WO2018093289A1

WO2018093289A1 - Solid oral drug dosage form and method for producing same

Info

Publication number: WO2018093289A1
Application number: PCT/RU2017/000187
Authority: WO
Inventors: Елена Сергеевна ХАЗАНОВА; Сергей Юрьевич НОГАЙ; Евгения Александровна ФИЛИППОВА
Original assignee: Общество с ограниченной ответственностью "Изварино Фарма"
Priority date: 2016-11-17
Filing date: 2017-03-30
Publication date: 2018-05-24
Also published as: RU2016145122A; RU2016145122A3; RU2670447C2

Abstract

The use of mycophenolic acid or a pharmaceutically acceptable salt thereof as a solid drug dosage form for treating or preventing rejection of an organ or tissue transplant, and a method for producing said drug dosage form, are disclosed. The object of the invention is the method used for producing the solid oral drug dosage form with mycophenolic acid or a pharmaceutically acceptable salt thereof comprises extrusion of a mixture of a pharmaceutically acceptable polymer and an active ingredient, followed by addition of excipients. The technical result is the provision of a more readily usable solid drug dosage form of mycophenolic acid, and production thereof while avoiding the use of organic solvents and by employing a shorter technological process, which does not include a granulation step.

Description

PERORAL SOLID MEDICINAL FORM AND METHOD FOR PRODUCING IT

The present invention relates to a solid dosage form of mycophenolic acid or its pharmaceutically acceptable salt, intended for use as an immunosuppressant for the treatment or prevention of organ or tissue transplant rejection. Moreover, the active substance is in the specified dosage form in the form of a solid dispersion, as well as to a method for producing the specified dosage form.

Mycophenolic acid, also referred to as MPA in this description, was first isolated in 1896 and has been intensively studied as a drug of potential commercial interest. It is known that it has antitumor, antiviral, immunosuppressive, anti-psoriatic and anti-inflammatory activity [see, for example, W.A. Lee et al. Pharmaceutical Research

(1990), 7, pp. 161-166 and references cited in this publication]. Known publications about IFC as an anticancer agent of specialists of the company Lilly, see, for example, M.J. Sweeney et al., Cancer Research (1972), 32, 1795-1802, and ICI, see, e.g., GB

1 157099 and GB 1203328, and as an immunosuppressant agent, see, for example, A. Mitsui et al. J. Antibiotics (1969) 22, pp. 358-363. In the above article, W.A. Lee et al. There is evidence that attempts have been made to increase the bioavailability or specificity of IFCs through the synthesis of derivatives. Inadequate bioavailability of the acid was believed to be caused by uncertain factors such as complexation of the drug in the gastrointestinal tract, narrow absorption window, metabolism prior to absorption, etc. It was described that the drug is based on morpholinoethyl ether, also known as mycophenolate mofetil (sometimes referred to in the present description MPM), has a significantly higher bioavailability than

IFC (100% for MFM and 43% for IFC). This derivative has recently begun to be marketed as an immunosuppressant to treat or prevent organ or tissue transplant rejection used in daily doses of from about 200 mg to about 3 g orally, for example, about 2 g orally. Compliance the patient’s regimen and treatment regimen is not ideal, including due to side effects, for example, side effects in the gastrointestinal tract, the origin of which is unknown. The most widely represented drug on the modern market is the enteric form of the drug described in patent RU 2203659. The enteric form or its imitation by delayed dissolution of the membrane disclosed in WO 2006/024479 improves the bioavailability and stability of the preparation.

The technology for producing the core of a solid dosage form, in the process of drug development, underwent several modifications. WO 03/032978 discloses a technology for producing a core by granulation using a non-aqueous solvent. According to studies by the authors, the technology disclosed in WO 03/032978 allows a dosage form of an acceptable size to be obtained and protects the active substance from contact with water.

Abbreviations Used

IFC - mycophenolic acid;

MFM - mycophenolate mofetil;

APS is an active pharmaceutical substance;

PEG - polyethylene glycol;

GPMC - hydroxypropyl methylcellulose;

Brief Description of the Figures

Figure 1. Analysis of the crystallinity of the pharmaceutical composition of Example 3 analyzed by SAXS Small Angle X-Ray Scattering (Anton Raag). Red color is APS, blue is a mixture of polymers included in the extrudate, green is a mixture of polymers after extrusion, black is a mixture of polymers and APS (ext. Dates).

Figure 2. Analysis of the crystallinity of the pharmaceutical composition of Example 3 analyzed using Small Angle X-Ray Scattering SAXS (Anton Paar). Red color is APS, blue is a mixture of polymers included in the extrudate, green is a mixture of polymers after extrusion, black is a mixture of polymers and APS (ext. Dates) after 1 month of storage.

Despite the vastness of the work carried out to date, in order to improve the dosage form of mycophenolic acid, there remains a need to develop a more convenient technology and a more acceptable dosage form.

The technological process of obtaining the core of a solid dosage form of mycophenolic acid or its pharmaceutically acceptable salt, using organic (non-aqueous) solvents, has several disadvantages:

- the need to control residual organic solvents in the finished dosage form;

- explosive / fire hazardous production;

- the complication of activities related to the protection of labor and the environment;

- additional technological stages and, accordingly, losses.

When creating the invention, it was unexpectedly found that containing pharmaceutically acceptable oral solid drugs containing mycophenolic acid or mycophenolate, in practically anhydrous form, can be obtained without the use of organic solvents and by a shortened process, without using a granulation step. More specifically, using extrusion.

Although the compositions according to the invention are specifically described below with the example of tablets, other types of oral solid drugs can be prepared, for example, effervescent tablets, fast disintegrating tablets, matrix tablets, mini tablets, multilayer tablets, pulse-release tablets, pellets, capsules, granules or powders, placed, for example, in a sachet or vial, these forms falling within the scope of the present invention.

According to the invention, the proposed drug contains the active substance in an amount of from 5.0 wt.% To 95.0% by weight of the dosage form, as well as pharmaceutically acceptable excipients in an amount of from 5.0% to 95.0% by weight of the finished dosage form.

Along with the active substance, the pharmaceutical composition may contain conventional excipients adopted in the preparation of medicines, such as binders, fillers, preservatives, flow regulators, emollients, wetting agents, dispersants, emulsifiers, solvents, antioxidants and / or propellants, prolonging agents Sucker et al .: Pharmazeutische Technologie, Thieme-Verlag, Stuttgard, 1991.

As a filler, the pharmaceutical composition may contain one or more of the following substances: sugars and their derivatives (lactose, modified lactose, sucrose, glucose, mannitol, modified mannitol, sorbitol, fructose), polysaccharides (cellulose and its derivatives, starch, modified starch, dextrin, dextrose, dextrate, maltodextrin, calcium and its salts (phosphates, carbonates, chlorides), magnesium and its derivatives (oxide, carbonate, stearate), crospovidone, copovidones, cyclodextrins, alginic acid and its salts, saccharin and e salt, sodium and its salts (chloride, citrate, fumarate, carbonate), aspartame, lactic acid and its salts, succinic acid, ascorbic acid, tartaric acid, colloidal silicon dioxide, cyclamate, benzoic acid and its salts, parabens and their salts .

Preferably, the pharmaceutical composition contains from 0.3 to 60% by weight of the above excipients (based on 100% by weight of the total solid dosage form).

A pharmaceutically acceptable polymer may be selected from the group consisting of water soluble polymers, water dispersible polymers and water swellable polymers and any mixtures thereof. Polymers are considered soluble in water if they form a clear, homogeneous solution in water. After dissolving at 20 ° C. in water at a concentration of 2% (w / v), the water-soluble polymer preferably has an apparent viscosity of 1 to 5000 mPa s, more preferably 1 to 700 mPa s and most preferably 5 to 100 MPa s Water-dispersible polymers are those which, when reacted with water, form colloidal dispersions rather than clear solution. When interacting with water or aqueous solutions, water-swellable polymers usually form a rubbery gel.

Preferably, the pharmaceutically acceptable polymer used in the present invention has a Tg value of at least 40 ° C, preferably at least + 50 ° C, most preferably from 80 to 120 ° C. "Tg" refers to the glass transition temperature. Methods for determining Tg values for organic polymers are described in Introduction to Physical Polymer Science, 2nd Edition by LHSperling, published by John Wiley & Sons, Inc., 1992. Tg values can be calculated as the weighted sum of Tg values for homopolymers formed from each individual monomer, i, which

at

are included in the polymer: Tg = Wj Xj, where W means the percentage by weight of the monomer i in the organic polymer and X means the Tg value for the homopolymer formed from monomer i. Tg values for homopolymers are given in Polymer Handbook, 2nd Edition by J. Brandrup and E. H. Immergut, Editors, published by John Wiley & Sons, Inc., 1975.

For example, preferred pharmaceutically acceptable polymers can be selected from the group consisting of water soluble polymers suitable for use in the pharmaceutical composition of the present invention, include, but are not limited to: N-vinyl lactam homopolymers and copolymers, especially Ν-vinyl pyrrolidone homopolymers and copolymers, for example polyvinylpyrrolidone (PVP), copolymers of Ν-vinylpyrrolidone and vinyl acetate or vinyl propionate; high molecular weight polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide; polyacrylates and polymethacrylates such as methacrylic acid / ethyl acrylate copolymers, methacrylic acid methylmethyl acrylate copolymers, butyl methacrylate / 2-dimethyl acrylate (polymethyl hydromethyl) ; polyacrylamides; vinyl acetate polymers such as copolymers of vinyl acetate and crotonic acid; polyvinyl alcohol; oligo and polysaccharides such as carrageenans; cellulose esters and cellulose ethers, in particular methyl cellulose and ethyl cellulose, hydroxyalkyl cellulose, hydroxyethyl cellulose, in particular hydroxypropyl methyl cellulose, in particular hydroxypropyl cellulose, cellulose succinates, in particular hydroxypropyl methyl cellulose succinate or hydroxypropyl methyl cellulose acetate succinate. In a preferred embodiment, said hydrophilic polymer comprises polyvinylpyrrolidone, polyalkylene oxide, in particular polyethylene oxide and / or a cellulose derivative, in particular hydroxypropyl methylcellulose.

Water-insoluble polymers that can be used in the present invention include, but are not limited to, the following materials: microcrystalline cellulose, low-substituted hyprolose (hydroxy-propyl cellulose).

Various additives contained in the melt-processed mixture or even in the most active ingredient (s) can have a plasticizing effect on the polymer and thereby reduce the polymer Tg, so that the final melt-processed mixture has a slightly lower Tg than the original polymer used for its preparation. Typically, the final melt extruded mixture has a Tg of 10 ° C or higher, preferably 15 ° C or higher, more preferably 20 ° C or higher, and most preferably 30 ° C or higher.

The specified low melting component, preferably a component with a melting point or melting range, or about 37 ° C, but not too high.

The predominantly low melting component does not rapidly thermally degrade near its melting point. For example, the melting point or melting range of the second component is in the range from about ambient temperature to 100 ° C, in particular in the range from 40 ° C to 100 ° C. Advantageously, the melting temperature or the melting range of the second component should not exceed 90 ° C, preferably the melting temperature or the melting range of the second component is in the range from> 40 ° C to 90 ° C. Advantageously, the second component is a component that cools quickly. Suitable components that can be used as the second component include hydrophilic polymers such as, for example, polyalkylene glycol, in particular polyethylene glycol, polyalkylene oxide, in particular polyethylene oxide, polyvinyl alcohol, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl and them. Plasticizers can be introduced depending on the polymer and the requirements of the method. They are mainly when used in the method of extrusion of hot melt, reduce the glass transition temperature of the polymer. Plasticizers also help in reducing the viscosity of the polymer melt and thereby reduce the processing temperature and rotation of the extruder during extrusion of the hot melt. Examples of plasticizers that may be used in the present invention include citrate ester type plasticizers such as triethyl citrate, citrate phthalate; propylene glycol; glycerol; low molecular weight polyethylene glycol (PEG) with molecular weights ranging from 400 to 8000, such as PEG 600, PEG 1000, PEG 1500, PEG 3000, PEG 4000, PEG 6000 or PEG 7000; triacetin; dibutyl sebacinate, tributyl sebacinate; dibutyl tartrate, dibutyl phthalate, but not limited to. It is preferably present in an amount in the range from 0% to 40% by weight of the finished composition.

Preferably, the pharmaceutical composition contains from 0.4 to 49.0 wt.% Of the above water-soluble polymers, surfactants, lubricants, excipients up to 100% of the total dosage form.

Preferably, the pharmaceutical composition contains from 0.4 to 49.0 wt.% The above water-soluble polymers, at least a water-insoluble polymer from 0.30 to 19 wt.% By weight of the entire finished dosage form, lubricants, surfactants , excipients to a mass of 100% of the entire finished dosage form.

According to an embodiment, the present invention may contain one or more disintegrating agents, which may include croscarmellose sodium, crospovidone, sodium starch glycolate, grain starch, potato starch, corn starch and modified starches, calcium silicates, low-substituted hydroxypropyl cellulose, but not limited to . The amount of degradable agent is preferably in the range of 1% to 10% by weight of the composition.

Accordingly, the present invention may further include one or more lubricants and glidants, which may include stearic acid and its derivatives or esters, such as sodium stearate, magnesium stearate and calcium stearate, and corresponding esters, such as sodium fumarate; talc and silicon dioxide, respectively, but are not limited to. The amount of lubricant and / or glidant is preferably in the range from 0.25% to 5% by weight of the composition.

Surfactants suitable for use in the pharmaceutical composition of the present invention include, but are not limited to: polysorbate 80 (e.g., TWIN-80 polysorbate), macrogol 6000 (polyethylene glycol 6000), poloxamers with hydrophilic-lipophilic balance more 16 (e.g., Poloxamer 124, Poloxamer 188, Poloxamer 237, Poloxamer 338, Poloxamer 407).

Preferably, the pharmaceutical composition contains from 0.3 to 5.0 wt.%, Preferably 3 wt.%, Surfactants (in terms of 100 wt.% Of the entire solid dosage form).

In the context of the present description, the term "pharmacologically effective amount" means the amount of active substance that stops or weakens the development of the condition to be treated, or which otherwise leads to the complete or partial cure of the condition or to its temporary relief. This amount can be determined using standard experiments.

An embodiment of the present invention relates to a tablet containing from 50 to 500 mg of mycophenolic acid or mycophenolate, for example, from 100 to about 500 mg of mycophenolic acid or mycophenolate, preferably from about 180 to about 360 mg of mycophenolic acid or from about 160 to about 385 mg mycophenolate.

If mycophenolates are used, then cationic salts of MPA can be used, for example, alkali metal salts, especially sodium salts, alkaline earth metal salts, ammonium salts or salts with an organic base. According to the present invention, a monosodium salt should preferably be used. It can be obtained in crystalline form by recrystallization, for example, from a mixture of acetone / ethanol, if necessary in the presence of water; 189-191 ° C. Another object of the present invention is an oral solid drug, for example, a tablet in which the sodium mycophenolate is in crystalline form.

In the dosage forms of the present invention, the active ingredient is contained as a solid dispersion. The term "solid dispersion" defines a system in the solid state (as opposed to a liquid or gaseous state) comprising at least two components in which one component is uniformly dispersed in another component or components. For example, an active ingredient or a combination of active ingredients is dispersed in a matrix comprising pharmaceutically acceptable polymer (s).

There is an extensive literature that describes the above, as well as other excipients and methods (see, in particular. Handbook of Pharmaceutical Excipients, 2nd ed., Edited by Ainley Wade and Paul J. Weller, American Pharmaceutical Association, Washington, USA, and Pharmaceutical Press, London; and Lexikon der Hilfsstoffe Fur Pharmazie, osmetik and angrenzende Gebiete, 4th ed., Edited by HP Fiedler, editable editors Cantor, Aulendorfn earlier editions, which are incorporated herein by reference).

Examples of glidants include, for example, colloidal silicon dioxide, for example, colloidal silicon dioxide, for example Aerosil® 200, magnesium trisilicate, powdered cellulose, starch, talc or tribasic calcium phosphate. Preferably, Aerosil® 200 may be used.

Examples of lubricants include, for example, Mg, A1 or Ca stearate, PEG 4000-8000, hydrogenated castor oil, glyceryl monostearate or talc. Preferably, magnesium stearate can be used.

To provide the specific desired properties of the tablet, one or more of these additives can be selected using standard experiments. The amount of each type of additive used, for example, a filler or diluent, a disintegrant, a binder, a glidant or a sizing agent, can be easily estimated using methods conventional in the art.

The absolute amounts of each additive and the relative proportions with other additives also depend on the desired properties of the tablet and can be selected using standard experiments. For example, you can choose the type of tablet with accelerated and / or delayed release of IFCs or mycophenolate with a quantitative control of the release of the active substance or with an uncontrolled release.

In the tablet of the present invention, magnesium stearate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone and colloidal silicon dioxide, pregelatinized starch are used as preferred adjuvants. The amount of additives used should depend on the amount of IFC or mycophenolate used. Stearate, for example magnesium stearate, is preferably used in an amount of from 0.1 to 5.0% by weight, for example from 0.5 to 2.0% by weight, most preferably 1% by weight of silicon dioxide is preferably used in an amount of from 0.1 to 10% %, for example, from May 0.5 to 5.0, most preferably 1% by weight.%, most preferably 1% by weight. Pregelatinized starch is used as a filler in an amount of from 0.3% to 60% by weight of the finished dosage form, preferably 4% by weight. Hydroxypropyl methylcellulose is used in an amount of from 3.0 mass% to 50.0 mass% by weight of the finished dosage form, preferably in an amount of 4 mass%. Hydroxypropyl cellulose is used in an amount of from 3.0 mass% to 50.0 mass% by weight of the finished dosage form, preferably in an amount of 7 mass%. Polyethylene glycol is used in an amount of from 3.0 mass% to 50.0 mass% by weight of the finished dosage form, preferably in an amount of 13.0 mass%. Polyvinylpyrrolidone is used in an amount of from 3.0 mass% to 50.0 mass% by weight of the finished dosage form, preferably in an amount of 18.5 mass%. The combination of polyvinylpyrrolidone and polyethylene glycol is used in an amount of from 3.0 mass% to 95.0 mass% by weight of the finished dosage form. The combination of polyvinylpyrrolidone and hydroxypropyl methylcellulose is used in an amount of from 3.0 mass% to 95.0 mass% of the mass of the finished dosage form. The combination of hydroxypropyl methylcellulose and polyethylene glycol is used in an amount of from 3.0 mass% to 95.0 mass% by weight of the finished dosage form. The combination of polyvinylpyrrolidone, hydroxypropylmethyl cellulose and polyethylene glycol is used in an amount of from 3.0 mass% to 95.0 mass% by weight of the finished dosage form ..%.

Another object of the invention is the above-described tablet having an enteric coating. The enteric coating can be applied not only to tablets, but also to the other oral dosage forms mentioned above, for example, granules, which can then be compressed into tablets, or onto a drug substance, which is MPA or mycophenolate.

In the context of the present description, the term "enteric coating" means any pharmaceutically acceptable coating that prevents the release of the active substance in the stomach and which decomposes sufficiently in the intestinal tract, preferably in the upper intestinal tract (in contact with approximately neutral or alkaline intestinal juices), providing absorption of the active substance by the walls of the intestinal tract. In vitro tests to determine whether a coating can be classified as enteric or not are published in the pharmacopoeia of various countries.

An object of the invention is also a method for the manufacture of oral solid dosage forms. Oral solid dosage forms are made by:

(I) mixing mycophenolic acid or mycophenolate with a pharmaceutically acceptable polymer,

(II) extrusion of the mixture obtained in stage (I),

(III) the preparation of the finished dosage form.

In the event that the finished dosage form is a tablet, then carry out:

- grinding the extrudate obtained in stage (II), - dusting with excipients of crushed extrudate, tabletting (pressing) of the mass

The stage of extrusion (II) can be carried out both in the thermoplastic version (with heating) and without heating, using a sufficiently plastic mass for extrusion.

Hot melt extrusion provides several advantages over traditional pharmaceutical processing methods, including the absence of solvents, a small number of processing steps, continuous operation, the possibility of formation of solid dispersions and improved bioavailability (cf. MMCrowley et al., Drug Dev Ind Pharm 2007, 33 (9), 909-26; and MARepka et al., Ibid. 33 (10), 1043-57).

Melting and / or stirring is carried out in an apparatus designed for this purpose. Extruders or kneading machines are particularly suitable. Suitable extruders include single screw extruders, extruders with screwed meshes, or even multi screw extruders, preferably twin screw extruders in which the screws can rotate in one or opposite directions, and optionally equipped with kneading discs or other screw elements for mixing or dispersion of the melt. It should be understood that the operating temperature will also depend on the type of extruder used or the type of extruder configuration. Part of the energy needed to melt, mix and dissolve the components in the extruder can be obtained from heating elements. However, friction and shear movements of the material in the extruder can also lead to the release of a significant amount of energy in the mixture and contribute to the formation of a uniform melt of components.

The extrudate exiting the extruder, in consistency, ranges from pasty to viscous.

One / several of the components will melt, and the other components will be dispersed in this melt. Melting typically involves heating above a point. softening the polymer. The preparation of the dispersion can occur in many ways. Mixing of the components may take place before, during or after the formation of a solid dispersion. For example, the components can be mixed first, and then the dispersion is extruded, or can be mixed and extruded simultaneously.

Typically, the melt temperature is in the range of from about 50 ° C to about 200 ° C, preferably from about 60 ° C to about 140 ° C, more preferably from about 80 ° C to about 120 ° C.

Suitable extruders include single screw extruders, coupled screw extruders or even multi-screw extruders, preferably twin screw extruders, which can be rotated or counter-rotating and, optionally, equipped with kneading discs. It will be understood that operating temperatures will also be determined by the type of extruder or the type of configuration within the extruder used.

The extrudates can be in the form of balls, granules, pipes, threads or cylinders, and they can be further processed into any desired shape.

As used herein, the term “extrudates” refers to solid dispersions of one or more drugs with one or more polymers and, optionally, pharmaceutically acceptable excipients.

The process described above may further include coating mycophenolic acid or mycophenolate and / or granules and / or tablet. The coating can be carried out in any suitable way.

If necessary, the film coating may be an enteric coating. The film coating typically includes a polymeric film-forming material such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, or acrylate or methacrylate copolymers. In addition to the film-forming polymer, the film coating may further include a plasticizer, for example, polyethylene glycol, a surfactant, for example, type Tween® and optionally a pigment, for example titanium dioxide or iron oxides, carotenoids, indigotine, for example, indicotine varnish, or chlorophyll. The film coating may also include talc as an anti-stick agent. Film coating is usually at least 5% of May. by weight of the dosage form.

The following examples are intended to further illustrate the present invention without limiting it.

Example

Process

The components that make up the tablet are: sodium mycophenolate, PEG 1500, Kollidon® 30 (I) are mixed;

(I) extruded at a temperature of 120 ± 5 C;

(Iii) grinding the extrudate;

(IV) the crushed extrudate is mixed with HPMC K 100 LV, colloidal silicon dioxide and magnesium stearate; compressed into tablets

(V) the tablets are coated in a coating machine. Example 2

Amount mg

Tablet composition

mg mg Sodium Mycophenolate 192.4 384.8

GPMC K 100 LV (hydroxypropyl methyl cellulose, grade K 100 LV) 13.6 27.2

PEG 1500 (polyethylene glycol, with a molecular weight of about 1500) 48.75 97.5

Kollidon® 30 (K30 grade polyvinylpyrrolidone) 48.75 97.5 colloidal silicon dioxide 3.25 6.5 magnesium stearate 3.25 6.5

The nominal weight of the tablet without shell 310 620

Process

Components included in the tablet: sodium mycophenolate, PEG 1500, Kollidon® 30

(I) are mixed;

(II) extruded at a temperature of 120 ± 5 C;

(Iii) grinding the extrudate;

(IV) the crushed extrudate is mixed with HPMC K 100 LV, colloidal silicon dioxide and magnesium stearate; compressed into tablets (V), the tablets are coated in a coating machine.

Example 3

Process

(I) are mixed;

(II) extruded at a temperature of 120 ± 5 C; (Iii) grinding the extrudate;

(IV) the crushed extrudate is mixed with pregelatinized starch, colloidal silicon dioxide and magnesium stearate; compressed into tablets (V), the tablets are coated in a coating machine.

Example 4

Process

Components included in the tablet: sodium mycophenolate, PEG 1500, Kollidon® 30, Klutzel EXF

(I) are mixed;

(II) extruded at a temperature of 120 ± 5 C;

(Iii) grinding the extrudate;

Example 5

Sodium Mycophenolate 192.4 384.8

Pregelatinized starch 10.25 20.5

PEG 1500 (polyethylene glycol, with a molecular weight of about 1500) 40.0 80.0

Kollidon® 17 (K17 grade polyvinylpyrrolidone) 57.5 1 15.0

Colloidal Silica 6.6 13.2

Magnesium Stearate 3.25 6.5

The nominal weight of the tablet without shell 310 620

Process

Components included in the tablet: sodium mycophenolate, PEG 1500, KoUidon® 30

(I) are mixed;

(II) extruded at a temperature of 105 ± 5 C;

(Iii) grinding the extrudate;

Example 6

Process

(I) are mixed;

(II) extruded at a temperature of 105 ± 5 C; (Iii) grinding the extrudate;

Example 7

Process

Components included in the tablet: sodium mycophenolate, PEG 1500, Kollidon® 30, Poloxamer 407

(I) are mixed;

(II) extruded at a temperature of 120 ± 5 C;

(Iii) grinding the extrudate;

(Iv) the crushed extrudate is mixed with colloidal silicon dioxide and magnesium stearate; compressed into tablets (V), the tablets are coated in a coating machine.

Example 8

Process

The components that make up the tablets: sodium mycophenolate, PEG 1500, Kollidon® 30, Poloxamer 338 (I) are mixed;

(II) extruded at a temperature of 120 ± 5 C;

(Iii) grinding the extrudate;

Example 9

Process Components that make up the tablet: sodium mycophenolate, PEG 1500, Kollidon® 30 (1/2 part)

(I) are mixed;

(II) extruded at a temperature of 120 ± 5 C;

(Iii) grinding the extrudate;

(IV) the crushed extrudate is mixed with HPMC EZ, Kollidon® 30 (1/2 part) colloidal silicon dioxide and magnesium stearate; compressed into tablets (V), the tablets are coated in a coating machine.

Example 10

Process

Components that make up the tablet: sodium mycophenolate, PEG 1500, Kollidon® 30 (1/2 part)

(I) are mixed;

(II) extruded at a temperature in the following temperature conditions 60 ± 5; 125 ± 5; 130 ± 5; 135 ± 5; 135 ± 5C

(Iii) grinding the extrudate;

(IV) the crushed extrudate is mixed with HPMC EZ, Kollidon® 30 (1/2 part) colloidal silicon dioxide and magnesium stearate; compressed into tablets (V), the tablets are coated in a coating machine. Example 1 1

Process

(I) are mixed;

(I) extruded at a temperature of 120 ± 5 C;

(Iii) grinding the extrudate;

(IV) the crushed extrudate is mixed with HPMC E15, Kollidon® 30 (1/2 part) colloidal silicon dioxide and magnesium stearate; compressed into tablets (V), the tablets are coated in a coating machine.

Example 12

(I) are mixed;

(Iii) grinding the extrudate;

Example 13

The SAXSpace - Small Angle X-ray Scattering (SAXS or SAXS) system is not a destructive method for studying the crystallinity and orientation of materials, the stability of dispersions. The extrudate (example 3) and the components included in the extrudate were analyzed using SAXS for crystallinity of materials. The presence of characteristic peaks in the extrudate in the region of 5-10 degrees indicates that the APS is in a crystalline state in a freshly prepared extrudate (Figure 1) and for 1 month the extrudate is stored at 20 ° C / 60HD for 2 months (Figure 2) .

Claims

CLAIM

1. A method of obtaining an oral solid dosage form with mycophenolic acid or a pharmaceutically acceptable salt thereof, comprising extruding a mixture of a pharmaceutically acceptable polymer with an active substance, followed by the addition of excipients and the manufacture of a finished dosage form.

2. The method according to claim 1, in which the finished dosage form is made by compression.

3. The method according to claim 2, in which the finished dosage form is a tablet.

4. The method according to claim 1, in which the active substance is a pharmaceutically acceptable salt of mycophenolic acid.

5. The method according to claim 4, in which the active substance is sodium mycophenolate.

6. The method of claim 5, wherein the sodium mycophenolate is in a crystalline state.

7. The method according to claim 1, wherein a pharmaceutically acceptable water-soluble polymer is used.

8. The method according to claim 7 ,. in which hydroxypropyl methylcellulose is used as a water-soluble polymer, in an amount of from 3.0 mass% to 50.0 mass% of the weight of the finished dosage form.

9. The method of claim 8. in which hydroxypropyl methylcellulose is used as a water-soluble polymer, in an amount of 4.0% by weight of the finished dosage form.

10. The method according to claim 7, in which polyethylene glycol is used as a water-soluble polymer in an amount of from 3.0 mass% to 50.0 mass% by weight of the finished dosage form.

1 1. The method according to claim 10, in which polyethylene glycol is used as a water-soluble polymer in an amount of 13.0% by weight of the finished dosage form.

12. The method according to claim 7, in which polyvinylpyrrolidone is used as a water-soluble polymer in an amount of from 3.0 mass% to 50.0 mass% by weight of the finished dosage form.

23

SUBSTITUTE SHEET (RULE 26)

13. Method no. 12, in which polyvinylpyrrolidone is used in an amount of 18.5% by weight of the finished dosage form.

14. The method according to claim 7. in which hydroxypropyl cellulose is used as a water-soluble polymer in an amount of from 3.0 mass% to 50.0 mass% by weight of the finished dosage form.

15. The method of claim 14, wherein hydroxypropyl cellulose is used in an amount of 7% by weight of the finished dosage form.

16. The method according to claim 7, in which a combination of polyvinylpyrrolidone and polyethylene glycol is used as a water-soluble polymer in an amount of from 3.0 mass% to 95.0 mass% by weight of the finished dosage form.

17. The method according to claim 7, in which a combination of polyvinylpyrrolidone and hydroxypropylmethyl cellulose is used as a water-soluble polymer, in an amount of from 3.0 mass% to 95.0 mass% by weight of the finished dosage form.

18. The method according to claim 7, in which a combination of hydroxypropyl methylcellulose and polyethylene glycol is used as a water-soluble polymer, in an amount of from 3.0 mass% to 95.0 mass% by weight of the finished dosage form.

19. The method according to claim 7. in which a combination of polyvinylpyrrolidone, hydroxypropylmethyl cellulose and polyethylene glycol is used as a water-soluble polymer in an amount of from 3.0 mass% to 95.0 mass% of the weight of the finished dosage form.

20. The method according to claim 1, in which glidant is used as auxiliary substances.

21. The method according to claim 20 ,. in which silicon dioxide is used as a glidant, in an amount of from 0, 1 to 10 wt.% by weight of the finished dosage form.

22. The method according to item 21, in which silicon dioxide is used in an amount of from 0.5 to 5.0 wt.% By weight of the finished dosage form.

23. The method according to item 22, in which silicon dioxide is used, in an amount of 1% of the mass by weight of the finished dosage form.

24. The method according to claim 1, in which lubricants are used as auxiliary substances.

25. The method according to paragraph 24, in which as a lubricant using magnesium stearate, in an amount of from 0.1 to 5.0 wt.% By weight of the finished dosage form.

24

SUBSTITUTE SHEET (RULE 26)

26. The method according A.25, which use ¹ CToapatt of magnesium, in an amount of from 0.5 to 2.0 wt.% By weight of the finished dosage form.

27. The method according to p. 26, in which magnesium stearate is used, in an amount of 1% of the mass by weight of the finished dosage form.

28. The method according to claim 1,. in which pregelatinized starch is used as auxiliary substances in an amount of from 0.3% to 60% by weight of the finished dosage form.

29. The method according to p. 28, in which pregelatinized starch is used in an amount of 4% by weight of the finished dosage form.

30. The method according to claim 1, in which surfactants are used as auxiliary substances.

31. The method according to p. 30, in which as a surfactant Poloxamer 407, in an amount of from 0.3% to 5.0% by weight of the finished dosage form.

32. The method according to p. which use Poloxamer 407, in an amount of 3% of the mass by weight of the finished dosage form.

33. The method according to clause 30. in which Poloxamer 338 is used as a surfactant, in an amount of from 0.3% to 5.0% by weight of the finished dosage form.

34. The method according to clause 33. which use Poloxamer 338, in the amount of 3% of the mass by weight of the finished dosage form.

35. The method according to p. 1, in which the extrusion is carried out by heating.

36. The method according to clause 35, in which the temperature of the extrusion from 60 to 140 ° C.

37. The method according to clause 36, in which the temperature of the extrusion is 120 ° C.

38. The method according to clause 36, in which the temperature of the extrusion of 105 ° C.

39. The method according to claim 1, in which the active substance is protected by an enteric coating.

40. An oral solid dosage form with mycophenolic acid or a pharmaceutically acceptable salt thereof for use as an immunosuppressant for treating or preventing organ or tissue transplant rejection obtained by the method according to any one of claims. 1 -39.

25

SUBSTITUTE SHEET (RULE 26)