WO2021106004A1

WO2021106004A1 - Pharmaceutical composition of s-adenosylmethionine

Info

Publication number: WO2021106004A1
Application number: PCT/IN2020/050091
Authority: WO
Inventors: Sanjeev Gupta; Rajeev Gupta; Tg CHANDRASHEKHAR; Swati Mukherjee; Amit Gupta
Original assignee: Kusum Healthcare Pvt. Ltd.
Priority date: 2019-11-25
Filing date: 2020-01-28
Publication date: 2021-06-03
Also published as: MX2022005714A; MD20220032A2; MD4877B1

Abstract

The present invention relates to a solid oral pharmaceutical composition of S-adenosylmethionine (SAMe) or its pharmaceutically acceptable salts and a method of preparing the same. The solid oral pharmaceutical composition prepared by the process of the invention is also stable when subjected to stress conditions at a temperature of 40°C. and relative humidity ("RH") of 75% for a period of at least three days.

Description

PHARMACEUTICAL COMPOSITION OF S-ADENOSYLMETHIONINE

FIELD OF THE INVENTION

The present invention relates to a solid oral pharmaceutical composition of S- adenosylmethionine (SAMe) or its pharmaceutically acceptable salts and a method of preparing the same.

BACKGROUND OF THE INVENTION

S-adenosylmethionine (SAMe) occurs naturally in tissues throughout the human body where it is involved in various metabolic pathways such as transmethylation, transsulfuration and aminopropylation. Deficiency of S-adenosylmethionine in the human body is related to the development of osteoarthritis, cirrhosis of liver, cystic fibrosis, depression, and disorders related to ageing such as Alzheimer's and Parkinson's disease.

SAMe is approved in several countries in the world including Italy, Germany, Spain, India, China etc. Its formulations are also marketed as a dietary supplement in the USA, Canada, Australia and several other countries.

SAMe is highly unstable and undergoes degradation at temperature above 0°C to produce S- adenosylhomocysteine (SAH), homoserine, methylthioadenosine (MTA), S-5 ‘-adenosyl- (5’)-3-methylpropylamine or decarboxylated SAMe (dcSAMe) and adenine. It is also sensitive to moisture. These attributes of the drug pose challenges during its manufacturing, transportation and storage. In order to improve stability of SAMe, various salts have been synthesized such as tosylate disulfate salt, 1,4-butanedisulfonate salt, di-para- toluene sulfonate disulfate salt, tri-para-toluene sulfonic acid salt and the like. However, most of these salts are hygroscopic and rapidly degrade upon exposure to moisture and heat. These characteristics adversely impact manufacturability of a dosage form of S- adeno s y lmethionine . SAMe is currently available in the market in form of tablets but there remains a need in the market of dosage forms of S-adenosylmethionine which is manufactured by a simple and cost effective process. Further, there also remains a need for alternate pharmaceutical composition of S-adenosylmethionine and /or its pharmaceutically acceptable salt which is suitable for oral administration to humans and exhibits desirable chemical and physical properties, disintegration, dissolution, stability and bioequivalence complying with demanding requirements and regulations of health and medicine regulatory agencies across the globe.

The Applicants have successfully developed a solid oral pharmaceutical composition comprising S-adenosylmethionine and /or its pharmaceutically acceptable salt, prepared by a process which is not only simple, robust, commercially viable but is also amenable to execution at ambient temperature. The solid oral pharmaceutical composition prepared by the process of the invention is also stable when subjected to stress conditions at a temperature of 40°C. and relative humidity ("RH") of 75% relative humidity for a period of at least three days.

SUMMARY OF THE INVENTION

It is a principal object of the present invention to provide a solid oral pharmaceutical composition of S-adenosylmethionine or its pharmaceutically acceptable salts.

Further object of the present invention is to provide a solid oral pharmaceutical composition of S-adenosylmethionine or its pharmaceutically acceptable salts, wherein said composition comprises a core tablet prepared by dry granulation and at least one enteric coat layer over the core tablet.

Another object of the present invention is to provide an environment friendly process for preparing a solid oral pharmaceutical composition of S-adenosylmethionine or its pharmaceutically acceptable salts, wherein said composition exhibits better stability and effective bioavailability by virtue of selection of excipients.

