Title of Invention	A GASTRIC RETENTIVE FLOATING DOSAGE FORM FOR CONTROLLED DELIVERY OF VITAMINS
Abstract	A pharmaceutical composition providing controlled delivery of methylcobalamin designed to improve the bioavailability of the drug in the upper gastrointestinal tract is described. The pharmaceutical composition is formulated into a tablet dosage form. The pharmaceutical composition comprises of a drug, a gas generating component which is also the buoyancy imparting agent, swelling agent, a gel forming polymer, a hydrophilic swellable polymer and a disintegrant.

Title of Invention

A GASTRIC RETENTIVE FLOATING DOSAGE FORM FOR CONTROLLED DELIVERY OF VITAMINS

Abstract

A pharmaceutical composition providing controlled delivery of methylcobalamin designed to improve the bioavailability of the drug in the upper gastrointestinal tract is described. The pharmaceutical composition is formulated into a tablet dosage form. The pharmaceutical composition comprises of a drug, a gas generating component which is also the buoyancy imparting agent, swelling agent, a gel forming polymer, a hydrophilic swellable polymer and a disintegrant.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; rule 13] 'A gastric retentive floating dosage form for controlled delivery of vitamins" (a) M/S. INDOCO REMEDIES LIMITED. (b) Indoco House, 166 C. S. T. Road, Santacruz (East), Mumbai - 400 098, Maharashtra, India (c) Indian company incorporated under the Companies Act 1956 The following specification describes the nature of the invention and the manner in which it is to be performed: Field of Invention: The present invention relates to an improved formulation of vitamin in swellable, buoyant, floating dosage form for controlled delivery of vitamin, preferably Methylcobalamin. Background of the Invention: It is well known to those skilled in the art that for ailments requiring multiple doses of a particular drug; the blood levels of a drug need to be maintained above its minimum effective level and below minimum toxic level in order to obtain the desired therapeutic effects and minimize side effects. When the blood levels of a drug are in this range, the drug is eliminated from the body at a particular rate. A controlled drug delivery system is designed to deliver the drug at this particular rate. Thus, safe and effective blood levels are maintained as long as the system continues to deliver the drug at this rate. Controlled drug delivery results in substantially constant blood level of the therapeutically active ingredient as compared to the uncontrolled fluctuations observed when multiple doses of quick releasing conventional dosage forms are administered to a patient. Controlled drug delivery results in optimum therapy, reduces the frequency of dosing and reduces the severity and frequency of side effects. A number of different oral controlled drug delivery systems are based on different release mechanisms have been developed, viz. dissolution controlled systems, diffusion controlled systems, ion exchange resins, osmotically controlled systems, erodible matrix systems, swelling controlled systems, etc. There has been an increased interest in novel dosage forms which possess not only a mechanism for the controlled release of a drug but also a controlled gastrointestinal transit time. One of the most feasible approaches is to control the gastrointestinal transit time. Dosage forms with a prolonged gastrointestinal transit time i.e. Gastroretentive dosage forms bring about a new and important therapeutic option. The 2 controlled gastric retention of solid dosage forms may be achieved by the mechanisms of mucoadhesion, floatation, sedimentation, expansion or by the simultaneous administration of pharmacological agents which delay gastric emptying. Vitamin B12 also referred to as Cobalamin is a member of the corrinoid family of molecules that contain a planar corrin nucleus made from a tetrapyrrolic ring structure. The centre of the tetra pyrrole ring contains a chelated cobalt atom that can be attached to a methyl, deoxyadenosyl, hydroxyl or a cyano group. Methylcobalamin is the active isoenzyme of Vitamin B12 i.e. is the naturally active form of Vitamin B12 whereas hydroxo and the cyano form require metabolic conversion in vivo. However this form is generally not available for therapeutic purposes. Absorption of Vitamin B12 occurs via intrinsic factor and the other by non intrinsic factor mediated diffusion. The latter route accounts for a small proportion of Vitamin B12 absorbed. Therefore the former process is the only reliable process for the absorption to ensure maximum bioavailability. In humans acid stable intrinsic factor is secreted. Uptake of Vitamin B12 involves the binding of Cobalamin to glycoproteins namely intrinsic factor and haptocorrins. The formation of haptocorrin complex provides protection for Vitamin B12 against acid hydrolysis in the stomach. At low gastric pH, Vitamin B12 binding affinity is higher for haptocorrins than intrinsic factor. However further along the gut in the jejunum, the combined effects of the higher pH and proteolytic digestion of the haptocorrin by pancreatic enzymes result in the release and transfer of Vitamin B12 from haptocorrin to intrinsic factor. When complexed with Cobalamin intrinsic factor is resistant to proteolytic degradation. Moreover complex formation serves to protect Vitamin B12 from catabolism by intestinal microflora and from hydrolytic attack by pepsin and chymotrypsin. Absorption of vitamin B12 occurs via interaction with intrinsic factor ehterocyte cell wall receptor. Only intrinsic factor bound cobalamin is absorbed by the intrinsic factor enterocyte cell wall receptor. This intestinal uptake also requires the presence of Ca2+, a pH of >6 and bile components. Thus, formulating Methylcobalamin into a dosage form with a prolonged gastric residence time namely as gastroretentive dosage form, the dosage form would release the drug in the stomach 3 over a period of time equivalent to the residence time of the unit in the stomach. Following the drug release in the stomach the drug will be taken up by the haptocorrin and intrinsic factor and exclusively absorbed in the intestine. Moreover incorporating a Calcium salt in the formulation the drug is stabilized and its absorption is enhanced. US Patent No. 5,417,983 describes a sustained release delivery system of methylcobalamin wherein the drug release controlling polymer (retardant) is responsive to the changes in temperature. It is well known to those skilled in the art, that such a system will not deliver / release the drug at the constant rate. The release characteristics of the polymer are dependant on its glass transition temperature. Hence minor changes in the polymer structure can affect its behaviour. The synthesis of such a polymer involves use of complex starting materials, number of complicated steps, a tedious and time consuming procedure and use of relatively toxic and highly inflammable solvents like methanol, hexane, diethyl ether, methanol and ethyl acetate. Moreover the drug release from any of these polymers has not been depicted in any of the sited examples and safety of these polymers is not guaranteed. U.S. Patent No. 4,777,033 discloses a controlled release delivery system for riboflavin and methylcobalamin. The formulation comprises of lower alkyl ether of cellulose (hydroxy propyl cellulose), polyacrylic acid or its pharmaceutically acceptable salt, a drug and an effective amount of an effervescent foaming agent. The composition is required to be retained in the stomach for a long time and release the drug at a slow, controlled rate. The formulations mentioned therein are in the form of granules or the so called pilules of particle size ranging from 0.5 mm to 2mm. It is well known to those skilled in the art that multiparticulate systems such as pellets, granules or pilules, because of their smaller size and increased surface area are distributed over the length of the gastrointestinal tract delivering the drug through out the tract. Thus, the purpose of localizing the drug specifically in the upper part of the gastrointestinal tract is not served. Moreover these multiparticulate systems have constant gastrointestinal transit time. Hence gastric residence time of these formulations may not be prolonged as single unit dosage forms. 