FORM2
THE PATEWT ACT 1970(39 Of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION: PHARMACEUTICAL COMPOSITIONS
2. APPLICANT (S)(a) NAME: WOCKHARDT LTD.(b) NAUONALITY: INDIAN(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra(East), Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTIONThe present invention provides pharmaceutical composition in the form of fixed combination comprising of mecobalamin, pyridoxine or salt thereof and folic acid along with other pharmaceutically acceptable carriers wherein the mecobalamin is present in an extended release form.
The follwing specification particularly describes the invention and the manner In which it is to be performed.
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4. DESCRIPTION
The present invention provides pharmaceutical composition in the form of fixed combination comprising of mecobalamin, pyridoxine or salt thereof and folic acid along with other pharmaceutically acceptable carriers wherein the mecobalamin is present in an extended release form.
Mecobalamin, also known as methylcobalamin is described chemically as Methyl-5,6-dimethylbenzimidazolylcobalamin of formula 1. Its molecular formula is C63H91C0N13O14P and molecular weight is 1344.38. Mecobalamin plays an important role in transmethylation as a coenzyme of methionine synthetase in the synthesis of methionine from homocysteine. It is also used in vitamin B12 deficiency (pernicious anemia) treatment.

Pyridoxine hydrochloride, also called. Vitamin B6, is one of eight water-soluble B vitamins chemically described as 5-hydroxy-6-methylpyridine-3,4-dimathanol monohydrochloride of formula 2. Pyridoxine is an especially important vitamin for maintaining healthy nerve and muscle cells and it aids in the production of DNA and RNA, the body's genetic material. It is necessary for proper absorption of vitamin 812 and for the production of red blood cells and cells of the Immune system. Pyrdioxine is considered an "anti-stress" vitamin because it is believed to
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enhance the activity of the immune system and improve the body's ability to with and stressful conditions.

Folic acid is a water-soluble vitamin in the B-complex group, chemically described as A/-[4-[[(2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl]amino] benzbyl]-L-giutamic acid of Formula 3. Folate is necessary for the production and maintenance of new cells. This is especially important during periods of rapid cell divisbn and growth such as infancy and pregnancy. Folate is needed to replicate DNA. it also helps prevent changes to DNA that may lead to cancer. Both adults and children need folate to make normal red blood cells and prevent anemia.

US Patent 4,337,246 provides solid preparation comprising cobamamide or mecobalamin and a red dye suitable for food as a stabilizer to light.
Japanese Application 2006143613 provides tablet composition comprising sucdhic add d-a-tocopherol and hydroxocobalamin and a granular composition
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comprising dicethiamine hydrochlorkle, riboflavin, pyridoxine hydrochloride, and calcium pantothenate with additives, and then the tablet was (coated with sugar-based layer.
Chinese Application 1742748 provides dispersible tablet dosage form comprising mecobalamin, sodium carboxymethyl starch, low substituted hydroxypropy! cellulose, microcrystalline cellulose, poiyvidone, micronized silica gel, stevioside, magnesium stearate and talcum powder.
Japanese Application 2000016940 provides vitamin B12 composition comprising vitamin B12 and alphatized starch coated with cellulose compounds or acrylic polymers.
The present invention is now directed to pharmaceutical compositions that comprise triple combination of mecobalamin, pyridoxine or salt thereof and folic acid along with other pharmaceutically acceptable carriers wherein the mecobalamin is present in an extended release form. Extended release form of mecobalamin reduces the dosing frequency of the drug from thrice a day dosing to once a day dose and thus further enhances the patient compliance.
In one of the aspects of the present invention there is provided a pharmaceutical solid dosage form for oral administration comprising triple combination of mecobalamin, pyridoxine or salt thereof and folic acid along with other pharmaceutically acceptable carriers wherein the mecobalamin is present in an extended release form.
Mecobalamin, an essential nutrient, is required for the nonnal activity of nerve cells, and works with folic acid and pyridoxine or salt thereof or vitamin B6 to tower blood levels of homocysteine, a chemical in the blood that is thought to contribute to heart disease. Vitamin 812 also plays a role in the body's manufacture of S-adenosylmethlonine. Because the B vitamins tend to work
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together, many nutritional experts recommend taking vitamin B12 with other B Vitamins In the form of a B-complex supplement.
The pharmaceutical compositions containing triple combination of mecobalamin, pyridoxine and folic acid disclosed herein are administered orally. The pyridoxine
and folic acid may be present in an Immediate release form and mecobalamin may be present in an extended release form. Little quantity of mecobalamin may also be present in an immediate release form along with pyridoxine and folic acid as it helps to immediately release the drug from the dosage form and provide desired therapeutic effect.
The oral dosage forms may be in the form of tablet in tablet, tablet in capsule, layered tablet, capsules, powder, granule, sachet, mini-tablet and the like. The combination can be employed in admixture with pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients can be diluent, filler, binder, lubricant. sweetener, coloring and flavoring agent, glidant and the like. Such deluients include inert diluents such as lactose, microcrystalline cellulose, maize starch, starch 1500, sodium bicarbonate, microcrystalline cellulose, lactose monohydrate and the like; granulating and disintegrating agents such as corn stare^, sodium starch glycolate, croscarmelbse sodium, crospovidone and the like; lubricating agents such as magnesium stearate, calcium stearate, talc and the like. The binders may be one or more of starch, sugars, gums, low molecular weight hydroxypropylmethyl cellulose, polyvinyl pyrrolidone and hydroxypropyl cellulose. The glidant may be one or both of colloidal silicon dioxide and talc or magnesium stearate. Suitable coloring and flavoring agents include those approved for use by the United States Food and Drug Administration (FDA) and are well known to those skilled in the art.
The dosage form can be further coated with one or more coats. The outer layer also can be called as seal coat is formed from an inert film former. The pharmaceutically acceptable seal Coat forming polymers can be selected from a
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group comprising of one or more of suitable cellulose ethers include one or more of hidroxypropyl methylcellulose, hydroxypropyl cellulose and other suitable cellulose ethers. The outer layer is further surrounded by protective coat.
In another aspect of the present Invention there is provided a pharmaceutical solid dosage form for oral administration comprising:
a) extended release granules comprising of mecobalamin, along with other pharmaceutically acceptable ingredients
b) immediate release granules comprising of pyridoxine or salt thereof, folic acid in a therapeutically effective amount along with other pharmaceutically acceptable ingredients, and
c) optionally comprising mecobalamin in the form of immediate release granules
wherein the said extended release granules and said immediate release granules are further compressed into bilayer tablets.
Therapeutically effective amount of mecobalamin, pyridoxine or salt thereof and folic acid is included in this combination. Extended release forming polymers are seleded from hydrophilic polymers such as xanthan gum, sodium carboxymethylcellulose, sodium alginate, hydroxypropyl methylcellulose and the like.
In yet another aspect of the present invention there is provided a pharmaceutical solid dosage form for oral administration comprising:
a) extended release pellets comprising of mecobalamin, along with other pharmaceutically acceptable ingredients and
b) immediate release granules comprising of pyridoxine or salt thereof, folic add in a therapeutically effective amount along with other pharmaceutically
acceptable ingredients, and
c) optionally comprising mecobalamin in the form of immediate release
granules

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wherein the said extended release pellets and said immediate release granules are contained within a hard gelatin capsule.
In another aspect of the present invention there is provided a pharmaceutical solid dosage form for oral administration comprising:
a) extended release tablet comprising of mecobalamin, along with other pharmaceutically acceptable ingredients and
b) immediate release granules comprising of pyridoxine or salt thereof, folic acid in a therapeutically effective amount along with other pharmaceutically acceptable ingredients, and
c) optionally comprising mecobalamin in the form of immediate release granules
wherein the said extended release tablet and said immediate release granules are contained within a hard gelatin capsule.
The extended release granules may be prepared by wet granulation. All the ingredients along with the active agent are weighed properly. Microcrystalline cellulose, Xanthan gum. Sodium CMC, Sodium alginate, Hydroxypropyl methylcellulose & Calcium Carbonate were mixed together, granulated with PVP K-30 and isopropyl alcohol and dried using fluid bed drier. Mecobalamin is mixed geometrically with maize starch, and lactose anhydrous. Croscarmellbse sodium, aerosil, sodium bicarbonate, purified talc, calcium stearate were mixed together and further added to above mix to lubricate the granules.
The immediate release granules may be prepared by wet granulation. All the ingredients along with the active agent are weighed properly. Microcrystalline cellulose, Pyridoxine HCI, Folic acid. Lactose monohydrate, Sodium starch glycollate are mixed properly, granulated with PVP K-30 and isopropyl alcohol and dried using fluid bed drier. Microcrystalline cellulose and sodium starch glycollate were mixed first and mecobalamin is mixed geometrically with this mix. All the granules mixed together and lubricated using calcium stearate. Both
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extended release and immediate release granules were compressed into double layer tablets. These bilayer tablets were further seal coated using PEG-4000, hydroxypropyl methylcellulose, isopropyl alcohol and methylene chloride, dried and further coated with protective coat containing isopropyl alcohol, methylene chloride and Opadry red.
The above extended release and immediate release granules can also be filled into capsules and thus capsule dosage form can be formulated.
For the tablet in capsule dosage form, extended release granules were compressed in to tablets and further filled into capsules along with immediate release granules.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES - Following formulation is representative of the preferred compositions of the present invention.
Table 1 provides composition of present invention
Table 2 provides the dissolution data of the tablets prepared as per the formula provided in Table 1. For determination of drug release rate of mecobalamin, 0.1 N HCI in 500 ml of medium using USP Type I Apparatus (basket #10, rpm 100) was used, and for determination of drug release rate of folic acid and pyridoxine, 6.8-pH phosphate buffer in 900 ml of medium using USP Type II Apparatus (rpm
50) was used.

Table 1 - Composition of batches.

Sr. No. Ingredients Quantity
EXTENDED RELEASE LAYER
1 Microcrystalline cellulose 5 to 25%
2 Xanthan gum 5 to 15%
3 Sodium CMC 0.5 to 10%
4 Sodium alginate 0.1 to 10%
5 Hydroxypropyl methylcellulose 1 to 30%
6 Calcium Carbonate 1 to 10%
7 PVP K-30 0.1 to 5%
8 Mecobalamin 0.14%
9 Maize starch dried 1 to 20%
10 Starch 1500 1 to 15%
11 Lactose anhydrous 1 to 10%
12 Croscarmellose sodium 1 to 10%
13 Talc 0.1 to 3%
14 Aerosil 0.1 to 7.0%
15 Calcium stearate 1 to 10%
16 Sodium bicarbonate 5 to 25%
17 Isopropyl alcohol
IMMEDIATE RELEASE LAYE =R
18 Pyridoxine Hydrochloride 5.10%
19 Folic acid 1.22%
20 Microcrystalline cellulose 10 to 70%
21 Lactose monohydrate 10 to 50%
22 PVP K-30 1 to 10%
23 Purified water Q. S.
24 Sodium starch glycollate 1 to 10%
25 Mecobalamin 0.12%
26 Calcium stearate 0.1 to 10%
SEAL COAT
27 Hydroxypropyl methylcellulose 1 to 10%
28 PEG-4000 0.1 to 5%
29 Isopropyl alcohol 10 to 50%
30 Methylene chloride 10 to 70%
PROTECTIVE COAT
31 Opadry red 1 to 10%
32 Isopropyl alcohol 10 to 50%
33 Methylene chloride 10 to 70%
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Procedure (Double Layered Tablets)-Extended Release Layer -
All the raw materials are weighed and sifted using stainless steel sieve fitted to a mechanical sifter. Isopropyl alcohol and PVP K-30 are mixed together for 4 to 5 minutes until clear solution is obtained. Microcrystalline cellulose, xanthan gum, sodium CMC, sodium alginate, hydroxypropyl methylcellulose, & calcium carbonate are mixed at slow speed of impeller and chopper for 5 minutes. Binding solution is added to above mix. This wet mass is sifted through #10 stainless steel sieve fitted to a mechanical sifter. This wet mass is dried using FBD till loss on drying is between 4.0-6.0% and sifted through # 60. Maize starch. Starch 1500, Lactose anhydrous are mixed and shifted through # 60, mecobalamin is mixed geometrically with this mix. Croscarmellose sodium, aerosil, sodium bicarbonate are mixed in octagonal blender for 5 minutes, Purified talc and Calcium stearate are added and mixed
Immediate Release Layer -
All the raw materials are weighed and sifted using stainless steel sieve fitted to a mechanical sifter. Purified water and PVP K-30 are mixed together for 4 to 5 minutes until clear solution is obtained. Microcrystalline cellulose, pyridoxine HOI,
folic acid, lactose monohydrate, sodium starch glycollate are mixed properly using RMG at slow speed. Binding solution is added to above mix. This wet mass
is dried using FBD till loss on drying is between 2.0-3.5% and sifted through # 20. Microcrystalline cellulose, Sodium starch glycollate are sifted through sieve # 40 and mecobalamin are added geometrically. Calcium stearate Is added to above granules and mixed properly.
Compression -
The above extended release and immediate release granules are compressed
into double layered tablets by adjusting specified weight, hardness and
thickness.
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Seal Coat -
Isopropyl alcohol and Methylene chloride is transferred to the stainless steel container. PEG-4000 and hydroxypropyl methylcellulose is added to this solution with continuous stirring. This solution is used to coat the tablet.
Protective Coat -
Isopropyl alcohol and methylene chloride is transferred to the stainless steel container. Opadry red is added to this solution with continuous stirring and the solution is used to coat the seal coated tablet.
Tablet in Capsule Dosage Form - For the tablet in capsule dosage form, extended release granules are compressed in to tablets and further filled into capsules along with immediate release granules
Capsule Dosage Form - The above extended release and immediate release granules are filled into capsules and thus capsule dosage form can be formulated.
Table 2 - The release pattern of the tablets of present invention.

Time (hrs) % Release
Mecobalamin Pyridoxine Hydrochloride Folic acid
1 47.30 112.10 106.70
4 64.40 - -
8 76.60 - -
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WE CLAIM:
1. A pharmaceutical solid dosage form for oral administration comprising triple combination of mecobalamin, pyridoxine or salt thereof and folic acid along with other pharmaceutically acceptable carriers wherein the mecobalamin is present in an extended release form.
2. A pharmaceutical solid dosage form for oral administration comprising:

a) extended release granules comprising of mecobalamin, along with other pharmaceutically acceptable ingredients
b) immediate release granules comprising of pyridoxine or salt thereof, folic acid in a therapeutically effective amount along with other pharmaceutically acceptable ingredients, and
c) optionally comprising mecobalamin in the form of immediate release
granules
wherein the said extended release granules and said immediate release granules are further compressed into bilayer tablets.
3. A pharmaceutical solid dosage form for oral administration comprising:
a) extended release pellets comprising of mecobalamin, along with other pharmaceutically acceptable ingredients and
b) imnmnedlate release granules comprising of pyridoxine or salt thereof, folic acid in a therapeutically effective amount along with other pharmaceutically acceptable ingredients, and
c) optionally comprising mecobalamin in the form of immediate release granules
wherein the said extended release pellets and said immediate release granules are contained within a hard gelatin capsule.
4. A pharmaceutical solid dosage form for oral administration comprising:
a) extended release tablet comprising of mecobalamin, along with other
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pharmaceutically acceptable ingredients and
b) immediate release granules comprising of pyridoxine or salt thereof, folic acid in a therapeutically effective amount along with other pharmaceutically acceptable ingredients,
c) optionally comprising mecobalamin in the form of immediate release granules
wherein the said extended release tablet and said immediate release granules are contained within a hard gelatin capsule.
5. A pharmaceutical solid dosage form for oral administration according to claims
1, 2, 3 and 4, wherein the dosage form further comprises coating thereon.
6. A pharmaceutical dosage form according to claims 1,2,3 and 4, wherein the
one or more pharmaceutically acceptable additives are selected from the group
consisting of a diluent, binder, extended release forming polymers, disintegrant,
lubricant, glidant, coloring agent, flavoring agent, sweetener and mixtures
thereof.
7. A pharmaceutical dosage form according to claims 1,2,3 and 4, wherein the extended release forming polymers are selected from hydrophilic polymers such as xanthan gum, sodium carboxymethylcellulose, sodium alginate, hydroxypropyl methylcellulose and the like.
8. A pharmaceutical dosage form according to claims 1,2,3 and 4, wherein the dosage form exhibits a dissolution profile such that 30% or more amount of mecobalamin is released in first hour, 50% or more amount of mecobalamin is released in two hours and up to about 80% amount of mecobalamin is released in eight hours and 85% or more amount of folic acid is released in first hour and 85% or more amount of pyridoxine is released in first hour when dissolution is measured in a 0.1 N HCI in 500 ml of medium using USP Type I Apparatus
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(basket #10, rpm 100) for mecobalamin, and 6.8-pH phosphate buffer in 900 ml of medium using USP Type II Apparatus (rpm 50) for folic acid and pyridoxine.
9. A pharmaceutical dosage form according to claims 1,2,3 and 4, wherein the diluents are selected from lactose, microcrystalline cellulose, maize starch,
starch 1500, sodium bicarbonate, microcrystalline cellulose, lactose monohydrate and the like.

Dated this 19th day of January, 2007
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