The following embodiments further describe the objects of the present invention, however, the disclosed invention is not restricted to the particular embodiments hereinafter described and extends to cover the modifications obvious to one of ordinary skill in the art. In a preferred embodiment, the solid oral pharmaceutical composition comprises: a) a core tablet comprising a therapeutically effective amount of S-adenosylmethionine or its pharmaceutically acceptable salt with at least one pharmaceutically acceptable excipient; b) an enteric coat layer over the core tablet comprising a solution of copolymer of methacrylic acid and ethyl acrylate in at least one non-aqueous solvent; and c) a secondary layer encompassing the enteric coat layer, said secondary layer comprising a solution or suspension of copolymer of methacrylic acid and ethyl acrylate in water.

In an another preferred embodiment, the solid oral pharmaceutical composition comprises: a) a core tablet prepared by dry granulation of a blend of a therapeutically effective amount of S-adenosylmethionine or its pharmaceutically acceptable salt with at least one pharmaceutically acceptable excipient; b) an enteric coat layer over the core tablet comprising a solution of copolymer of methacrylic acid and ethyl acrylate in at least one non- aqueous solvent; and c) a secondary layer encompassing the enteric coat layer, said secondary layer comprising a solution or suspension of copolymer of methacrylic acid and ethyl acrylate in water.

Another embodiment of the present invention provides a process for the preparation of a solid oral pharmaceutical composition of S-adenosylmethionine or its pharmaceutically acceptable salt, comprising the step of blending S-adenosylmethionine or its pharmaceutically acceptable salt with at least one pharmaceutically acceptable excipient, dry granulating the blend, mixing the granules with at least one pharmaceutically acceptable excipient, lubricating the granules, compressing the lubricated granules into a solid pharmaceutical composition; enteric coating the solid pharmaceutical composition with a solution of copolymer of methacrylic acid and ethyl acrylate in at least one non-aqueous solvent and optionally coating the enteric coated solid oral pharmaceutical composition with of a solution or suspension of copolymer of methacrylic acid and ethyl acrylate in water.

In the pharmaceutical composition or dosage form or formulation of the present invention, pharmaceutically acceptable salts of S-adenosylmethionine include but are not limited to, tosylate disulfate salt, 1,4-butanedisulfonate salt, di-para-toluene sulfonate disulfate salt, tri- para-toluene sulfonic acid salt and the like. The preferred pharmaceutically acceptable salt of S-adenosylmethionine for the composition of the present invention is 1,4-butanedisulfonate salt or its pharmaceutically acceptable solvates or hydrates. In the solid oral pharmaceutical composition of the present invention, the pharmaceutically acceptable excipient comprises diluents, disintegrants, lubricants, glidants, plasticizers, emulsifiers, neutralizing agents and antifoaming agents.

DETAILED DESCRIPTION OF THE INVENTION

While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.

As used herein, the term “composition”, as in pharmaceutical composition, is intended to encompass a drug product comprising S-adenosylmethionine or its pharmaceutically acceptable salts, solvates, polymorphs, enantiomers or mixtures thereof, and other inert ingredient(s). Such pharmaceutical compositions are synonymous with “formulation” and “dosage form”. Pharmaceutical compositions of the invention include, but are not limited to, granules, tablets, modified release tablets, mini-tablets and the like. Preferably, the pharmaceutical composition refers to enteric coated tablets.

The term “immediate release (IR)” as used herein, refers to pharmaceutical compositions comprising S-adenosylmethionine or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients, which do not contain any drug release rate controlling agent. As a result, release of the active ingredient from the composition results in an in-vitro release over a short period of time, i.e., (less than one hour). Preferably, more than 85% of the drug is released within 20 minutes.

The term “controlled release (CR)” as used herein, refers to pharmaceutical compositions comprising S-adenosylmethionine or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients, which contain at least one drug release rate controlling agent.

The term “delayed release (DR)” as used herein, refers to pharmaceutical compositions comprising S-adenosylmethionine or its pharmaceutically acceptable salt, at least one pH dependent drug release rate controlling agent, and one or more pharmaceutically acceptable excipients. For the purpose of this invention enteric-coated articles are delayed release dosage forms. The preferred enteric polymers for the composition of the present invention are methacrylic acid copolymers. Copolymers of methacrylic acid and ethyl acrylate are excellent enteric polymers and are commercially available from Degussa, Germany, under the brand names Eudragit^®L 100-55 (powder form), Eudragit^®L30 D- 55 (30% aqueous dispersion of Eudragit^®L 100-55), Eudragit L100 (powder form) and Eudragit^®S 100 (powder form). The enteric coating is applied to achieve a weight buildup of 5 to 35%.

The term "about" as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.