4 The main aim of the present invention is to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide useful alternative. Summary of the invention: According to the present invention, there is provided an oral sustained release formulation of vitamins preferably absorbed in the upper gastrointestinal tract comprising vitamin, preferably methyl cobalamin, colourant, stabilizer, antioxidants, gas generating component as buoyancy imparting agent, disintegrant, carbohydrate gum, gel forming polymer, hydrophilic swellable polymer, other excipients, etc. The gas generating component is selected from the class of alkali carbonates and bicarbonates and is used 9.7 -10 percent by weight of the dosage unit. The disintegrants are selected from the group comprising cellulose derivatives, cross linked polyvinyl pyrollidone, starch, croscarmellose sodium, sodium starch glycollate, etc and is used in the range of 5.9 - 6.7 percent by weight of the dosage unit. • The carbohydrate gums are selected form the group comprising xanthan gum, gum karaya, gum acacia, locust bean gum, etc and is used in the range of 1.4 - 1.7 percent by weight of the dosage unit. The gel forming polymers are selected from the group comprises the class of alkali metal alginates and cellulose derivatives and is used in the range of 1.4 - 1.7 percent by weight of the dosage unit. The cellulose derivative is selected from sodium carboxyl methyl cellulose is used in the concentration of 1.385 percent by weight of the dosage unit. The hydrophilic polymers are selected from the group comprising hydroxy propyl methyl cellulose HPMC K4M, Methyl cellulose Metolose SM400, Carbomer Carbopol 974P Carbopol 97IP, Carbopol 71G, etc and is used in the concentration 2-11 percent by weight of the dosage unit. 5 The excipients are optionally selected from the group comprising diluents, binders, glidants and lubricants. The diluents are selected from the group comprising from lactose, mannitol, microcrystalline cellulose, etc and is used in 16-37 percent by weight of the dosage unit. The binders are selected from the group comprising cellulose derivatives, polyvinyl pyrollidone, acrylates, starch, gelatin, etc. is 6-7 percent by weight of the dosage unit. The dosage form of the formulation is tablet. The tablet is prepared by wet granulation or direct compression method. Detailed description: The present invention provides controlled drug delivery system for gastric retentive floating dosage forms. The present invention provides improved formulation which is designed to deliver effectively a drug to a patient over a specific time and to a particular portion of the patient's gastrointestinal tract. According to them present invention the improved formulation comprises methyl cobalamine along with pharmaceutically acceptable excipeints such as hydrophilic swellable polymers, carbohydrate gums, gel forming polymers, disintegrants, other excipients etc. According to the present invention, hydrophilic, swellable polymers that have been used include, hydroxypropyl methyl cellulose, carbomer etc. The hydrophilic polymers are useful in the present invention in modifying the rate of release of drug. The hydrophilic polymers used in the present invention are in an amount from 0.5% to 20%, preferably about 0.5% to about 10%. 6 According to the present invention, the pharmaceutical composition comprises carbohydrate Gums obtained from the indigenous source. Carbohydrate gums include xanthan gum; tragacanth gum; gum karaya; guar gum; acacia and the like. The Carbohydrate gum helps in maintaining tablet integrity and in sustaining the release of drug. In the present invention; xanthan gum has been used preferably. The carbohydrate gum used in the present invention is an amount from about 0.1 % to about 30% by weight of the total weight of the composition, preferably from about 0.1% to about 10%) and more preferably from about 0.1 % to about 7%> by weight of the total weight of the composition. According to the present invention; the pharmaceutical composition comprises a gel forming polymer, preferably water soluble salt of one or more polyuronic acids. Water soluble salts of polyuronic acid are used in the present invention include sodium alginate, potassium alginate, ammonium alginate or cellulose derivatives namely sodium carboxy methyl cellulose derivatives. Generally, the gel forming polymer, is present in an amount 6 from about 0.1 % to about 20%) more preferably from about 0.5% to about 5% by weight of total weight of the composition. The gel forming polymer along with the buoyancy imparting agent causes the tablet to be retained in the stomach or upper part of the small intestine. The gel forming polymer swells and forms a hydrated matrix thereby providing sustained release. In the present invention; the disintegrants are used include cross linked polyvinyl pyrrolidone, cross linked carboxymethylcellulose sodium, sodium starch glycollate and the like. Cross linked PVP has been used preferably in the present invention. Incorporation of the disintegrants in the formulation enhances the buoyancy of the dosage unit. Disintegrants are used in amount from about 5% to about 20%; preferably from about 5% to about 10%) by weight of the total weight of composition. 7 The pharmaceutical composition may also contain other pharmaceutical excipients for example lactose, mannitol, microcrystalline cellulose, binder such as polyvinylpyrollidone and lubricants such as talc, magnesium steairate, colloidal silicon dioxide. In the present invention; colourants viz. erythrosine supra has been used as a protective agent for methylcobalamin. The pharmaceutical composition also contains stabilizer calcium carbonate antioxidants butyl hydroxy anisole and butyl hydroxy toluene in the amount of 0.025% by weight of the total weight of the composition. Calcium carbonate also provides calcium source and enhances the absorption of the drug. According to the present invention, the pharmaceutical composition is prepared by Wet granulation and Direct Compression Tableting Method. Wet Granulation Method involves mixing the drug Methylcobalamin with the colourant, stabilizer calcium carbonate, disintegrant, carbohydrate gum, gel forming polymer, hydrophilic swellable polymer, excipients and granulated with the binder solution made using non aqueous solvent and containing antioxidants. The granules obtained are dried at 60 deg C in dehumidified and subdued light conditions, graded and mixed with gas generating component and lubricants. The lubricated blend is then compressed into tablets. Direct Compression involves mixing the drug Methylcobalamin with the colourant, stabilizer calcium carbonate, antioxidants, disintegrant, carbohydrate gum, gel forming polymer, hydrophilic swellable polymer, directly compressible grade excipients. The blend is made in dehumidified and subdued light conditions and mixed with gas generating component and lubricants. The lubricated blend is then compressed into tablets. According to the present invention, the pharmaceutical composition in the form of tablets may be coated with a thin layer polymer that dissolves in gastric fluid. In a preferred embodiment of the present invention, the tablets were spray coated with an non aqueous coating composition containing 25.97 % w/w Eudragit EPo 8 (polymethylmethacrylate) the acid soluble polymer; 51.95% w/w talc as anti-tacking agent; 12.987% w/w titanium dioxide as opacifying protectant for methylcobalamine; 5.195% w/w colorant; Ponceau 4R lake; and 3.896 % w/w PEG 6000 as plasticizer. The tablets may be coated to a weight build up of about 0.3?/o- 3%. The coating provides an additional protective effect to the drug methylcobalamin. 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, modification 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 examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the invention. Examples: Example 1: Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P as the hydrophilic polymer which is also the release retardant, Sodium bicarbonate as the gas generating component which is also the buoyancy imparting agent. The pharmaceutical composition is given in Table 1 :- Table 1 Ingredient Wt(mg/tablet) %w/w Methylcobalamin 1.5 mg (+30% overages) 0.231 Colour Erythrosine Supra 4.5 mg 0.692 Sodium alginate 9.75 mg 1.5 Xanthan gum 9.75 mg 1.5 Carbopol 974P NF 65 mg 10 Lactose 220 mg 33.846 9 MCC 110 mg 16.923 Crospovidone(Polyplasdone XL) 40 mg 6.154 Calcium Carbonate 51 mg 7.85 PVP K 30 45.5 mg 7 BHA 0.13 mg 0.02 BHT 0.13 mg 0.02 Sodium bicarbonate 65 mg 10 Magnesium Stearate 4mg 0.6154 Talc 20 mg 3.1 Aerosil 200 3mg 0.462 Wt/tab=650 mg The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 2:- Table 2 Time (hr) Cumulative % Release 2 33.09 4 61.89 6 80.21 8 89.17 10 96.01 12 96.01 24 96.01 Example 2: In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P as the hydrophilic polymer, Sodium carbonate as the gas generating component. The pharmaceutical composition is given in Table 3:- 10 Table 3 Ingredient Wt(mg/tablet) %w/w Methylcobalamin 1.5 mg (+30% overages) 0.231 Colour Erythrosine Supra 4.5 mg 0.692 Sodium alginate 9.75 mg 1.5 Xanthan gum 9.75 mg 1.5 Carbopol 974P NF 65 mg 10 Lactose 220 mg 33.846 MCC 110 mg 16.923 Crospovidone (polyplasdone XL) 40 mg 6.154 Calcium Carbonate 51 mg 7.85 PVP K 30 45.5 mg 7 BHA 0.13 mg 0.02 BHT 0.13 mg 0.02 Sodium carbonate 65 mg 10 Magnesium Stearate 4mg 0.6154 Talc 20 mg 3.1 Aerosil 200 3mg 0.462 Wt/tab=650 mg The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 4:- Table 4 :- Time (hr) Cumulative % Release 2 43.25 4 78.47 6 89.5 8 89.5 10 89.5 12 89.5 24 89.5 11 Example 3: In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P as the hydrophilic polymer. Potassium bicarbonate as the gas generating component. The pharmaceutical composition is given in Table Si- Table 5 Ingredient Wt(mg/tablet) %w/w Methylcobalamin 1.5 mg (+30% overages) 0.231 Colour Erythrosine Supra 4.5 mg 0.692 Sodium alginate 9.75 mg 1.5 Xanthan gum 9.75 mg 1.5 Carbopol 974P NF 65 mg 10 Lactose 220 mg 33.846 MCC 110 mg 16.923 Crospovidone (Polyplasdone XL) 40 mg 6.154 Calcium Carbonate 51 mg 7.85 PVP K 30 45.5 mg 7 BHA 0.13 mg 0.02 BHT 0.13 mg 0.02 Potassium bicarbonate 65 mg 10 Magnesium Stearate 4mg 0.6154 Talc 20 mg 3.1 Aerosil 200 3 mg 0.462 Wt/tab=650 mg The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 6:- 12 Table 6 :- Time (hr) Cumulative % Release 2 62.75 4 93.96 6 95.56 8 95.56 10 95.56 12 95.56 24 95.56 Example 4: In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P and Hydroxy Propyl Methyl Cellulose HPMC K4M as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. The pharmaceutical composition is given in Table 7:- Table 7 Ingredient Wt(mg/tablet) %w/w Methylcobalamin 1.5 mg (+30% overages) 0.231 Colour Erythrosine Supra 4.5 mg 0.692 Sodium alginate 9.75 mg 1.5 Xanthan gum 9.75 mg 1.5 HPMC K4M 65 mg 10 Lactose 220 mg 33.846 MCC 110 mg 16.923 Crospovidone(Polyplasdone XL) 40 mg 6.154 Calcium Carbonate 51 mg 7.85 PVP K 30 45.5 mg 7 BHA 0.13 mg 0.02 BHT 0.13 mg 0.02 Sodium bicarbonate 65 mg 10 Magnesium Stearate 4mg 0.6154 Talc 20 mg 3.1 13 Aerosil 200 3mg 0.462 Wt/tab=650 mg The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table Si- Table 8 Time (hr) Cumulative % Release 2 25.297 4 39.39 6 60.54 8 77.4 10 79.78 12 79.78 24 79.78 Example 5: In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P Hydroxy Propyl Methyl Cellulose HPMC K4M, Methyl Cellulose Metolose SM 400 as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. The pharmaceutical composition is given in Table 9:- Table 9 Ingredient Wt(mg/tablet) %w/w Methylcobalamin 1.5 mg 0.231 Colour Erythrosine Supra 4.5 mg 0.692 Sodium alginate 9.75 mg 1.5% Xanthan gum 9.75 mg 1.5% HPMC K4M 45 mg 6.92% Methyl cellulose(Metolose SM 400) 20mg 3.08% Lactose 220 mg 34% 14 MCC 110 mg 17% Crospovidone(Polyplasdone XL) 40 mg 6.154% Calcium Carbonate 51 mg 7.85% PVP K 30 45.5 mg 7% BHA 0.13 mg 0.02% BHT 0.13 mg 0.02% Sodium bicarbonate 65 mg 10% Magnesium Stearate 4mg 0.6154% Talc 20 mg 3.1% Aerosil 200 3mg 0.46% Wt/tab=650 mg The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 10:- Table lO:- Time (hr) Cumulative % Release 2 79.52 4 93.43 6 93.43 8 93.43 10 93.43 12 93.43 24 93.43 Example 6: In the present example Xanthan Gum has been used as carbohydrate gum, sodium carboxy methyl cellulose as the gel forming polymer, Carbopol 974P as the hydrophilic polymer, Sodium bicarbonate as the gas generating component. The pharmaceutical composition is given in Table 11:- 15 Table 11 Ingredient Wt(mg/tablet) %w/w Methylcobalamin 1.5 mg (+30% overages) 0.231 Colour Erythrosine Supra 4.5 mg 0.692 Sodium carboxy methyl cellulose 1160 9.0 mg 1.385 Xanthan gum 9.0 mg 1.385 Carbopol 974P 65 mg 10 Lactose 166.12 25.56 MCC 166.12 25.56 Crospovidone(Polyplasdone XL) 40 mg 6.154 Calcium Carbonate 51 mg 7.85 PVP K 30 45.5 mg 7 BHA 0.13 mg 0.02 BHT 0.13 mg 0.02 Sodium bicarbonate 65 mg 10 Magnesium Stearate 4mg 0.6154 Talc 20 mg 3.1 Aerosil 200 3mg 0.46 Wt/tab=650 mg The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 12:- Table 12 :- Time (hr) Cumulative % Release 2 45.03 4 97.903 6 109.42 8 113.36 10 115.7 12 115.7 24 115.7 16 Example 7: In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 97IP as the hydrophilic polymer which is also a release retardant, mannitol as one of the diluents and Sodium bicarbonate as the gas generating component. The pharmaceutical composition is given in Table 13:- Table 13 Ingredient Wt(mg/tablet) %w/w Methylcobalamin 1.5 mg (+30% overages) 0.231 Colour Erythrosine Supra 4.5 mg 0.692 Sodium alginate 9.75 mg 1.5 Xanthan gum 9.75mg 1.5 Carbopol 97IP 65 mg 10 Mannitol 165.145 25.56 Microcrystalline Cellulose 165.145 25.56 Crospovidone(Polyplasdone XL) 40 mg 6.154 Calcium Carbonate 51 mg 7.85 PVP K 30 45.5 mg 7 BHA 0.13 mg 0.02 BHT 0.13 mg 0.02 Sodium bicarbonate 65 mg 10 Magnesium Stearate 4mg 0.6154 Talc 20 mg 3.1 Aerosil 200 3mg 0.46 Wt/tab=650 mg The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 14:- 17 Table 14:- Time (hr) Cumulative % Release 2 17.34 4 30.27 6 41.73 8 45.12 10 51.25 12 52.98 24 54.68 Example 8: In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 71G as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. Carbopol 71 G is incorporated in the formulation at the lubrication stage. The pharmaceutical composition is given in Table 15:- Table 15 Ingredient Wt(mg/tablet) %w/w Methylcobalamin 1.5 mg (+30% overages) 0.231 Colour Erythrosine Supra 4.5 mg 0.692 Sodium alginate 9.75 mg 1.5 Xanthan gum 9.75 mg 1.5 Lactose 190 mg 29.231 Microcrystalline Cellulose 191.55 29.469 Crospovidone(Polyplasdone XL) 40 mg 6.154 PVP K 30 45.5 mg 7 Carbopol 71G 65 mg 10 Sodium bicarbonate 65 mg 10 Magnesium Stearate 4mg 0.6154 Talc 20 mg 3.1 Aerosil 200 3mg 0.46 Wt/tab=650 mg 18 The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 16:- Table 16:- Time (hr) Cumulative % Release 2 41.96 4 59.797 6 66.1 8 70.01 10 71.4 12 72.66 24 75.83 Example 9: In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 971P and Carbopol 71G as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. In this formulation Carbopol 97IP is incorporated during the granulation and Carbopol 71G during lubrication The pharmaceutical composition is given in Table 17:- Table 17 Ingredient Wt(mg/tablet) %w/w Methylcobalamin 1.5 mg (+30% overages) 0.231 Colour Erythrosine Supra 4.5 mg 0.692 Sodium alginate 9.75 mg 1.5 Xanthan gum 9.75 mg 1.5 Carbopol 97IP 32.5 mg 5 Lactose 190 mg 29.231 Microcrystalline Cellulose 191.55 29.469 Crospovidone(Polyplasdone XL) 40 mg 6.154 PVP K 30 45.5 mg 7 Carbopol 71G 32.5 mg 5 19 Sodium bicarbonate 65 mg 10 Magnesium Stearate 4mg 0.6154 Talc 20 mg 3.1 Aerosil 200 3mg 0.46 Wt/tab=650 mg The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 1 Si- Table 18:- Time (hr) Cumulative % Release 2 18.94 4 35.57 6 46.18 8 52.74 10 61.88 12 64.69 24 69.61 Example 10:- In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. In this formulation Pharmatose DCL 15 (directly compressible grade lactose) is incorporated during the lubrication stage. The pharmaceutical composition is given in Table 19:- Table 19 Ingredient Wt(mg/tablet) %w/w Methylcobalamin 1.5 mg (+50% overages) 0.231 Colour Erythrosine Supra 4.5 mg 0.692 Sodium alginate 9.75 mg 1.5 Xanthan gum 9.75 mg 1.5 Carbopol 974P 52 mg 8 Lactose 220 mg 33.846 20 Microcrystalline Cellulose 110 mg 16.923 Crospovidone(Polyplasdone XL) 40 mg 6.154 Calcium Carbonate 51 mg 7.846 PVP K 30 45.5 mg 7 BHA 0.13 mg 0.02 BHT 0.13 mg 0.02 Pharmatose DCL 15 13 mg 2 Sodium bicarbonate 65 mg 10 Magnesium Stearate 4mg 0.6154 Talc 20 mg 3.1 Aerosil 200 3mg 0.46 Wt/tab=650 mg The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 20:- Table 20:- Time (hr) Cumulative % Release 2 67.87 4 99.65 6 105.75 8 110.4 10 113.5 12 113.5 24 118.28 Example 11: In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P and Carbopol 71G as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. Carbopol 974 P is incorporated in the formulation during the granulation stage whereas Carbopol 71G during the lubrication stage. The pharmaceutical composition is given in Table 21:- 21 Table 21 Ingredient Wt(mg/tablet) %w/w Methylcobalamin 1.5 mg (+50% overages) 0.231 Colour Erythrosine Supra 4.5 mg 0.692 Sodium alginate 9.75 mg 1.5 Xanthan gum 9.75 mg 1.5 Carbopol 974P 52 mg 8 Lactose 220 mg 33.846 Macrocrystalline Cellulose 110 mg 16.923 Crospovidone(Polyplasdone XL) 40 mg 6.154 Calcium Carbonate 51 mg 7.846 PVP K 30 45.5 mg 7 BHA 0.13 mg 0.02 BHT 0.13 mg 0.02 Carbopol 71G 13 mg 2 Sodium bicarbonate 65 mg 10 Magnesium Stearate 4mg 0.6154 Talc 20 mg 3.1 Aerosil 200 3mg 0.46 Wt/tab=650 mg The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 22:- Table 22:- Time (hr) Cumulative % Release 2 43.92 4 65.68 6 73.91 8 78.32 10 81.14 12 81.99 24 89.23 22 Example 12: In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P and Carbopol 71G as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. Carbopol 974 P is incorporated in the formulation during the granulation stage whereas Carbopol 71G and Pharmatose DCL 15 during the lubrication stage. The pharmaceutical composition is given in Table 23:- Table 23 Ingredient Wt(mg/tablet) %w/w Methylcobalamin 1.5 mg (+50% overages) 0.231 Colour Erythrosine Supra 4.5 mg 0.692 Sodium alginate 9.75 mg 1.5 Xanthan gum 9.75 mg 1.5 Carbopol 974P 52 mg 8 Lactose 220 mg 33.846 Microcrystalline Cellulose 110 mg 16.923 Crospovidone(Polyplasdone XL) 40 mg 6.154 Calcium Carbonate 51 mg 7.846 PVP K 30 45.5 mg 7 BHA 0.13 mg 0.02 BHT 0.13 mg 0.02 Carbopol 71G 6.5 mg 1 Pharmatose DCL 15 6.5 mg 1 Sodium bicarbonate 65 mg 10 Magnesium Stearate 4mg 0.6154 Talc 20 mg 3.1 Aerosil 200 3mg 0.46 Wt/tab=650 mg 23 The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 24:- Table 24:- Time (hr) Cumulative % Release 2 45.24 4 66.78 6 72.15 8 77.4 10 81.03 12 84.41 24 94.7 Example 13: In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P and Hydroxy Propyl Methyl Cellulose HPMC K4M as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. Carbopol 974 P is incorporated in the formulation during the granulation stage whereas HPMC K4M during the lubrication stage. The pharmaceutical composition is given in Table 25:- Table 25 Ingredient Wt(mg/tablet) %w/w Methylcobalamin 1.5 mg (+50% overages) 0.231 Colour Erythrosine Supra 4.5 mg 0.692 Sodium alginate 9.75 mg 1.5 Xanthan gum 9.75 mg 1.5 Carbopol 974P 52 mg 8 Lactose 220 mg 33.846 Microcrystalline Cellulose 110 mg 16.923 Crospovidone(Polyplasdone XL) 40 mg 6.154 Calcium Carbonate 51 mg 7.846 PVP K 30 45.5 mg 7 24 BHA 0.13 mg 0.02 BHT 0.13 mg 0.02 HPMC K4M 13 mg 2 Sodium bicarbonate 65 mg 10 Magnesium Stearate 4mg 0.6154 Talc 20 mg 3.1 Aerosil 200 3mg 0.46 Wt/tab=650 mg The tablets were tested for dissolution in 0.1 N HCI using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 26:- Table 26:- Time (hr) Cumulative % Release 2 62.17 4 81.2 6 90.14 8 97.28 10 101.82 12 102.55 24 105.64 Example 14: In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P and Hydroxy Propyl Methyl Cellulose HPMC K4M as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. Carbopol 974 P is incorporated in the formulation during the granulation stage whereas HPMC K4M during the lubrication stage. The pharmaceutical composition is given in Table 27:- Table 27 Ingredient Wt(mg/tablet) %w/w Methylcobalamin 1.5 mg (+50% overages) 0.228 25 Colour Erythrosine Supra 4.5 mg 0.685 Sodium alginate 9.75 mg 1.485 Xanthan gum 9.75 mg 1.485 Carbopol 974P 52 mg 7.921 Lactose 220 mg 33.511 Microcrystalline Cellulose 110 mg 16.756 Crospovidone(Polyplasdone XL) 40 mg 6.093 Calcium Carbonate 51 mg 7.768 PVP K 30 45.5 mg 6.931 BHA 0.13 mg 0.0194 BHT 0.13 mg 0.0194 HPMC K4M 19.5 mg 2.97 Sodium bicarbonate 65 mg 9.901 Magnesium Stearate 4mg 0.6093 Talc 20 mg 3.0465 Aerosil 200 3mg 0.457 Wt/tab=656.5 mg The tablets were tested for dissolution in 0.1 N HCI using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 28:- Table 28:- Time (hr) Cumulative % Release 2 48.47 4 85 6 88.35 8 — 10 — 12 — 24 — 26 Example 15: In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P and Hydroxy Propyl Methyl Cellulose HPMC K4M as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. Carbopol 974 P is incorporated in the formulation during the granulation stage whereas HPMC K4M during the lubrication stage. The pharmaceutical composition is given in Table 29:- Table 29 Ingredient Wt(mg/tablet) %w/w Methylcobalamin 1.5 mg (+50% overages) 0.226 Colour Erythrosine Supra 4.5 mg 0.679 Sodium alginate 9.75 mg 1.471 Xanthan gum 9.75 mg 1.471 Carbopol 974P 52 mg 7.843 Lactose 220 mg 33.183 Microcrystalline Cellulose 110 mg 16.591 Crospovidone(Polyplasdone XL) 40 mg 6.033 Calcium Carbonate 51 mg 7.692 PVP K 30 45.5 mg 6.863 BHA 0.13 mg 0.0196 BHT 0.13 mg 0.0196 HPMC K4M 26 mg 3.922 Sodium bicarbonate 65 mg 9.804 Magnesium Stearate 4mg 0.6033 Talc 20 mg 3.017 Aerosil 200 3mg 0.453 Wt/tab=663 mg The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 30:- 27 Table 30:- Time (hr) Cumulative % Release 2 37.37 4 59.0 6 62.06 8 — 10 — 12 — 24 — Example 16: In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P and Hydroxy Propyl Methyl Cellulose HPMC K4M as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. Carbopol 974 P is incorporated in the formulation during the granulation stage whereas HPMC K4M during the lubrication stage. The pharmaceutical composition is given in Table 31 :- Table 31 Ingredient Wt(mg/tablet) %w/w Methylcobalamin 1.5 mg (+50% overages) 0.224 Colour Erythrosine Supra 4.5 mg 0.672 Sodium alginate 9.75 mg 1.456 Xanthan gum 9.75 mg 1.456 Carbopol 974P 52 mg 7.767 Lactose 220 mg 32.86 Microcrystalline Cellulose 110 mg 16.43 Crospovidone(Polyplasdone XL) 40 mg 5.975 Calcium Carbonate 51 mg 7.618 PVP K 30 45.5 mg 6.796 BHA 0.13 mg 0.01942 BHT 0.13 mg 0.01942 28 HPMC K4M 32.5 mg 4.854 Sodium bicarbonate 65 mg 9.709 Magnesium Stearate 4mg 0.598 Talc 20 mg 2.987 Aerosil 200 3mg 0.4481 Wt/tab=669.5 mg The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 32:- Table 32:- Time (hr) Cumulative % Release 2 34.22 4 63.52 6 64.1 8 — 10 — 12 — 24 — Example 17: In the present example tablets are manufactured by direct compression method wherein Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 71G as the hydrophilic polymer, Sodium bicarbonate as the gas generating component. Directly compressible grade lactose (Pharmatose DCL 15) and Directly compressible grade lactose (Microcel PHI02) are incorporated as the diluents. The pharmaceutical composition is given in Table 33:- Table 33 Ingredient Wt(mg/tablet) %w/w Methylcobalamin 1.5 mg (+50% overages) 0.248 Colour Erythrosine Supra 4.5 mg 0.744 Sodium alginate 9.75 mg 1.612 Xanthan gum 9.75 mg 1.612 29 Carbopol 71 G 65 mg 10.744 Pharmatose DCL 15 220.5 mg 36.446 Microcel PH 102 110 mg 18.182 Crospovidone(Polyplasdone XL) 40 mg 6.612 Calcium Carbonate 51 mg 8.43 BHA 0.13 mg 0.0215 BHT 0.13 mg 0.0215 Sodium bicarbonate 65 mg 10.744 Magnesium Stearate 4mg 0.661 Talc 20 mg 3.306 Aerosil 200 3mg 0.496 Wt/tab=605 mg The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 34:- Table 34:- Time (hr) Cumulative % Release 2 56.33 4 76.79 6 86.66 8 — 10 — 12 — 24 — 30 We claim, 1. An oral sustained release formulation of vitamins preferably absorbed in the upper gastrointestinal tract comprising vitamin, preferably methyl cobalamin, colourant, stabilizer, antioxidants, gas generating component, disintegrant, carbohydrate gum, gel forming polymer, hydrophilic swellable polymer, other excipients, etc. 2. The formulation as claimed in claim 1, wherein said gas generating component is selected from the class of alkali carbonates and bicarbonates. 3. The formulation as claimed in claims 1 and 2, wherein said alkali carbonates and bicarbonates are selected from sodium bicarbonate, potassium bicarbonate and sodium carbonate. 4. The formulation as claimed in claim 3, wherein said alkali bicarbonate is preferably sodium bicarbonate. 5. The formulation as claimed in claim 4, wherein the concentration of said sodium bicarbonate is 9.7-10 percent by weight of the dosage unit. 6. The formulation as claimed in claim 1, wherein said disintegrants are selected from the group comprising cellulose derivatives, cross linked polyvinyl pyrollidone, starch, croscarmellose sodium, sodium starch glycollate, etc. 7. The formulation as claimed in claim 6, wherein said disintegrant is preferably cross linked pyrollidone. 8. The formulation as claimed in claim 7, wherein the concentration of cross linked polyvinyl pyrollidone is 5.9 - 6.7 percent by weight of the dosage unit. 9. The formulation as claimed in claim 1, wherein said carbohydrate gums are selected form the group comprising xanthan gum, gum karaya, gum acacia, locust bean gum, etc. 10. The formulation as claimed in claim 9, wherein said carbohydrate gum is preferably xanthan gum. 11. The formulation as claimed in claim 10, wherein the concentration of xanthan gum is 1.4 - 1.7 percent by weight of the dosage unit. 12. The formulation as claimed in claim 1, wherein the said gel forming polymers are selected from the group comprising the class of alkali metal alginates and cellulose derivatives. 31 13. The formulation as claimed in claim 12, wherein the said alkali metal alginates are selected from the group comprising sodium alginate, potassium alginate, ammonium alginate and the like. 14. The formulation as claimed in claim 13, wherein the said alkali metal alginate is preferably sodium alginate. 15. The formulation as claimed in claim 14, wherein the concentration of said sodium alginate is 1.4 - 1.7 percent by weight of the dosage unit. 16. The formulation as claimed in claim 12, wherein said cellulose derivative is selected from sodium carboxyl methyl cellulose. 17. The formulation as claimed in claim 16, wherein said cellulose derivative is used in the concentration of 1.385 percent by weight of the dosage unit. 18. The formulation as claimed in claim 1, wherein said hydrophilic polymers are selected from the group comprising hydroxy propyl methyl cellulose HPMC K4M, Methyl cellulose Metolose SM400, Carbomer Carbopol 974P Carbopol 97IP, Carbopol 71G, etc. 19. The formulation as claimed in claim 18, wherein the concentration of said hydrophilic polymer is 2-11 percent by weight of the dosage unit. 20. The formulation as claimed in claim 1, wherein said other excipients are optionally selected from the group comprising diluents, binders, glidants and lubricants. 21. The formulation as claimed in claim 20, wherein said diluents are selected from the group comprising lactose, mannitol, microcrystalline cellulose, etc. 22. The formulation as claimed in claim 21, wherein the concentration of said diluent is 16-37 percent by weight of the dosage unit. 23. The formulation as claimed in claim 20, wherein said binders are selected from the group comprising cellulose derivatives, polyvinyl pyrollidone, acrylates, starch, gelatin, etc. 24. The formulation as claimed in claim 23, wherein said binder is preferably polyvinyl pyrollidone PVP K30. 25. The formulation as claimed in claims 24, wherein the concentration of polyvinyl pyrollidone PVP K 30 is 6-7 percent by weight of the dosage unit. 26. The formulation as claimed in claims 1 to 25, wherein said formulation is in tablet form. 32 27. The formulation as claimed in claims 1 to 26, wherein said tablet is prepared by wet granulation. 28. The formulation as claimed in claims 1 to 22 and 26, wherein said tablet is prepared by direct compression method. 29. A sustained release formulation of vitamins, preferably methyl cobalamin for oral administration in humans as substantially described herein with reference to foregoing examples 1 to 17. 33 Abstract: A pharmaceutical composition providing controlled delivery of methylcobalamin designed to improve the bioavailability of the drug in the upper gastrointestinal tract is described. The pharmaceutical composition is formulated into a tablet dosage form. The pharmaceutical composition comprises of a drug, a gas generating component which is also the buoyancy imparting agent, swelling agent, a gel forming polymer, a hydrophilic swellable polymer and a disintegrant.

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
[See section 10; rule 13]
'A gastric retentive floating dosage form for controlled delivery of
vitamins"
(a) M/S. INDOCO REMEDIES LIMITED.
(b) Indoco House, 166 C. S. T. Road, Santacruz (East), Mumbai - 400 098, Maharashtra, India
(c) Indian company incorporated under the Companies Act 1956
The following specification describes the nature of the invention and the manner in which it is to be performed:

Field of Invention:
The present invention relates to an improved formulation of vitamin in swellable, buoyant, floating dosage form for controlled delivery of vitamin, preferably Methylcobalamin.
Background of the Invention:
It is well known to those skilled in the art that for ailments requiring multiple doses of a particular drug; the blood levels of a drug need to be maintained above its minimum effective level and below minimum toxic level in order to obtain the desired therapeutic effects and minimize side effects.
When the blood levels of a drug are in this range, the drug is eliminated from the body at a particular rate. A controlled drug delivery system is designed to deliver the drug at this particular rate. Thus, safe and effective blood levels are maintained as long as the system continues to deliver the drug at this rate.
Controlled drug delivery results in substantially constant blood level of the therapeutically active ingredient as compared to the uncontrolled fluctuations observed when multiple doses of quick releasing conventional dosage forms are administered to a patient. Controlled drug delivery results in optimum therapy, reduces the frequency of dosing and reduces the severity and frequency of side effects.
A number of different oral controlled drug delivery systems are based on different release mechanisms have been developed, viz. dissolution controlled systems, diffusion controlled systems, ion exchange resins, osmotically controlled systems, erodible matrix systems, swelling controlled systems, etc.
There has been an increased interest in novel dosage forms which possess not only a mechanism for the controlled release of a drug but also a controlled gastrointestinal transit time. One of the most feasible approaches is to control the gastrointestinal transit time. Dosage forms with a prolonged gastrointestinal transit time i.e. Gastroretentive dosage forms bring about a new and important therapeutic option. The
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controlled gastric retention of solid dosage forms may be achieved by the mechanisms of mucoadhesion, floatation, sedimentation, expansion or by the simultaneous administration of pharmacological agents which delay gastric emptying.
Vitamin B12 also referred to as Cobalamin is a member of the corrinoid family of molecules that contain a planar corrin nucleus made from a tetrapyrrolic ring structure. The centre of the tetra pyrrole ring contains a chelated cobalt atom that can be attached to a methyl, deoxyadenosyl, hydroxyl or a cyano group. Methylcobalamin is the active isoenzyme of Vitamin B12 i.e. is the naturally active form of Vitamin B12 whereas hydroxo and the cyano form require metabolic conversion in vivo. However this form is generally not available for therapeutic purposes. Absorption of Vitamin B12 occurs via intrinsic factor and the other by non intrinsic factor mediated diffusion.
The latter route accounts for a small proportion of Vitamin B12 absorbed. Therefore the former process is the only reliable process for the absorption to ensure maximum bioavailability. In humans acid stable intrinsic factor is secreted. Uptake of Vitamin B12 involves the binding of Cobalamin to glycoproteins namely intrinsic factor and haptocorrins. The formation of haptocorrin complex provides protection for Vitamin B12 against acid hydrolysis in the stomach. At low gastric pH, Vitamin B12 binding affinity is higher for haptocorrins than intrinsic factor. However further along the gut in the jejunum, the combined effects of the higher pH and proteolytic digestion of the haptocorrin by pancreatic enzymes result in the release and transfer of Vitamin B12 from haptocorrin to intrinsic factor.
When complexed with Cobalamin intrinsic factor is resistant to proteolytic degradation. Moreover complex formation serves to protect Vitamin B12 from catabolism by intestinal microflora and from hydrolytic attack by pepsin and chymotrypsin. Absorption of vitamin B12 occurs via interaction with intrinsic factor ehterocyte cell wall receptor. Only intrinsic factor bound cobalamin is absorbed by the intrinsic factor enterocyte cell wall receptor. This intestinal uptake also requires the presence of Ca2+, a pH of >6 and bile components. Thus, formulating Methylcobalamin into a dosage form with a prolonged gastric residence time namely as gastroretentive dosage form, the dosage form would release the drug in the stomach
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over a period of time equivalent to the residence time of the unit in the stomach. Following the drug release in the stomach the drug will be taken up by the haptocorrin and intrinsic factor and exclusively absorbed in the intestine. Moreover incorporating a Calcium salt in the formulation the drug is stabilized and its absorption is enhanced.
US Patent No. 5,417,983 describes a sustained release delivery system of methylcobalamin wherein the drug release controlling polymer (retardant) is responsive to the changes in temperature. It is well known to those skilled in the art, that such a system will not deliver / release the drug at the constant rate. The release characteristics of the polymer are dependant on its glass transition temperature. Hence minor changes in the polymer structure can affect its behaviour. The synthesis of such a polymer involves use of complex starting materials, number of complicated steps, a tedious and time consuming procedure and use of relatively toxic and highly inflammable solvents like methanol, hexane, diethyl ether, methanol and ethyl acetate. Moreover the drug release from any of these polymers has not been depicted in any of the sited examples and safety of these polymers is not guaranteed.
U.S. Patent No. 4,777,033 discloses a controlled release delivery system for riboflavin and methylcobalamin. The formulation comprises of lower alkyl ether of cellulose (hydroxy propyl cellulose), polyacrylic acid or its pharmaceutically acceptable salt, a drug and an effective amount of an effervescent foaming agent. The composition is required to be retained in the stomach for a long time and release the drug at a slow, controlled rate.
The formulations mentioned therein are in the form of granules or the so called pilules of particle size ranging from 0.5 mm to 2mm. It is well known to those skilled in the art that multiparticulate systems such as pellets, granules or pilules, because of their smaller size and increased surface area are distributed over the length of the gastrointestinal tract delivering the drug through out the tract. Thus, the purpose of localizing the drug specifically in the upper part of the gastrointestinal tract is not served. Moreover these multiparticulate systems have constant gastrointestinal transit time. Hence gastric residence time of these formulations may not be prolonged as single unit dosage forms.
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The main aim of the present invention is to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide useful alternative.
Summary of the invention:
According to the present invention, there is provided an oral sustained release formulation of vitamins preferably absorbed in the upper gastrointestinal tract comprising vitamin, preferably methyl cobalamin, colourant, stabilizer, antioxidants, gas generating component as buoyancy imparting agent, disintegrant, carbohydrate gum, gel forming polymer, hydrophilic swellable polymer, other excipients, etc.
The gas generating component is selected from the class of alkali carbonates and bicarbonates and is used 9.7 -10 percent by weight of the dosage unit.
The disintegrants are selected from the group comprising cellulose derivatives, cross linked polyvinyl pyrollidone, starch, croscarmellose sodium, sodium starch glycollate, etc and is used in the range of 5.9 - 6.7 percent by weight of the dosage unit. •
The carbohydrate gums are selected form the group comprising xanthan gum, gum karaya, gum acacia, locust bean gum, etc and is used in the range of 1.4 - 1.7 percent by weight of the dosage unit.
The gel forming polymers are selected from the group comprises the class of alkali metal alginates and cellulose derivatives and is used in the range of 1.4 - 1.7 percent by weight of the dosage unit.
The cellulose derivative is selected from sodium carboxyl methyl cellulose is used in the concentration of 1.385 percent by weight of the dosage unit.
The hydrophilic polymers are selected from the group comprising hydroxy propyl methyl cellulose HPMC K4M, Methyl cellulose Metolose SM400, Carbomer Carbopol 974P Carbopol 97IP, Carbopol 71G, etc and is used in the concentration 2-11 percent by weight of the dosage unit.
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The excipients are optionally selected from the group comprising diluents, binders, glidants and lubricants. The diluents are selected from the group comprising from lactose, mannitol, microcrystalline cellulose, etc and is used in 16-37 percent by weight of the dosage unit. The binders are selected from the group comprising cellulose derivatives, polyvinyl pyrollidone, acrylates, starch, gelatin, etc. is 6-7 percent by weight of the dosage unit.
The dosage form of the formulation is tablet.
The tablet is prepared by wet granulation or direct compression method.
Detailed description:
The present invention provides controlled drug delivery system for gastric retentive floating dosage forms.
The present invention provides improved formulation which is designed to deliver effectively a drug to a patient over a specific time and to a particular portion of the patient's gastrointestinal tract.
According to them present invention the improved formulation comprises methyl cobalamine along with pharmaceutically acceptable excipeints such as hydrophilic swellable polymers, carbohydrate gums, gel forming polymers, disintegrants, other excipients etc.
According to the present invention, hydrophilic, swellable polymers that have been used include, hydroxypropyl methyl cellulose, carbomer etc. The hydrophilic polymers are useful in the present invention in modifying the rate of release of drug.
The hydrophilic polymers used in the present invention are in an amount from 0.5% to 20%, preferably about 0.5% to about 10%.
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According to the present invention, the pharmaceutical composition comprises carbohydrate Gums obtained from the indigenous source. Carbohydrate gums include xanthan gum; tragacanth gum; gum karaya; guar gum; acacia and the like. The Carbohydrate gum helps in maintaining tablet integrity and in sustaining the release of drug. In the present invention; xanthan gum has been used preferably.
The carbohydrate gum used in the present invention is an amount from about 0.1 % to about 30% by weight of the total weight of the composition, preferably from about 0.1% to about 10%) and more preferably from about 0.1 % to about 7%> by weight of the total weight of the composition.
According to the present invention; the pharmaceutical composition comprises a gel forming polymer, preferably water soluble salt of one or more polyuronic acids. Water soluble salts of polyuronic acid are used in the present invention include sodium alginate, potassium alginate, ammonium alginate or cellulose derivatives namely sodium carboxy methyl cellulose derivatives.
Generally, the gel forming polymer, is present in an amount 6 from about 0.1 % to about 20%) more preferably from about 0.5% to about 5% by weight of total weight of the composition.
The gel forming polymer along with the buoyancy imparting agent causes the tablet to be retained in the stomach or upper part of the small intestine. The gel forming polymer swells and forms a hydrated matrix thereby providing sustained release.
In the present invention; the disintegrants are used include cross linked polyvinyl pyrrolidone, cross linked carboxymethylcellulose sodium, sodium starch glycollate and the like. Cross linked PVP has been used preferably in the present invention. Incorporation of the disintegrants in the formulation enhances the buoyancy of the dosage unit.
Disintegrants are used in amount from about 5% to about 20%; preferably from about 5% to about 10%) by weight of the total weight of composition.
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The pharmaceutical composition may also contain other pharmaceutical excipients for example lactose, mannitol, microcrystalline cellulose, binder such as polyvinylpyrollidone and lubricants such as talc, magnesium steairate, colloidal silicon dioxide.
In the present invention; colourants viz. erythrosine supra has been used as a protective agent for methylcobalamin. The pharmaceutical composition also contains stabilizer calcium carbonate antioxidants butyl hydroxy anisole and butyl hydroxy toluene in the amount of 0.025% by weight of the total weight of the composition. Calcium carbonate also provides calcium source and enhances the absorption of the drug.
According to the present invention, the pharmaceutical composition is prepared by Wet granulation and Direct Compression Tableting Method.
Wet Granulation Method involves mixing the drug Methylcobalamin with the colourant, stabilizer calcium carbonate, disintegrant, carbohydrate gum, gel forming polymer, hydrophilic swellable polymer, excipients and granulated with the binder solution made using non aqueous solvent and containing antioxidants. The granules obtained are dried at 60 deg C in dehumidified and subdued light conditions, graded and mixed with gas generating component and lubricants. The lubricated blend is then compressed into tablets.
Direct Compression involves mixing the drug Methylcobalamin with the colourant, stabilizer calcium carbonate, antioxidants, disintegrant, carbohydrate gum, gel forming polymer, hydrophilic swellable polymer, directly compressible grade excipients. The blend is made in dehumidified and subdued light conditions and mixed with gas generating component and lubricants. The lubricated blend is then compressed into tablets.
According to the present invention, the pharmaceutical composition in the form of tablets may be coated with a thin layer polymer that dissolves in gastric fluid. In a preferred embodiment of the present invention, the tablets were spray coated with an non aqueous coating composition containing 25.97 % w/w Eudragit EPo
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(polymethylmethacrylate) the acid soluble polymer; 51.95% w/w talc as anti-tacking agent; 12.987% w/w titanium dioxide as opacifying protectant for methylcobalamine; 5.195% w/w colorant; Ponceau 4R lake; and 3.896 % w/w PEG 6000 as plasticizer. The tablets may be coated to a weight build up of about 0.3?/o- 3%. The coating provides an additional protective effect to the drug methylcobalamin.
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, modification 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 examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the invention.
Examples:
Example 1:
Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P as the hydrophilic polymer which is also the release retardant, Sodium bicarbonate as the gas generating component which is also the buoyancy imparting agent. The pharmaceutical composition is given in Table 1 :-
Table 1

Ingredient Wt(mg/tablet) %w/w
Methylcobalamin 1.5 mg (+30% overages) 0.231
Colour Erythrosine Supra 4.5 mg 0.692
Sodium alginate 9.75 mg 1.5
Xanthan gum 9.75 mg 1.5
Carbopol 974P NF 65 mg 10
Lactose 220 mg 33.846
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MCC 110 mg 16.923
Crospovidone(Polyplasdone XL) 40 mg 6.154
Calcium Carbonate 51 mg 7.85
PVP K 30 45.5 mg 7
BHA 0.13 mg 0.02
BHT 0.13 mg 0.02
Sodium bicarbonate 65 mg 10
Magnesium Stearate 4mg 0.6154
Talc 20 mg 3.1
Aerosil 200 3mg 0.462
Wt/tab=650 mg
The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 2:-
Table 2

Time (hr) Cumulative % Release
2 33.09
4 61.89
6 80.21
8 89.17
10 96.01
12 96.01
24 96.01
Example 2:
In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P as the hydrophilic polymer, Sodium carbonate as the gas generating component. The pharmaceutical composition is given in Table 3:-
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Table 3

Ingredient Wt(mg/tablet) %w/w
Methylcobalamin 1.5 mg (+30% overages) 0.231
Colour Erythrosine Supra 4.5 mg 0.692
Sodium alginate 9.75 mg 1.5
Xanthan gum 9.75 mg 1.5
Carbopol 974P NF 65 mg 10
Lactose 220 mg 33.846
MCC 110 mg 16.923
Crospovidone (polyplasdone XL) 40 mg 6.154
Calcium Carbonate 51 mg 7.85
PVP K 30 45.5 mg 7
BHA 0.13 mg 0.02
BHT 0.13 mg 0.02
Sodium carbonate 65 mg 10
Magnesium Stearate 4mg 0.6154
Talc 20 mg 3.1
Aerosil 200 3mg 0.462
Wt/tab=650 mg
The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 4:-
Table 4 :-

Time (hr) Cumulative % Release
2 43.25
4 78.47
6 89.5
8 89.5
10 89.5
12 89.5
24 89.5
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Example 3:
In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P as the hydrophilic polymer. Potassium bicarbonate as the gas generating component. The pharmaceutical composition is given in Table Si-
Table 5

Ingredient Wt(mg/tablet) %w/w
Methylcobalamin 1.5 mg (+30% overages) 0.231
Colour Erythrosine Supra 4.5 mg 0.692
Sodium alginate 9.75 mg 1.5
Xanthan gum 9.75 mg 1.5
Carbopol 974P NF 65 mg 10
Lactose 220 mg 33.846
MCC 110 mg 16.923
Crospovidone (Polyplasdone XL) 40 mg 6.154
Calcium Carbonate 51 mg 7.85
PVP K 30 45.5 mg 7
BHA 0.13 mg 0.02
BHT 0.13 mg 0.02
Potassium bicarbonate 65 mg 10
Magnesium Stearate 4mg 0.6154
Talc 20 mg 3.1
Aerosil 200 3 mg 0.462
Wt/tab=650 mg
The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 6:-
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Table 6 :-

Time (hr) Cumulative % Release
2 62.75
4 93.96
6 95.56
8 95.56
10 95.56
12 95.56
24 95.56
Example 4:
In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P and Hydroxy Propyl Methyl Cellulose HPMC K4M as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. The pharmaceutical composition is given in Table 7:-
Table 7

Ingredient Wt(mg/tablet) %w/w
Methylcobalamin 1.5 mg (+30% overages) 0.231
Colour Erythrosine Supra 4.5 mg 0.692
Sodium alginate 9.75 mg 1.5
Xanthan gum 9.75 mg 1.5
HPMC K4M 65 mg 10
Lactose 220 mg 33.846
MCC 110 mg 16.923
Crospovidone(Polyplasdone XL) 40 mg 6.154
Calcium Carbonate 51 mg 7.85
PVP K 30 45.5 mg 7
BHA 0.13 mg 0.02
BHT 0.13 mg 0.02
Sodium bicarbonate 65 mg 10
Magnesium Stearate 4mg 0.6154
Talc 20 mg 3.1
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Aerosil 200 3mg 0.462
Wt/tab=650 mg
The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table Si-
Table 8

Time (hr) Cumulative % Release
2 25.297
4 39.39
6 60.54
8 77.4
10 79.78
12 79.78
24 79.78
Example 5:
In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P Hydroxy Propyl Methyl Cellulose HPMC K4M, Methyl Cellulose Metolose SM 400 as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. The pharmaceutical composition is given in Table 9:-
Table 9

Ingredient Wt(mg/tablet) %w/w
Methylcobalamin 1.5 mg 0.231
Colour Erythrosine Supra 4.5 mg 0.692
Sodium alginate 9.75 mg 1.5%
Xanthan gum 9.75 mg 1.5%
HPMC K4M 45 mg 6.92%
Methyl cellulose(Metolose SM 400) 20mg 3.08%
Lactose 220 mg 34%
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MCC 110 mg 17%
Crospovidone(Polyplasdone XL) 40 mg 6.154%
Calcium Carbonate 51 mg 7.85%
PVP K 30 45.5 mg 7%
BHA 0.13 mg 0.02%
BHT 0.13 mg 0.02%
Sodium bicarbonate 65 mg 10%
Magnesium Stearate 4mg 0.6154%
Talc 20 mg 3.1%
Aerosil 200 3mg 0.46%
Wt/tab=650 mg
The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 10:-
Table lO:-

Time (hr) Cumulative % Release
2 79.52
4 93.43
6 93.43
8 93.43
10 93.43
12 93.43
24 93.43
Example 6:
In the present example Xanthan Gum has been used as carbohydrate gum, sodium carboxy methyl cellulose as the gel forming polymer, Carbopol 974P as the hydrophilic polymer, Sodium bicarbonate as the gas generating component. The pharmaceutical composition is given in Table 11:-
15

Table 11

Ingredient Wt(mg/tablet) %w/w
Methylcobalamin 1.5 mg (+30% overages) 0.231
Colour Erythrosine Supra 4.5 mg 0.692
Sodium carboxy methyl cellulose 1160 9.0 mg 1.385
Xanthan gum 9.0 mg 1.385
Carbopol 974P 65 mg 10
Lactose 166.12 25.56
MCC 166.12 25.56
Crospovidone(Polyplasdone XL) 40 mg 6.154
Calcium Carbonate 51 mg 7.85
PVP K 30 45.5 mg 7
BHA 0.13 mg 0.02
BHT 0.13 mg 0.02
Sodium bicarbonate 65 mg 10
Magnesium Stearate 4mg 0.6154
Talc 20 mg 3.1
Aerosil 200 3mg 0.46
Wt/tab=650 mg
The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 12:-
Table 12 :-

Time (hr) Cumulative % Release
2 45.03
4 97.903
6 109.42
8 113.36
10 115.7
12 115.7
24 115.7
16

Example 7:
In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 97IP as the hydrophilic polymer which is also a release retardant, mannitol as one of the diluents and Sodium bicarbonate as the gas generating component. The pharmaceutical composition is given in Table 13:-
Table 13

Ingredient Wt(mg/tablet) %w/w
Methylcobalamin 1.5 mg (+30% overages) 0.231
Colour Erythrosine Supra 4.5 mg 0.692
Sodium alginate 9.75 mg 1.5
Xanthan gum 9.75mg 1.5
Carbopol 97IP 65 mg 10
Mannitol 165.145 25.56
Microcrystalline Cellulose 165.145 25.56
Crospovidone(Polyplasdone XL) 40 mg 6.154
Calcium Carbonate 51 mg 7.85
PVP K 30 45.5 mg 7
BHA 0.13 mg 0.02
BHT 0.13 mg 0.02
Sodium bicarbonate 65 mg 10
Magnesium Stearate 4mg 0.6154
Talc 20 mg 3.1
Aerosil 200 3mg 0.46
Wt/tab=650 mg
The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 14:-
17

Table 14:-

Time (hr) Cumulative % Release
2 17.34
4 30.27
6 41.73
8 45.12
10 51.25
12 52.98
24 54.68
Example 8:
In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 71G as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. Carbopol 71 G is incorporated in the formulation at the lubrication stage. The pharmaceutical composition is given in Table 15:-
Table 15

Ingredient Wt(mg/tablet) %w/w
Methylcobalamin 1.5 mg (+30% overages) 0.231
Colour Erythrosine Supra 4.5 mg 0.692
Sodium alginate 9.75 mg 1.5
Xanthan gum 9.75 mg 1.5
Lactose 190 mg 29.231
Microcrystalline Cellulose 191.55 29.469
Crospovidone(Polyplasdone XL) 40 mg 6.154
PVP K 30 45.5 mg 7
Carbopol 71G 65 mg 10
Sodium bicarbonate 65 mg 10
Magnesium Stearate 4mg 0.6154
Talc 20 mg 3.1
Aerosil 200 3mg 0.46
Wt/tab=650 mg
18

The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 16:-
Table 16:-

Time (hr) Cumulative % Release
2 41.96
4 59.797
6 66.1
8 70.01
10 71.4
12 72.66
24 75.83
Example 9:
In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 971P and Carbopol 71G as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. In this formulation Carbopol 97IP is incorporated during the granulation and Carbopol 71G during lubrication The pharmaceutical composition is given in Table 17:-
Table 17

Ingredient Wt(mg/tablet) %w/w
Methylcobalamin 1.5 mg (+30% overages) 0.231
Colour Erythrosine Supra 4.5 mg 0.692
Sodium alginate 9.75 mg 1.5
Xanthan gum 9.75 mg 1.5
Carbopol 97IP 32.5 mg 5
Lactose 190 mg 29.231
Microcrystalline Cellulose 191.55 29.469
Crospovidone(Polyplasdone XL) 40 mg 6.154
PVP K 30 45.5 mg 7
Carbopol 71G 32.5 mg 5
19

Sodium bicarbonate 65 mg 10
Magnesium Stearate 4mg 0.6154
Talc 20 mg 3.1
Aerosil 200 3mg 0.46
Wt/tab=650 mg
The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 1 Si-
Table 18:-

Time (hr) Cumulative % Release
2 18.94
4 35.57
6 46.18
8 52.74
10 61.88
12 64.69
24 69.61
Example 10:-
In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. In this formulation Pharmatose DCL 15 (directly compressible grade lactose) is incorporated during the lubrication stage. The pharmaceutical composition is given in Table 19:-
Table 19

Ingredient Wt(mg/tablet) %w/w
Methylcobalamin 1.5 mg (+50% overages) 0.231
Colour Erythrosine Supra 4.5 mg 0.692
Sodium alginate 9.75 mg 1.5
Xanthan gum 9.75 mg 1.5
Carbopol 974P 52 mg 8
Lactose 220 mg 33.846
20

Microcrystalline Cellulose 110 mg 16.923
Crospovidone(Polyplasdone XL) 40 mg 6.154
Calcium Carbonate 51 mg 7.846
PVP K 30 45.5 mg 7
BHA 0.13 mg 0.02
BHT 0.13 mg 0.02
Pharmatose DCL 15 13 mg 2
Sodium bicarbonate 65 mg 10
Magnesium Stearate 4mg 0.6154
Talc 20 mg 3.1
Aerosil 200 3mg 0.46
Wt/tab=650 mg
The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 20:-
Table 20:-

Time (hr) Cumulative % Release
2 67.87
4 99.65
6 105.75
8 110.4
10 113.5
12 113.5
24 118.28
Example 11:
In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P and Carbopol 71G as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. Carbopol 974 P is incorporated in the formulation during the granulation stage whereas Carbopol 71G during the lubrication stage. The pharmaceutical composition is given in Table 21:-
21

Table 21

Ingredient Wt(mg/tablet) %w/w
Methylcobalamin 1.5 mg (+50% overages) 0.231
Colour Erythrosine Supra 4.5 mg 0.692
Sodium alginate 9.75 mg 1.5
Xanthan gum 9.75 mg 1.5
Carbopol 974P 52 mg 8
Lactose 220 mg 33.846
Macrocrystalline Cellulose 110 mg 16.923
Crospovidone(Polyplasdone XL) 40 mg 6.154
Calcium Carbonate 51 mg 7.846
PVP K 30 45.5 mg 7
BHA 0.13 mg 0.02
BHT 0.13 mg 0.02
Carbopol 71G 13 mg 2
Sodium bicarbonate 65 mg 10
Magnesium Stearate 4mg 0.6154
Talc 20 mg 3.1
Aerosil 200 3mg 0.46
Wt/tab=650 mg
The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 22:-
Table 22:-

Time (hr) Cumulative % Release
2 43.92
4 65.68
6 73.91
8 78.32
10 81.14
12 81.99
24 89.23
22

Example 12:
In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P and Carbopol 71G as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. Carbopol 974 P is incorporated in the formulation during the granulation stage whereas Carbopol 71G and Pharmatose DCL 15 during the lubrication stage. The pharmaceutical composition is given in Table 23:-
Table 23

Ingredient Wt(mg/tablet) %w/w
Methylcobalamin 1.5 mg (+50% overages) 0.231
Colour Erythrosine Supra 4.5 mg 0.692
Sodium alginate 9.75 mg 1.5
Xanthan gum 9.75 mg 1.5
Carbopol 974P 52 mg 8
Lactose 220 mg 33.846
Microcrystalline Cellulose 110 mg 16.923
Crospovidone(Polyplasdone XL) 40 mg 6.154
Calcium Carbonate 51 mg 7.846
PVP K 30 45.5 mg 7
BHA 0.13 mg 0.02
BHT 0.13 mg 0.02
Carbopol 71G 6.5 mg 1
Pharmatose DCL 15 6.5 mg 1
Sodium bicarbonate 65 mg 10
Magnesium Stearate 4mg 0.6154
Talc 20 mg 3.1
Aerosil 200 3mg 0.46
Wt/tab=650 mg
23

The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 24:-
Table 24:-

Time (hr) Cumulative % Release
2 45.24
4 66.78
6 72.15
8 77.4
10 81.03
12 84.41
24 94.7
Example 13:
In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P and Hydroxy Propyl Methyl Cellulose HPMC K4M as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. Carbopol 974 P is incorporated in the formulation during the granulation stage whereas HPMC K4M during the lubrication stage. The pharmaceutical composition is given in Table 25:-
Table 25

Ingredient Wt(mg/tablet) %w/w
Methylcobalamin 1.5 mg (+50% overages) 0.231
Colour Erythrosine Supra 4.5 mg 0.692
Sodium alginate 9.75 mg 1.5
Xanthan gum 9.75 mg 1.5
Carbopol 974P 52 mg 8
Lactose 220 mg 33.846
Microcrystalline Cellulose 110 mg 16.923
Crospovidone(Polyplasdone XL) 40 mg 6.154
Calcium Carbonate 51 mg 7.846
PVP K 30 45.5 mg 7
24

BHA 0.13 mg 0.02
BHT 0.13 mg 0.02
HPMC K4M 13 mg 2
Sodium bicarbonate 65 mg 10
Magnesium Stearate 4mg 0.6154
Talc 20 mg 3.1
Aerosil 200 3mg 0.46
Wt/tab=650 mg
The tablets were tested for dissolution in 0.1 N HCI using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 26:-
Table 26:-

Time (hr) Cumulative % Release
2 62.17
4 81.2
6 90.14
8 97.28
10 101.82
12 102.55
24 105.64
Example 14:
In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P and Hydroxy Propyl Methyl Cellulose HPMC K4M as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. Carbopol 974 P is incorporated in the formulation during the granulation stage whereas HPMC K4M during the lubrication stage. The pharmaceutical composition is given in Table 27:-
Table 27

Ingredient Wt(mg/tablet) %w/w
Methylcobalamin 1.5 mg (+50% overages) 0.228
25

Colour Erythrosine Supra 4.5 mg 0.685
Sodium alginate 9.75 mg 1.485
Xanthan gum 9.75 mg 1.485
Carbopol 974P 52 mg 7.921
Lactose 220 mg 33.511
Microcrystalline Cellulose 110 mg 16.756
Crospovidone(Polyplasdone XL) 40 mg 6.093
Calcium Carbonate 51 mg 7.768
PVP K 30 45.5 mg 6.931
BHA 0.13 mg 0.0194
BHT 0.13 mg 0.0194
HPMC K4M 19.5 mg 2.97
Sodium bicarbonate 65 mg 9.901
Magnesium Stearate 4mg 0.6093
Talc 20 mg 3.0465
Aerosil 200 3mg 0.457
Wt/tab=656.5 mg
The tablets were tested for dissolution in 0.1 N HCI using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 28:-
Table 28:-

Time (hr) Cumulative % Release
2 48.47
4 85
6 88.35
8 —
10 —
12 —
24 —
26

Example 15:
In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P and Hydroxy Propyl Methyl Cellulose HPMC K4M as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. Carbopol 974 P is incorporated in the formulation during the granulation stage whereas HPMC K4M during the lubrication stage. The pharmaceutical composition is given in Table 29:-
Table 29

Ingredient Wt(mg/tablet) %w/w
Methylcobalamin 1.5 mg (+50% overages) 0.226
Colour Erythrosine Supra 4.5 mg 0.679
Sodium alginate 9.75 mg 1.471
Xanthan gum 9.75 mg 1.471
Carbopol 974P 52 mg 7.843
Lactose 220 mg 33.183
Microcrystalline Cellulose 110 mg 16.591
Crospovidone(Polyplasdone XL) 40 mg 6.033
Calcium Carbonate 51 mg 7.692
PVP K 30 45.5 mg 6.863
BHA 0.13 mg 0.0196
BHT 0.13 mg 0.0196
HPMC K4M 26 mg 3.922
Sodium bicarbonate 65 mg 9.804
Magnesium Stearate 4mg 0.6033
Talc 20 mg 3.017
Aerosil 200 3mg 0.453
Wt/tab=663 mg
The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 30:-
27

Table 30:-

Time (hr) Cumulative % Release
2 37.37
4 59.0
6 62.06
8 —
10 —
12 —
24 —
Example 16:
In the present example Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 974P and Hydroxy Propyl Methyl Cellulose HPMC K4M as the hydrophilic polymers, Sodium bicarbonate as the gas generating component. Carbopol 974 P is incorporated in the formulation during the granulation stage whereas HPMC K4M during the lubrication stage. The pharmaceutical composition is given in Table 31 :-
Table 31

Ingredient Wt(mg/tablet) %w/w
Methylcobalamin 1.5 mg (+50% overages) 0.224
Colour Erythrosine Supra 4.5 mg 0.672
Sodium alginate 9.75 mg 1.456
Xanthan gum 9.75 mg 1.456
Carbopol 974P 52 mg 7.767
Lactose 220 mg 32.86
Microcrystalline Cellulose 110 mg 16.43
Crospovidone(Polyplasdone XL) 40 mg 5.975
Calcium Carbonate 51 mg 7.618
PVP K 30 45.5 mg 6.796
BHA 0.13 mg 0.01942
BHT 0.13 mg 0.01942
28

HPMC K4M 32.5 mg 4.854
Sodium bicarbonate 65 mg 9.709
Magnesium Stearate 4mg 0.598
Talc 20 mg 2.987
Aerosil 200 3mg 0.4481
Wt/tab=669.5 mg
The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 32:-
Table 32:-

Time (hr) Cumulative % Release
2 34.22
4 63.52
6 64.1
8 —
10 —
12 —
24 —
Example 17:
In the present example tablets are manufactured by direct compression method wherein Xanthan Gum has been used as carbohydrate gum, sodium alginate as the gel forming polymer, Carbopol 71G as the hydrophilic polymer, Sodium bicarbonate as the gas generating component. Directly compressible grade lactose (Pharmatose DCL 15) and Directly compressible grade lactose (Microcel PHI02) are incorporated as the diluents. The pharmaceutical composition is given in Table 33:-
Table 33

Ingredient Wt(mg/tablet) %w/w
Methylcobalamin 1.5 mg (+50% overages) 0.248
Colour Erythrosine Supra 4.5 mg 0.744
Sodium alginate 9.75 mg 1.612
Xanthan gum 9.75 mg 1.612
29

Carbopol 71 G 65 mg 10.744
Pharmatose DCL 15 220.5 mg 36.446
Microcel PH 102 110 mg 18.182
Crospovidone(Polyplasdone XL) 40 mg 6.612
Calcium Carbonate 51 mg 8.43
BHA 0.13 mg 0.0215
BHT 0.13 mg 0.0215
Sodium bicarbonate 65 mg 10.744
Magnesium Stearate 4mg 0.661
Talc 20 mg 3.306
Aerosil 200 3mg 0.496
Wt/tab=605 mg
The tablets were tested for dissolution in 0.1 N HCl using USP apparatus I with basket speed at 100 rpm. The dissolution results are given in Table 34:-
Table 34:-

Time (hr) Cumulative % Release
2 56.33
4 76.79
6 86.66
8 —
10 —
12 —
24 —
30

We claim,
1. An oral sustained release formulation of vitamins preferably absorbed in the
upper gastrointestinal tract comprising vitamin, preferably methyl cobalamin, colourant, stabilizer, antioxidants, gas generating component, disintegrant, carbohydrate gum, gel forming polymer, hydrophilic swellable polymer, other excipients, etc.
2. The formulation as claimed in claim 1, wherein said gas generating component is
selected from the class of alkali carbonates and bicarbonates.
3. The formulation as claimed in claims 1 and 2, wherein said alkali carbonates and
bicarbonates are selected from sodium bicarbonate, potassium bicarbonate and sodium carbonate.
4. The formulation as claimed in claim 3, wherein said alkali bicarbonate is
preferably sodium bicarbonate.
5. The formulation as claimed in claim 4, wherein the concentration of said sodium
bicarbonate is 9.7-10 percent by weight of the dosage unit.
6. The formulation as claimed in claim 1, wherein said disintegrants are selected
from the group comprising cellulose derivatives, cross linked polyvinyl pyrollidone, starch, croscarmellose sodium, sodium starch glycollate, etc.
7. The formulation as claimed in claim 6, wherein said disintegrant is preferably
cross linked pyrollidone.
8. The formulation as claimed in claim 7, wherein the concentration of cross linked
polyvinyl pyrollidone is 5.9 - 6.7 percent by weight of the dosage unit.
9. The formulation as claimed in claim 1, wherein said carbohydrate gums are
selected form the group comprising xanthan gum, gum karaya, gum acacia, locust bean gum, etc.
10. The formulation as claimed in claim 9, wherein said carbohydrate gum is
preferably xanthan gum.
11. The formulation as claimed in claim 10, wherein the concentration of xanthan
gum is 1.4 - 1.7 percent by weight of the dosage unit.
12. The formulation as claimed in claim 1, wherein the said gel forming polymers
are selected from the group comprising the class of alkali metal alginates and cellulose derivatives.
31

13. The formulation as claimed in claim 12, wherein the said alkali metal alginates
are selected from the group comprising sodium alginate, potassium alginate, ammonium alginate and the like.
14. The formulation as claimed in claim 13, wherein the said alkali metal alginate is
preferably sodium alginate.
15. The formulation as claimed in claim 14, wherein the concentration of said
sodium alginate is 1.4 - 1.7 percent by weight of the dosage unit.
16. The formulation as claimed in claim 12, wherein said cellulose derivative is
selected from sodium carboxyl methyl cellulose.
17. The formulation as claimed in claim 16, wherein said cellulose derivative is used
in the concentration of 1.385 percent by weight of the dosage unit.
18. The formulation as claimed in claim 1, wherein said hydrophilic polymers are
selected from the group comprising hydroxy propyl methyl cellulose HPMC K4M, Methyl cellulose Metolose SM400, Carbomer Carbopol 974P Carbopol 97IP, Carbopol 71G, etc.
19. The formulation as claimed in claim 18, wherein the concentration of said
hydrophilic polymer is 2-11 percent by weight of the dosage unit.
20. The formulation as claimed in claim 1, wherein said other excipients are
optionally selected from the group comprising diluents, binders, glidants and lubricants.
21. The formulation as claimed in claim 20, wherein said diluents are selected from
the group comprising lactose, mannitol, microcrystalline cellulose, etc.
22. The formulation as claimed in claim 21, wherein the concentration of said diluent
is 16-37 percent by weight of the dosage unit.
23. The formulation as claimed in claim 20, wherein said binders are selected from
the group comprising cellulose derivatives, polyvinyl pyrollidone, acrylates, starch, gelatin, etc.
24. The formulation as claimed in claim 23, wherein said binder is preferably
polyvinyl pyrollidone PVP K30.
25. The formulation as claimed in claims 24, wherein the concentration of polyvinyl
pyrollidone PVP K 30 is 6-7 percent by weight of the dosage unit.
26. The formulation as claimed in claims 1 to 25, wherein said formulation is in
tablet form.
32

27. The formulation as claimed in claims 1 to 26, wherein said tablet is prepared by
wet granulation.
28. The formulation as claimed in claims 1 to 22 and 26, wherein said tablet is
prepared by direct compression method.
29. A sustained release formulation of vitamins, preferably methyl cobalamin for
oral administration in humans as substantially described herein with reference to foregoing examples 1 to 17.

33

Abstract:
A pharmaceutical composition providing controlled delivery of methylcobalamin designed to improve the bioavailability of the drug in the upper gastrointestinal tract is described. The pharmaceutical composition is formulated into a tablet dosage form. The pharmaceutical composition comprises of a drug, a gas generating component which is also the buoyancy imparting agent, swelling agent, a gel forming polymer, a hydrophilic swellable polymer and a disintegrant.

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1219-MUM-2003-ABSTRACT(24-11-2004).pdf

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1219-mum-2003-cancelled pages(10-09-2008).pdf

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1219-mum-2003-correspondence(10-09-2008).pdf

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1219-mum-2003-descripiton (complete).pdf

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1219-MUM-2003-DESCRIPTION(COMPLETE)-(24-11-2004).pdf

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Patent Number

225501

Indian Patent Application Number

1219/MUM/2003

PG Journal Number

07/2009

Publication Date

13-Feb-2009

Grant Date

14-Nov-2008

Date of Filing

25-Nov-2003

Name of Patentee

M/S. INDOCO REMEDIES LIMITED

Applicant Address

INDOCO HOUSE, 166 C.S.T. ROAD, SANTACRUZ (EAST), MUMBAI-400098.

Inventors:

#	Inventor's Name	Inventor's Address
1	KARE SURESH GOVIND	6th FLOOR REGENCY AVENUE, NORTH AVENUE ROAD, SANTACRUZ (WEST), MUMBAI-400054.
2	PANANDIKAR ADITI MILIND	DURGA NIVAS, NEHRU ROAD, VILE PARLE(EAST), MUMBAI-400057. MAHARASHTRA, INDIA.
3	NAIDU RAVI PEDDI	903-MANISHA TOWER, NAVGHAR 60 FEET ROAD, NEAR TATA COLONY, MULUND(EAST), MUMBAI-400081.
4	AMIN LIKHITA LAZMAN	A/10 'RASHMI', 4th FLOOR, VEERA DESAI ROAD, ANDHERI(WEST), MUMBAI-400058.

PCT International Classification Number

A61K9/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA