FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
THE PATENT (AMENDMENT) RULES, 2006
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
Extended Release Composition Of Methylcobalamin And/Or Its Pharmaceutically Acceptable Forms And Process For Preparing The Same
2. APPLICANT
NAME ; Troikaa Pharmaceuticals Ltd.
NATIONALITY : India
ADDRESS : Commerce House 1, opposite Judges Bunglow Road, Satya Marg,
Ahmedabad 380 054, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
COMPLETE
The following specification particularly describes the nature of this invention and the manner in which it is to be performed: -.

Field of the Invention The present invention relates to extended release pharmaceutical compositions. More particularly, it relates to novel extended release drug delivery system of Methylcobalamin and/or its pharmaceutically acceptable forms for oral administration and process for preparing the same.
Background of the Invention Methylcobalamin or Methyl B12 is an active Isoenzyme form of vitamin B12 and it is the only form of vitamin B12, which can directly participate in homocysteine metabolism. The administration of Methylcobalamin as a single immediate release dose has several drawbacks. Firstly, when Methylcobalamin is administered as a single high dose, the absorption is unpredictable. Further a large portion is excreted in the urine and, a large part of this excretion happens in the first 8 hours, after administration of methlycobalamin. Therefore, there is a need to develop an extended release formulation of methylcobalamin, which can provide sustained levels of aforesaid vitamin for several hours.
It is well known that methylcobalamin is required to combine with the intrinsic factor produced by parietal cells of gastric mucosa, prior to being absorbed from terminal ileum. This typical mechanism associated with methylcobalamin suggests that it would be desirable to have an extended release drug delivery system which releases large part of methylcobalamin in the stomach. Based on this understanding, slow release tablets using gastric retention technology were developed. Unlike the conventional extended release tablet, such gastric retention tablet will remain in the stomach for a long time and release the drug gradually in the stomach, thus ensuring adequate time for the released methylcobalamin to interact with intrinsic factor present in the stomach, thereby enabling a continuous absorption of the drug over a prolonged period and maintaining significant

levels of methylcobalamin in the blood for several hours. The major problem associated with gastric retentive drug delivery is the large size of the tablet which is required to produce desired gastric retentive behavior.
In light of the foregoing discussion, there still exists a need to provide a small size patient friendly, extended release formulation that provides desired blood levels of methylcobalamin for several hours without adopting gastric retention drug delivery, which is easier to manufacture as compared to a tablet manufactured as gastric retention
tablet.
Summary of the Invention The principal object of the present invention is to provide an oral pharmaceutical composition comprising Methylcobalamin and/or its pharmaceutically acceptable forms in sustained or extended release dosage form that provides desired blood levels of methylcobalamin for several hours, without the use of gastric retention drug delivery.
Still another object of the present invention is to provide a non-gastro-retentive dosage form of methylcobalamin that is smaller in size as compared to gastro retentive dosage forms of sustained release methylcobalamin.
The above and other objects of the present invention are attained according to following preferred embodiments of the present invention. However the scope of the invention is not restricted to the particular embodiments discussed herein after.
In accordance with a preferred embodiment of the present invention there is provided a non-gastro retentive composition comprising a therapeutically effective amount of methylcobalamin or its pharmaceutically acceptable forms used as such or stabilized in suitable stabilizer like mannitol, lactose etc, and matrix forming agents, wherein the composition provides sustained blood levels of an effective concentration of methylcobalamin for about 24 hours.

In accordance with another embodiment of the present invention, the non-gastro retentive composition further comprises complimentary vitamins selected from B-complex group including Vitamin Bl (thiamine), Vitamin B2 (riboflavin), Vitamin B3 (niacin or niacinamide), Vitamin B5 (pantothenic acid), Vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), Vitamin B7 (biotin), Vitamin B8 (inositol), Vitamin B9 (folic acid), micronutrients e.g. selenium, and mixtures thereof, in immediate release form.
In accordance with still another embodiment of the present invention, the non-gastro retentive composition is in the form of bi-layer tablets or capsules.
In accordance with yet another embodiment of the present invention the ratio of matrix forming agent to diluent in the pharmaceutical composition is about 1: 0.65 to about 1: 1.75.
In accordance with yet another embodiment of the present invention, one dose of the extended release composition, comprising three times the amount of methylcobalamin that is present in a single immediate release methylcobalamin composition, is bioequivalent to three doses of the immediate release methylcobalamin dosage form, given at 8 hour intervals.
Brief Description of the Accompanying Drawings Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures, wherein:
Figure 1: Illustrates a comparative bioequivalence study of one dose of 1500 mcg extended release tablets of methylcobalamin manufactured as per present invention in comparison with 500 mcg methylcobalamin immediate release tablets given 8 hourly, three times.

Detailed Description of the Invention It is understood that the present invention is not limited to the particular methodologies, protocols, fillers, excipients, etc., described herein, as these may vary. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include the plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to "a vitamin B 12" is a reference to one or more vitamins and includes equivalents thereof known to those skilled in the art and so forth.
Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.
Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Specific methods, devices, and materials are described, although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention.
The terms "active agent", "compound", "pharmacologically active agent", "medicament", "active", "active ingredient", "drug" and "drug component" are used interchangeably throughout this specification. The terms also encompass pharmaceutically acceptable and pharmacologically active ingredients of those active agents specifically mentioned herein including but not limited to salts, analogs and the like. When the terms "active agent", "compound", "pharmacologically active agent", "medicament", "active drug", "drug component" and "methylcobalamin" are used, then it is to be understood that this includes those compounds per se as well as pharmaceuticaliy acceptable salts, pharmacologically active salts, etc. The terms "agent", "compound" etc. may be a single