Unless otherwise stated the weight percentages expressed herein are based on the final weight of the composition or formulation or dosage form.

The present invention relates to a cost effective solid oral pharmaceutical composition of S- adenosylmethionine or its pharmaceutically acceptable salts.

A first aspect of the present invention provides a solid oral pharmaceutical composition comprising S-adenosylmethionine or its pharmaceutically acceptable salt, wherein the composition comprises: a) a core tablet prepared by dry granulation of a blend of S-adenosylmethionine or its pharmaceutically acceptable salt with at least one pharmaceutically acceptable excipient; b) an enteric coat layer over the core tablet comprising a solution of copolymer of methacrylic acid and ethyl acrylate in at least one non-aqueous solvent; c) optionally a secondary layer encompassing the enteric coat layer, said secondary layer comprising a solution or suspension of copolymer of methacrylic acid and ethyl acrylate in water.

It was found by the inventors of the present invention that a solid oral pharmaceutical composition comprising S-adenosylmethionine or its pharmaceutically acceptable salt having at least one layer of copolymer of methacrylic acid and ethyl acrylate exhibited excellent storage stability.

According to one embodiment of the above aspect, the solid oral pharmaceutical composition is an immediate release composition or a controlled release composition. The term controlled release composition is used interchangeably with modified release composition and includes delayed release composition, extended release composition or sustained release composition. In a preferred embodiment, the solid oral pharmaceutical composition is a delayed release composition.

According to another embodiment of the above aspect, the solid oral pharmaceutical composition is in the form of powder, granules, pellets, capsules, mini tablets or tablets. In a preferred embodiment, the solid oral pharmaceutical composition is in the form of tablets.

According to another embodiment of the above aspect, the coating is applied to achieve a weight build up in the range of about 5% to about 35%.

According to another embodiment of the above aspect, the pharmaceutically acceptable salt of S-adenosylmethionine comprises tosylate disulfate salt, 1,4-butanedisulfonate salt, di-para- toluene sulfonate disulfate salt, tri-para-toluene sulfonic acid salt and the like. In a preferred embodiment, the pharmaceutically acceptable salt is 1,4-butanedisulfonate salt.

According to another embodiment of the above aspect, the solid oral pharmaceutical composition comprises a therapeutically effective amount of S-adenosylmethionine or its pharmaceutically acceptable salt. S-adenosylmethionine or its pharmaceutically acceptable salt as per the composition of the present invention is present in an amount of about 500 mg to about 2000 mg. Preferably, the solid oral pharmaceutical composition comprises about 949 mg of 1,4-butanedisulphonate salt of S-adenosylmethionine corresponding to about 500 mg of S-adenosylmethionine cation.

In accordance with still another embodiment of the above aspect, there is provided a solid oral pharmaceutical composition comprising a therapeutically effective amount of S- adenosylmethionine or its pharmaceutically acceptable salt prepared by wet granulation, dry granulation, dry blending, dry mixing or direct compression process. Other formulation techniques are also contemplated within the scope of the present invention. Wet granulation can be performed using Rapid mixer granulator, Fluid bed granulator, Planetary mixer and the like; dry blending can be performed using V-blender or key blender; and dry granulation can be performed using roller compacter or slugging techniques or by any other method known in the art. Any pharmaceutically acceptable granulating solvent can be used for wet granulation. Preferable granulating solvents include, but are not limited to, water, esters such as ethyl acetate; ketones such as acetone; alcohols such as methanol, ethanol, isopropanol, butanol; dichloromethane, chloroform, dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), ether, diethyl ether and combinations thereof. In accordance with still another embodiment of the above aspect, there is provided a solid oral pharmaceutical composition comprising a therapeutically effective amount of S- adenosylmethionine or its pharmaceutically acceptable salt wherein, the composition comprises from about 20% to about 80% by weight of S-adenosylmethionine based on the total weight of the composition.

The term "pharmaceutically acceptable excipients," as used herein, refers to excipients that are routinely used in pharmaceutical compositions. The pharmaceutically acceptable excipients may comprise diluents, disintegrants, lubricants, glidants, plasticizers, emulsifiers, neutralizing agents, antifoaming agents, and the like.

Suitable fillers or diluents are selected from the group comprising calcium carbonate, calcium phosphate, dibasic anhydrous calcium phosphate, calcium phosphate tribasic, calcium sulphate, cellulose powdered, silicified microcrystailine cellulose, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, microcrystailine cellulose, polydextrose, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, trehalose and xylitol, and combinations thereof. In a preferred embodiment, the pharmaceutically acceptable diluent is microcrystailine cellulose.

Suitable disintegrants are selected from the group comprising alginic acid, calcium phosphate tribasic, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, magnesium aluminun silicate, methylcellulose, microcrystailine cellulose, povidone, sodium alginate, sodium starch glycolate, polacrilin potassium, silicified microcrystailine cellulose, starch or pre- gelatinized starch, and combinations thereof. In a preferred embodiment, the pharmaceutically acceptable disintegrant is sodium starch glycolate.

Suitable lubricants are selected from the group comprising calcium stearate, glycerine monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil type I, magnesium lauryl sulphate, magnesium stearate, medium- chain triglycerides, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc, sucrose stearate and zinc stearate. In a preferred embodiment, the pharmaceutically acceptable lubricant is magnesium stearate. Suitable glidant is selected from the group comprising stearates such as magnesium stearate or calcium stearate; silicate salts such as magnesium silicate, magnesium trisilicate, magnesium silicate anhydrous or calcium silicate; starches; mineral salts such as talc; and colloidal silicon dioxide. In a preferred embodiment, the pharmaceutically acceptable glidant is colloidal silicon dioxide.

Directly compressible grades of pharmaceutically acceptable excipients are also contemplated within the scope of the present invention. Directly compressible excipient is selected from the group comprising anhydrous lactose, spray dried lactose, dibasic calcium phosphate dihydrate, microcrystalline cellulose, powdered cellulose, low substituted hydroxypropyl cellulose, dextrose, sucrose, modified dextrin + sucrose, spray dried maltose, maltodextrin, mannitol, xylitol, sorbitol, lactitol, starch, pre-gelatinized starch and combinations thereof.

Suitable emulsifiers are selected from the group comprising anionic, cationic, nonionic, or zwitterionic surfactants, or combinations thereof. Suitable non-limiting examples of emulsifiers are sodium lauryl sulphate; cetrimide; polyethylene glycols; polyoxyethylene - polyoxypropylene block copolymers such as poloxamers; polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate; sorbitan fatty acid esters such as sorbitan monostearate; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate; polyethylene glycol fatty acid esters such as polyoxyethylene mono stearate; polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether; polyoxyethylene castor oil; and mixtures thereof. Preferably, the emulsifier is polyoxyethylene sorbitan monooleate.

Suitable plasticizer is selected from the group comprising triethyl citrate, dibutylsebacate, triacetin, acetylated triacetin, tributyl citrate, glyceryl tributyrate, diacetylated monoglyceride, rapeseed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin, sorbitol, diethyl oxalate, diethyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, polyethylene glycol and combinations thereof. In a preferred embodiment, the pharmaceutically acceptable plasticizer is polyethylene glycol.

Suitable non-limiting example of a pharmaceutically acceptable antiadherent is talc.

Suitable non-limiting example of pharmaceutically acceptable antifoaming agent comprises dimethicone and simethicone. In a preferred embodiment, the pharmaceutically acceptable antifoaming agent is simethicone. Suitable neturalising agent is selected from the group comprising organic acids, organic bases, inorganic acids and inorganic bases. Suitable non-limiting examples of neturalising agents are L-tartaric acid, citric acid, fumaric acid, ascorbic acid, malic acid, maleic acid, acetic acid, hydrochloric acid, sodium hydroxide, magnesium hydroxide, calcium hydroxide and the like. In a preferred embodiment, the pharmaceutically acceptable neturalising agent is sodium hydroxide.

According to another embodiment of the above aspect, the solid oral pharmaceutical composition is free of binder.

According to another embodiment of the above aspect, the solid oral pharmaceutical composition when administered orally to a patient in need thereof, is bioequivalent to the marketed tablet (Heptral^™) formulation. Bioequivalence is established by comparing pharmacokinetic parameters, for example, AUC and C_max of the pharmaceutical composition of the present invention with Heptral^™ formulation in healthy human subjects in fed as well as fasting conditions.

The term "AUC" refers to the area under the time/plasma concentration curve after administration of the pharmaceutical composition.

The term "C_max" refers to the maximum concentration of S-adenosylmethionine in the blood following administration of the pharmaceutical composition.

According to yet another embodiment of the above aspect, the solid oral pharmaceutical composition is stable when subjected to stress conditions at a temperature of about 40°C. and relative humidity ("RH") of about 75% relative humidity for a period of at least three days.

A second aspect of the present invention provides a process for the preparation of a solid oral pharmaceutical composition comprising S-adenosylmethionine or its pharmaceutically acceptable salt, comprising the following steps: a) blending S-adenosylmethionine or its pharmaceutically acceptable salt with at least one pharmaceutically acceptable excipient; b) dry granulating the blend obtained in step a); c) blending the granulated material obtained in step b) with at least one pharmaceutically acceptable excipient; d) lubricating the granules obtained in step c); e) compressing the lubricated granules obtained in step d) into a solid pharmaceutical composition; f) coating the solid pharmaceutical composition obtained in step e) with a solution of copolymer of methacrylic acid and ethyl acrylate in at least one non-aqueous solvent; g) optionally coating the solid oral pharmaceutical composition obtained in step f) with a solution or suspension of copolymer of methacrylic acid and ethyl acrylate in water.

According to one embodiment of the above aspect, coating is performed till a weight build up in the range of about 5% to about 35% is achieved.

According to another embodiment of the above aspect, the product temperature of the solid pharmaceutical composition during coating is kept at a temperature between 30°C and 50°C.

According to yet another embodiment of the above aspect, the process is carried out at a relative humidity in the range of 5 to 25%.

The process of the invention makes it possible to prepare a pharmaceutical composition of S- adenosylmethionine or its pharmaceutically acceptable salt, wherein the composition is stable and the process is consistent as well as environment friendly and therefore feasible for industrial production, while maintaining stability and bioequivalence.

A third aspect of the present invention relates to a solid oral pharmaceutical composition comprising S-adenosylmethionine or its pharmaceutically acceptable salt, prepared by a process comprising the following steps: a) blending S-adenosylmethionine or its pharmaceutically acceptable salt with at least one pharmaceutically acceptable excipient; b) dry granulating the blend obtained in step a); c) blending the granulated material obtained in step b) with at least one pharmaceutically acceptable excipient; d) lubricating the granules obtained in step c); e) compressing the lubricated granules obtained in step d) into a solid pharmaceutical composition; f) coating the solid pharmaceutical composition obtained in step e) with a solution of copolymer of methacrylic acid and ethyl acrylate in at least one non-aqueous solvent; g) optionally coating the solid oral pharmaceutical composition obtained in step f) with a solution or suspension of copolymer of methacrylic acid and ethyl acrylate in water.

A fourth aspect of the present invention provides a stable delayed release solid oral pharmaceutical composition comprising:

(a) a compressed core comprising S-adenosylmethionine or its pharmaceutically acceptable salt in an amount of about 10% to about 95% by weight, at least one diluent in an amount of about 5% to about 55% by weight, at least one disintegrant in an amount of about 0.5% to about 20% by weight, at least one glidant in an amount of about 0.2% to about 5.0% by weight, at least one lubricant in an amount of about 0.2% to about 5.0% by weight;

(b) an enteric coating layer comprising about 5.0% to about 35% by weight of enteric polymer, antiadherent in an amount of 0% to about 5.0% by weight, plasticizer in an amount of 0% to about 2.0% by weight;

(c) a secondary layer surrounding the enteric coating layer comprising about 5.0% to about 35.0% by weight of enteric polymer, antiadherent in an amount of 0% to about 5.0% by weight, plasticizer in an amount of 0% to about 2.0% by weight; wherein said compressed core is devoid of any binder.

In accordance with an embodiment of the above aspects, the compressed core comprising S- adenosylmethionine or its pharmaceutically acceptable salt is in the form of granules, pellets, capsules, mini tablets or tablets.

In accordance with a preferred embodiment of the above aspect, the compressed core comprises S-adenosylmethionine or its pharmaceutically acceptable salt in an amount of 70% to 90% by weight, at least one diluent in an amount of 5% to 20% by weight, at least one disintegrant in an amount of 0.5% to 20% by weight, at least one glidant in an amount of 0.2% to 2.0% by weight, at least one lubricant in an amount of 0.2% to 2.0% by weight;

In accordance with a preferred embodiment of the above aspect, the enteric coating layer comprises 2.0% to 7.0% by weight of enteric polymer, antiadherent in an amount of 0% to 4.0% by weight, plasticizer in an amount of 0% to 2.0% by weight;

In accordance with a preferred embodiment of the above aspect, the secondary layer surrounding the enteric coating layer comprises 0.5% to 3.0% by weight of enteric polymer, antiadherent in an amount of 0% to 2.0% by weight, plasticizer in an amount of 0% to 2.0% by weight.

In accordance with another embodiment of the above aspects, the pharmaceutical composition is in the form of a delayed release oral tablet comprising:

(a) a compressed core in the form of a tablet comprising S-adenosylmethionine or its pharmaceutically acceptable salt in an amount of about 78% by weight, diluent in an amount of about 11.0% by weight, disintegrant in an amount of about 1.75% by weight, glidant in an amount of about 0.6% by weight, lubricant an amount of about 0.2% by weight;

(b) an enteric coating layer comprising about 3.0% by weight of enteric polymer, antiadherent in an amount of about 1.67% by weight, plasticizer in an amount of about 0.5% by weight;

(c) a secondary layer surrounding the enteric coating layer comprising about 1.0% by weight of enteric polymer, antiadherent in an amount of about 0.5% by weight, plasticizer in an amount of about 0.15% by weight; wherein the compressed tablet core is devoid of any binder.

According to one embodiment of the above aspect, the tablets have a moisture content below 7% as determined by Karl fisher method.

The solid oral pharmaceutical composition prepared by the above process can be subjected to in vitro dissolution evaluation to determine the rate at which the active substance is released from the dosage form, and the content of the active substance can be determined in solution by high performance liquid chromatography or ultraviolet spectroscopy. When comparing the test and reference products, dissolution profiles should be compared using a similarity factor (f2). The similarity factor is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) of dissolution between the two curves. f₂ = 50 · log

where log is logarithm to base 10, n is the number of sampling time points, å is summation over all time points, R_t is the dissolution value of the reference product at time t, and T_t is the dissolution value of the test product at time t.

Two dissolution profiles are considered similar when the f2 value is equal to or greater than 50.

According to another embodiment of the above aspect, solid oral pharmaceutical composition exhibits a f₂ value of equal to or greater than 50 with respect to marketed reference product Heptral^® tablets by Abbott Laboratories.

In accordance with another embodiment of the above aspects, the solid oral pharmaceutical composition comprising S-adenosylmethionine or its pharmaceutically acceptable salt is a coated composition. Coating may be performed by applying the coating composition as a solution/suspension/blend using any conventional coating technique known in the art such as spray coating in a conventional coating pan, fluidized bed processor, dip coating, or compression coating. The percentage of the coating build-up shall be varied depending on the required drug release profile. Suitable solvents used for forming a solution or dispersion for coating are selected from the group comprising water, ethanol, methylene chloride, isopropyl alcohol, acetone, methanol, dichloromethane and combinations thereof.

In accordance with yet another embodiment of the above aspects, the solid oral pharmaceutical composition comprising S-adenosylmethionine or its pharmaceutically acceptable salt is packaged in a suitable package such as a bottle or blister packs. Preferably, the solid oral pharmaceutical composition comprising S-adenosylmethionine or its pharmaceutically acceptable salt is packaged in Alu/Alu cold form blister pack.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail method for the preparation and testing of S-adenosylmethionine pharmaceutical composition. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

Following examples are set out to illustrate the invention and do not limit the scope of the present invention.

Example I

Enteric coated tablets of S-adenosylmethionine were prepared using the quantitative formula as given in Table 1:

TABLE 1

Procedure: a) S-adenosylmethionine 1,4- butanedisulfonate, Microcrystalline Cellulose and Sodium starch glycolate were sifted through # 30 mesh sieve. The sifted blend was mixed for 15 minutes in a bin blender. b) Magnesium stearate was sifted through # 60 mesh sieve and added to the mixture obtained in step a) and mixed for 5 minutes. c) The mixture obtained in step b) was compacted in a roller compacter. d) The compacts obtained in step c) were passed through #20 ASTM sieve to form granules. e) The granules obtained in step d) were blended with Colloidal silicon dioxide in a bin blender for 10 minutes and lubricated with Magnesium Stearate. f) The lubricated granules obtained in step e) were compressed into a tablet at a temperature not more than 25°C and relative humidity not more than 20% RH. g) The tablets obtained in step f) were coated with a solution of copolymer of methacrylic acid and ethyl acrylate in a mixture of Isopropyl Alcohol and Dichloromethane . h) Enteric coated tablets obtained in step g) were coated with a suspension of copolymer of methacrylic acid and ethyl acrylate in water.

Example II

Enteric coated tablets of S-adenosylmethionine were prepared using the quantitative formula as given in Table 2:

TABLE 2

Procedure: a) S-adenosylmethionine 1,4- butanedisulfonate, Dibasic anhydrous calcium phosphate and Sodium starch glycolate were sifted through # 30 mesh sieve. The sifted blend was mixed for 15 minutes in a bin blender. b) Magnesium stearate was sifted through # 60 mesh sieve and added to the mixture obtained in step a) and mixed for 5 minutes. c) The mixture obtained in step b) was compacted in a roller compacter. d) The compacts obtained in step c) were passed through #20 ASTM sieve to form granules. e) The granules obtained in step d) were blended with Colloidal silicon dioxide in a bin blender for 10 minutes and lubricated with Magnesium Stearate. f) The lubricated granules obtained in step e) were compressed into a tablet at a temperature not more than 25°C and relative humidity not more than 20% RH. g) The tablets obtained in step f) were coated with a solution of copolymer of methacrylic acid and ethyl acrylate in a mixture of Isopropyl Alcohol and Dichloromethane . h) Enteric coated tablets obtained in step g) were coated with a suspension of copolymer of methacrylic acid and ethyl acrylate in water.

Example III

The dissolution profile of enteric coated tablets of S-adenosylmethionine prepared as per Example I was measured in 750 mL of 0.1 N HC1 using a paddle apparatus at a temperature of 37+0.5°C and a rotation speed of 50 revolutions per minute for 120 minutes. The dissolution profile of enteric coated tablets of S-adenosylmethionine prepared as per Example I was also measured in 1000 mL of Phosphate Buffer, pH 6.8 (750 mL 0.1 N HC1 + 250 mL Phosphate Buffer) using a paddle apparatus at a temperature of 37+0.5°C and a rotation speed of 50 revolutions per minute for 90 minutes (refer Table 3 below for exact time points). The dissolution test was conducted on the commercially available reference formulation HEPTRAL^® tablets (500 mg) manufactured by Abbott Laboratories in comparison to an enteric coated tablet dosage form prepared as per Example I. The dissolution data is provided in Table 3.

Table 3

When applying the acceptance limits of Ϊ2 value equal to or greater than 50 for determining similarity, dissolution profile of enteric coated tablets of S-adenosylmethionine prepared as per Example I was found to be similar to the dissolution profile of the reference Heptral tablet.

Example IV

Enteric coated tablets of S-adenosylmethionine prepared as per Example I were subjected to stress testing at temperature/relative humidity of 40°±2°C / 75%±5% RH for three days. The tablet dosage form was packaged in Alu/Alu strips and analyzed for related substances by a validated High Performance Liquid Chromatography (HPLC) method. The prepared dosage form was found to exhibit following results:

TABLE 4

Example V

Film coated tablets of S-adenosylmethionine were prepared using the quantitative formula as given in Table 5:

TABLE 5

Procedure: a) S-adenosylmethionine 1,4- butanedisulfonate, Microcrystalline Cellulose and Sodium starch glycolate were sifted through # 30 mesh sieve. The sifted blend was mixed for 15 minutes in a bin blender. b) Magnesium stearate was sifted through # 60 mesh sieve and added to the mixture obtained in step a) and mixed for 5 minutes. c) The mixture obtained in step b) was compacted in a roller compacter. d) The compacts obtained in step c) were passed through #20 ASTM sieve to form granules. e) The granules obtained in step d) were blended with Colloidal silicon dioxide in a bin blender for 10 minutes and lubricated with Magnesium Stearate. f) The lubricated granules obtained in step e) were compressed into a tablet at a temperature not more than 25°C and relative humidity not more than 20% RH. g) The tablets obtained in step f) were coated with a solution of Hypromellose in a mixture of Isopropyl Alcohol and Dichlorome thane.

Example VI

Film coated tablets of S-adenosylmethionine prepared as per Example V were subjected to stress testing at temperature/relative humidity of 40°±2°C / 75%±5% RH for three days. The tablet dosage form was packaged in Alu/Alu strips and analyzed for related substances by a validated High Performance Liquid Chromatography (HPLC) method. The prepared dosage form was found to exhibit following results:

TABLE 6

From the analysis of related substances of tablets prepared as per Example I and Example V, it is evident that the tablets prepared as per the present invention is a synergistic composition whereby the composition exhibits better stability by virtue of careful selection of excipients, their weight percentages and the manufacturing process employed.

While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope, and spirit of this invention.

Claims

WE CLAIM:

1. A solid oral pharmaceutical composition comprising S-adenosylmethionine or its pharmaceutically acceptable salt, wherein the composition comprises: a) a core tablet prepared by dry granulation of a blend of S-adenosylmethionine or its pharmaceutically acceptable salt with at least one pharmaceutically acceptable excipient; b) an enteric coat layer over the core tablet comprising a solution of copolymer of methacrylic acid and ethyl acrylate in at least one non-aqueous solvent; c) optionally a secondary layer encompassing the enteric coat layer, said secondary layer comprising a suspension of copolymer of methacrylic acid and ethyl acrylate in water.

2. The solid oral pharmaceutical composition as claimed in claim 1, wherein the solid oral pharmaceutical composition is a delayed release composition.

3. The solid oral pharmaceutical composition as claimed in claim 1, wherein the solid oral pharmaceutical composition is in the form of powder, granules, pellets, capsules, mini tablets or tablets.

4. The solid oral pharmaceutical composition as claimed in claim 1, wherein enteric coating is applied to achieve a weight build up in the range of about 5% to about 35%.

5. The solid oral pharmaceutical composition as claimed in claim 1, wherein S- adenosylmethionine or its pharmaceutically acceptable salt is present in an amount of about 500 to about 2000 mg.

6. The solid oral pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable salt of S-adenosylmethionine is selected from the group comprising 1,4-butanedisulfonate and disulfate P-toluene-sulfonate (tosylate).

7. The solid oral pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable excipient comprises diluents, disintegrants, lubricants, glidants, plasticizers, emulsifiers, neutralizing agents and antifoaming agents.

8. The solid oral pharmaceutical composition as claimed in claim 1, wherein solid oral the pharmaceutical composition is stable when subjected to stress conditions at a temperature of about 40°C. and relative humidity ("RH") of about 75% relative humidity for a period of at least three days.

9. A process for the preparation of a solid oral pharmaceutical composition comprising S-adenosylmethionine or its pharmaceutically acceptable salt, wherein the process comprises the following steps: a) blending S-adenosylmethionine or its pharmaceutically acceptable salt with at least one pharmaceutically acceptable excipient; b) dry granulating the blend obtained in step a); c) blending the granulated material obtained in step b) with at least one pharmaceutically acceptable excipient; d) lubricating the granules obtained in step c); e) compressing the lubricated granules obtained in step d) into a solid pharmaceutical composition f) coating the solid pharmaceutical composition obtained in step e) with a solution of copolymer of methacrylic acid and ethyl acrylate in at least one non-aqueous solvent; g) optionally coating the solid oral pharmaceutical composition obtained in step f) with a suspension of copolymer of methacrylic acid and ethyl acrylate in water.

10. The process as claimed in claim 9, wherein enteric coating is applied to till a weight build up in the range of about 5% to about 35% is achieved.

11. The process as claimed in claim 9, wherein the product temperature of the solid pharmaceutical composition during coating is kept at a temperature between 30°C and 50°C.

12. The process as claimed in claim 9, wherein the process is carried out at a relative humidity in the range of 5 to 25%.

13. The process as claimed in claim 9, wherein the process is carried out at a temperature not more than 25°C.

14. A solid oral pharmaceutical composition comprising S-adenosylmethionine or its pharmaceutically acceptable salt, prepared by a process comprising the following steps: a) blending S-adenosylmethionine or its pharmaceutically acceptable salt with at least one pharmaceutically acceptable excipient; b) dry granulating the blend obtained in step a); c) blending the granulated material obtained in step b) with at least one pharmaceutically acceptable excipient; d) lubricating the granules obtained in step c); e) compressing the lubricated granules obtained in step d) into a solid pharmaceutical composition; f) coating the solid pharmaceutical composition obtained in step e) with a solution of copolymer of methacrylic acid and ethyl acrylate in at least one non-aqueous solvent; g) optionally coating the solid oral pharmaceutical composition obtained in step f) with a suspension of copolymer of methacrylic acid and ethyl acrylate in water.

15. A stable delayed release solid oral pharmaceutical composition comprising:

(a) a compressed core comprising S-adenosylmethionine or its pharmaceutically acceptable salt in an amount of about 10% to about 95% by weight, diluent in an amount of about 5% to about 55% by weight, disintegrant in an amount of about 0.5% to about 20% by weight, glidant in an amount of about 0.2% to about 5.0% by weight, lubricant in an amount of about 0.2% to about 5.0% by weight;

(b) an enteric coating layer comprising about 5.0% to about 35.0% by weight of enteric polymer, antiadherent in an amount of 0% to about 5.0% by weight, plasticizer in an amount of 0% to about 2.0% by weight;

16. A stable delayed release oral tablet comprising: