WO2007085888A1

WO2007085888A1 - Controlled release formulations of methylcobalamin

Info

Publication number: WO2007085888A1
Application number: PCT/IB2006/002240
Authority: WO
Inventors: Chandrashekhar Dhundiraj Mainde
Original assignee: Wockhardt Limited
Priority date: 2006-01-27
Filing date: 2006-08-14
Publication date: 2007-08-02

Abstract

The present invention provides an oral pharmaceutical composition including methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof. The methylcobalamin can be in a sustained or modified release including a hydrophilic polymer matrix of gelling agents having at least one hydrophilic polymer, one or more gum or gum derivatives thereof, and optionally optional pharmaceutically acceptable excipients. The composition may be further coated using suitable polymers. The coating layer may optionally contain methylcobalamin or its pharmaceutically acceptable derivative along with suitable polymers.

Description

CONTROLLED RELEASE FORMULATIONS OF METHYLCOBALAMIN

Reference to Related Applications

[0001] This application claims priority from Indian Provisional application no. « 136/MUM/2006, filed on January 27, 2006, which is incorporated herein by reference.

Field of Invention [0002] The present invention relates to new pharmaceutical compositions. The invention also relates to a method of manufacture and a method for using these compositions for the treatment of vitamin Bi₂ deficiencies, hyperhomocysteinemia and other related disorders. In particular, the invention provides sustained or modified release formulations of methylcobalamine, pharmaceutically acceptable salts or derivatives thereof.

Background of Invention

[0003] Homocystinuria is a rare autosomal recessive genetic disorder that usually results from defective activity of cystathionine beta-synthase. Homocystinuria is associated with a syndrome of mental retardation, skeletal and visual problems as well as arterial venous thrombosis. There are two primary enzymes that can result in either homocystinuria or hyperhomocysteinemia, when a defect is present.

[0004] Homocysteine, naturally occurring sulfur containing amino acid compound, which is found in the body. It is required for several cellular reactions within the human body. Homocysteine can be rapidly oxidized in plasma to form the disulfides homocystiene and cysteine-homocysteiene. These disulfides can metabolize into three components methionine, cystethionine, and cysteine, which can be further used by the body. If the pathways to either cysteine or methionine are blocked, then homocysteine levels may rise.

[0005] There are three enzymes that are reported to be associated with elevated levels of homocysteine. These enzymes are methylenetetrahydrofolate reductase (MTHFR), cystathionine beta-synthase (CBS) and methionine synthase (MS). Methionine synthase (MS) requires Vitamin B]₂ (methylcobalamin) to carry out its reaction. If a patient does not have an adequate supply of vitamin B₁₂, then homocysteine is not converted to methionine, which can result is an increase in homocysteine. Methylenetetrahydrofolate reductase (MTHFR) is required to form 5-methyl tetrahydrofolate. This is required in order to convert homocysteine to methionine. If this cannot be formed, then homocysteine levels will increase. The final enzyme associated with elevated homocysteine levels is CBS. This enzyme is required in order to convert homocysteine to cysteine. If CBS is not present, then homocysteine levels can increase.

[0006] Vitamin B i₂, an imperative cofactor in the transmethylation pathway needs to be converted to its active form, methylcobalamin for action. Deficiency of Vitamin B₁₂, even in the presence of normal enzyme levels of methionine synthase, has been reported to lead to hyperhomocysteinemia, as Vitamin B₁₂ can act as a co-factor for the enzyme methionine synthase. Up to 73% of the serum Vitamin Bi₂ is in the active methylcobalamin form. Methylcobalamin has been reported to reach a maximum concentration of 972 pg/mL in 3.5 hours and has a reported half-life of 12.5 hours.

[0007] Folic acid is a vitamin that occurs in diet as a folate, in various oxidation states, which can be converted into an active "coenzyme" tetrahydrofolate (THF) in the body. The bioactivated, reduced state, acts as a source of the one carbon group (methyl) required for the synthesis of methionine from homocysteine. Deficiency of folic acid can increase plasma homocysteine level by blocking the methyl source for methionine synthesis. [0008] Pyridoxine in its active form, pyridoxal 5'-phosphate is a co-factor for enzyme cystathione β-synthase for two successive reactions in the trans-sulfuration pathway of homocysteine to cystathione and cysteine. Vitamin B₆ deficiency (dietary) or increased requirements (in renal failure) may predispose to hyperhomocysteinemia even with normal enzyme levels. [0009] Thus, the metabolic pathway of homocysteine involves vitamins, coenzymes and substrates including vitamin B6, folic acid and vitamin B 12. Methionine in turn gets converted to homocysteine via demethylation. The tetrahydrofolate substrate required for the methionine/homocysteine metabolism is obtained from folic acid. Thus folic acid, vitamin B₆, B₂ and Bj₂ are all-important constituents of this cycle. Administration of folic acid and the other vitamins can lower and regulate the homocysteine levels in the plasma without apparent toxicity.