molecule or a composite of molecules.
The terms "sustained, controlled or extended 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.
By the term "effective amount" or "therapeutically effective amount" of active ingredient/drug as used herein means that a sufficient amount of active ingredient/drug is used to provide the desired therapeutic effect or the desired pharmacological, physiological or biochemical event including the amelioration of symptoms being treated or prevented. Of course, undesirable effects, e.g. side effects, are sometimes manifested along with the desired therapeutic effect; hence, a practitioner balances the potential benefits against the potential risks in determining an appropriate "effective amount".
The terms "delivery" and "administration" are used interchangeably throughout the specification to mean the act of providing the dosage form to an individual. The term "administering" is considered herein synonymous with "administration", "use', "providing", "introducing" or "swallowing",
Herein, the term "methylcobalamin" includes the individual stereoisomers, mixtures of stereoisomers, including the racemates, pharmaceutically acceptable salts, solvates, polymorphs and any mixtures thereof.
Herein, the term "pharmaceutically acceptable forms" means various pharmaceutical equivalent isomers, enantiomers, complexes, hydrates, polymorphs, salts etc. of methylcobalamin.
The present invention provides a novel non-gastro retentive drug delivery system comprising methylcobalamin and/or its pharmaceutically acceptable forms used as such or stabilized in suitable stabilizer like mannitol, lactose etc. in extended drug delivery

composition, matrix forming agents, diluents, binders, coating agents for tablets/pellets, and other optional excipients and a process of preparing the same.
In accordance with one embodiment of the present invention the non-gastro retentive composition comprises a therapeutically effective amount of methylcobalamin or its pharmaceutically acceptable forms used as such or stabilized in suitable stabilizer like mannitol, lactose etc., and matrix forming agents, wherein the composition provides sustained blood levels of an effective concentration of methylcobalamin for about 24 hours.
In another embodiment, the non-gastro retentive drug delivery system/pharmaceutical composition further comprises complimentary vitamins like Vitamin Bl (thiamine), Vitamin B2 (riboflavin), Vitamin B3 (niacin or niacinamide), Vitamin B5 (pantothenic acid), Vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), Vitamin B7 (biotin), Vitamin B8 (inositol), Vitamin B9 (folic acid), and other vitamins of the B-complex groups, selenium, and other micro nutrients in immediate release form.
According to the present invention the oral extended release drug delivery system of methylcobalamin and/or its pharmaceutically acceptable forms provide sustained blood levels of methylcobalamin for several hours without having prolonged gastric retention, thereby providing the required sustained levels of methylcobalamin, even though the composition moves forward from the stomach to the small intestine, without being retained in the stomach.
One possible mechanism that enables absorption is that intrinsic factor release by the parietal cell is absorbed in to the matrix which contains methycobalamin and combines with it. This complex of methylcobalaimin with the instrinsic factor is gradually released from the matrix and then absorbed as the dosage form moves along the intestine. Another possible mechanism is that absorption occurs due to diffusion across the intestinal mucosa.

In addition, the present invention provides extended release formulation of methylcobalamin and/or its pharmaceutically acceptable forms, which provides enhanced blood levels of the drug over a sustained period of up to about 24 hours. Further the non-gastro retentive, extended drug delivery pharmaceutical composition is smaller in size than gastro-retentive sustained release dosage forms of methylcobalamin composition. Hence compositions provided as per the present disclosure are easy to swallow and hence patient friendly.
The pharmaceutical composition/dosage form according to the invention can be a tablet or capsule, wherein the tablet is in coated or uncoated form.
The present invention also provides a bi-layer tablet dosage form, wherein one layer provides matrix based extended delivery of methylcobalamin and/or its pharmaceutically acceptable forms, and the second layer provides other complimentary vitamins like Vitamin Bl (thiamine), Vitamin B2 (riboflavin), Vitamin B3 (niacin or niacinamide), Vitamin B5 (pantothenic acid), Vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), Vitamin B7 (biotin), Vitamin B8 (inositol), Vitamin B9 (folic acid), and other vitamins of the B-complex groups, selenium, and other micro nutrients in immediate release form. The bi-layer tablets may be coated or uncoated.
In another embodiment, the novel compositions are presented in the form of capsules. The capsules are filled with matrix based extended release tablets of methylcobalamin, manufactured in accordance with the present invention along with complimentary vitamins like Vitamin Bl (thiamine), Vitamin B2 (riboflavin), Vitamin B3 (niacin or niacinamide), Vitamin B5 (pantothenic acid), Vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), Vitamin B7 (biotin), Vitamin B8 (inositol), Vitamin B9 (folic acid), and other vitamins of the B-complex groups, selenium, and other micro nutrients in immediate release form.
In another embodiment, the novel compositions are presented in the form of capsules. The capsules are filled with slow release pellets of methylcobalamin. The pellets

containing methylcobalamin are divided into three parts and each part is coated with varying amounts of suitable coating agents such that the pellets when swallowed gradually release methylcobalamin to produce the desired therapeutic response.
In another embodiment, such pellets can also be provided in capsule along with complimentary vitamins like Vitamin Bl (thiamine), Vitamin B2 (riboflavin), Vitamin B3 (niacin or niacinamide), Vitamin B5 (pantothenic acid), Vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), Vitamin B7 (biotin), Vitamin B8 (inositol), Vitamin B9 (folic acid), and other vitamins of the B-complex groups, selenium, and other micro nutrients in immediate release form.
The proportion of matrix forming agent with respect to the diluents, when manufacturing a tablet in accordance with the present invention, is maintained in such manner that the tablet undergoes slow dissolution over several hours as it travels from the stomach in to the small intestine without being retained in the stomach. Preferably according to the invention the ratio of matrix forming agent to diluent is about 1:0.65 to about 1:1,75. One or more matrix forming agents may be used to achieve the desired results, though it is preferable to use one matrix forming agent. The matrix forming agents used preferably according to the invention include hydroxyl propyl methyl cellulose and polyethylene oxides. However other matrix forming agents can also be used. As a result of the above mentioned proportion of the matrix forming agent to the diluents, the following dissolution profile (Table 1) for release of methylcobalamin from the matrix is obtained when dissolution is carried out in 500 ml Distilled Water at 37.5 + 1 degrees °C.
Table 1

Hours(Hr) Percentage release of the drug(%)
1stHr: 10-45%
4th Hr: 45 - 85 %
8th Hr: Not less than 80%
This dissolution profile ensures that the tablets/capsules release methylcobalamin in such

a manner that following ingestion the tablet/capsule provides desired enhanced blood levels of methylcobalamin up to about 24 hours after ingestion. Last time point of dissolution profile is kept at 8 hours. This is keeping in view the fact that Vitamin B12 has a half life of about 12 hours and hence a dissolution profile as stated above is expected to provide sustained drug levels for up to about 24 hours. Further, this dissolution profile provides extended release of methylcobalamin from the tablet/capsule in such a manner that one dose of the novel extended release pharmaceutical composition, comprising three times the amount of methylcobalamin that is present in a single immediate release methylcobalamin composition, is bioequivalent to three doses of immediate release methylcobalamin given at 8 hour intervals.
For example, one novel extended release pharmaceutical composition comprising 1500 mcg of methylcobalamin will be bio-equiva!ent to three tablets of the immediate release methycobalamin dosage form, given at 8 hours interval.
Tablets with dissolution profile that matches the above, can be presented as capsules filled with such slow release tablets of methylcobalamin manufactured in accordance with the present invention, along with complimentary vitamins like Vitamin Bl (thiamine), Vitamin B2 (riboflavin), Vitamin B3 (niacin or niacinamide), Vitamin B5 (pantothenic acid), Vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), Vitamin B7 (biotin), Vitamin B8 (inositol), Vitamin B9 (folic acid), and other vitamins of the B-complex groups, selenium, and other micro nutrients in immediate release form.
Additionally, the present invention provides a capsule filled with slow release pellet of methylcobalamin having similar dissolution profile, as demonstrated above, for an extended release of methylcobalamin along with immediate release of complimentary vitamins like Vitamin Bl (thiamine), Vitamin B2 (riboflavin), Vitamin B3 (niacin or niacinamide), Vitamin B5 (pantothenic acid), Vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), Vitamin B7 (biotin), Vitamin B8 (inositol), Vitamin B9 (folic acid) and other vitamins of the B-complex groups, selenium, and other

micro nutrients in immediate release form.
By "pharmaceutically acceptable excipient" is meant a pharmaceutical vehicle comprised of a material that is not biologically or otherwise undesirable, i.e. the dosage form may be administered to a subject along with active ingredient/drug without causing any or a substantial adverse reaction. Excipients may include carriers and other additives such as diluents, binders, coloring agents, preservatives, glidants, lubricants, disintegrants, and coating excipients like hydroxyl propyl methyl cellulose, polyvinyl alcohol, ethyl cellulose, and the like, conventionally used for the purpose of tablet/pellet coating.
The disintegrants used according to the invention are selected from starch (corn or maize), pregelatinized starch e.g. Starch 1500 G, clays (Veegum or Bentonite), microcrystalline cellulose, cellulose or powdered cellulose. Super disintegrants include sodium starch glycolate, the sodium salt of carboxymethyl starch, modified cellulose and cross- linked polyvinyl pyrrolidone. Sodium starch glycolate is available commercially under the trade names Explotab® (Edward Mendell Co.), Primojel® (Generichem Corp) and Tablo® (Blanver, Brazil). An example of modified cellulose includes croscarmellose, the sodium salt of carboxymethyl cellulose. Croscarmellose is available commercially under the trade names AcDiSol® (FMC Corf.), Nymcel ZSX® (Nyma, Netherlands), Primellose® (Avebe, Netherlands), Solutab® (BIanver,Brazil). An example of a cross-linked polyvinyl pyrrolidone includes crospovidone. The disintegrants used are selected from cross linked polyvinylpyrrlidone, cross linked carboxymethylcellulose sodium, sodium starch glycollate and the like, preferably crosspovidone and sodium starch glycollate. Incorporation of the disintegrants in the formulation enhances the buoyancy of the dosage unit.
Disintegrants are used in amount from about 2% to 10%, preferably from about 5% to 7%. by weight of the total weight of immediate release composition.
The binding agents according to the invention includes microcrystalline cellulose, starch, corn maize starch, modified corn starch, wheat starch, modified wheat starch, potato

starch, pregelatinized starch e.g. available commercially as Starch 1500 G or Prejel; polymers and cellulose derivatives or combinations thereof. If the binding agent includes a polymer, suitably it is polyvinyl pyrrolidone or povidone (PVP), polyvinyl alcohol (PVA), polyethylene oxide, polaxamer, polymethacrylate e.g. a carbomer, polyethylene glycol (PEG) such as PEG 3350 and calcium polycarbophil; or a combination of two or more thereof. If the binding agent includes a cellulosic derivative, suitably it is hydroxypropyl cellulose (HPC) (low to medium viscosity versions thereof) e.g. as may be available commercially under the brand name Klucel® from the Aqualon division of Hercules Inc., Dow Chemical Company e.g. Klucel GF, Klucel JF, Klucel LF and Klucel EF; hydroxypropylmethyl cellulose (HPMC) (low to medium viscosity versions thereof) e.g. as may be available commercially under the brand name Methocel CR) from the Dow Chemical Company e.g. Methocel E15Premium, Methocel E3Premium LV,Methocel KIOOLV; microcrystaUine cellulose (MCC), carboxymethylcellulose (MC), sodium carboxymethylethyl cellulose; or a combination of two or more thereof.
The diluents used are selected from sucrose, glucose, lactose, fructose, dextrose, poly dextrose, maltose, dextrin, starch, pre-gelatinized starch, manitol, lacititol, sorbitol, xylitol, malto dextrin, maltitol, lacititol, iso-malt, erythritol and the like.
The lubricant agents according to the invention are selected from calcium stearate, hydrogenated castor oil, glycerine monostearate, magnesium lauryl sulphate, magnesium stearate, myristic acid, sodium stearyl fumarate, stearic acid, talc, zinc stearate, colloidal silica dioxide and the tike.
The matrix forming agents according to the invention are selected from derivatives of cellulose, mixtures of polyvinylacetate and polyvinylpyrrolidone, glyceryl, behenate, shellac, hydrogenated castor oil, cetostearyl alcohol, stearyl alcohol, glyceryl monosterate. glyceryl palmitosterate, guar gum, palmitic acid, sodium alginate, hydrogenated vegetable oils, cetyl esters wax, microcrystaUine wax, and such other suitable matrix forming agents.

According to the present invention, the pharmaceutical tablet composition comprising methylcobalamin in non-gastro retentive, matrix based drug delivery tablet, is prepared by wet granulation method, to ensure uniformity of content of methylcobalamin in the tablet compositions.
In one embodiment, the present invention provides a process for manufacturing the composition of present invention. The process comprises following steps:
1) The matrix forming agent and the diluent are sifted through 40 # sieve. This mixture is charged to rapid mixer granulator and methylcobalamin or stabilized methylcobalamin is added. The rapid mixture granulator is operated at slow impeller speed with chopper off.
2) The requisite binder solution is added to the mixture of step (1) and rapid mixer granulator is operated till the wet mass is formed.
3) The wet mass of step (2) is passed through multi-mill to obtain wet granules.
4) The granules of step (3) are loaded in fluid bed dryer and dried to obtain granules with requisite physical properties suitable for compression into tablets.
(5) The granules of step (4) are subjected to sifting to obtain requisite granules suitable for compression into the tablets.
6) The granules of step (5) along with lubricant/glidants are charged in octagonal
blender and blended.
7) The granules of step (6) are compressed in suitable tabletting machine to produce
the extended release methylcobalamin tablet.
In another embodiment the present invention provides a process for manufacturing the bi-layer composition of present invention. The process comprises following steps:
A) Process to manufacture granules of the slow release layer of said composition, comprises following steps:
i) The matrix forming agent and the diluent are sifted through 40# sieve. This
mixture is charged to rapid mixer granulator and methylcobalamin or stabilized

methylcobalamin is added. The rapid mixture granulator is operated at slow impeller speed with chopper off.
2) The requisite binder solution is added to the mixture of step (1) and rapid mixer granulator is operated till the wet mass is formed.
3) The wet mass of step (2) is passed through multi-mill to obtain wet granules.
4) The granules of step (3) are loaded in fluid bed dryer and dried to obtain granules with requisite physical properties suitable for compression into tablets.
(5) The granules of step (4) are subjected to sifting to obtain requisite granules suitable for compression into the tablets.
6) The granules of step (5) along with lubricant/glidants are charged in octagonal blender and blended.
B) Process to manufacture granules of the immediate release layer of said composition
comprises following steps:
1) The diluent, disintegrating agent, vitamins of the B-complex groups other than Vitamin B12 and micro-nutrients are sifted through 40# sieve. This mixture is charged to rapid mixer granulator. The rapid mixture granulator is operated at slow impeller speed with chopper off.
2) The requisite binder solution is added to the mixture of step (1) and rapid mixer granulator is operated till the wet mass is formed.
3) The wet mass of step (2) is passed through multi-mill to obtain wet granules.
4) The granules of step (3) are loaded in fluid bed dryer and dried to obtain granules with requisite physical properties suitable for compression into tablets.
(5) The granules of step (4) are subjected to sifting to obtain requisite granules suitable for compression into the tablets.
6) The granules of step (5) along with lubricant/glidants are charged in octagonal blender and blended.
C) The granules of part (A) and part (B) are charged in respective hoppers of a
tabletting machine suitable for compression of bi-layered tablet. The weight of each layer

is adjusted in such manner that the respective layers contain active pharmaceutical
ingredients as per the label claim.
Optionally,
7) Prepare the coating solution in colloidal mill by stirring isopropyl alcohol & Hydroxymethyl Propyl Methyl cellulose for requisite time to get homogenized mixing.
8) The solution of step (7) is subjected to addition of Methylene Chloride & Polyethylene Glycol 6000 & stirring for requisite time.
9) The bi-layer tablet of step (C) is coated with the coating solution of step (8).
In another embodiment the present invention provides a process for manufacturing capsule filled with extended release tablet of methylcobalamin along with vitamins of B-complex group excluding vitamin B12 in immediate release form. The process comprises following steps:
1) Blend the vitamins of B-complex except vitamin B12. Optionally blend micronutrients with the vitamins. Further optionally vitamins/micronutrients can be converted to free flowing granules using suitable binder.
2) Fill the capsule of appropriate size with extended release tablet of methylcobalamin, manufactured as per present invention and pre-mix/granules of vitamins/micronutrients on a suitable capsule filling machine.
Similarly in another embodiment the present invention provides a process for
manufacturing capsule filled with extended release pellets of methyicobaiamin. The
process comprises:
Preparing pellets containing methylcobalamin. The pellets are divided into three parts,
each part coated with varying amount of suitable coating agent such that the pellets,
when swallowed, gradually release methylcobalamin to produce the desired therapeutic
response. The pellets are filled in capsule.
Optionally the pellets may be blended with pre-mix of vitamins of B-complex except
vitamin B12 and then filled in capsule.

Further, according to the invention the methylcobalamin continues to be released from the tablet, independent of the change in the pH of the environment. The tablets according to the present invention may be film coated,
Additionally the compositions as per present invention are not retained in the stomach but move from the stomach to the duodenum to the small intestine, gradually releasing methylcobalamin and providing desired therapeutic action.
The present disclosure provides a process for preparing the non-gastro retentive pharmaceutical composition of methylcobalamin and a method of administration thereof to patients suffering from deficiency disorders of methylcobalamin.
Herein the terms "deficiency disorders" "therapeutic benefit" "treating", and "treatment" as used herein refer to reduction or amelioration in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause and/or prevention of the occurrence of symptoms and/or their underlying cause. Thus, for example, "treating" a subject involves prevention of a particular disorder or adverse physiological event in a susceptible individual as well as treatment of a clinically symptomatic individual by inhibiting or causing regression of a particular condition. In present case the compositions of present invention are used for the prevention and treatment of vitamin B12 deficiencies and other related disorders.
It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modifications and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be falling within the scope of the invention.

The following non-limiting examples illustrate in detail about the invention. However, they are not intended to be limiting the scope of present invention in any way.
Example 1

CODE MATERIAL Quantity Per Tablet O.A.
% Total Quantity Per Tablet
SUSTAINED RELEASE LAYER
**MIXING-I (METHYL COBALAMIN PART)**
RMS011 HYDROXYPROPYLMETHYLCE
LLULOSE2210(K4M) 48.00 0.00 48.00
RMM106 MECOBALAMIN (5.0%) IN MANNITOL 30.00 25.00 37.50
RMM004 MICRO CRYSTALLINE
CELLULOSE 43.75 0.00 43.75
**BINDING-I (METHYL COBALAMIN PAR
RMI004 ISOPROPYL ALCOHOL 0.20 0.00 0.20
RMP002 POLYVINYLPYRROLIDONE K-
30 12.00 0.00 12.00
**LUBRICATION-I (METHYL COBALAMIN PART)**
RMA001 COLLOIDAL SILICON DIOXIDE 0.75 0.00 0.75
RMM006 MAGNESIUM STEARATE 3.5 0.00 3.5
RMT001 TALC 4.5 0.00 4.5
IMMEDIATE RELEASE LAYER
**MIXING-II (FOLIC ACID & PYRIDOXINS HCL PART)
RMF008 FOLIC ACID 5 15.00 5.75
RMM004 MICRO CRYSTALLINE CELLULOSE 93.50 0.00 93.50
RMS002 ! SODIUM STARCH GLYCOLLATE 7.00 0.00 7.00
RMP005 ' VITAMIN B6 20.00 15.00 23
**BINDING -II (FOLIC ACID & PYRIDOXINE I HCL PART) T\**

RMI004 ISOPROPYL ALCOHOL 0.11 0.00 0.11
RMP002 POLYVINYLPYRROLIDONE K-
30 8.0 0.00 8.00
**LUBRICATION-II (FOLIC ACID & PYRIDOXINE HC L PART)**
RMA001 COLLOIDAL SILICON DIOXIDE 0.75 0.00 0.75
RMC045 CROSPOV1DONE 4.0 0.00 4.00
RMM006 MAGNESIUM STEARATE 3.5 0.00 3.50
RMT001 TALC 4.5 0.00 4.50
**COATING**
RMH003 HYDROXYPROPYLMETHYLCEL
LULOSE2910(E15) 7.50 0.00 7.50
RMI004 ISOPROPYL ALCOHOL 0.081 0.00 0.081
RMM011 METHYLENE CHLORIDE 0.191 0.00 0.191
RMP020 POLYETHYLENE GLYCOL - 6000 0.98 0.00 0.98
Procedure:
1.1 MANUFACTURING PROCESS FOR METHYLCOBALAMIN SR LAYER
BLEND
Step 1: DRY MIXING:
1.2 Sift Hydroxy propyl methyl cellulose (K4M), Micro crystalline cellulose through 40# on sifter and collect in double polyethylene lined air tight containers.
1.3 Charge the sifted materials of step 1 and Methylcobalamin (5%) in Mannitol into rapid mixer granulator and operate it for 25 minutes at slow impeller speed with chopper off.
Step 2: BINDING:
2.1 BINDER PREPARATION:
Sift Polyvinylpyrrlidone K-30 through 40# and dissolve it in Isopropyl Alcohol (IPA) with continuous stirring in a suitable capacity S.S. container & filtered

through 200 #.
2.2 MASS BINDING:
2.2.1 Add binder solution of step 2.1 to a powder mix of step 1.2 in Rapid Mixer granuiator and mix for 3 minutes at slow impeller speed with chopper off, until desired granulation point is achieved. Unload the material from rapid mixer granuiator into S.S. bowl of fluid bed drier trolley.
2.2.2 Mill the wet mass of step 2.2.1 using multi mill.
2.3 DRYING:
2.3.1 Operate FBD to dry the wet mass at 40 °C ± 5 °C inlet temperature for 40-50 minutes, keeping damper open at 25% or until dried. Check the loss on drying of dried granules at 65°C ± 3°C temperature for 5.0 minutes using IR moisture balance. It should not be more than 3.0% w/w.
2.4 SIFTING OF OVERSIZE GRANULES:
2.4.1 Sift the dried granules obtained from step 2.3.1 through 20# on sifter and collect it in double polyethylene-lined containers.
2.4.2 Collect the sized material in double polyethylene lined containers.
2.5 BLENDING AND LUBRICATION:
2.5.1 Transfer the granules of step 2.4.2 into octagonal blender.
2.5.2 Sift Colloidal silicon dioxide, Talc through sieve 40# on sifter.
2.5.3 Add sifted materials of step 2.5.2 into Octagonal blender of step 2.5,1 and blend the materials for 20 minutes at slow speed.
2.5 A Sift Magnesium Stearate through 80 # on sifter. Add sifted Magnesium Stearate
to octagonal blender and mix for 2 minutes at slow speed.
MANUFACTURING PROCESS FOR PYRIDOXINE HYDROCHLORIDE AND FOLIC ACID IMMEDIATE RELEASE LAYER
2.6 RAW MATERIALS SIFTING AND MIXING

2.6.1 Sift Pyridoxine Hydrochloride, folic acid, Micro crystalline cellulose and Sodium starch Gtycolate) through 40# and collect in double polyethylene lined air tight containers.
2.6.2 Charge the sifted materials of step 2.6.1 into rapid mixer granulator and operate it for 15 minutes at slow impeller speed and chopper off.
2.7 BINDING :
2.7.1 BINDER PREPARATION :
2.7.1.1 Sift Polyvinylpyrrolidone K-30 through 40# and dissolve it in Isopropy! Alcohol (1PA) with continuous stirring in a suitable capacity S.S. container & filtered through
200 #.
2.7.2 MASS BINDING :
2.7.2.1 Add binder solution of step 2.7.1.1 to a powder mix of step 2.6.2 in Rapid Mixer granulator and mix for 3 minutes at slow impeller speed and chopper off or until desired granulation point is achieved. Unload the material from rapid mixer granulator into S.S. bowl of fluid bed drier trolley at slow impeller speed and Chopper at slow speed.
2.7.2.2 Mill the wet mass of step 2.7.2.1 using multi mill.
2.8 DRYING:
2.8.1 Operate FBD at 40 °C ± 5 °C inlet temperature for 30-40 minutes, keeping damper open at 25% or until dried.
2.8.2 Check the loss on drying of dried granules at 65°C ± 3°C temperature for 5.0 minutes using IR moisture balance. It should not be more than 3.0% w/w.
2.9 SIFTING OF OVERSIZE GRANULES :
2.9.1 Sift the dried granules obtained from step 2.8.1 through sieve 20# on sifter in double polyethylene lined containers.
2.10 BLENDING AND LUBRICATION :
2.10.1 Transfer the granules of step 2.9.1 in to octagonal blender.

2.10.2 Sift Cross povidone ,Aerosil ,Talc through sieve 40# on sifter.
2.10.3 Add sifted materials of step 2.10.2 into Octagonal blender of step 2.10.1 and blend the materials for 20 minutes at slow speed as per SOP NO. TA-066.
2.10.4 Sift Magnesium Stearate through 80 # on sifter. Add sifted Magnesium Stearate to octagonal blender and mix for 2 minutes at slow speed.
2.11 COMPRESSION OF BILAYER TABLET:
All processes and material transfer to be carried out under sodium vapour lamp at temperature NMT 25° C and relative humidity below 50% during compression.
2.11.1 Compress the released granules on rotary tablet machine using 12/32"SC Round
shape keeping
Theoretical weight of Methylcobalamin (SR part) : 150 mg
Theoretical weight of Pyridoxine Hydrochloride and folic acid part (IR part): 150
mg
Total Weight of Bilayer tablet: 300 mg
2.12 COATING
2.12.1 Take Isopropyl alcohol in colloid mill and transfer hydroxypropylmethylcellulose (El5). Operate colloidal mill for 5 mins to get Homogenous mixing and Discharge suspension then add Methylene chloride & melt polyethylene glycol 6000 and add into the solution & stirring it for 5 min.
2.12.2 Coat the Tablet using coating solution of step 2,12.1 Dissolution Studies:

% of Methylcobalamin. Dissolved.
Time Interval Tab 1 Tab 2 Tab 3 Tab 4 Tab 5 Tab 6 Minimum Maximum Average
After l.0Hr 27.62 27.03 30.52 25.77 28.06 29.17 25.77 30.52 28.03
After 4 Hours 72.41 78.75 76.88 69.54 65.36 73.12 65.36 78.75 72.67
After 8.00 Hrs 108.71 103.54 106.44 97.74 98.92 100.27 97.74 108.71 102.60

(METHYL COBALMIN SUSTAINED RELEASE TABLETS)

CODE MATERIAL Quantity Per Tablet O.A.
% Total Quantity Per Tablet
Methylcobalamine sustained Release tablets 1500mcg
**MIXING-I (METHYL COBALAMIN PART)**
RMS011 HYDROXYPROPYLMETHYLCE
LLULOSE2210(K4M) 48.00 0.00 48.00
RMM106 MECOBALAMIN (5.0%) IN MANN1TOL 30.00 25.00 37.50
RMM004 MICRO CRYSTALLINE CELLULOSE 49.75 0.00 49.75
**BINDING-I (METHYL COBALAMIN PART)**
RMI004 ISOPROPYL ALCOHOL 0.20 0.00 0.20
RMP002 POLYVINYLPYRROLIDONE K-30 12.00 0.00 12.00
**LUBRICATION-I (METHYL COBALAMIN PART)**
RMA001 COLLOIDAL SILICON DIOXIDE 0.75 0.00 0.75
RMM006 MAGNESIUM STEARATE 3.5 0.00 3.5
RMT001 TALC 4.5 0.00 4.5
Procedure:
MANUFACTURING PROCESS FOR METHYLCOBALAMIN SR LAYER
BLEND
Stepl : DRY MIXING:
1.1 Sift Hydroxy propyl methyl cellulose (K4M), Micro crystalline cellulose through
40# on sifter and collect in double polyethylene lined air tight containers.
1.2 Charge the sifted materials of step 1.1 and Methylcobalamin (5%) in Mannitoi into
rapid mixer granulator and operate it for 25 minutes at slow impeller speed and
chopper off.

Step 2 BINDING:
2.1 BINDER PREPARATION:
Sift Polyvinylpyrrolidone K-30 through 40# and dissolve it in of Isopropyl Alcohol (IPA) with continuous stirring in a suitable capacity S.S. container & filtered through 200 #.
2.2 MASS BINDING :
2.2.1 Add binder solution of step 2.1 to a powder mix of step 1.2 in Rapid Mixer granulator and mix for 3 minutes at slow impeller speed and chopper off. until desired granulation point is achieved. Unload the material from rapid mixer granulator into S.S. bowl of fluid bed drier trolley.
2.2.2 Mill the wet mass of step 2.2.1 using multi mill.
2.3 DRYING :
2.3.1 Operate FBD to dry the wet mass at 40°C±5 °C inlet temperature for 40-50
minutes, keeping damper open at 25% or until dried. Check the loss on drying of dried granules at 65°C ± 3°C temperature for 5.0 minutes using IR moisture balance. It should not be more than 3.0%w/w.
2.4 SIFTING OF OVERSIZE GRANULES :
2.4.1 Sift the dried granules obtained from step 2.3.1 through 20# on sifter and collect it in double polyethylene-lined containers.
2.4.2 Collect the sized material in double polyethylene lined containers.
2.5 BLENDING AND LUBRICATION:
2.5.1 Transfer the granules of step 2.4.2 into octagonal blender.
2.5.2 Sift Colloidal silicon dioxide ,Talc through sieve 40# on sifter .
2.5.3 Add sifted materials of step 2.5.2 into Octagonal blender of step 2.5.1 and blend the materials for 20 minutes at slow speed.

2.5.4 Sift Magnesium Stearate through 80 # on sifter. Add sifted Magnesium Stearate to octagonal blender and mix for 2 minutes at slow speed.
2.6 COMPRESSION OF TABLET:
2.6.1 All processes and material transfer to be carried out under sodium vapour lamp
at temperature NMT 25° C and relative humidity below 50% during
compression
2.6.2 Compress the released granules on rotary tablet machine using 9/32"SC Round
shape keeping Theoretical weight of Tablet: 156 mg
Dissolution Studies:

% of Methylcobalamin Dissolved.
Time Interval Tab l Tab 2 Tab 3 Tab 4 Tab 5 Tab 6 Minimum Maximum Average
After l.0Hr 26.5 26.03 28.52 25.69 29.17 25.77 25.69 29.17 26.95
After 4 Hours 74.33 79.65 76.88 70.54 75.36 79.83 70.54 79.83 76.10
After 8.00 Hrs 108.71 102.56 99.29 100.10 98.92 102.15 98.92 108.71 101.96
Example 3 Methylcobalmin ,Folic Acid & Vitamin B6 Sustained Release capsules (Methylcobalamin in sustained release form) B.No: 330/01

CODE MATERIAL Quantity Per Tablet O.A.
% Total Quantity Per Tablet
METHYLCOBALMIN TABLETS
**MIXING-I (METHYL COBALAMIN PART)**
RMS011 HYDROXYPROPYLMETHYLCE
LLULOSE2210(K4M) 48.00 0.00 48.00
RMM106 MECOBALAMIN (5.0%) IN MANNITOL 30.00 25.00 37,50
RMM004 MICRO CRYSTALLINE CELLULOSE 38.75 0.00 38.75

**BINDING-I (METHYL COBALAMIN PART)**

RM1004 ISOPROPYL ALCOHOL 0.20 0.00 0.20
RMP002 POLYVINYLPYRROLIDONE K-
30 12,00 0.00 12.00
**LUBRICATION-I (METHYL COBALAMIN PART)**
RMA001 COLLOIDAL SILICON DIOXIDE 0.75 0.00 0.75
RMM006 MAGNESIUM STEARATE 3.5 0.00 3.5
RMT001 TALC 4.5 0.00 4.5
VITAMIN MIX
**MIXING-II (FOLIC ACID & PYRIDOXINS HCL PART)**
RMF008 FOLIC ACID 5 15.00 5.75
RMM004 MICRO CRYSTALLINE CELLULOSE 93.50 0.00 93.50
RMS002 SODIUM STARCH GLYCOLLATE 7.00 0.00 7.00
RMP005 VITAMIN B6 20.00 15.00 23
**BINDING-II (FOLIC ACID & PYRIDOXINE HCL PART)**
RMI004 ISOPROPYL ALCOHOL 0.11 0.00 0.11
RMP002 POLYVINYLPYRROLIDONE K-
30 8.0 0.00 8.00
**LUBRICATION-II (FOLIC ACID & PYRIDOXINE HCL PARI **
RMA001 COLLOIDAL SILICON DIOXIDE 0.75 0.00 0.75
RMC045 CROSPOVIDONE 4.0 0.00 4.00
RMM006 MAGNESIUM STEARATE 3.5 0.00 3.50
RMT001 TALC 4.5 0.00 4.50
Procedure:
Manufacturing Process For Methylcobalamin SR Tablet
Step 1 : DRY MIXING:
1.1 Sift Hydroxy propyl methyl cellulose (K4M) , Micro crystalline cellulose through

40# on sifter and collect in double polyethylene lined air tight containers. 1.2 Charge the sifted materials of step 1.1 and Methylcobalamin (5%) in Mannitol into rapid mixer granulator and operate it for 25 minutes at slow impeller speed and chopper off
2 BINDING:
2.1 BINDER PREPARATION:
Sift Polyvinylpyrrlidone K-30 through 40# and dissolve it in Isopropyl Alcohol (JPA) with continuous stirring in a suitable capacity S.S. container & filtered through 200 #.
2.2 MASS BINDING :
2.2.1 Add binder solution of step 2.1 to a powder mix of step 1.2 in Rapid Mixer granulator and mix/or 3 minutes at slow impeller speed and chopper off. until desired granulation point is achieved. Unload the material from rapid mixer granulator into S.S. bowl of fluid bed drier trolley.
2.2.2 Mill the wet mass of step 2.2.1 using multi mill.
2.3 DRYING :
2.3.1 Operate FBD to dry the wet mass at 40°C±5 °C inlet temperature for 40-50
minutes, keeping damper open at 25% or until dried. Check the loss on drying of dried granules at 65°C ± 3°C temperature for 5.0 minutes using IR moisture balance. It should not be more than 3.0%w/w.
2.4 SIFTING OF OVERSIZE GRANULES :
2.4.1 Sift the dried granules obtained from step 2.3.1 through 20# on sifter and collect it in double polyethylene-lined containers.
2.4.2 Collect the sized material in double polyethylene lined containers.
2.5 BLENDING AND LUBRICATION:
2.5.1 Trans fer the granu les of step 2.4.2 i nto octagonal blender.

2.5.2 Sift Colloidal silicon dioxide ,Talc through sieve 40# on sifter.
2.5.3 Add sifted materials of step 2.5.2 into Octagonal blender of step 2.5.1 and blend the materials for 20 minutes at slow speed.
2.5 4 Sift Magnesium Stearate through 80 # on sifter. Add sifted Magnesium Stearate
to octagonal blender and mix for 2 minutes at slow speed.
2.6 COMPRESSION OF TABLET:
2.6.! All processes and material transfer to be carried out under sodium vapour lamp at temperature NMT 25° C and relative humidity below 50% during compression
2.6.2 Compress the released granules on rotary tablet machine using 7/32"SC Round
shape keeping theoretical weight of Tablet: 145 mg
MANUFACTURING OF VITAMIN MIX:
2.7 RAW MATERIALS SIFTING AND MIXING
2.7.1 Sift Pyridoxine Hydrochloride, folic acid, Micro crystalline cellulose and Sodium starch Glycolate ) through 40# and collect in double polyethylene lined air tight containers.
2.7.2 Charge the sifted materials of step 2.7.1 into rapid mixer granulator and operate it for 15 minutes at slow impeller speed and chopper off.
2.8 BINDING :
2.8.1 BINDER PREPARATION :
2.8.1.1 Sift Polyvinylpyrrolidone K-30 through 40# and dissolve it in Isopropyl Alcohol (IPA) with continuous stirring in a suitable capacity S.S. container & filtered through 200 #.
2.9 MASS BINDING:
2.9.1 Add binder solution of step 2.8.1.1. to a powder mix of step 2.7.2 in Rapid Mixer granulator and mix for 3 minutes at slow impeller speed and chopper off or until

desired granulation point is achieved. Unload the material from rapid mixer granulator into S.S. bowl of fluid bed drier trolley at slow impeller speed and Chopper at slow speed. 2.9.2 Mill the wet mass of step 2.9.1 using super mill.
2.10 DRYING:
2.10.1 Operate FBD at 40 °C • 5 °C inlet temperature for 30-40 minutes, keeping damper open at 25% or until dried.
2.10.2 Check the loss on drying of dried granules at 65°C • 3°C temperature for 5.0 minutes using IR moisture balance. It should not be more than 3.0%w/w.
2.11 SIFTING OF OVERSIZE GRANULES :
2.U.1 Sift the dried granules obtained from step 2.W.1 through sieve 20# on sifter rn double polyethylene lined containers.
2.12 BLENDING AND LUBRICATION :
2.12.1 Transfer the granules of step 2.11.1.1 in to octagonal blender.
2.12.2 Sift Cross povidone ,Aerosil ,Talc through sieve 40# on sifter.
2.12.3 Add sifted materials of step 2.12.2 into Octagonal blender of step 2.12.1 and blend the materials for 20 minutes at slow speed as per SOP NO. TA-066.
2.12.4 Sift Magnesium Stearate through 80 # on sifter. Add sifted Magnesium Stearate to octagonal blender and mix for 2 minutes at slow speed,
2.13 CAPSULE FILLING:
2.13.1 Fille in"0" size Capsule the Tablet of Step No 2.6.2 & Vitamin Mix of step No: 2.12.4. on a suitable capsule filing machine.

Dissolution Studies:

% of Methylcobalamin Dissolved.
Time Interval CAP 1 CAP2 CAP3 CAP4 CAP5 CAP6 Minimum Maximum Average
After l.OHr 25.5 27.03 27.12 24.19 26.12 26.72 24.19 27.12 26.11
After 4 Hours 71.14 72.19 70.10 68.85 71.85 77.10 68.85 77.10 71.87
After 8.00 Hrs 100.71 99.56 97.90 99.10 98.54 100.01 97.90 100.71 99.30
Example 4
Dissolution studies
Dissolution studies were conducted on tablets manufactured as per present invention containing 1500 meg of methylcobalamin, manufactured in our Research and Development lab, Batch No. 119/01, in 500ml Distilled Water at 37.5 ± 1 degrees °C and the tablets were found to exhibit the aforesaid dissolution profile.
Bioequivalence Studies
A bioequivalence study of the tablets manufactured as per present invention containing 1500 mcg of methylcobalamin, Batch No. 119/01, manufactured in our Research and Development lab, in comparison with methylcobalamin immediate release tablets, 500 mcg (brand name: Methycobal Tablets), Batch No. 94023, manufactured by M/s Wockhardt Ltd., India, was conducted on 15 healthy human volunteers. The volunteers were given one tablet of 500 mcg methylcobalamin immediate release (brand name: Methycobal Tablets, Wockhardt Ltd, India) at 8 hours intervals totaling to 3 tablets in 24 hours and blood levels of methylcobalamin were measured.
Subsequently, after wash out period, the volunteers were given 1 tablet of 1500 mcg extended release dosage form of methylcobalamin and blood levels of methylcobalamin were then monitored for 24 hours. The results of the blood levels of methylcobalamin produced by the two dosage forms are depicted in Figure 1.


The results of the study showed that the extended release formulation of methylcobalamin 1500 mcg manufactured as per present invention was found to be bioequivalent to three doses of immediate release methylcobalamin tablets of 500 mcg, given at 8 hours intervals. The Cmax (C=concentration) achieved by the test formulation is significantly higher as compared to the Cmax produced by the three, eight hourly doses of the immediate release market preparation. More importantly, the AUC (area under curve) value of the tablets manufactured as per the present invention is equivalent to the AUC value produced by three eight hourly doses of the immediate release methylcobalamin tablets of 500 mcg.
While this invention has been described with an emphasis upon preferred embodiments, it will be obvious to those of ordinary skill in the art that variations in the preferred methods of the present invention may be used and that it is intended that the invention may be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications encompassed within the spirit and scope of the invention as defined by the following claims,

We Claim:
1. An extended release composition comprising:
a) a therapeutically effective amount of methylcobalamin or its pharmaceutical acceptable forms;
b) optionally one or more stabilizers; and
c) matrix forming agents,
wherein the composition provides sustained blood levels of an effective concentration of methylcobalamin for about 24 hours, without being retained in the stomach.
2. The composition according to claim 1, wherein the pharmaceutically acceptable form of methylcobalamin is selected from the group consisting of isomers, enantiomers, complexes, hydrates, polymorphs, salts and any mixtures thereof.
3. The composition according to claim 1, wherein the composition further comprising complimentary vitamins.
4. The composition according to claim 3, wherein the complimentary vitamins are selected from B-complex group including folic acid, Vitamin B6 Vitamin B1, Vitamin B2, selenium and mixtures thereof
5. The composition according to claim 1, wherein the composition is in the form of bi-layer tablets or capsules.
6. The composition according to claim 5, wherein one layer of the bilayer tablet comprises matrix based extended delivery of methylcobalamin or its pharmaceutically acceptable forms and the second immediate release layer consisting of complimentary vitamins.
7. The composition according to claim 5, wherein the capsules are filled with tablets or pellets comprising methylcobalamin or its pharmaceutically acceptable forms in extended release formulation and complimentary vitamins in immediate release form.

8. The composition according to claim 1, wherein the tablet or capsule is small in size than gastro-retentive sustained release dosage forms of methylcobalamin composition.
9. The composition according to claim 1, wherein the stabilizer is mannitol.
10. The composition according to claim 1, wherein the matrix forming agent is selected from hydroxyl propyl methyl cellulose or polyethylene oxides or mixture thereof.
11. The composition according to claim 1, wherein the composition further comprising pharmaceutical^ acceptable excipients such as diluents, binders, disintegrants, lubricants or giidants.
12. The composition according to claim 11, wherein the diluents are selected from the group consisting of microcrystalline cellulose, lactose, di-calcium phosphate or starch.
13. The composition according to claim 12, wherein the ratio of matrix forming agent to diluent in the pharmaceutical composition is about 1:0.65 to about 1: 1.75.
14. The composition according to claim 11, wherein the binders are selected from polyvinylpyrollidoneand hydroxypropyl methyl cellulose.
15. The composition according to claim ll, wherein the disintegrants are selected from cross linked crosspovidone, cross linked carboxymethylcellulose sodium and sodium starch glycol late.
16. The composition according to claim 1, wherein one dose of the extended release composition, comprising three times the amount of methylcobalamin that is

present in a single immediate release methylcobalamin composition, is bioequivalent to three doses of immediate release methylcobalamin given at 8 hour intervals.
17. The composition according to claim 1, wherein the composition is prepared by wet granulation method.
18. The composition according to claim 1, wherein the composition releases the methylcobalamin throughout the gastrointestinal tract(GIT).
19. The composition according to claim 18, wherein the release of the methylcobalamin from the composition is independent of change in pH in the GIT.