to 1:1, including about 9:1, about 8:1, about 7:1 to about 6:1, about 5:1 to about 4:1, about 3:1, about 2:1 or about 1:1.

In other embodiments, the layer of slow release contains a combination of water-insoluble polymer (as described in this description of the invention) with a water-soluble polymer. Non-limiting examples of suitable water-soluble polymers include polyvinylpyrrolidone (e.g. Povidone K-25), polyethylene glycol (e.g. PEG 400), hydroxypropyl methylcellulose and hydroc�propylethylene.

The ratio of insoluble polymer to water soluble polymer is in the range from about 95/5 to about 50/50, including the ratio of about 95/5, about 90/10, about 85/15, about 80/20, about 75/25, about 70/30, about 65/35, about 60/40, about 55/45 or about 50/50, including all ranges and subranges between these values. In other embodiments cusomisable layer containing a combination of water-insoluble polymer and a water-soluble polymer, is applied to the core containing high-dose drug with a coating weight of about 3%, about 5%, about 7%, about 10%, about 12%, about 15%, about 17%, about 20%, about 22%, about 25%, about 27%, about 30%, about 35%, about 40%, about 45% and about 50 wt.%, including all values, ranges and subranges between these values.

In some other embodiments of the present invention relates to pharmaceutical compositions containing core high-dose drug having a coating with modified release, containing at least one therapeutic agent or its pharmaceutically acceptable salt, solvate and/or ester;

water-insoluble polymer (e.g. ethylcellulose), the second possible cover, located on top of the first coating containing cosecretary�th polymer and, perhaps water-insoluble polymer (e.g. ethylcellulose and hypromellose phthalate in a ratio of from about 9:1 to about 5:5).

Layer with modified release or cusomisable layer can be unplasticized or plasticized. For example, particles containing a drug, to mask the taste of ethylcellulose by coacervation in a solvent using a phase separation without the need for plasticizer or of a suitable pharmaceutically acceptable solvent, using a device for coating in a fluidized bed. For coatings with modified release, containing various polymers, such as Eudragit NE30D, or different hydrophobic waxes, in the device for coating fluidized bed usually does not require a plasticizer.

When it is desirable and convenient to use plasticizer, non-limiting examples of suitable plasticizers include glycerol and its esters (for example, acetylated mono - or diglycerides, including commercially available Myvacet® 9-45), glycerylmonostearate, glyceryltrinitrate, glyceryltrinitrate, phthalates (e.g. dibutyl phthalate, diethyl, dimethyl phthalate, dioctyl phthalate, and so forth), tributeby ether acetylamino acid, tritely ether acetylamino acid, tributyltin, acetyltributyl, Tr�utiltity, glyceryltrinitrate; dialysability, dibutylsebacate, dibutylamine, dibutylaniline, dibutylsebacate, chlorobutanol, polyethylene glycols, vegetable oils, diethylfumarate, diethylmaleate, important reagent, dibutylamine, dibutylphthalate, esters of catelouge alcohol, malonate (e.g. diethylmalonate and so on), castor oil, Polysorbate, N-butylbenzenesulfonamide, N-methylpyrrolidone and mixtures thereof. In some embodiments it is desirable to use natality plasticizer. In various embodiments of the present invention, the amount of plasticizer in kusamakura layer relative to the amount of water-insoluble polymer is in the range from about 3% to about 30 wt%.In another embodiment, the amount of plasticizer is in the range from 10% to about 25 wt%. water-insoluble polymer. In other embodiments the amount of plasticizer relative to the weight of the water-insoluble polymer is about 3%, about 5%, about 7%, about 10%, about 12%, about 15%, about 17%, about 20%, about 22%, about 25%, about 27% and about 30%, including all ranges and subranges between these values. Specialist in the art knows how to choose the type of plasticizer on the basis of the polymer or polymers and the nature of the covering system (e.g. water-based or races�of varicella, solution or on the basis of dispersion, and total solids). In a particular embodiment the plasticizer is a hydrogenated castor oil.

In some embodiments cusomisable layer may also contain an agent that prevents adhesion, to reduce aggregation kusamakura particles. Suitable anti-adherence agents include talc and/or magnesium stearate.

In one embodiment kusamakura polymer coating contains plasticized, water-insoluble polymer, such as ethylcellulose (EU-10), with a coating mass of about 5-50% wt.

In some embodiments the core with a modified release (sustained release and/or taste masked) containing high-dose drug, is covered with a sealing layer, for example to minimize attrition or agglomeration of nuclei with masked taste or, alternatively, to prevent the contact between the high-dose drug in the core and, for example, a low-dose drug layer of a low-dose of the drug. The composition and the applied weight of the sealing layer such as described in this specification.

A layer of a low-dose of the drug is applied directly on top of a kernel, containing high-dose drug, and�and on top of the sealing cover, and/or kernel with masked taste. Low doses, the drug can be applied as a coating on a core containing a high-dose drug, by any suitable method, for example by coating installation for coating or fluidized bed, using a solution of low doses of the drug (in a pharmaceutically acceptable solvent), possibly in combination with a polymeric binder, as described in this description of the invention. For example, solution coating of a low-dose of the drug may contain a suitable solvent (for example, water, pharmaceutically acceptable organic solvent, such as acetone or alcohol, or an aqueous organic solvent), in which low doses dissolved drug and possibly a binder (e.g. hydroxypropyl cellulose, polyvinylpyrrolidone, and so on).

The obtained microparticles containing high-dose drug/low-dose drug can then be coated, if necessary, additional sealing layer (as described in this description of the invention) and/or kusamakura layer (as described in this description of the invention). Thus, in some embodiments the final microparticles containing high�kolosovo drug/low-dose drug include a core containing a high-dose drug (as described in this description of the invention), possible covered with a sealing coating, kusamakura layer (e.g. containing water-insoluble polymer or water-insoluble polymer in combination with water soluble or glucocortoids polymer), a layer of a low-dose of the drug, the second possible sealing layer and the second kusamakura layer (e.g. containing water-insoluble polymer or water-insoluble polymer in combination with water soluble or glucocortoids polymer).

Microparticles containing high-dose drug/low-dose drug may can contain one or more sealing layer, where the sealing layers may have the same composition or different compositions and may be applied with the same coating mass or with different masses of the coating. Similarly, if microparticles containing high-dose drug/low-dose drug, include two kusamakura layer, these two kusamakura layer can have the same composition or different compositions and/or the same mass of coating or a different coating mass. For example, internal cusomisable layer may contain insoluble in�e polymer and the outer cusomisable layer may contain a combination of water-insoluble polymer and a water-soluble polymer and/or glucocortoids polymer and so on.

In other embodiments flavoring coating layer (which may include the sweetener and/or flavoring, as described in this description of the invention) may be located on top of a layer containing a low-dose drug (for example, instead kusamakura layer), so that microparticles containing high-dose drug/low-dose drug have included, for example a core containing a high-dose drug (as described in this description of the invention), possible covered with a sealing coating, kusamakura layer (e.g. containing water-insoluble polymer or water-insoluble polymer in combination with water soluble or glucocortoids polymer)layer a low-dose of the drug, the second possible sealing layer and flavoring with a covering layer.

Flavoring coating layer contains a combination of flavors and binders. Suitable binders include those described in this description of the invention. Flavor includes water-soluble sweeteners, such as Sucralose, saccharin, aspartame, neotame, Acesulfame K, sodium saccharinate, neohesperidin, lactitol, maltitol, sorbitol and mixtures thereof, or alternatively, flavors such as strawberry and cherry, peppery� mint, strawberry and mixtures thereof. In one embodiment the binder is a hydroxypropyl cellulose and a flavoring represents the energy.

Weight flavoring coating can vary from about 1% to about 10 wt.%, including ranges from about 3.0% to about 8%, from about 5% to about 7.5%, and from about 5% to about 10% by weight of the core with a coating or about 1%, about 2%, about 3% , about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10%, including all ranges and subranges between these values.

As described in this description of the invention, microparticles with masked taste, containing high-dose/low-dose drug can include layers in addition to kusamakura layer (e.g. possible sealing layers and so on). Thus, cusomisable layer may be located directly on the core containing high-dose drug, or the sealing layer may be placed between the core containing high-dose drug, and kusamakura layer. In other embodiments, the layer containing a low-dose drug covered kusamakura layer containing water-insoluble polymer in combination with glucocortoids polymer, such as�tinny the copolymer dimethylaminoethyl-methyl acrylate.In another embodiment cusomisable layer, located on top of a layer of a low-dose drugs that contains water-insoluble polymer and does not contain water-soluble or glucocortoids polymer. In an alternate embodiment of the covering flavoring layer (for example with a coating weight from about 1% to about 10%) containing a water-soluble sweetener, is located directly on top of a layer of a low-dose of the drug, or over the sealing layer (such as hydroxypropyl cellulose with a coating weight from about 1% to about 10%), located on top of a layer of low doses of the drug. Microparticles of the present invention containing high-dose drug/low-dose drug, provide rapid dissolution of high-dose and low-dose drugs in the test for dissolution using the Apparatus 1 USP (United States Pharmacopoeia) (baskets at 100 rpm) or Apparatus 2 USP (blade at 50 rpm) in 900 ml of medium (pH of 1.2, pH of 5.8, pH 6.8 or pH 7 (water)) at 37°C.

As described in this description of the invention, pharmaceutical compositions containing microparticles of the present invention containing high-dose drug/low-dose drug with the coating with modified release, which provide a uniform mixture, and�e uniformity of dosage according to the requirements of USP, which is difficult to achieve in other ways (for example by mixing the particles containing high-dose drug with the second set of particles containing a low-dose drug), especially when the ratio of the high-dose drug to a low-dose drug is about 20/1 or higher (e.g. about 20/1, approximately 25/1, about 30/1, about 35/1, about 40/1, about 45/1, about 50/1, about 60/1, about 70/1, about 80/1, about about 90/1 100/1 and so on).

High-dose drug and low doses, the drug may contain any drugs that are intended for use in combination to treat the condition or disease in a patient. For example, pharmaceutical compositions of the present invention can include combinations of high-dose and low-dose drugs, such as non-opioid analgesics (such as acetaminophen and nonsteroidal anti-inflammatory medicines such as aspirin, ibuprofen, Ketoprofen, meloxicam, diclofenac potassium, etodolac, sulindac, indomethacin, celecoxib, and so forth) in combination with one or more opioid analgesics (of the hydrocodone bitartrate, Oxymorphone, buprenorphine, fentanyl, hydromorphone) for pain management of moderate �about strong. Similarly, the antidiabetic combination of high-dose and low-dose drugs suitable for the treatment of diabetes mellitus by lowering glucose levels in the blood), includes at least one of biguanide (for example Metformin) in combination with at least one sulfonylurea (such as glipizide, gliclazide, glyburide, glikvidon, pilopine, glimepiride), meglitinides (such as Repaglinide, nateglinide), or tiazolidindionom (such as rosiglitazone, pioglitazone, troglitazone). Alternatively, high-dose medicament (e.g. nicotinic acid) in combination with low-dose drugs (such as lovastatin, fluvastatin, atorvastatin, cerivastatin, simvastatin, mevastatin, rosuvastatin, pravastatin) is useful to reduce levels of cholesterol (VLDL) and triglycerides in people with cardiovascular disease or risk of such disease. The combination of high-dose drugs, such as pseudoephedrine hydrochloride, pseudoephedrine sulfate, or Fexofenadine, and low doses of the drug, such as cetirizine, loratidine and phenylephrine, useful for the treatment of allergies arising in the premises, and allergies that occur outdoors. In a particular embodiment of a low-dose drug n�establet a therapeutically effective amount of hydrocodone bitartrate of, and high-dose medicament is a therapeutically effective amount of acetaminophen for treatment of pain. In another specific embodiment of the high-dose drug is a therapeutically effective amount of Metformin and a low-dose drug is a therapeutically effective amount of rosiglitazone for the treatment of hyperglycemia.

In one embodiment the pharmaceutical composition of the present invention can contain Niacin (nicotinic acid) as a high-dose of the drug, made in the form of particles high-dose drugs with masked taste profile of immediate release (IR), covered with a layer of a statin and kusamakura coverage. Alternative, Niacin can be made in the form of particles high-dose drug with a slow release (SR) having a coating with modified release, for the manufacture of pharmaceutical compositions with modified release.

Pharmaceutical compositions of the present invention contain microparticles containing high-dose/low-dose drug. In an alternative embodiment the pharmaceutical composition of the present invention may also contain WTO�second set of microparticles, containing high-dose drug. Microparticles containing high-dose drug, include, for example, a core containing a high-dose drug (as described in this description of the invention) coated with a water-insoluble polymer, for example with a coating weight from about 15% to about 35%, whereby particles with a slow release (SR) containing high-dose drug. The combination of microparticles containing high-dose/low-dose drug, and particles containing high-dose drug SR, demonstrates the profiles of quick release low doses of the drug and prolonged release profiles high-dose drug (modified release).

Pharmaceutical compositions of the present invention can be used for the manufacture of oral dosage forms such as tablets, capsules and ODT. Tablets can be manufactured by combining the pharmaceutical compositions of the present invention with a suitable pharmaceutically acceptable excipient, and subsequent extrusion of the mixture with the formation of tablets. Alternative capsules can be filled with the pharmaceutical compositions of the present invention (� possible excipienti).

In a particular embodiment, the pharmaceutical compositions of the present invention can be combined with bistrotdepierrerue microgranules with the formation of oral disintegrating tablets (ODT). ODT is a tablet that is designed to essentially disintegrate in the oral cavity after injection (without chewing) within about 60 seconds after contact with saliva (in the mouth) or artificial salivary fluid (for example, when tested according to the test for disintegration <701> USP). In specific embodiments ODT essentially disintegrates within about 30 seconds. The disintegration of the ODT in the oral cavity of the patient provides a smooth, easy-to-swallow suspension having no sand taste or aftertaste, and at the same time provides the pharmacokinetic profiles of drugs contained in ODT (for example profiles based on the concentration in plasma from time to time), which are bioequivalent to the corresponding reference listed drug (RLD).

ODT of the present invention contains a pharmaceutical composition of the present invention in combination with bistrotdepierrerue microgranules. Bistrotdepierrerue microbeads can be produced as described in US 2006/0078614, 2006/0105038, 2005/0232988 or 2003/0215500 (each of which are included in this about�isana of the invention by reference in its entirety for all purposes), by granulating a disintegrant-sugar alcohol and/or saccharide having an average particle size of not more than about 30 μm. Granulation can be performed, for example, in the granulator high shear rate is approximately 20-25% of water as a granulating liquid and, if necessary, to grind wet and dry for the manufacture bistrotdepierrerue microbeads, for example having an average particle size of not more than about 300 μm (e.g. approximately 175-300 μm).

The ratio of baking powder to the sugar alcohol, saccharide or mixtures thereof in bistrotdepierrerue the microgranules is in the range from about 90/10 to about 99/01, for example, about 90/10, about 91/9, about 92/8, about 93/7, about 94/6, about 95/5, about 96/4, about 97/3, about 98/2, about 99/1, including all values, ranges and subranges between these values.

Attitude bistrotdepierrerue microbeads to particles with masked taste, containing analytical drug is in the range of from about 5/1 to about 1/1, including approximately 5/1, 4/1, 3/1, 2/1, 1/1, including all values, ranges and subranges between these values.

Microparticles with masked taste, containing a non-opioid analgesic/opioid analgesic drug included in the dosage forms� ODT, must also have a sufficiently small particle size, so that after the falling ODT in the oral cavity of the patient was smooth, easy-to-swallow suspension. In •most embodiments in which the pharmaceutical compositions of the present invention proposed in the form of an ODT dosage form, the average particle size of microparticles with masked taste, containing a non-opioid analgesic/opioid analgesic drug equal to not more than about 400 μm, or in some embodiments not more than about 300 microns.

Dosage form ODT, as described in this description of the invention may also include pharmaceutically acceptable excipients normally used in the compositions of disintegrating tablets, such as microcrystalline cellulose and spray-dried mannitol (compressible diluents), croscarmellose sodium or copovidone (superathletes), dyes and possibly magnesium stearate or sodium fumarate (lubricant, mixed vnutrigrudne, or applied topically to lubricate the surfaces of the dies and punches).

Tableted dosage forms, including ODT dosage form containing the pharmaceutical composition of the present invention, have low brittleness, for example less than about 1% (e.g., less than about 0.9, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, and so on, including all ranges and subranges between these values) in order to have a sufficient strength to withstand handling, shipping and/or packing in blister with torn layer.

Non-limiting list of suitable disintegrants for bistrotdepierrerue microbeads include copovidone (cross-linked PVP (polyvinylpyrrolidon)), sodium starch glycolate, cross-linked sodium carboxymethylcellulose, calcium silicate and nitrosamino hydroxypropyl cellulose. The amount of baking powder in ODT is typically in the range from about 1% to about 10 wt.%, including about 1%, about 2%, about I/o, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10%, including all ranges and subranges between these values. In a particular embodiment, the baking powder for bistrotdepierrerue microbeads selected from the group consisting of polyplasdone, crosslinked sodium carboxymethylcellulose and nitrosamines of hydroxypropyl cellulose. In a more specific embodiment, the baking powder for bistrotdepierrerue microbeads represents polyplasdone.

Non-limiting list of suitable sugar alcohols include m�net, sorbitol, xylitol, maltitol, Arabic, ribitol, dulcet, Edith, isomalt, lactitol, aritra and combinations thereof. In a specific embodiment, the sugar alcohol mannitol is a. Non-limiting list of suitable saccharides include lactose, sucrose, maltose and combinations thereof. In a specific embodiment, the saccharide is a lactose. The amount of a sugar alcohol and/or saccharide in ODT is in the range from about 30% to about 70 wt.%, including, for example, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65% or about 70%, including all ranges and subranges between these values.

Pharmaceutically acceptable excipients include fillers, diluents, sliding substances, disintegrants, binders, lubricants and so on. Other pharmaceutically acceptable excipient include acidifiers, alkalinizing agents, preservatives, antioxidants, buffering agents, chelating agents, colorants, chelating agents, emulsifiers and/or solubilizers agents, flavoring agents and fragrances, humectants, sweeteners, wetting agents and so on.

Examples of suitable fillers, diluents and/or binders include lactose (e.g. spray-dried lactose, α-lactose, β-lactose, Tabletose®, various mark� Pharmatose®, Microtose® or Fast-Flo®), microcrystalline cellulose (various grades of Avicel®, Ceolus®, EIcema®, Vivacel®, Ming Tai or Solka-Floc®), hydroxypropyl cellulose, L-hydroxypropyl cellulose (nitrosamino), low molecular weight hydroxypropyl methylcellulose (HPMC) (e.g. Methocel E, F and K from Dow Chemical, Metolose SH from Shin-Etsu, Ltd.), hydroxyethyl cellulose, sodium carboxymethylcellulose, and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins, starches or modified starches (including potato starch, maize starch and rice starch), calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate), calcium sulfate, calcium carbonate, sodium alginate, collagen and so on.

Examples of suitable diluents include, for example, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dekstrana, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, klasterizovannykh starch, sucrose, sugar and so on.

Examples of suitable disintegrants include, e.g., alginic acid or alginates, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, Crespo�icon, polacrilin potassium, sodium starch glycolate, starch, klasterizovannykh starch, carboxymethylcel (e.g. Primogel® and Explotab®) and so on.

Specific examples of sliding agents and lubricants include stearic acid, magnesium stearate, calcium stearate or other metal stearates, talc, waxes and glycerides, light mineral oil, PEG (polyethylene glycol), glycerinated, colloidal silicon dioxide, hydrogenated vegetable oils, corn starch, sodium fumarate, polyethylene glycols, alkylsulfate, sodium benzoate, sodium acetate, and so on.

Other excipient include, for example, fragrances, dyes, kusamakura agents, pH-regulating agents, buffering agents, preservatives, stabilizers, antioxidants, wetting agents, regulating humidity agents, surface active agents, suspendresume agents that enhance the absorption agents, agents for modified release, and so on.

The present invention also is directed to methods of making pharmaceutical compositions and dosage forms described in this description of the invention. In one embodiment microparticles containing high-dose/low-dose drug, produced by a method comprising:

(a) the manufacture of cores containing high-dose medicines�tively tool as described in this description of the invention (e.g. non-opioid analgesic, such as acetaminophen, diclofenac potassium, and so forth);

(b) applying a layer of a low-dose drugs (eg containing a low-dose drug, as described in this description of the invention, such as the hydrocodone bitartrate) a core containing high-dose drug;

(b) coating the core containing high-dose medicinal product from stage (a) at least one kusamakura layer and/or coating layer with modified release, and particle phase (b) containing high-dose/low-dose drug, at least one kusamakura layer or layer of flavoring.

Stage (a) the manufacture of the nucleus can be performed by any method known in the art; for example, by layering on inert pellet (e.g. sugar, microcrystalline cellulose, mannitol-microcrystalline cellulose, silicon dioxide and so on) of a solution containing a drug and possibly a polymer binder (for example by coating in a fluidized bed or in a plant for coating). Alternatively, the core may contain crystals of the drug to the desired particle size (e.g. example�about 50-500 μm, including 100-250 μm), obtained by crystallization of the drug from a suitable solvent or by grinding crystals of the drug to particles of the desired size. In other embodiments the core may contain the pellets obtained by controlled spheronization.

In a particular embodiment, the microspheres containing high-dose medicament (e.g. non-opioid analgesic or anti-diabetic drug) can be prepared in the usual way granulating with large shear or planetary granulation process or pellets containing high-dose drug can be manufactured in the usual way granulation-extrusion-spheronization, including, for example, acetaminophen, polymeric binder, and one or more fillers/diluents.

Stage (b) comprises coating the core with masked taste, containing high-dose drug, low-dose medication using a solution for drug layering, as described in this description of the invention (e.g., containing a solution of a low-dose of the drug and possible binder). A layer of low doses of medicinal product can be applied using any suitable method, for example to�pamam layer, in the installation for coating, coacervate and so on.

Stage (b) comprises coating the core containing high-dose drug, and/or the layer containing a low-dose drug kusamakura layer. In some embodiments cusomisable layer is applied directly onto the core containing high-dose drug, or a sealing layer is applied on the core containing high-dose drug, before the coating layer containing a low-dose drug, and/or kusamakura layer. Similarly, the sealing layer can be applied to the layer containing a low-dose drug, before coating kusamakura layer or flavoring layer, as described in this description of the invention (for example contains a sweetener and/or flavoring and possible polymer binder, such as hydroxypropyl cellulose, applied in the form of a solution or suspension). Cusomisable layer contains water-insoluble polymer or water-insoluble polymer in combination with water soluble or glucocortoids polymer (binder), for example, any of the compositions described in this description of the invention, such as ethylcellulose (Ethocel Standard 100 Premium, with a coating mass of about 10%), or combined�tion of ethyl cellulose with glucocortoids polymer (e.g. Eudragit E100) with a coating mass of approximately 25%.

After applying a layer of a low-dose of the drug, the resulting particles may be coated with a sealing layer (as described in this description of the invention and then coated kusamakura layer or a fragrance layer (as described in this description of the invention). For example, cusomisable layer deposited on the layer of low doses of the drug (or a sealing layer deposited on the layer of a low-dose drugs), may contain water-insoluble polymer (e.g. ethylcellulose) or a combination of water-insoluble polymer and a water-soluble or glucocerebrosidase polymer (e.g. ethylcellulose in combination with Eudragit E100). Alternatively, instead kusamakura layer of flavoring coating may be deposited on the layer of a low-dose drug or the protective sealing layer deposited on the layer of low doses of the drug.

In specific embodiments the method comprises applying, by means of coacervation in a solvent kusamakura layer directly on the core containing high-dose drug, or the sealing layer located on the core containing high-dose drug where cusomisable layer contains insoluble in water ethylcellulose (Ethocel Stadard 100 Premium) with a coating weight of approximately 6%. In other embodiments, the method comprises coating water-insoluble ethyl cellulose (Ethocel Standard 10 Premium) in combination with water-soluble hydroxypropylcellulose in the ratio of 7:3 or glucocortoids Eudragit E100 at a ratio of 8:7 with the coating mass to about 20% by coating in a fluidized bed.

In another specific embodiment the method comprises applying, by means of coacervation in a solvent kusamakura layer directly on the layer containing a low-dose drug or the sealing layer on the layer containing a low-dose drug, for example by means of water-insoluble ethyl cellulose (Ethocel Standard 100 Premium) with a coating weight of approximately 6%. In other embodiments, the method comprises coating water-insoluble ethyl cellulose (Ethocel Standard 10 Premium) in combination with water-soluble hydroxypropylcellulose in the ratio of 7:3 or glucocortoids Eudragit E100 at a ratio of 8:7 in the amount of about 20 wt%.in the calculation of the total mass of the particles, coated in a fluidized bed. Kusamakura coverage can be obtained and applied as described, for example, in patent publications US 2006/0078614 and 2006/0105038.

In yet another specific embodiment the method comprises coating the layer containing a low-dose drug with sealing�OYA, containing hydrophilic hydroxypropyl cellulose with a coating weight of about 5%, the subsequent coating kusamakura layer containing a sweetener, such as Sucralose, with a coating mass of approximately 5% of the mass.

The final dosage form comprising microparticles with masked taste, containing high-dose/low-dose drug of the present invention, can then be manufactured in a variety of ways known in the pharmaceutical industry, such as filling an appropriate amount of microparticles with masked taste, containing high-dose/low-dose drug, such as gelatin capsules or container suitable for the storage of slurry, sachet and so on. In other embodiments microparticles with masked taste, containing high-dose/low-dose drug of the present invention, combined with suitable pharmaceutically acceptable excipients and compressed to form tablets. Tablets containing pharmaceutical compositions of the present invention may contain an internal lubricant (e.g. magnesium stearate), or may be compressed into tablets using external lubrication in which the lubricant is sprayed on the surface of dies and punches, and not include in the mixture d�I pressing. Outside lubrication and methods of compaction that can be used for the manufacture of oral dosage forms (e.g. tablets, ODT) containing pharmaceutical compositions of the present invention, described for example in US 5996902 and US 6776361.

When the ultimate dosage form is an ODT, the method also includes manufacturing bistrotdepierrerue microbeads containing a disintegrant and a sugar alcohol, a saccharide or a mixture thereof, where each of the disintegrant, a sugar alcohol and/or saccharide have an average particle diameter of not more than 30 μm; subsequent Union bistrotdepierrerue microbeads the microbeads containing high-dose/low-dose drug with a masked taste, and possibly other pharmaceutically acceptable excipients, for example in a mixer or a V-shaped mixer; and finally compressing the mixture bistrotdepierrerue microbeads and microbeads containing high-dose/low-dose drug with masked taste in ODT, for example using a tablet press with external lubrication for receiving the ODT with desirable characteristics of the tablets (such as sufficient hardness, friability <0.6%, the lowest time - the falling and the rapid dissolution). Bistrotdepierrerue microspheres can be manufactured according to the methods riskrating patent publications US 2006/0078614, 2006/0105038, 2006/0105039 and 2005/0232988.

In specific embodiments bistrotdepierrerue microspheres and microparticles containing a drug with masked taste, may be present in a ratio of from about 4/1 to 2/1 to achieve a smooth mouth-feel. Bistrotdepierrerue microbeads can be produced, as described in this description of the invention by granulating a disintegrant, such as Polyplasdone XL-10, with a sugar alcohol or a saccharide or a combination thereof, each of which has the average particle diameter of not more than about 30 μm, with water or water-alcohol mixture in a conventional granulator or pelletizer with high shear and drying equipment fluidized bed or in a shelf drier to obtain granules with an average particle size of not more than about 400 μm (preferably not more than about 300 microns).

The final dosage form can contain one set of microparticles with masked taste, containing high-dose/low-dose drug of the present invention, in combination with excipients, bistrotdepierrerue microgranules and so on, or may include a combination of microparticles with masked taste, containing high-dose/low-dose drug in combination with particles containing high-dose generic�military means, or, alternatively, may contain two or more together different microparticles with masked taste, containing high-dose/low-dose drug. The ratio of different populations of microparticles containing high-dose/low-dose drug, or microparticles containing high-dose/low-dose drug, and particles containing high-dose drug, can be varied to provide a suitable dosage high-dose and low-dose drugs.

Alternatively, the final dosage form can contain one set of microparticles with masked taste, containing high-dose/low-dose drug, according to the present invention, in combination with excipients, bistrotdepierrerue microgranules and so on, or may include a combination of microparticles with masked taste, containing high-dose/low-dose drug in combination with microparticles containing high-dose the drug having a coating with modified release (such as taste masked or sustained release), or, alternatively, may contain two or more together different microparticles with masked taste containing high-dose/low-dose l�drug remedy where microparticles containing high-dose the drug having a coating with a slow release, contain water-insoluble polymer, possibly in combination with water-soluble or enteric polymer deposited before the formation of layers of a low-dose of the drug. The ratio of different populations of microparticles containing high-dose/low-dose drug, or microparticles containing high-dose/low-dose drug and microparticles containing high-dose drug with masked taste or to have coating sustained release, can vary to provide the appropriate dosage of high-dose and low-dose medicinal components.

Oral dosage forms of the present invention produced by the methods described in this description of the invention provide an in vivo plasma concentrations and release profiles that mimic RLD. According to specific embodiments, pharmaceutical compositions of the present invention contain microbeads or extruded/spheronization pellets containing acetaminophen, a polymeric binder, which imparts elastic properties of the dried micro-granules/pellets, a hydrophilic filler/diluent, and the possibility�about flavour, sweetener and/or baking powder.

In specific embodiments of the present invention is directed to compositions of the present invention containing at least one set of microparticles containing a non-opioid analgesic/opioid analgesic drug, in combination with microparticles containing a non-opioid analgesic drug with the characteristics of release of the medicinal product, suitable for regimens twice or once a day, where one or more sets of microparticles containing a non-opioid analgesic drug contain microparticles containing a non-opioid analgesic drug with one or more covering layers containing water-insoluble polymer, enteric polymer, or enteric polymer in combination with a polymer, insoluble in water.

In most embodiments of the pharmaceutical compositions of the present invention with masked taste demonstrate the following properties:

1) acceptable masking of taste that leaves no aftertaste, when the composition is placed in the oral cavity for 3 minutes, more particularly for 2 minutes and in some embodiments for 60 seconds, and in other embodiments as long as it does not swallow;

2) uniformly acceptable�th mixture in accordance with the requirements of United States Pharmacopoeia; and

3) rapid, essentially complete release of the dose upon entering the stomach, the release of no less than 75% of the total dose within 30 minutes when dissolution testing using the Apparatus 1 USP (baskets at 100 rpm) or Apparatus 2 (the blade at 50 rpm in 900 ml of medium for dissolution at 37±0.5°C).

ODT, manufactured according to specific embodiments of the present invention, may exhibit the following properties:

1) show reasonable uniformity of dosage forms, as defined in the USP;

2) disintegrate upon contact with saliva in the oral cavity forming a smooth, easy-to-swallow suspension containing microparticles with masked taste;

3) leave no aftertaste after swallowing (no sandy or chalky taste);

4) provide a rapid, essentially complete release of the dose upon admission into the stomach; or

5) ODT, when dissolution testing using the Apparatus 1 USP (baskets at 100 rpm) or Apparatus 2 (the blade at 50 rpm) in 900 ml buffer, release not less than 75% of the dose in about 30 minutes.

In another specific embodiment of the pharmaceutical composition of the present invention contains acetaminophen as high-dose drugs and the hydrocodone bitartrate in Kutch�as low doses of the drug. After oral administration acetaminophen is rapidly and almost completely absorbed from the GI (gastrointestinal) tract. Peak plasma concentrations are reached within 30-60 minutes (binding to serum proteins is approximately 25% after normal therapeutic dosages) and the elimination half-life from plasma ranging from 1 to 2.5 hours in normal healthy patients. After about 8 hours, you can only detect traces of drugs.

Pharmaceutical compositions of the present invention containing a therapeutically effective amount of microparticles with masked taste, containing high-dose/low-dose drug, are effective in the treatment of various diseases or conditions. For example, pharmaceutical compositions of the present invention containing a therapeutically effective amount of a nonsteroidal anti-inflammatory drugs, such as aspirin, ibuprofen, Ketoprofen, meloxicam, diclofenac potassium, etodolac, sulindac, indomethacin, celecoxib, or mixtures thereof, in combination with an opioid analgesic like the hydrocodone bitartrate, Oxymorphone, buprenorphine, fentanyl, hydromorphone, or mixtures thereof (for example, a combination of acetaminophen and hydrocodone) are effective for the relief of acute, chronic or postoperative�evident in the degree of pain from mild to moderate, or disabling pain of terminal conditions such as cancer.

In a particular embodiment, the pharmaceutical compositions of the present invention contain a therapeutically effective amount of acetaminophen in combination with a therapeutically effective amount of hydrocodone or its salts, for example of of hydrocodone bitartrate. In a particular embodiment, the pharmaceutical compositions of the present invention contain 500 mg of acetaminophen and 5 mg of hydrocodone bitartrate, or 300 mg of acetaminophen and 100 mg of hydrocodone bitartrate. The compositions of the present invention containing acetaminophen/hydrocodone, to be bioequivalent to known compositions acetaminophen/hydrocodone, such as Vicodin®, Panadol® and Xodol®. The compositions of the present invention containing 500 mg acetaminophen/5 mg of hydrocodone bitartrate, have the Gusto acetaminophen 80-125% 6115 ng/ml, the Relish of hydrocodone bitartrate of 80-125% 20,14 ng/ml, AUC (area under the curve) of acetaminophen 80-125% 19920 NGC/ml and AUC of hydrocodone bitartrate of 80-125% of 141 ng/ml. the Composition according to the present invention, containing 300 mg acetaminophen/10 mg of hydrocodone bitartrate, have the Gusto acetaminophen 80-125% 3915 ng/ml, the Relish of hydrocodone bitartrate of 80-125% 40,53 ng/ml, AUC for acetaminophen of 80-125% 12794 NGC/ml and AUC of hydrocodone bitartrate of 80-125% from 280 NGC/ml.

Similarly, the pharmaceutical compositions of us�oedema to the invention, containing a therapeutically effective amount of Niacin in combination with a statin, such as atorvastatin, lovastatin, fluvastatin, cerivastatin, simvastatin, mevastatin, rosuvastatin, pravastatin, or mixtures thereof, are effective to reduce levels of cholesterol (VLDL) and triglycerides in patients with the disease or with risk of cardiovascular disease.

Similarly, the pharmaceutical compositions of the present invention containing a therapeutically effective amount of Metformin in combination with a drug such as glipizide, glyburide, glimepiride, Repaglinide, nateglinide, rosiglitazone, pioglitazone, troglitazone (such as the combination of Metformin and rosiglitazone), are effective in the treatment of hyperglycemia, for example in patients with diabetes.

Finally, the pharmaceutical compositions of the present invention containing a therapeutically effective amount of pseudoephedrine hydrochloride, pseudoephedrine sulfate, or Fexofenadine, combinations with drugs such as cetirizine or loratidine, are effective in the treatment of allergies arising in the premises, or allergies that occur outside of the premises.

EXAMPLE 1

1.And IR Pellets (download medicines: approximately 5%, of hydrocodone bitartrate):

Hydroc�don bitartrate (81,1 g) was slowly added to a solution of hydroxypropyl cellulose (8.1 g Nisso HPC-L-FP) in a mixture of acetone/water(1453/782) and well stirred to dissolve. Sugar spheres 60-80 mesh (1500 g) were coated with the composition for the layering of the drug in the device for coating in a fluidized bed Glatt (Glatt GPCG 3 equipped with a 7-inch insert Wurster in the lower nozzle, column 7 13/16", column height of 25 mm, a plate for air distribution, and a sieve for retaining product 200 mesh) in the following conditions: air temperature at inlet: 70±5°C; product temperature: 45±5°C;

the spraying air pressure of 2.43 bar (2,43×105PA); hole size: 1.0 mm; flow rate: 2 g/min was increased in stages to 15 g/min, air flow: 25% off valve. After layering the drug hydroxypropylcellulose grout sealer (32,4 g in a mixture 457/51 acetone/water) was sprayed onto the pellets covered with a layer of medicines, for the mass of coating of 2%. Dry granules with immediate release (IR) was sieved through a sieve of 50 and 80 mesh with practical common access to 88.4%.

1.In Granules with masked taste (download medicines: approximately 3.5% of hydrocodone bitartrate):

The IR pellets (140 g) from Example 1.And above were covered with ethylcellulose (Ethocel Standard Premium 100 from Dow Chemicals) by means of coacervation in the solvent of the coating mass to 30%. Ethylcellulose (60 g) and polyethylene (40 g Epolene C-10 from Eastman Chemicals) was dissolved/suspended in 2000 g of cyclohexane at a speed stirring� 300 rpm. The tank was heated to 80°C to dissolve the ethyl cellulose, and then the vessel was cooled to a temperature below 30°C to obtain microcapsules of hydrocodone bitartrate of taste masked. Microcapsules was separated by decantation, then filtered and washed with fresh cyclohexane and dried in air in proluvial.

1.With micro-Particles with a taste-masked coating in a fluidized bed:

Pellets IR (1001,3 g), obtained as described in Example 1.As above, covered with a solution of ethyl cellulose (Ethocel Standard Premium 10 SP, hereinafter referred to as the EU-10)/Eudragit E100 (188,6 g each), plasticized diacetylbenzene monoglycerides (Myvacet 9-45; 30,0 g) and kosher magnesium stearate (30,0 g) dissolved in a mixture of 80/20 acetone (3086 g)/water (771 g) with a coating weight of 30%. Samples were collected in the coating process with the coating mass of about 10%, 15%, 20% and 25% and dissolution testing to evaluate the influence of the value of coating on dissolution and organoleptic properties. Coated pellets were dried/cured at 60°C for 10 minutes in a Glatt GPCG 3, and sieved to get rid of agglomerates.

1.D Standard acetaminophen microcapsules (RE*):

On acetaminophen microcapsules obtained in an industrial scale using a granular acetaminophen (particle size: 45-80 mesh or 177-350 µm) from Covidien, coated, using STRs�about, similar to that described above in Example 1.In, and using 200-gallon, 500-gallon or 1000 gallon system, and applying computerized prescription process (for example the number to 200 - gallon system with 10% coated - acetaminophen: 94,1 kg; Ethocel 100:10.5 kg, Epolene: 2.1 kg and cyclohexane: 146,0 gallon or 547,5 l). The controlled cooling to <30°C, the layer of microcapsules is subjected to vacuum filtration and washed with cyclohexane to flush residual polyethylene. Microcapsules were transferred to the dryer fluidized bed, were subjected to the procedure of drying and dried for 4-6 h to reduce the level of cyclohexane to no greater than 1000 million'1.

1.E Bistrotdepierrerue microbeads:

Bistrotdepierrerue microbeads contain sugar alcohols, such as mannitol, and/or saccharide, such as lactose, and a leavening agent, such as copovidone. Sugar alcohol and/or saccharide, and a disintegrant are usually present in bistrotdepierrerue the microspheres in a ratio from about 99:1 to about 90:10 (a sugar alcohol and/or saccharide:baking powder). For example, bistrotdepierrerue microbeads,' used in the ODT compositions disclosed in the various examples according to the present invention produced by granulating 95 parts of D-mannitol with average particle size of about 15 microns and 5 parts polyplasdone (Polyplasdone XL-10) in the mixer � high shear rate (e.g. GMX 600 from Vector Corporation) with water as a granulating fluid, drying of wet mass in the dryer fluidized bed (e.g., Glatt GPCG 200 or Fluid Air FA0300), and screening/grinding to obtain granules with an average particle size less than 400 microns. Alternatively, wet milled granules are dried in a shelf drier to the value of loss at drying is less than 1% of the mass.

1.F ODT of the hydrocodone bitartrate/acetaminophen. 5 mg/500 mg:

Granules (172,4 g) was obtained as described in Example 1.In (coating weight 30%) above; standard capsules acetaminophen (RE, 531,9 g) produced in Example 1.D above, and bistrotdepierrerue microbeads (803,4 g) from Example 1.E above was mixed with a previously prepared mixture containing polyplasdone XL-10. 80,0 g), energy (5.6 g) and strawberry flavor (6.7 g), was then pressed in oral disintegrating tablets (19 mm diameter) 5 mg/500 mg of the hydrocodone bitartrate/acetaminophen, weighing approximately 1600 mg using a Carver tablet press with a compression force of 1 metric ton (1000 kg).

EXAMPLE 2

2.And Microparticles of hydrocodone bitartrate/acetaminophen (download drugs: 3%):

Of the hydrocodone bitartrate (47,5 g) was slowly added to a solution of hydroxypropyl cellulose (5.3 g from Nisso HPC-L-FP) in a mixture of 50/50 acetone/water (452 g each) and well stirred to dissolve. Capsules acetaminophen (RE) from Example 1.D with 6% coverage of the EU-100 (1500 g) were coated with the composition for layering Lek�stannage means in the device for coating Glatt GPCG 3 fluid bed. After layering the drug onto the pellets covered with a layer of medicines, sprayed sealing solution coating of hydroxypropyl cellulose (31,7 g in a mixture 447/50 acetone/water) with a coating weight of 2%. Dried IR granules were sifted through a sieve 35 and 80 mesh with a practical total yield of 99.0%.

2.In Microparticles of hydrocodone bitartrate/acetaminophen with masked taste:

Particles IR (1100 g), obtained as described in Example 2.As above, covered with a solution of ethyl cellulose (EC-10; 43%)/Eudragit E100 (43%), plasticized diacetylbenzene monoglycerides (Myvacet 9-45, with 7%) and kosher magnesium stearate (7%) dissolved in a mixture of 80/20 acetone (3294 g)/water (848 g) with a weight increase of 30%. Samples were collected in the coating process with the coating mass of approximately 5%, 10%, 15%, 20% and 25%, and dissolution testing to evaluate the influence of the value of coating on dissolution and organoleptic properties. Coated pellets were dried at the same temperature settings in Glatt GPCG 3 and sieved to get rid of agglomerates, General practical access to 98.9%.

2.With OPT of of hydrocodone bitartrate/acetaminophen. 10 mg/300 mg:

Coated 20% EC-10/E100 (10,01% of granules of hydrocodone bitartrate/acetaminophen with download of hydrocodone bitartrate 15%) in Example 2. In above; standard capsules acetaminophen (RE, 35,46%) from Example 1.D above and would�redispersible microbeads (48,76%) from Example 1 above was mixed with a previously prepared mixture, containing polyplasdone XL-10 with 5.0 per cent), energy (0,35%) and strawberry flavor (0,42%), was then pressed in orally disintegrating tablets 10 mg/300 mg of hydrocodone bitartrate/acetaminophen (15 mm diameter), with a weight of approximately 900 mg, using a Carver tablet press with a compression force of 1 metric ton (1000 kg).

2.D ORT of the hydrocodone bitartrate/acetaminophen. 5 mg/500 mg:

Pellets with 30% coverage (10,78%) in Example 2.In the above, the standard capsules acetaminophen (RE, 33,24%) from Example 1.D above and bistrotdepierrerue microbeads (37,71%) from Example 1.E above was mixed with a previously prepared mixture containing microcrystalline cellulose (12,5% Avicel PH101), polyplasdone (5,0% XL-10), energy (0,35%) and strawberry flavor (0,42%), was then pressed in oral disintegrating tablets (diameter 17 mm) 5 mg/500 mg of the hydrocodone bitartrate/acetaminophen, weighing approximately 1600 mg using a rotary Hata tablet press equipped with external lubrication (Matsui Ex-Lub System) to lubricate the surfaces of dies/punches by spraying magnesium stearate before each pressing.

EXAMPLE 3

3.And acetaminophen Microparticles with masked taste:

Acetaminophen (granular brand from Covidien (A100); 2000 g) was covered in GIatt GPCG 3 (7-inch insert Wurster in the lower nozzle and the nozzle hole size 1.00 mm) RA�a tvory ethyl cellulose (10 SP; 114,3 g)/Eudragit E100 (100,0 g), plasticized polyethylene glycol (PEG 400; 42,9 g) and kosher magnesium stearate (28.6 g), homogeneously suspended in a mixture of acetone (1359,5 g)/isopropyl alcohol (672,7 g)/water (770,8 g) weight of 12.5%. The dried particles were sieved using sieves 35 and 80 mesh to get rid of agglomerates/fine-grained fractions (practical output: 93,6%).

3.In Low level of the hydrocodone bitartrate/acetaminophen:

Of the hydrocodone bitartrate applied layer on acetaminophen (Granular A100) by spraying compositions for the layering of the drug (composition see Table 1, column "Low-level") in the device for coating GIatt GPCG 3 in a fluidized bed. After layering a drug solution sealing coating was sprayed over the coated layer of the drug particles with a coating weight of 2%, then struck kusamakura coating using a mixture EU 10/E100/PEG 400/magnesium stearate in the ratio 40/35/15/10 with a coating weight of 22%, using the method disclosed in Example 3.And above.

3.With the high level of the hydrocodone bitartrate/acetaminophen:

Of the hydrocodone bitartrate applied layer on acetaminophen (Granular A100) by spraying compositions for the layering of the drug (composition see Table 1, column "Low-level") in the device for applying pokr�rd Glatt GPCG 3 in a fluidized bed. Following the drug layering, the grout sealer was sprayed over the coated layer of the drug particles with a coating weight of 2%, then struck kusamakura coating using a mixture EU 10/E100/PEG 400/magnesium stearate in the ratio 40/35/15/10 with a coating weight of 27%.

Table 1: Low level (RE)/highly active (RE) of hydrocodone" the bitartrate/acetaminophen (A100) with masked taste

IngredientsPercentageThe required amount (g)
Hydrocodone /acetaminophen-RE (ON)/RE (VA) or acetaminophen RE, taste maskedLow level (ON)Highly active (WA)RELow-activeHighly active and
ON/VA NME acetaminophen (A100)
Acetaminophen granular (A100)96,0690,222500,02000,0
Of hydrocodone bit�Strat, NF1,757,00Over 45.5155,2
Hydroxypropyl-cellulose, NF (Klucel LF)0,1960,785,117,2
Acetone NF432,71474.1
Purified water, USP432,71474,1
Hydroxypropylcellulose for (Klucel ® LF)1,701,7044,237.7
Magnesium stearate NF0,300,307,86,7
Acetone NF 611,6520,9
Purified water, USPThe amount of 203.9173,6
Total100,0100,02602,62216,8
Kusamakura coverage (5% solids)
acetaminophen, covered with a layer ON/VA of hydrocodone78,0073,002000,01500,0
Acetaminophen granular (A100)2000,0
Ethylcellulose NF (Ethocel®Standart10 Premium)8,8010,80114,3225,6221,9
Aminoalkylation th copolymer E (Eudragit®E100)7,709,48100,0By 197.4194,2
Polyethylene glycol NF (Carbowax® 400)3,304,0542,984,683,2
Magnesium stearate NF2,202,7028,656,455,5
Acetone NFtracestraces1359,52684,12639,8
Isopropyl alcohol, USP*tracestraces672,71328,21306,3
Purified water, USPtracestraces770,81521,9149,8
Total100,0100,02285,82564,02054,8

3.D OPT of hydrocodone bitartrate/acetaminophen. 5 mg/500 mg:

Acetaminophen (12.5% coating of Example 3.And above, hydrocodone/acetaminophen, with 22% of the coating from Example 3.In the above, bistrotdepierrerue microgranules from Example 1.E above was mixed with a previously prepared mixture containing microcrystalline cellulose (Avicel PH101), (Parteck M200), polyplasdone, energy and strawberry flavoring, then pressed in oral-disintegrating tablet of hydrocodone bitartrate/acetaminophen 5 mg/500 mg (diameter 17 mm) weighing approximately 1600 mg using a rotary Hata tablet press equipped with external lubrication (Matsui Ex-Lub System) to lubricate the surfaces of dies/punch before each pressing with a force compression from 18 to 24 kN.

3.E ORT of the hydrocodone bitartrate/acetaminophen. 10 mg/300 mg:

Acetaminophen (12.5% coating of Example 3.And above;

hydrocodone/acetaminophen with 27% of the coating from Example 3.With the above and bistrotdepierrerue microgranules from Example 1.E above, was mixed with a previously prepared mixture containing microcrystalline cellulose (Avicel PH101), mannitol (Parteck M200), kresovi�it, the energy and strawberry flavoring, then pressed in oral disintegrating tablets (diameter 17 mm) of hydrocodone bitartrate/acetaminophen 5 mg/500 mg, with a weight of approximately 1000 mg using a rotary Hata tablet press equipped with external lubrication (Matsui Ex-Lub System) to lubricate the surfaces of the stamp/punch before each pressing with a force of compression from 10 to 15 kN (see Table 2).

Table 2
ODT of of hydrocodone bitartrate/acetaminophen 5 mg/500 mg and 10 mg/300 mg
RoomIngredientODT of hydrocodone/acetaminophen
PF401 (5 mg/500 mg)RR(10 mg/300 mg)
% tabletsg/party% tabletsg/party
1Low level of the hydrocodone bitartrate/acetaminophen (RE) taste masked22,89572,25
2High activity of the hydrocodone bitartrate/acetaminophen with masked taste (RE)15,66391,5
3Microcapsules acetaminophen (RE)16,11402,7515,60390,0
4Bistrotdepierrerue microbeadsOf 40.151003,7549,701242,5
5Mannitol USP (Parteck® M200)The 4.25106,255,00125,0
6Microcrystalline cellulose, NF10,00250,010,00250,0
7Polyplasdone, NF (XL-10)The 5.25131,25 5,26131,3
8Sucralose, NF0,35The 8.750,358,8
9Artificial strawberry flavoring1,0025,001,0025,0
10Magnesium stearateTracesTracesTracesMark s
Total100,02500,0100,02500,0
Weight of tablets (mg)1600,01250,0-

EXAMPLE 4

4.While the implementation of the pilot RK (pharmacokinetic) studies:

ODT of of hydrocodone bitartrate/acetaminophen with two forces of action, 5 mg/500 mg and 10 mg/300 mg, and three different compositions of particles with masked taste used between the two si�AMI action tablet: 1) crystals of acetaminophen (A100 - the standard size of particles, 177-350 µm) with a composition kusamakura coverage in both the ODT compositions; 2) the crystals of acetaminophen (standard particle size) with a layer of the drug of 1.75% of the mass./mass. of of hydrocodone bitartrate and subsequent kusamakura coating used in the tablet with the power of action 5 mg/500 mg; and (3) the crystals of acetaminophen (standard particle size) with a layer of the drug 7% wt./mass. of of hydrocodone bitartrate and subsequent kusamakura coating used in the tablet with the power of the action of 10 mg/300 mg. Kusamakura coating composition was the same for all particles, but the amount of coverage in units of mass./mass.varies from 12.5% for acetaminophen (RE), 22% to 1.75% of hydrocodone bitartrate/acetaminophen (RE) used in ODT 5 mg/500 mg (PF401), up to 27% to 7% of hydrocodone bitartrate/acetaminophen (RE) used in ODT 10 mg/300 mg (PF402). The mixture for pressing pressed together in ODT of of hydrocodone bitartrate/acetaminophen, using a tablet press Elizabeth Hata, equipped with a lubrication system Matsui Ex-Lub, which uses magnesium stearate as an external lubricant. Each has individual dosages of the mixture and was obtained using different tableting parameters (see Table 3 below). Batch data ODT was prepared as described � Examples 3.A-3.E (composition see Tables 1 and 2). Intermediate and finished products are tested using the methods of qualified analytical testing, and used in a pilot study of the Republic of Kazakhstan in healthy volunteers.

Table 3
The tableting parameters for ODT of of hydrocodone bitartrate/acetaminophen:
ODT 5 mg/500 mgDT 10 mg/300 mg
Processing - a round, flat face, rounded edge17 mm15 mm
Target weight of tablets (mg)16001250
Lower target weight pills ×0,985 (mg)15761231
Target weight pills ×1,015 (mg)16241269
The speed of the turntable in the range (rpm)15(10-20)15(10-20)
Depth of fill (mm)10,94-10.985,11
Main position (mm)10,6-11,14,44
Pre-position (mm)6,2-6,44,61
The graduations on the feed Shoe2(0-4)2(0-4)
Weight of tablets (mg)15971248,6
Hardness in range (n)6,80At 6.92-6,95
Thickness range (mm)47-4940-42
The fragility in the range (%)0,25-0,310,24-0,31

4.In a Pilot RK (pharmacokinetic) study:

ODT of of hydrocodone bitartrate/acetaminophen, with dosages of 5 mg/500 mg and 10 mg/300 mg, tested in pilot RK (pharmacokinetic) study in 4 groups, involving 16 healthy subjects per group in comparison with the corresponding RLD, Abbott's VICODIN® (Vicodin) 5 mg/500 mg, Mikart's Xodol® (Extol) 10 mg/300 mg. Profiles based on the concentration of acetaminophen and hydrocodone bitartrate of plasma from time to time for these ODT shown in Fig.2 and 3.

Table 4
RK Settings for ODT of hydrocodone/acetaminophen
Test ODTRLDIRActive substanceTest ODTRLDRatio
5/500 mgVicodinAcetaminophenWithmax(NG/ML)Test/RLDMin-max
5013,866115,4981,9967,79-99,15
AUC0inf(ng.h/ml)Test/RLDMin-max
19205,9819917,7696,4379,17-117,4
10/300 mgExtolAcetaminophen Withmax(NG/ML)Test/RLDMin-max,
3159,553914,1680,7267,80-of 96.10
AUC0inf(ng.h/ml)Test/RLDMin-max
12196,4912794,8595,3279,55-114,2
5/500 mgVicodinHydrocodoneWithmax(ng/ml)Test/RLDMin-max
19,70820,13997,8690,44-105,9
AUC0inf(ng.h/ml)Test/RLDMin-max
141,36141,4099,9793,56-106,8
10/300 mgExtolHydrocodoneWithmax(NG/ML)Test/RLDMin-max
38,71940,53095,5388,87-102,7
AUC0inf(ng.h/ml)Test/RLDMin-max
286,33279,06102,696,25-109,4

Fig.4 shows the profiles based plasma concentrations of acetaminophen observed in another of the pilot study in 3 groups involving 24 healthy subjects per group, where ODT 500 mg of acetaminophen in the presence or in the absence of water was injected abstaining from food healthy volunteers compared with the corresponding RLD, GSK's Panadol® (Panadol) Flavor 500 mg. of acetaminophen by palomaki brand (A) with smaller distribution of particle size 53-177 μm masked by coacervate in solvent using Ethocel Standard Premium 100 SP to a coating mass of 10-12%. For the manufacture of orally disintegrating tablets these microcapsules were mixed with fast�usperheroine microgranules (RE, made from mannitol 25/polyplasdone 95/5, as disclosed in Example 1.E above), polyplasdone, microcrystalline cellulose, aspartame (sweetener) and strawberry flavour in a V-shaped mixer and then pressed on a rotary tablet press equipped with a system of external lubrication. These tablets (composition see Table 5) was released at least 85% within 15 min when tested using USP Apparatus 2 (blades at 75 rpm, buffer pH of 5.8 (see data on dissolution in Table 6))

Table 5
Composition ORT acetaminophen
Ingredients% tabletODT (mg/tablet)Quantity (kg)/party
250 mg500 mg250 mg/500 mg
Acetaminophen (A) with masked taste (10-12%)39,68277,8555,563,5
Bistrotdepierrerue granules (RE)42,12 294,8589,767,4
Microcrystalline cellulose (Avicel PH101)10,0070,0140,08,0
Polyplasdone NF (XL-10)5,0035,070,016,0
Sucralose NF1,6011,222,42,56
Strawberry flavour1,6011,22242,56
Total100,0700,01400,0160,0

RK (pharmacokinetic) parameters for acetaminophen ODT versus tylenol the following:

Mode T1: acetaminophen ODT (R-300) with water

Mode T2: acetaminophen ODT (R-300) without water

Mode 3: the Reference tablet (Panadol®), swallow with water

RKTest 1 (ODT) Test 2 (ODT)90% confidence interval90% confidence interval
with waterwithout waterTest T1 vs. RLDTest T2 vs. RLD
The SMAC (NG/ML)7,2407,63590,94-110,2594,04-114,01
AUC0→t(ng.h/ml)21,4421,0099,61-106,1998,06-104,53
AUC0→inf(ng.h/ml)22,4321,6999,41-106,3396,83-103,57

The above results confirm that the tested product, 500 mg acetaminophen ODT, when administered with or without water is bioequivalent to the reference product, Panadol® 500 mg, swallow with water. Data on dissolution in vitro at different speeds (50, 75 and 100 rpm) and different pH (water, pH 1, 2, 4,5, 5,8, 6,8) received in batches of 5 mg/500 mg and 10 mg/300 mg ODT tablets of Examples 3 and 4, and 250 mg and 500 mg ODT tablets of Example 4, and a set of comparative data �predstavljena in Table 6. As for the manufacture of batches of 5 mg/500 mg - 10 mg/300 mg ODT tablets and 250 mg - 500 mg tablets ODT, respectively, have been using various brands of medicinal substances, such as granulated acetaminophen and palomaki acetaminophen, determined the size distribution of particles in some batches of the drug substance and the corresponding batches of microcapsules. Table 7 shows data on the distribution of particle average size.

Table 6
Data on dissolution for IR tablets and ODT of hydrocodone/acetaminophen and acetaminophen ODT
TimePF401EA0001PF402EA0001Vicodin*ExtolPF407EA0001APF408EA0002A
(min)5 mg/500 mg10 mg/300 mg5 mg/500 mg10 mg/300 mg250MG500 mg
00000 00
523284940
105360658775
15758771849588
301011037693
*→Vicodin is released by USP test 2, which is a medium of 0.1 n HCl

Table 7
The size distribution of the particles of the drug substance and microcapsules acetaminophen
The medicinal substance acetaminop�n Microcapsules
Mark% retained particleCoating% retained particle% analyze (STD)
Granular
(The average of several batches)>80% <425-180 µm>6% (500/1000 gallon)95% <425-180 µm>93±1,37
Palimaka
(The average of several batches)90% <150-53 µm>12% (5-gallon)87% <250-74 µm>87.9
A89.5% of <150-53 µm>12% (500-gallon)90% <250-74 µm>Representing 86.8
AOf 86.2% <150-53 µm>10% (500-gallon)89.5% of <250-74 mesh> 89,7

ODT tablets of acetaminophen/hydrocodone (5 mg/500 mg, or 10 mg/300 mg ODT) contain two of the three types of microencapsulated particles of the drug acetaminophen - granulated acetaminophen and granulated particles of the drug acetaminophen, is covered with a layer of hydrocodone at low or high drug loading, all tastefully masked with a coating of the mixture ethylcellulose/Eudragit EPO. To improve the dissolution and bioequivalence to the RLD and to improve the stability of hydrocodone when applying a layer directly on the particles of acetaminophen, it was decided to use the medicinal substance with smaller distribution of particle size (for example palomaki acetaminophen) tablet composition for the manufacture of "smaller acetaminofeno microcapsules".

When evaluating different kusamakura coatings on microparticles containing the hydrocodone bitartrate, with respect to their ability to give acceptable organoleptic properties, found that the coating containing the sweetener in combination with the sealing layer of the coating containing hydroxypropyl cellulose (Klucel LF), was effective in masking the bitter taste of of hydrocodone bitartrate.

EXAMPLE 5

5.And acetaminophen Microparticles with masked taste (6%):

VK�with acetaminophen (polumenta mark from Covidien with a particle size of 80-270 mesh or 53-177 μm (A); 1800,0 g) masked by coacervation in a solvent in a 5-gallon system. 5-galanou system filled with 10,000 g of cyclohexane, was loading ethylcellulose (Ethocel Standard Premium 100 from Dow Chemicals; USD 114.9 g), polyethylene (Epolene C-10; 50 g) and a drug. The system was subjected to cycle adjustable heating until a temperature of 80°C to dissolve ethyl cellulose, meanwhile stirred the contents at a speed of 300 Rev/min the system is subjected to cycle adjustable computer cooling to<28°C for at least 45 min to encapsulate the drug crystals with a smooth coating with a coating weight of 6% and to avoid the formation of agglomerates. Microcapsules was separated by decantation, washed with fresh cyclohexane and dried in proluvial. Microcapsules with a size less than 35 mesh were collected to mask the taste (practical output: 98,0%).

5.In Microcapsules of of hydrocodone bitartrate/acetaminophen with masked taste:

Of the hydrocodone bitartrate (57.4 g), acetaminophen (polumenta mark A; 1742,6 g), ethylcellulose (process is 156.5 g), polyethylene (50.0 g) was suspended in cyclohexane in 5-galanoy system, and microencapsulated particles NME/acetaminophen with 8% of the mass.coating EC-100 produced by following the procedure of Example 5.And. On microencapsulated particles of hydrocodone bitartrate/acetaminophen (1518,8 g) apply�and sealing coating of a mixture of Klucel LF (288,6 g) magnesium stearate (15.2 g) and, in addition, provided a second kusamakura membrane containing a mixture of ethylcellulose (EU-10)/Eudragit EIOO/Myvacet/stearate ratio 286,6/253,5/31,8/35,7 in Glatt GPCG 3 for a coating weight of 25% as described in Example 3.

5.With Microcapsules of of hydrocodone bitartrate/acetaminophen with masked taste:

Of the hydrocodone bitartrate (60,0 g and 6.7 g of Klucel LF) was applied with a layer of microcapsules on acetaminophen (polumenta A coated EC-100 weight of 6% in Example 5.A; 1205,3 g) in a Glatt GPCG 3 for a coating weight of 8% as described in Example 3. After layering the drug sealing coating from Klucel LF (28.0 g) was sprayed on the particles, covered with a layer of hydrocodone, followed kusamakura coated with a mixture of EC-10/E100/PEG 400/Myvacet 9-45 ratio 40/35/15/10 coating weight of 35%.

5.D OPT of hydrocodone bitartrate/acetaminophen:

The mixture for extrusion containing microparticles of hydrocodone/acetaminophen in Example 5.B, above, with masked taste or microparticles hydrocodone/acetaminophen with masked taste from Example 5.From above, combined with bistrotdepierrerue microgranules from 1-E above and pre-prepared mixture containing microcrystalline cellulose, copovidone, energy and strawberry flavor, and extruded into ODT of of hydrocodone bitartrate/acetaminophen 5 mg/500 mg and 10 mg/300 mg (composition see Table�e 8), using a tablet press Elizabeth Hata, equipped with a lubrication system Matsui Ex-Lub, which uses magnesium stearate as an external lubricant.

Table 8
Composition ODT acetaminophen
Ingredients (mg/tablet)ODT, 5 mg/500 mgODT, 10 mg/300 mg
1300-0861300-0881300-0851300-087
Hydrocodone/acetaminophen with masked taste (Example 5.In)287,4344,8
Hydrocodone/acetaminophen with masked taste (Example 5.(C)172,4344,8
Microcapsules acetaminophen (RE)Of 378.4445,4123,3123,3
Bistrotdepierrerue granules (RE)496,9544,9445,5445,5
Microcrystalline cellulose (Avicel R)140,0140,0110,0110,0
Polyplasdone NF (XL-10)70,070,055,055,0
Sucralose NF4,94,93,853,85
Strawberry flavour22,42,417.617,6
Total1400,01400,01100,01100,0

Table 9 presents the dissolution profiles of of hydrocodone bitartrate and acetaminophen from ODT. Slightly thicker coating on the particles of the drug acetaminophen by coetzer�ation (EU-100) or a thicker coating in a fluidized bed (EC-10/E100), as it turned out, had little influence on the dissolution rate of the drug.

101
Table 9
Data on dissolution for ODT of of hydrocodone bitartrate/acetaminophen
Time (min)Of the hydrocodone bitartrate released (%)Acetaminophen released (%)
ODT(10 mg/300 mg)(ODT 5 mg/500 mg)ODT (10 mg/300 mg)(ODT 5 mg/500 mg)
1300-0851300-0871300-0861300-0881300-0851300-0871300-0861300-088
000000000
590879854494751
10941049110191808181
159410492101102959392
3095104931021051039898

EXAMPLE 6

6.And Microencapsulation acetaminophen:

200-gallon system in a solvent coacervation (146 kg) loaded acetaminophen (polumenta mark A; 75.5 kg), ethylcellulose (EU-100; 4.8 kg), Epolene (2.1 kg) and the taste of acetaminophen masked by coacervate in solvent 200-gallon system, with stirring at a speed of 80±5 rpm �egularly computer cycle heating to 80°C and the extract used for temperatures of 80°C to dissolve the ethyl cellulose in the system of coacervation. Thereafter, the system was subjected to cooling cycle to <28°C for at least 45 min to encapsulate the crystals of acetaminophen a smooth coating with a mass of 6% and to avoid the formation of agglomerates. Microcapsules were filtered in vacuum, washed with cyclohexane and dried in the dryer fluidized bed, using a 3-step temperature (e.g. 25°C, 35°C, 99°C) for 4-6 hours to achieve a residual level of less than 1000 cyclohexane mn-1. Microcapsules were sieved through a sieve 35 US mesh. Following the same procedure has received several batches of microcapsules (size of the party: 80 kg) with a coating weight of 6% 200-gallon system.

6.In Microparticles of hydrocodone/acetaminophen with masked taste:

Of the hydrocodone bitartrate (composition and number of batches, see Table 10) was applied with a layer of microcapsules on acetaminophen (6% coverage EU-100; 3375,0 g) from Example 6.And, above, by spraying the composition for layering medicines containing hydroxypropyl cellulose (10% solids) in a Glatt GPCG 5 (by 9 inch Wurster, 25 mm gap separation, the retention of the product by a sieve of 200 mesh, the diameter of the tip nozzle 1.0 mm, 'C'plate air distribution in the lower part; a product temperature: 37±3°C; air volume at the inlet: 40-45 CFM (cubic feet per minute) (1,13-1,27 cubic meters per min); spraying speed: 8 to 24 ml/min) to download hydrocodo�and the bitartrate of 9.0%. The sealing solution hydroxypropylamino coating (5,0% or 73,68 g was dissolved in a mixture of 50/50 acetone/water with 10% solids) was sprayed on the particles, covered with a layer of the drug (1400 g) in Glatt GPCG 3 for obtaining a coating of 5% and then kusamakura coating Sucralose (5,0%), dissolved in an aqueous solution of hydroxypropyl cellulose (1,24%; when the ratio of Sucralose/LDC 80/20) using the following process conditions: inlet temperature: 57±2°C; product temperature: 37±2°C; spray rate: 8 ml/min; volume of the entering air: 6 CFM (of 0.17 cubic meters per minute).

6.With Microparticles of hydrocodone/acetaminophen with masked taste:

Of the hydrocodone bitartrate (composition and value of the parties, see Table 10) was applied with a layer of capsules acetaminophen (6% coverage EU-100; 3733,3 g) from Example 6.And, above, by spraying the composition for layering medicines containing hydroxypropyl cellulose (10% solids) in a Glatt GPCG 5, as described in Example 6.B, above. After coating on microparticles were applied sealing coating of hydroxypropyl cellulose in an amount of 5% in the same device, were dried for 5 minutes to reduce residual moisture and sieved through a sieve of 30 and 80 mesh, to get rid of particles of other sizes and fine-grained fractions.

Table 10
Microparticles of a mixture of 5.0% Sucralose/5.0% LDC/the hydrocodone bitartrate/acetaminophen
IngredientsPercentageThe required amount (g)
microcapsules 5.0% Sucralose/5% of hydrocodone, covered LDC /acetaminophenFormula AndThe formula InFormula AndThe formula In
The application of a medicinal product - (10% solids)
Microcapsules ARAR (A) (6% layer)80,1684,243375,03733,3
Of the hydrocodone bitartrate, NF8,025,41337,5240,0
Hydroxypropyl cellulose, NF (Klucel LF)0,890,60A 37.526,7
Acetone, NFtracesSL�dy 2400,0
Purified water, USPtracestraces3375,02400,0
The sealing coating LDCs (6% solids)
Microcapsules hydrocodone/acetaminophen89,0790,251400,04000,0
Hydroxypropyl cellulose, NF (Klucel LF)4,694,7573,68210,5
Acetone, NFtracestraces614,01649,1
Purified water, USPtracestraces614,01649,1
Coating Sucralose (15% solids)
Hydrocodone/acetaminophen, covered LDCs93,7695,001300,0 3400,0
Sucralose, NF5,005,0069,33179,0
Hydroxypropyl cellulose, NF (Klucel LF)1,2417,19
Purified water, USPtracestraces490,271014,0
Total100,0100,01386,523578,9

6.D ORT of hydrocodone/acetaminophen:

The mixture for extrusion containing microparticles of hydrocodone/acetaminophen with masked taste from Example 6.In, above, or microparticles of hydrocodone/acetaminophen with masked taste from Example 6.With, above, was combined with bistrotdepierrerue microgranules from 1.E above and pre-prepared mixture containing microcrystalline cellulose, copovidone, energy and strawberry flavor, and was pressed into ODT of of hydrocodone bitartrate/acetaminophen 10 mg/300 mg, and 5 mg/500 mg (composition see Table 11) using a tablet press Elizabeth Hata. At the time ODT lot# 1334-JMC-142 was pressed to form a using magnesium stearate as an external lubricant, ODT lot# 1198-JMC-046 and 1198-JMC-062've pressed using sodium fumarate (PRUV*) as internal lubricants. Tabletting properties are listed in Table 12.

Table 11
OPT of of hydrocodone bitartrate/acetaminophen. 5 mg/500 mg and 10 mg/300 mg
No.Ingredient (mg/tablet)ODT of hydrocodone/acetaminophen
UMG/300 mg10 mg/300 mg5 mg/500 mg
1334.JMC-1421198-JMC-0621198-046
mg tabletmg tabletmg tablet
1Sucralose/LDC/9%hydrocodone/acetaminophen (from Example 6.In)123,11
Sucralose/LDC/5.7% of hydrocodone/acetaminophen (from Example 6.(C) 184,5092,25
2Microcapsules of acetaminophen (10%)225,88172,33476,35
3Bistrotdepierrerue granules542,01443,97454,10
4Microcrystalline cellulose, NF110,0110,00140,00
5Mannitol, USP(Parteck® M200)110,00140,00
6Polyplasdone55,01
Croscarmellose sodium (Ac-Di-Sol)33,042,00
7Sucralose, NF13,7518,7023,80
8Artificial wee�of Navy flavoring 19,2516,5017,50
9Citric acid11,00
Magnesium stearate (external)traces
The sodium fumarate (PRUV)11,0014,00
Total1100,01100,01400,0

Table 12
Tabletting properties of ODT of hydrocodone bitartrate/acetaminophen
Series No.The compression forceWeightThicknessStrengthThe fragility
ODT 10 mg/300 mg
13 kN1102 mg6.12 mm41.3 H0,51%
14 kN1101 mg6,03 mm46,4 H0,37%
1198-06212,5 kN1099 mg6,09 mm46,0 N0,20%
ODT 5 mg/500 mg
1198-04618 kN1402 mg6,11 MM53 H0,18%
20 kN1394 mg6,03 mm61 H0,05%
22 kN1390 mg5,97 mm67 H0,17%

EXAMPLE 7

7.And Microparticles of Metformin with masked taste:

On Metformin hydrochloride (1000,0 g) in a Glatt GPCG 3 was coated with a solution of ethyl cellulose (Ethocel Standrd 10 Premium; 78,5 r)/Eudragit E100 (75,0 g), plasticized polyethylene glycol (PEG 400; 25,9 g) and kosher magnesium stearate (15.6 g) dissolved in a mixture of 80/20 acetone (1359,5 g)/isopropyl alcohol (672,7 g)/water (770,8 g) to obtain a coating mass of 17.5%. The dried particles are sieved using sieve 35 and 80 mesh to get rid of agglomerates/fine-grained fractions. Batch of microcapsules of Metformin with masked taste also prepare a coating weight of 25%. Also use 5% sealing coating Klucel LF, to avoid possible interactions between the cationic polymer kusamakura membrane and a low-dose drug (such as rosiglitazone). For immediate inclusion in the ODT composition are also preparing another batch of microparticles of Metformin with taste masked with a coating composition having the same ratio and the same % solids for coating mass 25%;

7.In Rosiglitazone/Metformin with masked taste:

Rosiglitazone maleate is applied a layer of microcapsules of Metformin with the sealing coating from Example 7.As above, in a Glatt GPCG 3 for the increase in coating weight of 2.5%, using a method similar to that described in Example 5.B, above. Following the drug layering, a sealant coating 2 wt%. solution of Klucel LF is sprayed onto the particles, covered with a layer of rosiglitazona, then put the VC�smackeroos coating from a mixture of EC-10/E100/PEG 400/magnesium stearate in the ratio 40/35/15/10 with a coating weight of 20%.

7.With OPT rosiglitazone/Metformin:

Micro-particles of rosiglitazone maleate/Metformin hydrochloride from Example 7.In, above, microparticles of Metformin hydrochloride with masked taste from Example 7.And, above, bistrotdepierrerue microgranules from Example 1.E, above, and a pre-prepared mixture containing microcrystalline cellulose, energy, strawberry flavoring and polyplasdone, mixed together in a V-shaped mixer and pressed into ODT rosiglitazone/Metformin 1 mg/500 mg 2 mg/500 mg, 4 mg/500 mg and 4 mg/1 g using a tablet press Elizabeth Hata, equipped with a lubrication system Matsui Ex-Lub, which uses magnesium stearate as an external lubricant for lubricating the surfaces of the punch and the stamp before pressing.

These examples demonstrate that the ODT composition comprising microparticles containing high-dose Metformin HCI/low-dose rosiglitazone maleate (e.g. 500 mg/1 mg, 500 mg/2 mg or 500 mg/4 mg), demonstrate acceptable tabletting properties (e.g. hardness, friability, uniformity of dosage forms, low disintegration time in vitro/in vivo, rapid dissolution of acceptable organoleptic properties), which greatly improves patient compliance with treatment regimens. In addition, the pharmaceutical composition and oral dosage forms prepared�s of them) of the present invention exhibit acceptable taste masking and provide fast, essentially complete release of the dose on entry into the stomach, thus providing the appropriate bioequivalence to the reference product with immediate-release(IR).

EXAMPLE 8

8.And Niacin Microparticles by controlled spheronization

Povidone (PVP K-30; 50 g) is slowly added to purified water (500 g), stirring constantly to obtain a solution of a polymeric binder with 10% wt./mass. solids. Niacin (or nicotinic acid from Lonza Corporation; 2000 g) was mixed with 10 g of colloidal silicon dioxide (enlarger fluidity Cab-0-Sil M-5P from Cabot Corporation) and povidone (50 g) in a V-shaped mixer and loaded into a reservoir for the product Granurex GX-35 from Vector Corporation (Iowa, USA). A 10% solution of binder PVP sprayed in a rotating layer of a substance with variable speed. Optimized process parameters during formation of the pellets technological air temperature: ~19-20°C; product temperature: 16±2°C; rotation speed: 425 rpm; the inflow of external air: 150 l/min; spray rate: 15 rpm (~8 ml/min); pressure drop at the gap: 1,3-11 mm in water. Optimized process parameters during drying of pellets and technology volume of air: 30 CFM (cubic feet per min) (0,85 CBM, min); process air temperature: ~60°C; product temperature: 35°C (until the end of drying); rotation speed: 180 rpm; Volum�m air gap: 10 CFM (cubic feet per min) or 0.28 cubic meters per min); processing time: 40 min. Approximately 65% of the pellets, thus prepared, have a size in the range of 40-80 mesh.

8.In the Niacin Microparticles with SR-coating

On Niacin microparticles (1600 g) from stage 8.As above, applied to SR-coating of ethyl cellulose (Ethocel Standard 10 Premium; 180 g)/TES (triethylcitrate, a plasticizer; 20 g) dissolved in a mixture of 90/10 acetone/water with a weight increase of 15%. Samples are selected with a coating of 7.5, 10 and 12.5 wt%.to test the release of the drug. The dried particles are sieved using sieves 30 and 80 mesh, to get rid of agglomerates/fine-grained fractions. Also put 2% sealing coating Klucel LF, to avoid possible interaction between the mixture of polymer/plasticizer and a low-dose drug (e.g. atorvastatin).

Another batch of microparticles of Niacin with masked taste are also using the coating composition with the same ratio and the same % solids to obtain increase of 15 mass% based on the total weight of the coated microparticles for direct inclusion in the ODT composition.

8.With Niacin Microparticles covered with atorvastatin:

Atorvastatin calcium is applied a layer covered with a sealing layer of microcapsules of Niacin with stage 8.In, above, in a Glatt GPCG 3 to increase the mass by 4%, as described in the Prima�e 1.With that above. After layering the drug sealing coating Klucel LF (2% of the mass. sprayed on the particles, covered with a layer of atorvastatin, followed by application kusamakura coating of EC-10/E100/PEG 400/stearate ratio 40/35/15/10 to increase the weight by 20%.

8.D SR-ODT atorvastatin/Niacin:

Microparticles of atorvastatin calcium/Niacin with masked taste from stage 8.With higher Niacin microparticles with masked taste from stage 8.In, above, bistrotdepierrerue microbeads with stage 1-E, above, and a pre-prepared mixture containing microcrystalline cellulose, energy, strawberry flavoring and polyplasdone, were mixed together in a V-shaped mixer and pressed into ODT atorvastatin/Niacin, 2.5 mg/500 mg, 5 mg/500 mg and 10 mg/500 mg, using a tablet press Elizabeth Hata, equipped with a lubrication system Matsui Ex-Lub, which uses magnesium stearate as an external lubricant for lubricating the surfaces of punches and dies before pressing.

Specialists in the art can be produced by changes in the structure, and the various components, and in the layout described in this description of the invention, or in stages or sequence of stages of a method of manufacturing described herein, without deviating from the essence and scope of the invention as described�ANO in this description.

1. Pharmaceutical composition, containing a first set of microparticles that contain high-dose/low-dose drug, and the second set of particles containing high-dose drug, where the micro-particles of the first population containing high-dose/low-dose drug include:
(a) a core containing a high-dose drug;
(b) a first coating located on top of a kernel, containing a low-dose drug; and
(b) second cover located over a core containing water-insoluble polymer; and where the
the particles of the second population containing high-dose drug include
(1) a second core containing a high-dose drug; and
(2) the fourth coating containing water-insoluble polymer, located on top of a second core, where the water-insoluble polymer of the fourth layer is the same as the water-insoluble polymer of the second coating, or different from it.

2. Pharmaceutical composition according to claim 1, where the mass ratio of high-dose drug to a low-dose drug in the pharmaceutical composition is at least about 20:1.

3. Pharmaceutical composition according to claim 1, wherein the core containing high-dose �carstone means, contains particles high-dose drug, where the second coating is a sheath with modified release, containing water-soluble polymer.

4. Pharmaceutical composition according to claim 1, wherein the coating with a low-dose medicament further comprises a binder.

5. Pharmaceutical composition according to claim 4, wherein the binder is a pharmaceutically acceptable water-soluble polymer.

6. Pharmaceutical composition according to claim 1, wherein the second coating further comprises a plasticizer, where the plasticizer does not contain phthalates or plasticizer selected from the group consisting of glycerol, esters of glycerol, acetylated mono - or diglycerides, glyceryl monostearate, glyceryltrinitrate, glyceryltrinitrate, phthalates, dibutyl phthalate, diethyl, dimethyl phthalate, dioctyl phthalate, citrates, tributional aether acetylamino acid, createlogo aether acetylamino acid, tributyltin, acetyltributyl, triethylcitrate, glyceryltrinitrate, sebacinales, diethylbenzene, dibutylsebacate, adipates, azelates, benzoate, chlorobutanol, polyethylene glycols, vegetable oils, fumarates, diethylfumarate, malate, diethylmaleate, oxalates, diethyloxalate, succinates, dibutylamine, butyrate, clonycavan of catelouge alcohol, malonate, diethylmalonate, castor oil, and combinations thereof.

7. Pharmaceutical composition according to claim 1, wherein the second coating is substantially masks the taste of high-dose medications and/or low doses of the drug, and is located below the first cover.

8. Pharmaceutical composition according to claim 7, where the second coating further comprises glucocortoids polymer or glucocortoids the blowing agent.

9. Pharmaceutical composition according to claim 8, wherein the water-insoluble polymer selected from the group consisting of water-insoluble ethers of cellulose, ethyl cellulose, water-insoluble esters of cellulose, cellulose acetate, cellulose triacetate, acetobutyrate cellulose, polyvinyl acetate, neutral copolymers methylacrylate acid/methyl methacrylate, and mixtures thereof; and glucocortoids a blowing agent selected from the group consisting of maltina, copolymers of aminoalkylsilane, Eudragit®E100, Eudragit®EPO, diethylaminoacetate of polyvinylacetal, AEA®, terpolymers based dimethylaminoethylmethacrylate, butyl methacrylate and methyl methacrylate, calcium carbonate, calcium phosphate, saccharide calcium, calcium succinate, calcium tartrate, acetate of iron (III) hydroxide iron (III) phosphate, iron (III), magnesium carbonate, magnesium citrate, hydroxide �Agnes, magnesium phosphate and mixtures thereof.

10. Pharmaceutical composition according to claim 1, wherein the second coating is substantially modifies the release of high-dose drugs.

11. Pharmaceutical composition according to claim 10, wherein the second coating further comprises a water soluble polymer or enteric polymer.

12. Pharmaceutical composition according to claim 10, wherein the second coating is disposed between the core and the first coating.

13. Pharmaceutical composition according to claim 12, further comprising a third coating, located on top of the first coating, where the third coating contains a water-insoluble polymer that is the same as the water-insoluble polymer of the second coating, or different from it.

14. Pharmaceutical composition according to claim 13, wherein the third coating substantially masks the taste of low doses of the drug.

15. Pharmaceutical composition according to claim 7, further comprising a third coating, located between the core and the first coating, where the third coating contains a water-insoluble polymer that is the same as the water-insoluble polymer of the second coating, or different from it.

16. Pharmaceutical composition according to claim 15, where the third coating substantially masks the taste of high-dose drugs.

17. Pharmaceutical composition according to claim 16, g�e third coating further comprises glucocortoids polymer or glucocortoids the blowing agent.

18. Pharmaceutical composition according to claim 1, wherein the high-dose drug contains non-opioid analgesic drug, and a low-dose drug contains an opioid analgesic drug; or high-dose drug contains biguanide, and a low-dose drug contains a sulfonylurea; or high-dose drug contains nicotinic acid, and a low-dose drug contains a statin; or high-dose drug contains a decongestant or an antagonist of histamine, and a low-dose drug contains an antagonist of histamine or decongestant.

19. Pharmaceutical composition according to claim 18, where the second coating is disposed between the core and the first coating and the second coating substantially slows the release of high-dose drugs.

20. Pharmaceutical composition according to claim 19, further comprising a third coating, located on top of the first coating, where the third coating contains a water-insoluble polymer that is the same as the water-insoluble polymer of the second coating, or different from him or a third coating contains flavoring coating; and a third coating substantially masks the taste of low�oz medicines.

21. Pharmaceutical composition according to claim 18, where the high-dose drug is a nonsteroidal anti-inflammatory drug, and a low-dose drug is an opioid analgesic drug.

22. Pharmaceutical composition according to claim 18, where the high-dose drug is a Metformin and a low-dose drug selected from the group consisting of glipizide, glyburide, glimepiride, repaglinida, nateglinide, rosiglitazone, pioglitazone and troglitazone.

23. Pharmaceutical composition according to claim 18, where the high-dose drug is a nicotinic acid, and a low-dose drug selected from the group consisting of lovastatin, fluvastatin, atorvastatin, cerivastatin, simvastatin, mevastatin, rosuvastatin and pravastatin.

24. Pharmaceutical composition according to claim 18, in which high-dose medicament selected from the group consisting of hydrochloride or sulfate pseudoephedrine, Fexofenadine, and a low-dose drug selected from the group consisting of cetirizine, loratadine and phenylephrine.

25. Pharmaceutical composition according to claim 1, wherein the fourth coating further comprises a water soluble polymer or enteric-coated polyester�R.

26. Pharmaceutical composition according to claim 1, wherein the water-insoluble polymer of the fourth coating selected from the group consisting of water-insoluble ethers of cellulose, ethyl cellulose, water-insoluble esters of cellulose, cellulose acetate, cellulose triacetate, acetobutyrate cellulose, polyvinyl acetate, neutral copolymers methylacrylate acid/methyl methacrylate, and mixtures thereof; water-soluble polymer selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, hydroxypropylmethylcellulose and hydroxypropyl cellulose; and the enteric polymer is selected from the group consisting of acatitla cellulose phthalate of hydroxypropylmethylcellulose, acetosyringone of hydroxypropylmethylcellulose, polyvinyl acetate phthalate, the pH-sensitive copolymers methylacrylate acid/methyl methacrylate, shellac and mixtures thereof.

27. Pharmaceutical composition according to claim 1, wherein the fourth coating further comprises glucocortoids the blowing agent.

28. Dosage form containing the composition according to claim 1 and one or more than one pharmaceutically acceptable excipient.

29. Pharmaceutical form according to claim 28, further comprising bistrotdepierrerue granules containing the disintegrant and sugar alcohol and/or saccharide; where the dosage form is an ODT (oral p�spodumene tablets).

30. A method of manufacturing a pharmaceutical composition according to claim 1, including:
(1) obtaining cores containing high-dose drug;
(2) coating the cores with stage (1) containing high-dose drug layer of a low-dose of the drug, thereby forming microparticles containing high-dose/low-dose drug;
(3) coating the cores with stage (1) containing high-dose drug, and/or microparticles from step (2) containing high-dose/low-dose drug, a second coating containing water-insoluble polymer;
(4) obtaining cores of the second population of particles containing high-dose drug, where the kernel with stages (1) and (4) containing high-dose drug are the same or different; and
(5) coating the cores conjunction with the second stage (4) containing high-dose drug, kusamakura coating, thus obtaining cores with masked taste, containing high-dose drug.

31. A method of manufacturing a dosage form according to claim 28, including:
(1) the manufacture of cores containing high-dose drug;
(2) coating the core with stage (1) containing high-dose drug coatings for�slow release containing water-insoluble polymer, pharmaceutically acceptable solvent and possibly a plasticizer;
(3) coating the cores with stage (2) containing high-dose drug and coated with a slow release, low-dose drug, pharmaceutically acceptable solvent and possibly a binder, thereby forming microparticles containing high-dose/low-dose drug;
(4) coating the microparticles with stage (3) containing high-dose/low-dose drug kusamakura coatings containing water-insoluble polymer and a pharmaceutically acceptable solvent; or flavoring coatings containing sweetener, pharmaceutically acceptable solvent and possibly a binder;
(5) the manufacture of cores of the second population of particles containing high-dose drug, where the kernel with stages (1) and (5) containing high-dose drug are the same or different;
(6) the application of the kernel conjunction with the second stage (5) containing high-dose drug, kusamakura coating, thus obtaining cores with masked taste, containing high-dose drug;
(7) mixing the microparticles with� stage (4), containing high-dose/low-dose drug and coated with flavouring or kusamakura coating, and nuclei with masked taste from stage (6) containing high-dose drug with at least one pharmaceutically acceptable excipient; and
(8) forming tablets or capsules.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of the general formula

,

wherein R1/R2 independently represent hydrogen, (CR2)o-C3-7 cycloalkyl optionally substituted by a lower alkyl or hydroxy, or represent a lower alkyl or tetrahydropyranyl, and o represents 0 or 1; and R can be identical or different, and represent hydrogen or a lower alkyl; or R1 and R2 can form together with a N atom to which they are attached, a heterocycloalkyl group specified in a group consisting of pyrrolidinyl, piperidinyl, 3-aza-bicyclo[3.1.0]hex-3-yl or 2-aza-bicyclo[3.1.0]hex-2-yl which are optionally substituted by hydroxy; R3 represents an S-lower alkyl, lower alkyl, lower alkoxy or C3-7 cycloalkyl; R3′ represents hydrogen, a lower alkyl substituted by a halogen, lower alkyl or lower alkoxy; R4 represents a lower alkyl substituted by a halogen; X represents -O- or -CH2-; X' represents -O- or -CH2-; provided one of X or X' always represent -O- and the other represents -CH2-; or a pharmaceutically acceptable acid-additive mixture, a racemic mixture, or a respective enantiomer and/or an optical isomer.

EFFECT: compounds of the general formula (I) are good inhibitors of glycine transporter 1 (GlyT-1) and hence can be used for treating schizophrenia and other neurological conditions, including pain.

13 cl, 1 tbl, 63 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel N-containing heteroaryl derivatives of formula I or II or their pharmaceutically acceptable salts, which possess properties of JAK kinase, in particular JAK3, and can be applied for treating such diseases as asthma and chronic obstructive pulmonary disease (COPD). In formulae A represents carbon and B represents nitrogen or A represents nitrogen and B represents carbon; W represents CH or N; R1 and R2, independently represent hydrogen, C1-4alkyl, halogenC1-4alkyl, -CN; R3 represents C1-4alkyl, R9-C1-4alkyl, Cy1, where Cy1 is optionally substituted with one or several substituents R10; R4 represents hydrogen, C1-4alkyl, R12R7N-C0alkyl, where one of R7 and R12 represents hydrogen, and the other represents C1-4alkyl or group R13, which is selected from C1-5alkyl, Cy2-C0alkyl; R5 represents hydrogen; R6 represents hydrogen, C1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0alkyl, Cy1; R7 represents hydrogen or C1-4alkyl; R9 represents halogen, -CN, -CONR7R12, -COR13, CO2R12, -OR12, -SO2R13, -SO2NR7R12, -NR7R12, -NR7COR12; R10 represents C1-4alkyl or R9-C0-4alkyl; R11 represents C1-4alkyl, halogen, -CN, -NR7R14; R12 represents hydrogen or R13; R13 represents C1-5alkyl, hydroxyC1-4alkyl, cyanoC1-4alkyl, Cy2-C0alkyl or R14R7N-C1-4alkyl; where Cy2 is optionally substituted with one or several constituents R11; R14 represents hydrogen or C1-4alkyl; R16 represents C1-4alkyl, halogenC1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl or cyanoC1-4alkyl; Cy1 represents monocyclic carbocyclic unsaturated or saturated ring, selected from C3-C6cycloalkyl, phenyl, or saturated monocyclic 4-6-membered heterocyclic ring, containing from 1 to 2 heteroatoms, selected from N and S, or partially unsaturated 10-membered bicyclic heterocyclic ring, containing oxygen atom as heteroatom, which can be substituted with group R11, where said ring is bound with the remaining part of molecule via any available C atom, and where one or several ring C or S atoms are optionally oxidised with formation of CO or SO2; and Cy2 represents monocyclic carbocyclic unsaturated ring, selected from C3-C6cycloalkyl, or aromatic monocyclic 4-6-membered heterocyclic ring, containing from 1 to 2 heteroatoms, selected from N and S, or unsaturated 10-membered bicyclic heterocyclic ring, containing oxygen atom as heteroatom, which can be substituted with group R11, where said ring is bound with the remaining part of molecule via any available atom C or N.

EFFECT: obtaining novel heteroaryl derivatives.

27 cl, 41 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula I, possessing ability of binding with delta-opioid receptors. In formula R1 is selected from the group, consisting of i) phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxyl, di(C1-4alkyl), aminocarbonyl, chlorine and fluorine, in such a way that only one di(C1-4alkyl)aminocarbonyl is present; ii) naphthyl; iii) pyridinyl, optionally substituted with one substituent, selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxy, fluorine, chlorine and cyano; iv) pyrimidin-5-yl; v) furanyl; vi) thienyl; vii) 5-oxo-4,5-dihydro-[1,2,4]oxodiazol-3-yl; and viii) di(C1-2alkyl)aminocarbonyl; Y represents ethyl, vinyl or bond; or Y represents O, when R1 represents optionally substituted phenyl, where substituent represents C1-4alcoxy; R2 represents phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, fluorine, chlorine and cyano, trifluoromethoxy and hydroxy; or R2 represents phenyl, substituted with one aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4alcoxycarbonyl or carboxysubstituent; R3 is selected from the group, consisting of i) 3-aminocyclohexyl; ii) 4-aminocyclohexyl; iii) piperidin-3-yl; iv) piperidin-4-yl; v) pyrrolodin-2-yl-methyl, in which pyrrolodin-2-yl is optionally substituted by 3-rd or 4-th position with one or two fluorine-substituents; vi) azetidin-3-yl; vii) 2-(N-methylamino)ethyl; viii) 3-hydroxy-2-aminopropyl; ix) piperidin-3-yl-methyl; x) 1-azabicyclo[2.2.2]octan-3-yl; and xi) 8-azabicyclo[3.2.1]octan-3-yl; or R3 together with Ra and nitrogen atom, which they both are bound to, form piperazinyl, optionally substituted with 4-C1-4alkyl; Ra represents hydrogen, 2-(N-methylamino)ethyl or C1-2alkyl, optionally substituted with azetidin-3-yl.

EFFECT: compounds can be used in treatment of pain in the range from medium to strong, caused by diseases or conditions, such as osteoarthritis, migraine, burn, fibromyalgia, cystitis, rhenite, neuropathic pain, idiopathic neuralgia, toothache, etc.

21 cl, 4 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to substituted phenylureas and phenylamides of formula in which X stands for CR3 or N, where R3 stands for H; C1-10alkyl, saturated or unsaturated, branched or non-branched, non-substituted; or CF3; A stands for N or CR5b; R1 stands for substructure , which has the formula, given below. The other radicals and symbols have the values, given in the invention formula. The invention also relates to methods of obtaining formula (If) compounds, to pharmaceutical compositions, containing the said compounds, as well as to the application of the said compositions for the preparation of the pharmaceutical compositions.

EFFECT: formula (If) compounds possess activity with respect to the vanilloid receptor of I subtype (receptor VR1/TRPV1).

7 cl, 1 tbl, 147 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a novel compound of formula

(I)

or its pharmaceutically acceptable salt, possessing properties of the IKKβ and TNFα inhibitor. The compound can be used with an additional therapeutic agent, selected from vincristine, camptothecin hydrochloride (CPT-11), lefunomid, dexamethasone and TNFα. Preferable are compounds of formula (I), corresponding to 2-{5-chloro-2-[(1R,2R)-2-hydroxycyclopentylamino]pyrimidin-4-yl}-N-cyclopropyl-1H-indole-4-carboxamide and 2-{5-chloro-2-[(1R,2S)-2-hydroxycyclopentylamino]pyrimidin-4-yl}-N-cyclopropyl-1H-indole-4-carboxamide.

EFFECT: compound can be applied in the treatment of inflammatory diseases such as rheumatoid arthritis, chronic obstructive lung disease, bronchial asthma, multiple sclerosis and intestinal inflammatory diseases, or cancer diseases, such as multiple myeloma, colon cancer, pancreas cancer and ovary cancer, by IKKβ inhibition.

30 cl, 4 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: method includes treating crushed Echinacea purpurea (L.) Moench roots and rhizome with steam, extraction with ethyl alcohol, then steeping, stirring, steeping, draining a portion of the extract which is equal to the amount of the loaded Echinacea purpurea (L.) Moench roots and rhizome, after draining a portion of the extract, adding ethyl alcohol to the treated material, draining the whole extract; extracting crushed Echinacea purpurea (L.) Moench herbs with ethyl alcohol, steeping, then stirring, steeping, draining a portion of the extract which is equal to the amount of the loaded Echinacea purpurea (L.) Moench herbs, after draining a portion of the extract, adding ethyl alcohol to the treated herbs, draining the whole extract; all obtained extracts are mixed, cooled and filtered under certain conditions. An Echinacea purpurea (L.) Moench tincture. Use of the method to obtain an Echinacea purpurea (L.) Moench tincture.

EFFECT: method preserves the biological activity of components of the tincture and medicinal properties.

3 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I), their pharmaceutically acceptable salts, tautomers or stereoisomers. In formula R1 represents benzimidazolyl optionally substituted by C1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl, dimethylaminoC1-4alkyl or oxo group; benzioxazolyl optionally substituted by C1-4alkyl or amino group; benzotriazolyl optionally substituted by C1-4alkyl; dihydrobenzisothiazol-1,1-dionyl; pyrimidyl; dihydroisoquinolinonyl optionally substituted by oxo group; imidazopyridyl; indazolyl optionally substituted by C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, tetrahydropyranylamino, piperidinylamino, halogen, trifluoromethyl or amino group; indolinyl optionally substituted by C1-4alkyl, hydroxyC1-4alkyl, carboxylate or oxo group; isoindolinyl optionally substituted by C1-4alkyl, aminoC1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl or oxo group; phenyl optionally substituted by C1-4alkyl, C1-4alkoxy, halogen, cyano, trifluoromethyl, carbamoyl, methylcarbamoyl, piperidinylcarbamoyl, methylpiperidinylcarbamoyl, aminoC1-4alkyl, carboxyl, amino, dialkylamino, imidazolyl, pyrrolidin-2-one, triazolyl, morpholinyl, C1-4alkylcarbonylamino, C1-4alkoxyC1-4alkoxy or hydroxyC1-4alkyl; pyrazolopyridyl optionally substituted by C1-4alkyl; pyridyl optionally substituted by C1-4alkyl, C1-4alkoxy, halogen, cyano, hydroxy, amino, morpholinyl, carbamoyl, monoC1-4alkylamino, diC1-4alkylamino, aminoC1-4alkoxy, aminoC1-4alkylamino, hydroxypiperidinyl, hydroxyC1-4alkyl, hydroxyC1-4alkoxy, pyrrolidinylC1-4alkylamino, pyrrolidinylC1-4alkoxy; pyrrolopyridinyl optionally substituted by oxo group; quinolinyl optionally substituted by amino or hydroxy group; or triazolopyridyl substituted by C1-4alkyl. The other radical values are presented in the patent claim. The invention also refers to individual compounds, to a pharmaceutical composition, possessing kinase inhibitory activity and containing an effective amount of the compound of the invention, to a method for kinase inhibition in a cell, to a method of treating or preventing inflammatory conditions, immunological conditions, allergic conditions, rheumatic conditions, cancer, and neuroinflammatory diseases.

EFFECT: there are prepared new compounds possessing Syk, FLT3, JAK1, JAK2 inhibitory activity.

21 cl, 1 tbl, 133 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new hydrate of 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol hydrochloride salt in the crystalline form with the characteristics below. The hydrate can be used for producing a drug or for treating or preventing a transplanted organ or tissue rejection, or autoimmune diseases in a therapeutically effective amount. The above hydrate is characterised by an X-ray powder diffractogram having peaks at approximately 2.9, 17.2, 30.6, 28.2, 24.4, 8.6 and 25.9 degrees 2-Theta with a limit of error of ±0.2 degrees for each value of 2θ, having a purity of 90% or more, and containing 5.2 to 5.9% of water.

EFFECT: invention also characterises a pharmaceutical composition with using the above hydrate.

4 cl, 4 dwg, 8 tbl, 14 ex

FIELD: biotechnology.

SUBSTANCE: invention relates to a low-toxic (E)-2-(4-{[3-(2,4-dimethoxyphenyl)acrylamido]methyl}-1H-1,2,3-triazole-1-yl)-2-isopropyl-9-(4-methyl piperazine-1-yl)-3,7-dioxo-3,7-dihydro-2H-furo[3,2-g]chromen of formula (I) , having the analgesic activity in the test "acetic acid-induced writhing". The said property enables to use this compound in medicine.

EFFECT: compound of formula I is prepared from furocoumarin peucedanine contained in the plant Peucedanum morisonii.

1 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, novel biologically active substances of the class of N-hetarylamides of 4-aryl-2,4-dioxobutanoic acids, and specifically to 2-(5-ethyl-1,3,4-thiadiazolyl)amide of 2-(4-bromophenyl)-4-oxo-4-phenyl-2-butenoic acid. The compound is obtained by reacting 4-bromophenyl-5-aryl-3-imino-3H-furan-2-one with 2-amino-5-ethyl-1,3,4-thiadiazole with equimolar ratio of reactants in a medium of anhydrous toluene while boiling, followed by separation of the end product.

EFFECT: obtaining compounds having analgesic effect, as well as low toxicity

1 tbl

FIELD: medicine.

SUBSTANCE: pharmaceutical composition in the form of a tablet contains a core coated with a separating layer and an enteric coating. The core contains an active substance, sodium rabeprazole, and additives - calcium carbonate, lactose, starch, hydroxypropylmethyl cellulose, stearic acid salt in the amounts specified in the patent claim. What is also described is a method for producing the pharmaceutical composition of rabeprazole. The invention enables to extend the range of medical products applicable for treating gastric ulcer.

EFFECT: low in foreign impurities and having good stability.

3 cl, 3 tbl, 5 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.

SUBSTANCE: this invention aims at pharmaceutical compositions and methods for making these compositions containing a number of controlled-release particles. At least one assembly of said particles comprises a nucleus containing weakly basic drug substance, an alkaline buffer layer above the nucleus, and a controlled-release coating. The weakly basic drug substance contains at least one nitrogen-containing fragment with pKa from approximately 5 to approximately 14, with a solubility from at least 200 mg/ml at room temperature in an aqueous solution at pH approximately pH 1.2-6.8 and solubility of no more than approximately 10 mg/ml at pH 8 and more. The controlled-release coating contains a water-insoluble polymer. The pharmaceutical composition also contains rapidly degrading microgranules. This invention also aims at pharmaceutical dosage forms containing orally degrading tablets, classical tablets and capsules, as well as methods for making them.

EFFECT: invention provides the sustained release of the weakly basic drug substance in the small intestine.

65 cl, 1 dwg, 1 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention provides a solid hypolipidemic dosage form containing rosuvastatin or its pharmaceutically acceptable salt in an amount of 3 to 15%, processing additives and a pharmaceutically acceptable excipient containing microcrystalline cellulose, lactose monohydrate, polyvinylpyrrolidone and croscarmellose sodium. The above excipient represents granulate in an amount of 79 to 95 wt % of the dosage form containing absorbed moisture within the range of 0.5% to 1.5%. What is also described is a method for preparing the dosage form.

EFFECT: uniform distribution of the active substance and storage stability of the dosage form of rosuvastatin.

11 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: as active component pharmaceutical composition contains dihydrochloride of 9-(2-morpholine ethyl)-2-(4-fluorophenyl)imidazo[1,2-α]benzimidasol, and as additional substances - fillers, binding, sliding and film coatings, in quantities, given in the invention formula. Composition can be made in form of solid medication form, mainly in form of tablets and capsules.

EFFECT: obtained solid medication forms satisfy the requirements of the State Pharmacopoeia.

7 cl, 2 dwg, 3 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and medicine, namely to manufacturing drug preparations for treating allergic diseases, such as allergic rhinitis and urticaria. According to the first version, the pharmaceutical composition contains an active substance that is desloratadine, and additives, including citric acid, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, starch, lactose, magnesium stearate, and talc. According to the second version, the pharmaceutical composition contains an active substance that is desloratadine, and additives, including Pearlitol 100SD-Mannitol, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, starch, magnesium stearate, and talc. According to the third version, the pharmaceutical composition contains an active substance that is desloratadine, and additives, including sodium carboxymethyl starch, microcrystalline cellulose, colloidal silicone dioxide, and sodium sodium stearyl fumarate. According to the fourth version, the pharmaceutical composition contains an active substance that is desloratadine, and additives, including sodium carboxymethyl starch, microcrystalline cellulose, Pearlitol 100SD-Mannitol, magnesium stearate, and talc. The pharmaceutical composition is presented in the form of a film-coated tablet.

EFFECT: pharmaceutical composition according to the invention is storage-stable and releases the active substance quickly in the gastrointestinal tract.

10 cl, 9 tbl, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claim describes a standard solid dosage form for oral administration which represents a mini-tablet having a core and an outer coating, wherein the core contains a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt, while the outer coating represents a film coating containing a taste masking material specified in polyacrylates, and/or a release modifying ingredient of the coating specified in cellulose derivatives and acryl copolymers, and a mixture thereof. The above mini-tablet has a size of 1 mm to 4 mm and contains aliskiren in an amount making 2 mg/tablet to 4 mg/tablet. The oral solid dosage form is preferentially applied in paediatrics.

EFFECT: according to the invention, the dosage form of aliskiren can be dosed and possesses a taste that makes it applicable for children, and maintains a biological availability at a level comparable to that of the available medicinal product for adults.

19 cl, 13 dwg, 5 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to systems of a film coating for preparations with an immediate release for application on peroral dosed forms, such as pressed tablets and other perorally administered substrates, which possess an improved barrier protection means against moisture. The film coating composition contains 28-5 wt % of polyvinyl alcohol, 1-8 wt % of a polymer with pH-dependent solubility and, optionally, a plasticiser, a lubricant, an anti-adhesion substance, an alkalising substance and a pigment. Preferably, the polymer with pH-dependent solubility represents a copolymer of methacrylic acid and polyvinylacetophthalate (PVAP). Also described are compositions of the film coating, containing water suspension of powder mixtures, methods of applying the coatings on substrates and the substrates with the coating.

EFFECT: invention provides fast disintegration of the compositions in a medium with different pH (less than 30 minutes) and satisfactory characteristics of the anti-moisture barrier.

18 cl, 1 tbl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of modifying envelopes of polyelectrolyte capsules with magnetite nanoparticles. The disclosed method involves producing a container matrix in form of porous calcium carbonate microparticles, forming envelopes of polyelectrolyte capsules by successive adsorption of polyallyl amine and polystyrene sulphonate and modifying with magnetite nanoparticles on the surface of the container matrix or after dissolving the matrix through synthesis of magnetite nanoparticles via chemical condensation.

EFFECT: invention enables to obtain modified polyelectrolyte capsules, designed to deliver medicinal substances which do not harm the human body.

3 cl, 4 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention is aimed at pharmaceutical compositions and methods of producing such compositions, where compositions include combination of particles with synchronised impulse release (SIR-particles) and particles with fast release (FR-particles). Each SIR-particle includes core, covered with SIR-layer; core includes weakly basic poorly soluble medicinal substance and pharmaceutically acceptable organic acid, which are separated from each other by layer with delayed release. Each FR-particle includes granule, which contains weakly basic poorly soluble medicinal substance, pharmaceutically acceptable binding substance, at least, one auxiliary substance and, at least, one backing powder. As organic acid, fumaric acid is preferably applied. FR-granules are conjoined with SIR-granules in single pharmaceutical formula, for example, in capsule.

EFFECT: medical form by invention has improved profile of release of weakly basic poorly soluble medicinal substances and is suitable for oral introduction once per day.

32 cl, 11 dwg, 2 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: presented group of inventions refers to medicine. What is presented is a pharmaceutical composition representing a tablet formulation containing ritonavir in a first layer and atazanavir in a second layer, and a polymer. What is presented is a method for preparing the above pharmaceutical composition wherein a hot melt of rinonavir is extruded to prepare an extrudate to be placed into the first tablet layer, and atazanavir - into the second layer; the first and second layers are combined providing a single multilayer tablet. What is presented is a composition prepared by the method described above to be used in treating HIV or AIDS, and a method of treating HIV or AIDS.

EFFECT: presented group of inventions is effective in creating the multilayer tablet providing a good bioavailability for ritonavir, wherein atazanavir is not degraded in preparation.

19 cl, 5 tbl, 4 ex

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