[0010] However, a deficiency of one or more of these vitamins is seen in nearly two- thirds of the patients with hyperhomocysteinemia. The three vitamins (vitamin B₁₂, folic acid and vitamin B₆) play an imperative role in the two major pathways; transmethylation and trans-sulfuration involved in the synthesis of methionine and cysteine from homocysteine. Meta-analysis of various trials has shown folic acid alone to reduce plasma homocysteine levels by 25%. Folic acid, with vitamin B₁₂ (methylcobalamin) in the same studies further reduced plasma homocysteine levels by another 7%. Use of folic acid alone has a disadvantage that it may mask underlying vitamin B₁₂ deficiency leading to macrocytic anaemia/subacute combined degeneration of the spinal cord. High levels of folic acid may also cause central and peripheral nervous system damage. Vitamin B₁₂ requires conversion to methylcobalamin on absorption. Therefore, methylcobalamin is preferred over Vitamin Bj₂ because it is the biologically active form of the Vitamin B₁₂ and has been reported to have a higher absorption level. Further, there is an increased utilization and tissue retention of methylcobalamin, reducing the plasma concentration of homocysteine to a greater extent. Although no studies using only vitamin B₆ as a supplement have shown a significant reduction in plasma homocysteine levels, a study with a diet fortified with vitamins B₆, Bj₂ and folic acid reduced plasma homocysteine levels by 65%, as compared to 3.5% reduction with folic acid alone. Vitamin B₆ is known to decrease vascular events, which is independent of its effect on plasma homocysteine. Patients with pyridoxine deficiency are found to be at increased risks for ischemic strokes. Patients with renal failure, on dialysis, can be at an increased risk of developing hyperhomocysteinemia due to a deficiency in Vitamin B₆.

[0011] Therefore, methylcobalamin is the active form of Vitamin B₁₂ that acts as a cofactor for methionine synthase in the conversion of homocysteine to methionine, thus lowering blood levels of homocysteine. Methylcobalamin acts as a methyl donor and participates in the synthesis of SAM-e (S-adenosylmethionine), a nutrient that has powerful mood elevating properties. [0012] Vitamin Bi₂ comes in several forms including hydroxy-, cyano-, and adenosyl-, but only the methyl form is used in the central nervous system. Vitamin Bi₂ plays an important role in red blood cells, prevention and treatment of anemia, methylation reactions, and immune system regulation. Literature reports that methylcobalamin has metabolic and therapeutic applications not shared by the other forms of Vitamin Bi₂. Vitamin Bi₂ is required for normal growth, cell reproduction, myelin and nucleoprotein synthesis, and the formation of red blood cells. A Vitamin Bi₂ deficiency can be caused by a wide range of factors including low gastric acidity (common in older people) use of acid blockers such as Prilosec™ or excessive laxative use, lack of intrinsic factor, poor absorption from the intestines, lack of calcium, heavy metal toxicity, or excessive Vitamin Bj₂ degradation. Oral methylcobalamin or injections have been reported to work well, with the added feature of maintaining high levels in the blood over time. Methylcobalamin is believed to help protect brain cells against glutamate toxicity. Hence, scientists emphasize ongoing intake of methylcobalamin as to protect against development of neurological diseases. This means that high doses may be used to treat degenerative neurological diseases.

[0013] In general, humans ingest about 10 - 20 μg / day of Vitamin Bi₂ in dietary form. Only about 2 to 3 μg of Vitamin Bi₂ is absorbed, with the help of intrinsic factor (IF) in the lower ileum. (Intrinsic factor (IF) dependent absorption during normal doses).

[0014] However, when Vitamin Bi₂ is administered orally in large doses, it some Vitamin Bi₂ is absorbed through diffusion, i.e., large oral doses are concentration- dependently absorbed in the upper and lower ileum. Total serum Bi₂ levels were reported to increase significantly up to 10 hours after a small dose of methylcobalamin. This suggests an intrinsic factor dependent absorption between 8 and 12 hrs after administration. [0015] Total serum Bi₂ levels has been reported to increase slightly after a single dose of 1500 μg, but absorption contributes to the increase in serum Bi₂ only slightly. With higher doses, no intrinsic factor dependent absorption was reported. Increases in total serum Bi₂ levels are not necessarily proportional to dosage levels. This can be because free Vitamin B]₂ is rapidly excreted in the urine. Generally with a dose of about 1 meg the rate of absorption was reported at about 60 % or more. That is, about 0.6 meg of cobalamin was absorbed after a dose of 1 meg, whereas after high oral doses (500 to 1000 meg) the rate of absorption was about 2 to 5 %. The amount of absorption ranged from about 10 to 50 meg. Therefore, a sustained/extended release formulation of methylcobalamin (1500 meg) with release of the active vitamin over longer period of time may be superior to the conventional or immediate release preparation.

[0016] These data indicate that Vitamin B₁₂ may be absorbed more efficiently when administered in smaller doses rather than in higher doses, because at lower doses the absorption is mediated by the intrinsic factor. By the time the intrinsic factor is free to transport the available Vitamin B₁₂, the parallel processes of metabolism and elimination can decrease the levels of Vitamin B i₂ allowing for a higher percentage of the Vitamin Bi₂ to be used by the body.

[0017] This can be accomplished by using a sustained/controlled or modified release Vitamin Bi₂ so that the concentration of Vitamin Bi₂ available at the site of absorption will be lower due to the controlled release. This can make the absorption predominantly intrinsic factor dependent and can achieving higher serum Bi₂ concentrations.

[0018] Several formulations of methylcobalamin have been reported in the literature. Dosage forms available include capsules, immediate release tablets, sublingual tablets, sprays and injection formulations. Typically, methylcobalamin is formulated alone or in combination with other B vitamin as a B-vitamin complex preparation and with folic acid and minerals.

[0019] International patent application WO 2005/094842 Al discloses compositions that include one or more Vitamin Bi₂ compounds with one or more excipients that are said to enhance solubility of the Vitamin B₁₂ compounds. The excipients include alcohols, in particular ethanol, propylene glycol, a polyethylene glycol (PEG), glycerol, mannitol, sorbitol, Tween 20, or dimethylsulfoxide or a combination thereof. The compositions optionally includes one or more therapeutic agents in addition to the Vitamin Bi₂ compound. The invention also contemplates processes by which the compositions can be made; kits containing them (or one or more of the components thereof); and methods of using them to treat patients who have a Vitamin B₁₂ deficiency, a proliferative disease, an inflammatory disease, or a viral disease.

[0020] U.S. Patent No. 6,605,646 discloses Vitamin B₁₂ supplement compositions including Vitamin Bi₂ with or without the addition of folic acid that is essentially free of antioxidants, such as vitamin C, as well as iron. Also disclosed are methods of using these vitamin compositions to prevent brain and nervous system damage, such as peripheral nerve damage, as well as pernicious anemia, such as where such anemia is caused by a Vitamin Bi₂ deficiency.

[0021] Controlled release or sustained release oral solid dosage forms are very popular due to their advantages over conventional dosage forms. However, gastrointestinal (GI) transit time and where window of absorption is in the upper GI tract are the limiting factors for drug absorption. Gastroretentive delivery systems (GRDS) have been developed to resist GI transit, especially to prolong the gastric residence time to overcome such limitations caused by inherent physiological conditions.

[0022] Typically, gastroretentive systems are designed to be assist in improving the oral sustained delivery of drugs that have an absorption window in a particular region of the gastrointestinal tract. These systems are intended to restrain and localize the drug delivery device in the stomach or within the upper parts of the small intestine until the entire drug is released and can help in continuously releasing the drug before it reaches the absorption window, thus ensuring optimal bioavailability. [0023] Various mechanisms of achieving gastric retention include (1) floatation or buoyancy systems (2) mucoadhesion (bioadhesive systems), (3) sedimentation (high- density systems) (4) expansion (swelling and expanding systems) and (5) geometry (modified-shape systems.

[0024] A successful gastroretentive delivery system must satisfy certain requirements. One of the key issues is that the dosage form must be able to withstand the forces caused by peristaltic waves in the stomach and the constant contractions and grinding and churning mechanisms. A gastric retention dosage form must resist premature gastric emptying. Additionally, since the stomach is one of the desired absorption sites for weakly acidic drugs, there should be no lag time, in drug release from the GRDS system. [0025] Therefore, there is a need for a controlled or modified release form of methylcobalamin to fill a gap in the medical armamentarium. The present invention therefore could significantly improve the treatment of degenerative neurological diseases and other Vitamin Bi₂ deficiency disorders through significantly enhanced patient compliance because of ease of administration and a reduced frequency of dosing.

Summary of the Invention

[0026] The present invention provides an oral pharmaceutical composition including methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof. In one embodiment, the methylcobalamin is in a sustained or modified release including a hydrophilic polymer matrix of gelling agents having at least one hydrophilic polymer, one or more gum or gum derivatives thereof, and optionally optional pharmaceutically acceptable excipients. The composition may be further coated using suitable polymers. The coating layer may optionally contain methylcobalamin or its pharmaceutically acceptable derivative along with suitable polymers. [0027] In another embodiment the present invention provides an oral pharmaceutical composition including Vitamin Bi₂ in a controlled or modified release formulation that can increase the total absorption of Vitamin Bi₂ and enhance patient compliance (without the necessity for taking Vitamin Bj₂ three times a day as required when using an immediate release formulation). [0028] In another embodiment the present invention provides a dosage form including a modified release GRDS system for releasing methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof over a period of about 12 hours using a hydrophilic polymer matrix and optional excipients to form a core, which may optionally be coated with suitable polymers. [0029] In another embodiment the present invention provides a process for preparing an oral sustained or modified release pharmaceutical composition and a method for administration of methylcobalamin to patients suffering from deficiency disorders of methylcobalamin. [0030] In another embodiment the present invention provides a sustained or modified release solid pharmaceutical composition including methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof adapted for oral administration.

[0031] In another embodiment the present invention provides an oral sustained or modified release formulation of methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof suitable for once-a-day administration.

[0032] In another embodiment the present invention provides an oral sustained release composition, which can release methylcobalamin over a time period of at least about 12 to about 24 hours after exposure to the gastrointestinal tract.

[0033] In another embodiment the present invention provides a sustained or modified release methylcobalamin composition including methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof in a core formed by the drug and a hydrophilic polymer matrix having gelling agents and including a hydrophilic polymer with one or more gum or gum derivatives thereof. The core is optionally further coated using suitable polymers wherein the coating may further include methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof with suitable coating excipients.

[0034] In another embodiment the present invention provides a sustained or modified release pharmaceutical formulation including methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof along with a hydrophilic polymer matrix having gelling agents including at least one hydrophilic polymer with one or more gum or gum derivatives thereof and optional pharmaceutically acceptable excipients. The core can optionally be further coated using suitable polymers where the coating may include methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof with suitable coating excipients. [0035] In another embodiment the present invention provides a sustained or modified release formulation of methylcobalamin or pharmaceutically acceptable derivatives thereof suitable for once-a-day administration wherein the formulation includes methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof in a core having a hydrophilic polymer matrix and optionally suitable polymers in a coating layer.

[0036] The present invention further provides a method of administering to a subject in need of treatment a pharmaceutical product or formulation substantially as hereinbefore described and in particular a sustained or modified release composition which can be administered orally and as such is particularly suited for the treatment of vitamin B 12 deficiency and other related disorders.

[0037] In another embodiment the present invention provides a core including methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof with hydrophilic polymer matrix having gelling agents including at least one hydrophilic polymer with one or more gum or gum derivatives and optional pharmaceutically acceptable excipients wherein the drug and the polymer and optional excipients are mixed together, granulated using suitable methods of granulation known in the art and then compressed together to provide tablets.

[0038] In another embodiment the present invention provides a sustained release oral solid dosage form for absorption of methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof in the gastrointestinal tract, said drug having an effective amount of methylcobalamin; and a hydrophilic polymer matrix having gelling agents including at least one hydrophilic polymer with one or more gum or gum derivatives thereof when exposed to gastrointestinal fluid, the dosage form providing a therapeutic effect for about 12 hours after oral administration.

[0039] In another embodiment the present invention provides the use of methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof in the manufacture of a medicament for the treatment of Vitamin B₁₂ deficiency and other related disorders. The medicament, of the present invention, includes a sustained or modified release formulation substantially as described herein.

[0040] In another embodiment the present invention provides a process for manufacturing a sustained or modified release composition having methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof with a hydrophilic polymer matrix having gelling agents including at least one hydrophilic polymer with one or more gum or gum derivatives thereof and optional suitable pharmaceutically acceptable excipients. The core is optionally coated using suitable polymers where the coating may further contain methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof with suitable coating excipients.

[0041] The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. The description that follows more particularly exemplifies illustrative embodiments. In several places throughout the application, guidance is provided through lists of examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.

Brief Description of the Drawing

[0042] Figure 1 illustrates a comparative dissolution profile of methylcobalamin from immediate release market preparations and the methylcobalamin sustained release tablets of the present invention.

Detailed Description of the Invention

[0043] In this specification and the appended claims, the singular forms "a", "an" and "the" include plural reference unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs.

[0044] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the invention belongs. Although any methods, devices and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods, devices and materials are now described. [0045] As used herein, the term "methylcobalamin" includes the individual stereoisomers, mixtures of stereoisomers, including the racemates, pharmaceutically acceptable salts, solvates,- polymorphs and any mixtures thereof.

[0046] The present invention provides a sustained or modified release composition including methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof with hydrophilic polymer matrix having gelling agents including at least one hydrophilic polymer with one or more gum or gum derivatives and other optional pharmaceutically acceptable excipients. The core is optionally coated using suitable polymers where the coating may contain methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof and suitable coating excipients. The said composition releases the drug over about 12 hours.

[0047] As used herein, the term "pharmaceutically acceptable derivative" means various pharmaceutical equivalent isomers, enantiomers, complexes, hydrates, polymorphs, salts etc. of methylcobalamin.

[0048] As used herein, the term "composition" includes but is not limited to solutions, suspensions, dispersions, concentrates, ready mix, powders, granules, tablets, micro- tablets, capsules, pellets, including methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof in a core including the drug and a hydrophilic polymer matrix including at least one hydrocolloid gelling agent which may further be coated using methylcobalamin and suitable coating polymer in the coating layer of the composition.

[0049] The term "therapeutically effective amount" means an amount of the drug which is capable of eliciting a physiological response in a human patient. More specifically, the term "therapeutically effective amount" means the amount of drug which is capable of treating Vitamin Bi₂ deficiency and other related disorders. [0050] The terms "sustained, controlled or modified release" mean that the therapeutically active medicament is released from the composition at a controlled rate such that therapeutically effective blood levels of the medicament are maintained over an extended period of time, e.g., from about 12 hours to 24 hours of a therapeutic effect. [0051] The term "gelling agents" means colloids in a more solid form than a sol.

Usually gelling agent or gel forming agents are defined as semi-solid systems consisting of either suspensions made up of small inorganic particles, or large organic molecules interpenetrated by a liquid. Gels consist of organic macromolecules uniformly distributed throughout a liquid in such a manner that no apparent boundaries exist between the dispersed macromolecules and the liquid. Gel-forming polymers produce materials that span a range of rigidities, beginning with a sol and increasing in rigidity to gel and hydrogel.

[0052] The medicament of the present invention includes a formulation substantially as described herein, and, in particular, a capsule, a tablet, micro-tablets, granules or pellets filled in capsule formulation, typically in the form of a sustained or modified release tablet formulation substantially as described herein.

[0053] Suitably a formulations of the present invention provide a novel sustained release dosage form, preferably tablets having a core including methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof along with hydrophilic polymer matrix having gelling agents including at least one hydrophilic polymer with one or more gum or gum derivatives thereof and optional pharmaceutically acceptable excipients and wherein the core is optionally coated with suitable coating material that can optionally contain the drug and a process for preparing the same.

[0054] In a preferred embodiment, the present invention provides a sustained release or modified release formulation including a pharmaceutically active agent

(methylcobalamin) along with suitable excipients. In particular, the present invention provides sustained release tablet formulations having methylcobalamin in a sustained release form, hi a formulation of the present invention, after oral administration, methylcobalamin can be released over a period of about 12 hours. It has been observed that tablets, prepared according to the present invention, produce uniform blood levels of methylcobalamin over an extended period of therapy, by oral administration. A sustained or modified release is achieved in a formulation substantially as described herein.

[0055] In a preferred embodiment, the present invention provides a sustained release formulation having at least one pharmaceutically active agent, which may be formulated for release of the drug being held, wherein the release of the drug is pH-independent. The composition can release the drug in the gastro-intestinal tract.

[0056] The sustained release tablet dosage forms of methylcobalamin of the present invention may be formulated by mixing (blending) the drug with diluent(s), followed by gelling agents, including at least one hydrophilic polymer having one or more gum or gum derivatives thereof to form hydrophilic polymer matrix. In particular, the present invention provides a controlled release pharmaceutical formulation which can release methylcobalamin at a controlled rate independent of the pH of the environment. The methylcobalamin is released in vivo at a steady rate so that throughout the gastrointestinal tract. Preferably, the sustained release pharmaceutical formulation of the invention will be in the form of a tablet and includes methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof; in a pH-dependent polymer which preferably is a water soluble salt of alginic acid with a pH-independent hydrophilic polymer together forming a hydrophilic polymer matrix with suitable diluents and optional excipients, i.e., the present invention provides a gastroretentive system having methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof.

[0057] The polymers of the hydrophilic matrix systems, when exposed to an aqueous medium, do not disintegrate. Immediately after hydration these polymers develop a highly viscous gelatinous surface barrier which controls the drug release from the core and the liquid penetration into the center of the matrix system. [0058] Therefore, upon oral ingestion of the sustained release tablet of the invention, in an acid aqueous environment, such as the stomach the pH-independent hydrophilic polymer hydrates to form a gel layer at the surface of the tablet. The gel layer formed acts as a pH independent system by absorbing large amount of fluid and causing the matrix to swell and expand significantly which helps to release the drug in a controlled manner from the expanded/swollen matrix. Erosion of the gel layer gradually exposes more dry matrix that can hydrate to replenish the gel layer. Drug dissolves in the gel layer and diffuses out into the surrounding aqueous environment.

[0059] In another embodiment, the present invention provides, a hydrophilic polymer matrix is incorporated in the matrix along with a preblended drug (with optional diluent(s)). The matrix can provide a sustained release of methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof.

[0060] In another embodiment, the present invention provides a hydrophilic polymer matrix having gelling agents including at least one hydrophilic polymer and one or more gum or gum derivatives along with the optional pharmaceutical excipients are mixed and granulated and the granules are mixed (blended) with methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof, pre-blended with optional diluent(s) and compressed to form a tablet. The core is further coated with suitable coating polymers.

[0061] In another embodiment, the present invention provides sustained release tablets having a sustained release source including a hydrophilic polymer matrix having gelling agents including at least one hydrophilic polymer with one or more gum or gum derivatives thereof and optional pharmaceutically acceptable excipients such as diluents, binders, disintegrants, glidants, lubricants and the like.

[0062] Non-limiting examples of hydrophilic polymers include, cellulose polymers, in such as methyl cellulose, cellulose alkyl hydroxylates such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, cellulose alkyl carboxylates such as carboxymethyl cellulose, alkali metal salts of cellulose alkyl carboxylates, povidone, vinyl copolymers, polyethylene oxide, derivatives thereof, propylene glycol esters, carbomers, derivatives thereof, gums, gum derivatives such as vegetable gums, such as alginates, xanthan gum, gum karaya, pectin, agar, tragacanth, acacia, carrageenan, chitosan, alginic acid, polysaccharide gums, mixtures thereof, carboxymethylether, propylene glycol esters, carbomers, derivatives thereof, polyvinyl pyrrolidones, derivatives thereof, and the like.

[0063] In general, the present invention provides a process for the manufacture of a pharmaceutical product. The said composition is prepared by using wet granulation or dry granulation technique known in the art.

[0064] The process for preparing said composition includes blending of gelling agents having at least one hydrophilic polymer with one or more gum or gum derivatives and granulated using suitable granulator with or without the use of suitable binders and using aqueous or non-aqueous or hydroalcoholic solvents. The resultant granules are sized and blended with a drug pre-blended with optional diluent(s) and optional disintegrants, release modifiers, gas entrapping viscolysing agents, glidants, lubricants, and the like. The lubricated granules are compressed on a suitable compression machine. The tablets are coated using suitable polymers. A seal coat may be applied followed by coating with methylcobalamin with suitable polymer followed by a protective coating optionally including a polymer, wax with color, and optional coating excipients.

[0065] Alternatively, a second process for preparing the modified release composition having a blend of methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof with optional diluent followed by further blending with hydrophilic polymer, disintegrants, release modifiers, other polymers or binders, gum or gum derivatives, glidants, lubricants, and the like and compacting (compressing) the mixture using a suitable compactor/granulator. The granular mixture is milled, sized and lubricated and then finally compressed on a suitable compression machine. The tablets are further coated using suitable polymers. A seal coat may be applied followed by coating with methylcobalamin with suitable polymer followed by a protective coating optionally including a polymer, wax with color, and optional coating excipients.

[0066] The methylcobal compositions of the present invention may be formulated to allow the release of the drug in a sustained or modified release manner, subsequent to the desired release profile provided by the inclusion of hydrophilic polymer matrix. [0067] Non-limiting examples of suitable excipients for the pharmaceutical composition of the present invention include commonly used pharmaceutically acceptable excipients such as saccharide, including monosaccharides, disaccharides, polyhydric alcohols and/or mixtures thereof. Examples of suitable diluents include starch, lactose, various forms of lactose, mannitol, sucrose, dextrose, microcrystalline cellulose, powdered cellulose, starches, sorbitol, dibasic calcium phosphate, calcium carbonate, sodium bicarbonate, magnesium oxide, and other mineral bases.

[0068] Additional non-limiting pharmaceutically acceptable excipients include (a) binders, such as povidone, acacia, alginic acid, carbomer, carboxymethyl cellulose sodium, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, magnesium aluminum silicate, methyl cellulose, pregelatinized starch, sodium alginate, starch, dextrin, gelatin, hydrogenated vegetable oils, polymethacrylates, zein, and the like; (b) lubricants (c) glidants; and (d) coatings and protective matrices, e.g., polymeric substances or waxes.

[0069] The composition of the present invention may also include pharmaceutically acceptable lubricants and glidants. The artisan can select appropriate lubricants and glidants in order to obtain good flow to aid in compression of the tablets.

[0070] Examples of suitable lubricants and glidants include magnesium stearate, calcium stearate, glyceryl behenate, light mineral oil, polyethylene glycol, sodium steryl fumarate, stearic acid, talc, hydrogenated castor oil, calcium silicate, magnesium silicate and colloidal silicon dioxide, and the like. The most preferred lubricant and glidants are talc, colloidal silicon dioxide and calcium stearate.

[0071] In another embodiment, the present invention provides a process for preparing a pharmaceutical product, or a pharmaceutical composition, or a medicament substantially as described herein. [0072] The tablets of the present invention including methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof, are prepared by blending hydrophilic polymer matrix having gelling agents including at least one hydrophilic polymer and one or more gum or gum derivatives, preferably hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose with xanthan gum, and sodium alginate, with optional diluents preferably microcrystalline cellulose and calcium carbonate. The ingredients are blended and granulated with a povidone solution (using aqueous or nonaqueous or hydroalcoholic solvents) in a suitable granulator. The granules are dried and mixed (blended) with methylcobalamin (optionally pre-blended with a diluent, preferably starch) and other optional excipients such as croscarmellose sodium, colloidal silicon dioxide, sodium bicarbonate, talc, calcium stearate and the like. The lubricated granules are further compressed to the desired shape and size and coated. An optional seal coating may be applied using suitable polymers, preferably hydroxypropyl methyl cellulose followed by an optional polymer coating containing methylcobalamin and finally an optional protective coating using polymer, wax, color and other suitable excipients to provide a quality product.

[0073] The tablets of the present invention include methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof, are prepared by blending polymer matrix having gelling agents including at least one hydrophilic polymer and one or more gum or gum derivatives with optional excipients and granulating the mixture. The granular mixture may be sized and mixed and blended with pre-blended methylcobalamin (blended with optional diluents), disintegrants, glidants, release retardants, lubricants, and the like. The final granular blend may then be compressed and further coated using optional polymers and an optional coating that contains the methylcobalamin.

[0074] The following experimental examples describe the invention in greater particularity and are intended to be a way of illustrating but not limiting the invention. Further, different strengths of the formulation may be achieved by proportionately using a dose weight scale-up or scale-down formula. The concentrations of the ingredients, e.g., excipients may also be varied or modified by a skilled artisan to achieve a desired dissolution profile.

Examples Example 1

[0075] Sustained release methylcobalamin tablets were prepared using the following ingredients in the quantities indicated:

** - Removed in the process of drying Procedure:

[0076] Microcrystalline cellulose, xanthan gum, sodium CMC, sodium alginate, hydroxypropyl methylcellulose and calcium carbonate are mixed in a suitable mixer (blender) and mixed thoroughly. The PVP solution (in isopropyl alcohol) is added to the mixture. The mixture is granulated in a suitable granulator. The granules are dried and sized.

[0077] Methylcobalamin, maize starch, and anhydrous lactose are blended in a suitable mixer (blender). The dried granules and methylcobalamin blend are mixed and homogenized. Croscarmellose sodium, talc, aerosil and sodium bicarbonate are added to the homogenized mixture and blended. The calcium stearate is added to lubricate the granules. The lubricated granules are compressed into tablets. The tablets are coated with a seal coating followed by a drug coating and finally an Opadry red protective coating using suitable coating equipment.

Example 2 [0078] Sustained release tablets were prepared using the following materials in the stated quantities:

*Removed in the process of drying except in traces.

Procedure:

[0079] Microcrystalline cellulose, xanthan gum, sodium CMC, sodium alginate, hydroxypropyl methylcellulose and calcium carbonate are mixed in a suitable mixer (blender) and mixed thoroughly. The PVP solution (in isopropyl alcohol) is added to the mixture. The mixture is granulated in a suitable granulator. The granules are dried and sized.

[0080] Methylcobalamin, maize starch, microcrystalline cellulose, and anhydrous lactose are blended in a suitable mixer (blender). The dried granules and methylcobalamin blend are mixed and homogenized. Croscarmellose sodium, talc, aerosil and sodium bicarbonate are added to the homogenized mixture and blended. The calcium stearate is added to lubricate the granules. The lubricated granules are compressed into tablets. The tablets are coated with a seal coating followed by a drug coating and finally an Opadry red protective coating using suitable coating equipment.

Example 3:

[0081] The compositions of the invention were tested and compared against commercial products. The samples tested were Cobamet^® - available from Sun Pharmaceuticals Ltd., Meconerve^® - available from Micro Labs Ltd., Methylcobal - available from Merind Ltd., and Nuroday^®- available from Wockhardt Ltd. (Sustained Release). The comparative dissolution profiles of methylcobalamin from the methylcobalamin immediate release preparations and methylcobalamin sustained release tablets were determined using 0.1 N Hydrochloric acid as dissolution medium. The results are illustrated in figure 1.

[0082] The details of one or more embodiments of the invention are set forth in the description and the examples below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. [0083] All documents cited herein are expressly incorporated herein by reference in their entirety in this disclosure. Illustrative embodiments of this disclosure are discussed and reference has been made to possible variations within the scope of this disclosure. These and other variations and modifications in the disclosure will be apparent to those skilled in the art without departing from the scope of the disclosure, and it should be understood that this disclosure and the claims shown below are not limited to the illustrative embodiments set forth herein.

Claims

We Claim:

1. An pharmaceutical composition comprising, a therapeutically effective amount of methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof; and a hydrophilic polymer matrix comprising a gelling agent; wherein the polymer matrix comprises at least one hydrophilic polymer, and one or more gum or gum derivatives, and optionally pharmaceutically acceptable excipients; wherein the composition provides a sustained or modified release of methylcob alamin.

2. The pharmaceutical composition of claim 1 , wherein the composition further comprises a polymer coating layer, and the coating layer may comprise methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof.

3. The pharmaceutical composition of claims 1 or 2, wherein the hydrophilic polymer is selected from a group consisting of cellulose polymers, cellulose alkyl hydroxylates, cellulose alkyl carboxylates, alkali metal salts of cellulose alkyl carboxylates, vinyl copolymers, polyethylene oxide, propylene glycol esters, carbomer, polyvinyl pyrrolidones, derivatives thereof and mixtures thereof.

4. The pharmaceutical composition of claim 3, wherein the cellulose alkyl hydroxylate is selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and mixtures thereof.

5. The pharmaceutical composition of claim 3, wherein the cellulose alkyl carboxylate is selected from the group consisting of carboxymethyl cellulose, carboxyethyl cellulose, alkali metal salts thereof and mixtures thereof.

6. The pharmaceutical composition of claim 4, wherein the cellulose alkyl hydroxylate comprises hydroxyl propyl cellulose, hydroxypropyl methyl cellulose or a mixture thereof.

7. The pharmaceutical composition of any of claims 1 to 6, wherein the gum or gum derivative is a vegetable gum selected from the group consisting of alginates, xanthan gum, gum karaya, pectin, agar, tragacanth, acacia, carrageenan, chitosan, alginic acid, other polysaccharide gums, and mixtures thereof.

8. The pharmaceutical composition any of claims 1 to 7, wherein the composition is a capsule, tablet, granules, pills, granules in capsule, micro-tablets in capsules or combinations thereof.

9. The pharmaceutical composition of claim 8, wherein the composition is in the form of a tablet.

10. The pharmaceutical composition of claim 9, wherein the composition is administered orally.

11. The pharmaceutical composition of any of claims 1 to 7, wherein the composition is in the form of a kit.

12. The pharmaceutical composition of claim 9, wherein the tablet comprises sustained released niethylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof with a hydrophilic polymer matrix mixed compressed together.

13. The pharmaceutical composition of claim 9, wherein the tablet further comprises a coating material.

14. The pharmaceutical composition of claim 13, wherein and the coating layer comprises methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof.

15. A method for preparing the pharmaceutical composition of any of claims 1 to 14, comprising the steps of: (i) mixing methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof with a hydrophilic polymer matrix and granulating to form a granular composition;

(ii) compressing the granular composition to form tablets; and (iii) coating the methylcobalamin tablets with one or more suitable polymers.

16. The method of claim 15, wherein the coating layer comprises methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof.

17. The method of claims 15 or 16, wherein the granular composition is prepared using a suitable granulation technique.

18. The method of claim 17, wherein the granular composition is prepared using wet granulation techniques. .

19. The method of any of claims 15 to 18, wherein the method comprises blending methylcobalamin, a pharmaceutically acceptable salt, derivative or mixture thereof with gelling agents comprising a hydrophilic polymer, a gum or gum derivatives and pharmaceutical acceptable diluents; and granulating the mixture using aqueous solvents to provide a granular composition.

20. The method of any of claims 15 to 19, wherein the hydrophilic polymer is selected from a group comprising cellulose polymers selected from the group consisting of cellulose ethers, cellulose alkyl hydroxylates, and cellulose alkyl carboxylates;, vinyl copolymers, polyethylene oxide and derivatives thereof, propylene glycol esters, carbomers and derivatives thereof, polyvinyl pyrrolidones and derivatives thereof.

21. The method of claim 20, wherein the cellulose alkyl hydroxylate is selected from the group consisting of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxy ethyl cellulose and mixtures thereof.

22. The method of claim 21 , wherein the hydrophilic polymer comprises hydroxyl propyl cellulose, hydroxypropyl methyl cellulose or a mixture thereof.

23. The method of claim 20, wherein the cellulose alkyl carboxylate is selected from the group consisting of carboxymethyl cellulose, carboxyethyl cellulose alkali metal salts thereof and mixtures thereof.

24. The method of any of claims 15 to 20, wherein the gum and gum derivative is vegetable gum.

25. The method of claim 24, wherein the vegetable gum is selected from the group consisting of alginates, xanthan gum, gum karaya, pectin, acacia, carrageenan, tragacanth, chitosan, agar, alginic acid, other polysaccharide gums and mixtures thereof.

26. The method of claim 25, wherein the gum or gum derivative is sodium alginate, xanthan gum, or a mixture thereof.

27. The method of any of claims 15 to 20, wherein further comprising a diluent selected from the group consisting of microcrystalline cellulose, lactose, calcium carbonate, sodium carboxymethyl cellulose, and a mixture thereof.

28. The method of any of claims 15 to 20, wherein the granular composition further comprises a binder.

29. The method of any of claims 15 to 20; wherein the granular composition further comprises a lubricants and an anti-adherant.

30. The method of any of any of claims 15 to 29, wherein the granular composition is packaged into an oral solid dosage form selected from the group consisting of a capsule, tablet, granules, pills, granules-in-capsule, micro-tablets-in-capsules and combinations thereof.

31. The method of claim 30, wherein the dosage form is a tablet.

32. The method of claim 31 , wherein the tablet is optionally coated and the said coating layer may optionally comprise of methylcobalamin or its pharmaceutically acceptable derivative thereof.

33. A method for prevention or treatment of homocystinuria and related deficiencies in a subject in need of said treatment, wherein the method comprises administering to the subject a pharmaceutical composition of any of claims 1 to 14.

34. Use of the pharmaceutical composition of any of claims 1 to 14in the manufacture of a medicament for treating homocystinuria and related deficiencies.