KR100491274B1 - Enteric-Coated Pharmaceutical Compositions of Mycophenolate - Google Patents

Abstract

The present invention provides a pharmaceutical composition containing a mycophenolate salt, modified to release mycophenolate at the top of the intestine.

Description

Enteric Coated Pharmaceutical Compositions of Mycophenolate

<Example 1>

Composition

Capsule content

MPA mono sodium salt 53.43 mg (= 50 mg MPA)

Lactose (1: 1 mixture of 100/200 mesh) 256.57 mg

Silica (Aerosil) 3.1 mg

Magnesium Stearate 1.55 mg

314.65 mg

Capsule is size 1.

Enteric coating (about 17 mg)

Hydroxypropyl methyl cellulose phthalate (HP50) 9 parts

Triacetin part 1

Way

The capsule ingredients are mixed and filled into size 1 capsules. This capsule is coated with a fluid bed coater with a solution of enteric coating components in ethanol (containing 10% acetone). The coating amount on each capsule is about 17 mg. The capsules conform to the enteric coating test described herein and do not degrade in 2 hours in artificial gastric juice (pH 1, HCl). The composition is stable for 2 years, for example at room temperature.

If necessary, larger capsules containing 534.3 mg of MPA mono sodium salt can be prepared in the same manner, while reducing the amount of lactose. This is well tolerated in clinical trials.

<Example 2>

Capsules of size 1 were prepared as in Example 1. Enteric coating solutions consist of:

270 g of hydroxypropyl methyl cellulose phthalate (HP50)

30 g of triacetin

Acetone 900 g

1800 g of ethanol

600 g of this enteric coating solution is used for 1 kg (about 2400) capsules. The amount of coating used for each capsule is about 25 mg giving a film thickness of 5 to 6 mg / cm ² .

The present invention relates to mycophenolic acid.

Mycophenolic acid, also referred to herein as MPA, was first isolated in 1896 and has been extensively studied as a potential commercial benefit agent. Mycophenolic acids are well known for having antitumor, antiviral, immunosuppressive, anti- psoriasis, and anti-inflammatory activities. See, for example, WA Lee et al., Pharmaceutical Research (1990), 7, pp. 161-166) and references cited therein]. Literature on MPA as an anticancer agent is described by Lilly scientists (see MJ Sweeney et al., Cancer Research (1972), 32, 1795-1802), and by ICI scientists (UK Patent Nos. 1,157,099 and 1,203,328). And immunosuppressants, see A. Mitsui et al., J. Antibiotics (1969) 22 , pp. 358-363. The above-mentioned document by Lee et al. States that attempts have been made to increase the bioavailability or specificity of MPA by preparing derivatives. Poor bioavailability of mycophenolic acid was thought to be caused by unidentified factors such as drug complexation in the gastrointestinal lumen, narrow absorption window, and metabolic action before absorption. Also, of morpholinoethyl esters (100% for MMF and 43% for MPA) with significantly higher bioavailability than MPA, also known as mycophenolate mofetil (sometimes referred to herein as MMF). The preparation method is described. This derivative has recently been introduced commercially as an immunosuppressant for the treatment or prevention of organ or tissue transplant rejection, at a daily dosage of about 200 mg to about 3 g orally, for example about 2 g orally. Acceptable compliance of MMFs is not ideal, in particular because of unknown causes such as, for example, gastrointestinal side effects.

After thorough testing, we found that mycophenolate salts are homologous to organs, tissues, or cells when the mycophenolate salts are enteric coated or modified such that they are released from the top of the intestine, such as the duodenum, jejunum, and / or ileum. It is a drug that has good resistance to immunosuppressive use for the treatment or prevention of tissue transplantation or xenograft rejection, or for the treatment or prevention of immune-mediated diseases (autoimmune diseases), and has interesting bioavailability and stability characteristics. I found that. In addition, administration is easier because it must be administered in a smaller unit dosage form than MMF.

The present invention provides, in one aspect, pharmaceutical compositions containing mycophenolate salts, hereinafter referred to as compositions of the present invention, modified to release mycophenolate at the top of the intestine. The composition may be modified in any conventional manner, preferably in a modified manner to prevent mycophenolate release from the stomach and to ensure release at the top of the intestinal tract. In a further aspect of the invention there is provided a pharmaceutical composition comprising a pharmaceutically acceptable, coated mycophenolate salt.

Such salts are, for example, salts of alkali metals, in particular cationic salts such as sodium salts. Sodium mycophenolate salts are known, for example, from South African Patent No. 68/4959. We prefer to use mono-sodium salts. Mono sodium salt can be obtained in crystalline form from acetone / ethanol by recrystallization with water if necessary. Melting point 189-191 ° C.

The present invention more particularly provides a solid enteric coated composition in oral unit dosage form, wherein the core of the composition contains sodium mycophenolate in solid or liquid form.

"Core" includes, if necessary, sodium mycophenolate (or other cationic salt) in admixture with additional physiologically acceptable materials, which may be wrapped with an enteric coating. The term “core” broadly includes tablets, pellets or granules as well as capsules (eg, soft or hard capsules of gelatin or starch). Such cores can be prepared by conventional methods. The inventors have found that mycophenolate salts, in particular their sodium salts, are of particular interest for the manufacture of tablets. When using tablet cores, they preferably have a hardness of about 10 to 70 N.

As will be explained later, after the application of the enteric coating, the pellets or granules can be used on their own or to fill capsules, such as hard gelatin capsules. Alternatively, if desired, the capsule may be enterically coated in a conventional manner.

For example, other pharmaceutically acceptable ingredients commonly used in the manufacture of pharmaceutical compositions may include, for example, fillers such as lactose, glidants such as silica, and lubricants such as magnesium stearate. .

The term "enteric coating" prevents the release of the active ingredient in the stomach and in the intestinal tract all pharmaceuticals that allow it to be sufficiently degraded (due to contact with almost neutral or alkaline enteric juices) to allow the active ingredient to be reabsorbed through the intestinal wall. Possible coatings are included. Several in vitro tests have been published in the pharmacopoeias of various countries to determine which coatings can be classified as enteric coatings.

More particularly, the term "enteric coating" as used herein, when contacting an artificial gastric juice such as HCl at pH 1 at 36 to 38 ° C, remains for at least 2 hours, preferably after KH at pH 6.8 Refers to a coating that degrades within 30 minutes in artificial intestinal juice, such as ₂ PO ₄ buffer solution.

Coating thicknesses may vary and depend in particular on their permeability in water and acids. Conventional coatings may be up to about 16-30, such as 16-20 or 25 mg or less in size 1 gelatin capsules. Other formulations will be applied at similar thicknesses.

In general, satisfactory results are obtained with a coating having a thickness of 5 to 100 μm, preferably 20 to 80 μm. The coating is suitably selected from macromolecules. Suitable polymers are described, for example, in L. Lachman et al., The Theory and Practice of Industrial Pharmacy, 3rd edition, 1986, pp. 365-373, H. Sucker et al., Pharmazeutische Technologie, Thieme, 1991, pp. 355-359, Hagers Handbuch der pharmazeutischen Praxis, 4th edition, Vol. 7, pp. 739-742, and 766-778, (Springer Verlag, 1971), and Remington's Pharmaceutical Sciences, 13th edition, pp. 1689 to 1691 (Mack Publ., Co., 1970), for example, cellulose ester derivatives, cellulose ethers, acrylic resins (eg, methylacrylate copolymers and aerials of maleic and phthalic acid derivatives). Coalescence).

Preferred membranes include cellulose acetate phthalate and trimellitate; From methacrylic acid copolymers (e.g., copolymers derived from methylacrylic acid and esters thereof, including at least 40% methylacrylic acid, and especially hydroxypropyl methylcellulose phthalate).

Methylacrylates include, for example, compounds having a molecular weight greater than 100,000 Daltons based on methyl acrylate of about 1: 1 and methyl or ethyl methylacrylate. Typical products include Endragit L, for example L 100-55, sold by Rohm GmbH, Darmstadt, Germany.

Typical cellulose acetate phthalates have a viscosity of about 45 to 90 cP, an acetyl content of 17 to 26% and a phthalate content of 30 to 40%.

Typical cellulose acetate trimellitates have a viscosity of about 15-20 cS, an acetyl content of 17-26%, and a trimellityl content of 25-35%. An example of a suitable cellulose acetate trimellitate is the commercial product CAT (Eastman Kodak Company, USA).

Hydroxypropyl methylcellulose phthalate typically has a molecular weight of 20,000 to 100,000 Daltons, for example 80,000 to 130,000 Daltons, for example, 5-10% hydroxypropyl content, 18-24% methoxy content and It has a phthalyl content of 21 to 35%.

An example of a suitable cellulose acetate phthalate is the commercially available product CAP (Eastman Kodak, Rochester, NY).

Examples of suitable hydroxypropyl methylcellulose phthalates include a hydroxypropyl content of 6-10%, 20-24%, known under the trade name HP50 of Shin-Etsu Chemical Co. Ltd. (Tokyo, Japan). Products having a methoxy content, a phthalyl content of 21 to 27%, and a molecular weight of about 84,000 Daltons, and a hydroxypropyl content, methoxy content and phthalyl content, respectively known under the trade name HP55 available from the same company, from 5 to Products with 9%, 18-22% and 27-35%, and molecular weight 78,000 Daltons are commercially available.

HP50 is the preferred coating.

Enteric coating can be carried out by conventional methods, for example by spraying a core with an enteric coating solution.

Suitable solvents for enteric coatings include, for example, alcohols such as ethanol, ketones such as acetone, halogenated hydrocarbons such as CH ₂ Cl ₂ or mixtures of such solvents (e.g., 1: 1 to 10: 1 ethanol / Acetone).

Typically emollients such as di-n-butylphthalate or triacetin are added to such a solution, for example, in a ratio of 1 to about 0.05 to about 0.3 coating material to softener.

If desired, cellulose phthalate and other acidic coating materials may be ammonium salts, and aqueous solutions may be used.

Fluid bed coaters can be used for coating.

Typically, the cores are treated at room temperature or warmed up to 40 ° C. with warm air at 40-70 ° C. prior to spraying. In order to prevent the core from becoming tacky, it is desirable to stop the spraying process at predetermined time intervals and then to warm up again. However, it is also possible to proceed the spraying process without interruption, for example by automatically adjusting the spraying amount in view of the exhaust temperature and / or the temperature of the core.

Spray pressures can vary over a wide range and generally satisfactory results are obtained with spray pressures of about 1 to about 1.5 bar.

The compositions of the present invention are useful as immunosuppressive agents, as indicated by standard tests.

The activity and properties of the compositions of the present invention can be represented by the following standard tests.

a) Standard clinical trials (eg, to see if there is an initial acute rejection episode or treatment failure within 6 months after renal transplantation, or if the rejection status remains within 6 months after initiation of treatment according to the present invention). When the composition of the present invention is administered in a range of 0.5 to 2.0 g / day, for example, about 1.5 g / day, the rate of acute rejection decreases when administered during the period near the transplant surgery, Patients older than 3 months remain without rejection. For example, the compositions of the present invention may be prepared by conventional steroids and cyclosporine (e.g., Neoral, where the cyclosporine dosage is a typical dosage of, for example, about 8 ± 3 mg / kg for kidney transplantation). And twice a day at a dose of about 0.5 g for the initial 72 hours after transplantation. The steroid will be administered about 2.5 mg / kg for 4 days following transplantation, then 1 mg / kg for 1 week, then 0.6 mg / kg for 2 weeks, and then 0.3 mg / kg for 1 month of prednisone.

b) Standard animal test (eg, observe kidney allograft response in rats). In this test, one kidney from a female P. 344 rat was implanted using end-to-end anastomosis into the renal vessels of a WF transplanted rat with one (left) kidney removed. Ureteral anastomosis is also an end-to-end anastomosis. Treatment started on the day of implantation and continued for 14 days. The transplant was left to rely on the function of the feeding kidneys and the other kidneys were excised 7 days after transplantation. Survival of the graft is accepted as a parameter of functional graft tissue. Typical dosages of the compositions of the invention are about 1 to 30 mg / kg orally.

The composition of the present invention is particularly useful for the following symptoms.

a) treatment and prevention of allograft or xenotransplantation rejection of natural or transgenic organs, tissues or cells, including the treatment and prevention of acute rejection, for example, heart, lung, combined heart-lung, Treatment of transplants such as liver, kidney, pancreas, skin, pancreatic islet cells, nerve cells or cornea transplants; Superacute rejection reactions, eg, treatment and prevention of superacute rejection reactions associated with xenograft rejection; And chronic rejection reactions, eg, treatment and prevention of chronic rejection reactions associated with graft-vascular disease. The compositions of the present invention are also required for the treatment and prevention of graft-versus-host diseases, such as after bone marrow transplantation.

b) treatment and prevention of autoimmune diseases, eg inflammatory symptoms related to etiology, including immune-mediated diseases and inflammatory diseases, in particular immunological factors such as arthritis (eg rheumatoid arthritis, arthritis chronic) Treatment and prevention of progrediente and arthritis deformans and rheumatoid diseases. Specific immune-mediated diseases in which the compositions of the invention can be used include autoimmune blood disorders (including hemolytic anemia, aplastic anemia, sedated anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, scleroderma, Wegener granulosis, dermatitis, polymyositis, chronic acute hepatitis, primary biliary cirrhosis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, pemphigus, idiopathic sprue, inflammatory bowel disease (e.g., Ulcerative colitis and Crohn's disease), endocrine eye disease, Graves' disease, sarcoidosis, multiple sclerosis, combustible diabetes (diabetes mellitus type I), non-infectious uveitis (allergic uveitis and posterior uveitis), dry keratoconjunctivitis And spring keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, vasculitis, glomerulonephritis (with and without nephrotic syndrome, eg idiopathic nephrotic syndrome) Comprises a modification comprising at least nephropathy) and juvenile dermatomyositis, but are not limited to.

Of course, the appropriate dosage of the composition of the present invention will vary depending, for example, on the condition to be treated (eg, the type of disease or nature of resistance), the MPA salt used, the desired result and mode of administration.

However, generally satisfactory results are obtained by oral administration of, for example, about 1 to about 30 mg salt per kg body weight per day, at one time or divided up to four times a day. Thus, the appropriate daily dose of the patient is orally 200 mg to 3 g, for example about 50 to 100% of the mycophenolate mofetil dosage. In the case of the preferred mono sodium salt, the dose of salt is about 2/3 of the mycophenolate mofetil dose.

Representative unit dosage forms comprise from about 50 mg to about 1.5 g (eg 100 mg) of pharmaceutically acceptable mycophenolate salt.

The bioavailability characteristics of the compositions of the present invention can be determined by conventional methods such as oral administration to hounds. The dosage is typically 50 mg of salt, eg, about 3-5 mg of salt per kg of animal body weight. Dogs are grown dogs (about 10 kg, eg 6-14 kg) and fasted. About 200 g of food was given 3 hours after administration. Blood samples were drawn from the cerebral veins before and after 10, 30 and 45 minutes after administration, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours. The plasma content of free MPA is determined by HPLC analysis (with UV detection).

In the relative bioavailability test of the male hound described above, animal weights were orally administered to the Example 1 composition described below, and to an MPA or MMF formulation similar to the Example 1 composition but comprising the same amount of MPA or commercially available MMF. 3.8 mg of sugar salt was administered.

The result is as follows.

Example 1 The coefficient of variation (CV) of the AUC (20%) and Cmax (34%) of the composition was significantly less than the CV of the reference composition. This means that for the composition of Example 1 the rate of change between and within subjects is small.

Example 1 The area under the curve (AUC) and Cmax of the composition were greater than the reference composition.

Of course, the beneficial bioavailability properties of the compositions of the present invention can be confirmed by standard clinical bioavailability tests. For example, in a crossover trial, 12 healthy volunteers may be administered a single dose of 200 mg to 1.5 g of the Example 1 composition, MPA, and MMF. Example 1 An increase in AUC and Cmax can be observed in the composition.

Surprisingly, the compositions of the present invention have better resistance than MMF while inducing less gastrointestinal side effects such as diarrhea and burning. They show, for example, that the side effects period is shorter in the colon.

The compositions of the present invention may be used alone or in combination with other immunosuppressive agents, for example with simultaneous or separate administration, with other immunosuppressive agents, for example graft-versus-host disease, transplant rejection, or immune-mediated disease. It may be administered in immunosuppressive uses such as the treatment and prophylaxis of medicaments, and the compositions of the present invention may be cyclosporin or ascomycin, or immunosuppressive analogs thereof, such as cyclosporin A, FK-506 (tacrolimus), such as rapamycin. ; Corticosteroids; Cyclophosphamide; Azithioprine; Methotrexate; Brequina; Leflunomide; Miso bean; Deoxysperguarine; Immunosuppressive monoclonal antibodies such as analogues thereof and monoclonal antibodies of leukocyte receptors (eg, MHC, CD2, CD3, CD4, CD7, CD25, CD28, CTLA4, B7, CD45, or CS58 or ligands thereof) Immunosuppressive analogs thereof, such as; Or in combination with other immunomodulatory compounds.

When the composition of the present invention is administered in combination with such other immunosuppressive agents, the dosage of other immunosuppressive agents may be reduced to 1/2 to 1/3 of the dose when used alone.

Representative dosages of cyclosporin to be used are, for example, 1 to 10, for example 1 to 2 mg / kg / day.

In another aspect, the present invention provides uses, methods and compositions as defined in the claims which follow.

Those that do not describe the details of excipients herein include, for example, Handbook of Pharmaceutical Excipients, Second Edition, edited by Ainley Wade and Paul J. Weller, American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London; And Lexikon der Hilfsstoffe fuer Pharmazie, Kosmetik and angrenzende Gebiete, H.P. Fiedler Compilation, 4th Edition, Edito Cantor, Aulendorf and previous editions.

The following merely illustrates the composition of the present invention by way of example.

Claims (9)

A pharmaceutical composition comprising a pharmaceutically acceptable enteric coated mycophenolate salt. Allogeneic transplantation or xenograft of natural or transgenic organs, tissues or cells for immunosuppression, including pharmaceutically acceptable enteric coated mycophenolate salts, optionally administered simultaneously or separately with another immunosuppressant A medicament for the prevention or treatment of transplant rejection or for the treatment or prevention of immune-mediated and / or inflammatory diseases. The medicament according to claim 2, wherein the pharmaceutically acceptable mycophenolate salt is a mono-sodium salt. The medicament according to claim 2 or 3, wherein the other immunosuppressant is cyclosporin A, FK 506 or rapamycin. The pharmaceutical composition according to claim 1, wherein the coating comprises cellulose acetate phthalate and trimellitate, or methacrylic acid copolymer containing at least 40% methacrylic acid, or hydroxypropyl methylcellulose phthalate. The pharmaceutical composition according to claim 1 or 5, which is in the form of a tablet. The pharmaceutical composition according to claim 1 or 5, wherein the salt is a mono-sodium salt. 8. A pharmaceutical composition according to claim 7, wherein the monosodium salt is in crystalline form. 6. A pharmaceutical composition according to claim 1 or 5 containing about 50 mg to 1.5 g of pharmaceutically acceptable mycophenolate salt.