Indian Patents. 207119:CONTROLLED RELEASE FORMULATION FOR WATER SOLUBLE DRUGS AND PROCESS FOR PREPARING IT

Title of Invention	CONTROLLED RELEASE FORMULATION FOR WATER SOLUBLE DRUGS AND PROCESS FOR PREPARING IT
Abstract	The present invention discloses a controlled release formulation for a water soluble drug comprising, a water soluble active pharmaceutical ingredient, a polysaccharide gum, a lipophilic ingredient, an inert carrier and pharmaceutically acceptable excipients, diluents and additives.

Full Text	The present invention relates to a controlled release formulation for a water soluble drug comprising, a water soluble active pharmaceutical ingredient, a polysaccharide gum, a lipophilic ingredient, an inert carrier and pharmaceutically acceptable excipients, diluents and additives. The novel combination of polysaccharide gum and glyceryl behenate or other lipophilic ingredients provides the distinct release profile of the present invention and reduces the initial immediate release of the active pharmaceutical ingredient. Isosorbide -5- mononitrate is a vasodilator used for the long terra treatment of cardiac insufficiency. The development of a controlled release dosage form is desirable as it provides a uniform plasma concentration and avoids peak plasma levels and the side effects associated with it. However, isosorbide -5- mononitrate exhibits some typical drawbacks such as high water solubility, the tendency to generate high static electricity when processed alone in a dry form and sublimation, which make it difficult to formulate as a controlled release product. US Patent No. 5,453,283 describes a solvent free orally administered pharmaceutical preparation containing isosorbide -1- -5- mononitrate in delayed release form wherein the drug is melt blended with water insoluble matrix former like polyvinyl acetate and water soluble substances like lactose as carrier, together with water insoluble substances like silicon dioxide and talcum, wherein the talcum acts as a mechanical obstacle, prolonging the diffusion path and resulting in a slowing down of the active substance released, us Patent No. 4,812,316 discloses stabilized isosorbide -5- mononitrate tablets in retard form where the drug is formulated in a stable solid solution with polyvinyl pyrrolidone and retard effect is obtained by using Hydroxy propylmethylcellulose, namely, methocel, either singly or in various combinations. WO 98/05306 discloses a controlled release tablet formulation of isosorbide -5- mononitrate where the active ingredient is granulated with a solution of a polyvinyl pyrrolidone and the drug granules are blended with cellulose based controlled release agent like Hydroxypropylmethyl cellulose. The tablet formed can be placed in capsules along with a second active ingredient such as aspirin, US Patent No. 4,855,143 refers to a method of preparing a controlled long acting pharmaceutical tablet containing a drug and cellulose ether carrier base. The method discloses mixing the drug and the cellulose ether base material such as Hydroxypropylmethylcellulose and allowing the mixture to stand for a period of time so as to allow bonding of the drug and Hydroxypropylmethylcellulose and compressing portions of -2- the mixture into tablets. US Patent No. 5,334,393 reveals a sustained release tablet in which isosorbide -5- mononitrate in powder form having different particle sizes is added to hydrophilic swelling component such as Hydroxypropylmethylcellulose, natural gums, alginic acid derivatives, etc. and at least one diluent component. US Patent No. 5,851,555 discusses controlled release dosage forms for water soluble drugs containing the active agents such as isosorbide - 5- mononitrate, niacin, etc. inert carrier, cellulosic polymer and a lipophillic ingredient. The drug was processed using either solid dispersion or melt blended with a lipophilic ingredient, milling the mass into a granulate and then blending the granulate with celluosic polymer such as Hydroxypropylmethylcellulose. EP Patent no. 234670 discloses that xanthan gum has also been used in controlled release tablet formulation. US Patent No. 4,994,276, 5,128,143 and 5,135,757 describe the use of xanthan gum in combination with other gums such as locust bean gum as controlled release agent. Hence, various polysaccharide gums and cellulosic ethers such as, Hydroxypropylmethylcellulose, carboxy methyl cellulose, methyl cellulose, alginates, xanthan gums etc. are known and they have all been used as controlled release agents. However, the "cellulosics" are Newtonian at low shear rates and become pseudoplastic as the shear rate increases, that is, they exhibit shear thining. -3- Xanthan gum on the other hand is characterized in being extremely pseudoplastic and having a high at rest viscosity, displaying four times higher viscosity compared to Hydroxypropylmethylcellulose at low shear rates, making it almost ideal as a controlled release agent. Xanthan gum also displays viscoelasticity with high elastic modulus, which provides erosion resistance to hydrated layer. Lipophilic ingredients are used as a processing aid for preparations involving a solid dispersion, or hot melt blend technique and also act as sustained release agents. The lipophilic ingredient generally used are fatty acid esters such as glyceryl behenate, waxes, hydrogenated castor oil, hydrogenated vegetable oil, cetyl alcohol, etc. Combinations of cellulosic polymer such as Hydroxypropylmethylcellulose together with lipophilic ingredient glyceryl behenate are known (US 5,851,555). The "cellulosic" based controlled release formulations suffer from drawbacks such as a relatively fast drug release profile of 10 to 12 hours for 60 mg isosorbide -5-mononitrate tablet and immediate release within the first hour of more than 25% which is normally associated with Hydroxypropylmethylcellulose based formulations. The tablets are also relatively large due to a large amount of matrix forming material required. The object of the invention is to provide a controlled release formulation wherein the dose dumping of the drug during the initial 60 minutes following administration is -4- minimized. A further object of the invention is to provide a controlled release formulation which exhibits a sustained drug release profile over a longer period of time of 10 to 24 hours. A still further object of the invention is to provide a controlled release dosage form wherein ratio of drug to controlled release matrix agent is maintained below 1:2.55 and wherein the size is kept relatively small, thus making the formulation economical and easy to swallow. The ratio of drug to controlled release matrix agent in the prior art US 5,851,555 is 1:2:75. Accordingly, the present invention provides a controlled release formulation for a water soluble drug comprising, a water soluble active pharmaceutical ingredient, a polysaccharide gum, a lipophilic ingredient, an inert carrier and pharmaceutically acceptable excipients, diluents and additives optionally in association with a second active ingredient. The controlled release formulation for oral admininstration includes matrix formulations such as matrix tablets, granules or pellets, or coated formulations such as coated tablets, granules or pellets, caplets, soft chews, gel capsules and microcapsules. The present invention also provides a process for the preparation of a controlled release formulation for a water soluble drug comprising, (a) mixing a water soluble active pharmaceutical ingredient, a lilophilic ingredient and part or all of the polysaccharide -5- gum with diluents; (b) hot melting of the mixture to form aggregates; (c) cooling and granulating the aggregates; (d) blending the granulates with the remaining polysaccharide gum and pharmaceutically acceptable excipients and additives; and (e) compressing either alone or as a bilayer matrix formulation with a second active pharmaceutical ingredient or as a coated formulation or optionally as caplets, soft chews, gel capsules and microcapsules. The invention deals with controlled release formulations and processes for making orally deliverable dosage forms containing water soluble active pharmaceutical ingredients, which processes overcome the processing difficulties encountered with these active pharmaceutical ingredients, and which controlled release formulations exhibit a sustained drug release profile over a longer period of time of 10 to 24 hours wherein the immediate rapid release of the drug (dose dumping) during the initial 60 minutes following administration is minimized. Further, the size is kept relatively small, thus making the formulation economical and easy to swallow. The present invention provides a controlled release formulation for a water soluble active pharmaceutical ingredient comprising, a water soluble active pharmaceutical-ingredient, a polysaccharide gum, a lipophilic ingredient, an inert carrier and pharmaceutically acceptable excipients, -6- diluents and additives. Preferably, the formulations of the invention contain, as essential ingredients, a water soluble active pharmaceutical ingredient in the range 5 to 50%; polysaccharide gum in the range 5 to 50%; and lipophilic ingredient in the range 5 to 50%, Preferred ranges of the essential ingredients are a water soluble active pharmaceutical ingredient in the range 20 to 40%; polysaccharide gum in the range 10 to 40%; and lipophilic ingredient in the range 10 to 40%. The novel combination of xanthan gum and glyceryl behenate or other lipophilic ingredients provides the distinct release profile of the present invention and reduces the initial immediate release of the active pharmaceutical ingredient. Polysaccharide gum is selected from the group comprising xanthan gum, gellan gum, locust bean gum, gum caraya, etc. The preferred polysaccharide gum is xanthan gum. Xanthan gum exhibits a high affinity for water and hydrates rapidly forming a gel layer around the formulation thus minimizing the immediate rapid release of the drug during the initial 60 minutes following administration, which is a characteristic of Hydroxypropylmethylcellulose. Isosorbide -5- mononitrate and the lipophilic ingredient such as glyceryl behenate are melted together, when the molten drug gets dispersed in the wax phase. The molten wax is cooled, and the isosorbide -5- mononitrate crystalizes -7- first due to its high melting point (90°C). The isosorbide -5- mononitrate crystals formed are surrounded by molten wax. On further cooling, this molten wax forms a uniform coating on the isosorbide -5-mononitrate crystals. The invention provides drug release sustained over a longer period of time of 10 to 24 hours upon oral administration. Further, as xanthan gum has a faster hydration rate and is highly pseudoplastic and viscoelastic as compared to cellulose, hence, less xanthan gum is required and the dosage form weight and thereby size is kept relatively small with less matrix forming ingredient, making the oral dosage form of the formulation economical and easy to swallow. The lipophilic ingredient is selected from a fatty acid ester such as glyceryl behenate, hydrogenated castor oil, hydrogenated vegetable oil, wax and cetyl alcohol either alone or in combination with the fatty acid ester. The preferred carriers are lactose, mannose, etc. The ratio of the active agent to the carrier is in the range of 4:1 to 2:1. Examples of water soluble active pharmaceutical ingredients are isosorbide -5- mononitrate, isosorbide dinitrate, venlafaxine hydrochloride, propranolol hydrochloride, metformin hydrochloride, diltiazem hydrochloride their combinations and other pharmaceutically acceptable water soluble active ingredients thereof. -8- Lubricants such as stearic acid, magnesium stearate, etc may be used. Colorants such as pigments, lakes, iron oxide, etc may by used. The formulation thus prepared may be compressed alone as a tablet or may be compressed as bilayered tablet along with a second active ingredient. One of the suitable second active ingredients is Aspirin. Aspirin in the form of "Encapsulated Aspirin"(available under the brand name "Gattaprine" from Gattafosse) may also be used which minimizes the side effect such as gastric irritation associated with Aspirin. It also enhances the stability of Aspirin. The following examples are included by way of illustration and do not in any way restrict the scope of the invention. EXAMPLES Example 1 Ingredients mg/tablet isosorbide-5-mononitrate 75 mg Lactose Premix (4:1) Compritol 888 ATO (glyceryl behenate) 75 mg Xanthan Gum 40 mg Aerosil 5 mg The ingredients are mixed in a planetary mixer for 30 minutes. Heated to 70 to 100°C and mixed for 30 minutes. The hot mass is cooled and milled to get a particle size of #16 mesh (about 1190 microns). -9- This granulate was further blended as follows: Granulate 195 mg Xanthan Gum 45 mg Talc 2 mg Aerosil 5 mg Yellow oxide of Iron 0.2 mg The tablet was compressed at 247.2 mg using 8.7 mm round punches. The hardness may be in the range of 50 to 150 N, preferably between 75 to 110 N. The in vitro drug release of the tablets was studied by employing standard dissolution techniques in a USP Apparatus (type 1) at 75 rpm with 1000 ml of distilled water at 37.5°C. The results are as follows: Time(Hour) % Dissolved 1 13.88 2 27.72 4 50.90 8 79.65 10 85.96 12 89.99 15 95.20 24 100.02 The results indicate that the tablets made according to the invention, reduce dose dumping during the initial hour as well as provide drug release over 10 to 15 hours. The dissolution studies compared the properties of the hot melt blend tablets of the present invention to the isosorbide -5- mononitrate controlled release tablets prepared using Hydroxypropylmethylcellulose as controlled -10- release agent. The isosorbide-5-mononitrate controlled release tablets using Hydroxypropylmethylcellulose as controlled release agent were prepared as per formulation given below : Ingredients mg/tablets lsosorbide-5-mononitrate : 75 mg Lactose premix (4:1) Lactose 175 mg Methocel - K4M (Hydroxypropylmethylcellulose K4M) 85 mg Methocel E15LV (Hydroxypropylmethylcellulose E15LV) 15 mg Magnesium Stearate 6 mg Talc 4 mg The isosorbide - 5 - mononitrate controlled release tablets using hydroxypropylmethylcellulose as controlled release agent were prepred as given below : -1. Sift isosorbide -5- mononitrate, lactose and Methocel K4M (Hydroxypropyl methylcellulose K4M) through # 40 mesh (about 400 microns) and mix in a planetary mixer. -2. Dissolve Methocel E 15VL (Hydroxypropyl methylcellulose E15LV) in suitable solvent (isopropyl alcohol : methylene chloride 1 : 1) and granulate the powder mix in step 1 with the resulting solution. -3. Mill the resulting wet mass through 12.6 mm sieves and dry. -4. Size the dried granule to get # 20 mesh (about 841 microns) granules. Lubricate the granules with magnesium stearate and talcum. -11- 5. Compress the granulate on a rotary tablet compression machine using 10.3 mm round punches at 360 mg/ tablet weight. The in vitro release profile of the hot melt blend tablets of the present invention was compared to the isosorbide -5- mononitrate controlled release tablets prepared using hydroxypropylmethylcellulose as controlled release agent (as per formulation given above). The results are as given below: Hour Invention HPMC Tablet 1 13.88 31.23 2 27.72 45.32 4 50.90 65.26 8 79.65 89.02 10 85.96 95.12 12 89.99 98.55 15 95.20 24 100.02 From the result it is apparent that the invention reduces the drug release during the first hour, sustains drug release upto 24 hours and provides for a smaller size. Example 2 The granulate from Example 1 may be compressed as a bilayered tablet with a second active pharmaceutical ingredient such as Aspirin. I. Isosorbide - 5- mononitrate fraction: -12- Ingredients mg/tablet Granulate from Example 1 247.2 mg II Aspirin Fraction Ingredients mg/tablet Granular Aspirin/ Encapsulated Aspirin 50.0 mg Microcrystalline cellulose 13.0 mg Sodium Starch Glycolate 8.0 mg Talc 4.0 mg Colloidal Silicon Dioxide 5.0 mg All ingredients of the Aspirin fraction are sifted and blended together. Isosorbide -5- mononitrate fraction (Average weight: 247,2 rag) and Aspirin fraction (Average weight: 180.0 mg) are compressed as bilayered tablet using 9.56 mm round punches on a Press Kota cadmach machine. -13- WE CLAIM : 1. A controlled release formulation for water soluble drug comprising, a water soluble active pharmaceutical ingredient, a polysaccharide gum, a lipophillic ingredient, and inert carrier and pharmaceutically acceptable excipients, diluents and additives optionally in association with a second active ingredient.. 2. The controlled released formulation as claimed in claim 1, wherein, the percentage range by weight of composition for water soluble active pharmaceutical ingredient is 5 to 50%;polysaccharide gum is 5 to 50% and lilophilic ingredient is 5 to 50 %. 3. The controlled release formulation as claimed in claim 2, wherein the percentage range by weight of composition for the water soluble active pharmaceutical ingredient is 20 to 40%. 4. The controlled release formulation as claimed in claim 2, wherein the percentage range by weight of composition tor the polysaccharide gum is 10 to 40%. 5. The controlled release formulation as claimed in claim2, wherein the percentage range by weight of composition for the lilophilic ingredient is 10 to 40%. 6. The controlled release formulation as claimed in any of claims 1 and 2, wherein the preferred active pharmaceutical ingredient is selected from the group consisting of isosorbide-5-mononitrate, isosorbide dinitrate, venlafaxine hydrochloride, propranolol hydrochloride, metformin hydrochloride and diltiazem hydrochloride. 14 7. The controlled release formulation as claimed in claims 1 and 2, wherein the polysaccharide gum is selected from the group consisting of xanthan gum, gellan gum, locust bean gum and gum caraya. 8. The controlled release formulation as claimed in any of claims 1 and 2, wherein the lipophilic ingredient is selected from the group consisting of a fatty acid ester, hydrogenated castor oil, hydrogenated vegetable oil, wax or cetyl alcohol either alone or in combination with the fatty acid ester. 9. The controlled release formulation as claimed in any of claims 1 and 2, wherein the lipophilic ingredient is the fatty acid ester glyceryl behenate. 10. A process for the preparation of a controlled release formulation for a water soluble drug comprising, (a) mixing a water soluble active pharmaceutical ingredient, a lipophilic ingredient and part or all of the polysaccharide gum with diluents; (b) hot melting of the mixture to form aggregates; (c) cooling and granulating the aggregates; (d) blending the granulates with the remaining polysaccharide gum and pharmaceutically acceptable excipients and additives; and (e) compressing either alone or as a bilayer matrix formulation with a second active pharmaceutical ingredient or as a coated formulation or optionally as caplets, soft chews, gel capsules and microcapsules. 11. A process as claimed in claim 10, wherein the second -15- active pharmaceutical ingredient is Aspirin. 12. A controlled release formulation for a water soluble drug substantially as herein described particularly with reference to the examples. 13. A process for the preparation of a controlled release formulation for a water soluble drug substantially as herein described particularly with reference to the examples. 14. The controlled release formulation as claimed in any of the claims 1 to 9, wherein the formulation contains a second active ingredient. 15. The formulation as claimed in claim 14, wherein said second active ingredient is aspirin. 16. The formulation as claimed in claim 15, wherein the said formulation is in the form of bi-layered tablet. The present invention discloses a controlled release formulation for a water soluble drug comprising, a water soluble active pharmaceutical ingredient, a polysaccharide gum, a lipophilic ingredient, an inert carrier and pharmaceutically acceptable excipients, diluents and additives.

Full Text

The present invention relates to a controlled release formulation for a water soluble drug comprising, a water soluble active pharmaceutical ingredient, a polysaccharide gum, a lipophilic ingredient, an inert carrier and pharmaceutically acceptable excipients, diluents and additives.
The novel combination of polysaccharide gum and glyceryl behenate or other lipophilic ingredients provides the distinct release profile of the present invention and reduces the initial immediate release of the active pharmaceutical ingredient.
Isosorbide -5- mononitrate is a vasodilator used for the long terra treatment of cardiac insufficiency. The development of a controlled release dosage form is desirable as it provides a uniform plasma concentration and avoids peak plasma levels and the side effects associated with it. However, isosorbide -5- mononitrate exhibits some typical drawbacks such as high water solubility, the tendency to generate high static electricity when processed alone in a dry form and sublimation, which make it difficult to formulate as a controlled release product.
US Patent No. 5,453,283 describes a solvent free orally administered pharmaceutical preparation containing isosorbide
-1-

-5- mononitrate in delayed release form wherein the drug is melt blended with water insoluble matrix former like polyvinyl acetate and water soluble substances like lactose as carrier, together with water insoluble substances like silicon dioxide and talcum, wherein the talcum acts as a mechanical obstacle, prolonging the diffusion path and resulting in a slowing down of the active substance released, us Patent No. 4,812,316 discloses stabilized isosorbide -5- mononitrate tablets in retard form where the drug is formulated in a stable solid solution with polyvinyl pyrrolidone and retard effect is obtained by using Hydroxy propylmethylcellulose, namely, methocel, either singly or in various combinations.
WO 98/05306 discloses a controlled release tablet formulation of isosorbide -5- mononitrate where the active ingredient is granulated with a solution of a polyvinyl pyrrolidone and the drug granules are blended with cellulose based controlled release agent like Hydroxypropylmethyl cellulose. The tablet formed can be placed in capsules along with a second active ingredient such as aspirin,
US Patent No. 4,855,143 refers to a method of preparing a controlled long acting pharmaceutical tablet containing a drug and cellulose ether carrier base. The method discloses mixing the drug and the cellulose ether base material such as Hydroxypropylmethylcellulose and allowing the mixture to stand for a period of time so as to allow bonding of the drug and Hydroxypropylmethylcellulose and compressing portions of
-2-

the mixture into tablets.
US Patent No. 5,334,393 reveals a sustained release tablet in which isosorbide -5- mononitrate in powder form having different particle sizes is added to hydrophilic swelling component such as Hydroxypropylmethylcellulose, natural gums, alginic acid derivatives, etc. and at least one diluent component.
US Patent No. 5,851,555 discusses controlled release dosage forms for water soluble drugs containing the active agents such as isosorbide - 5- mononitrate, niacin, etc. inert carrier, cellulosic polymer and a lipophillic ingredient. The drug was processed using either solid dispersion or melt blended with a lipophilic ingredient, milling the mass into a granulate and then blending the granulate with celluosic polymer such as Hydroxypropylmethylcellulose.
EP Patent no. 234670 discloses that xanthan gum has also been used in controlled release tablet formulation.
US Patent No. 4,994,276, 5,128,143 and 5,135,757 describe the use of xanthan gum in combination with other gums such as locust bean gum as controlled release agent.
Hence, various polysaccharide gums and cellulosic ethers such as, Hydroxypropylmethylcellulose, carboxy methyl cellulose, methyl cellulose, alginates, xanthan gums etc. are known and they have all been used as controlled release agents. However, the "cellulosics" are Newtonian at low shear rates and become pseudoplastic as the shear rate increases, that is, they exhibit shear thining.
-3-

Xanthan gum on the other hand is characterized in being extremely pseudoplastic and having a high at rest viscosity, displaying four times higher viscosity compared to Hydroxypropylmethylcellulose at low shear rates, making it almost ideal as a controlled release agent. Xanthan gum also displays viscoelasticity with high elastic modulus, which provides erosion resistance to hydrated layer.
Lipophilic ingredients are used as a processing aid for preparations involving a solid dispersion, or hot melt blend technique and also act as sustained release agents. The lipophilic ingredient generally used are fatty acid esters such as glyceryl behenate, waxes, hydrogenated castor oil, hydrogenated vegetable oil, cetyl alcohol, etc. Combinations of cellulosic polymer such as Hydroxypropylmethylcellulose together with lipophilic ingredient glyceryl behenate are known (US 5,851,555).
The "cellulosic" based controlled release formulations suffer from drawbacks such as a relatively fast drug release profile of 10 to 12 hours for 60 mg isosorbide -5-mononitrate tablet and immediate release within the first hour of more than 25% which is normally associated with Hydroxypropylmethylcellulose based formulations. The tablets are also relatively large due to a large amount of matrix forming material required.
The object of the invention is to provide a controlled release formulation wherein the dose dumping of the drug during the initial 60 minutes following administration is
-4-

minimized.
A further object of the invention is to provide a controlled release formulation which exhibits a sustained drug release profile over a longer period of time of 10 to 24 hours.
A still further object of the invention is to provide a controlled release dosage form wherein ratio of drug to controlled release matrix agent is maintained below 1:2.55 and wherein the size is kept relatively small, thus making the formulation economical and easy to swallow. The ratio of drug to controlled release matrix agent in the prior art US 5,851,555 is 1:2:75.
Accordingly, the present invention provides a controlled release formulation for a water soluble drug comprising, a water soluble active pharmaceutical ingredient, a polysaccharide gum, a lipophilic ingredient, an inert carrier and pharmaceutically acceptable excipients, diluents and additives optionally in association with a second active ingredient. The controlled release formulation for oral admininstration includes matrix formulations such as matrix tablets, granules or pellets, or coated formulations such as coated tablets, granules or pellets, caplets, soft chews, gel capsules and microcapsules.
The present invention also provides a process for the preparation of a controlled release formulation for a water soluble drug comprising,
(a) mixing a water soluble active pharmaceutical ingredient, a lilophilic ingredient and part or all of the polysaccharide
-5-

gum with diluents;
(b) hot melting of the mixture to form aggregates;
(c) cooling and granulating the aggregates;
(d) blending the granulates with the remaining polysaccharide gum and pharmaceutically acceptable excipients and additives; and
(e) compressing either alone or as a bilayer matrix formulation with a second active pharmaceutical ingredient or as a coated formulation or optionally as caplets, soft chews, gel capsules and microcapsules.
The invention deals with controlled release formulations and processes for making orally deliverable dosage forms containing water soluble active pharmaceutical ingredients, which processes overcome the processing difficulties encountered with these active pharmaceutical ingredients, and which controlled release formulations exhibit a sustained drug release profile over a longer period of time of 10 to 24 hours wherein the immediate rapid release of the drug (dose dumping) during the initial 60 minutes following administration is minimized. Further, the size is kept relatively small, thus making the formulation economical and easy to swallow.
The present invention provides a controlled release formulation for a water soluble active pharmaceutical ingredient comprising, a water soluble active pharmaceutical-ingredient, a polysaccharide gum, a lipophilic ingredient, an inert carrier and pharmaceutically acceptable excipients,
-6-

diluents and additives.
Preferably, the formulations of the invention contain, as essential ingredients, a water soluble active pharmaceutical ingredient in the range 5 to 50%; polysaccharide gum in the range 5 to 50%; and lipophilic ingredient in the range 5 to 50%, Preferred ranges of the essential ingredients are a water soluble active pharmaceutical ingredient in the range 20 to 40%; polysaccharide gum in the range 10 to 40%; and lipophilic ingredient in the range 10 to 40%.
The novel combination of xanthan gum and glyceryl behenate or other lipophilic ingredients provides the distinct release profile of the present invention and reduces the initial immediate release of the active pharmaceutical ingredient.
Polysaccharide gum is selected from the group comprising xanthan gum, gellan gum, locust bean gum, gum caraya, etc. The preferred polysaccharide gum is xanthan gum.
Xanthan gum exhibits a high affinity for water and hydrates rapidly forming a gel layer around the formulation thus minimizing the immediate rapid release of the drug during the initial 60 minutes following administration, which is a characteristic of Hydroxypropylmethylcellulose.
Isosorbide -5- mononitrate and the lipophilic ingredient such as glyceryl behenate are melted together, when the molten drug gets dispersed in the wax phase. The molten wax is cooled, and the isosorbide -5- mononitrate crystalizes
-7-

first due to its high melting point (90°C). The isosorbide -5- mononitrate crystals formed are surrounded by molten wax. On further cooling, this molten wax forms a uniform coating on the isosorbide -5-mononitrate crystals.
The invention provides drug release sustained over a longer period of time of 10 to 24 hours upon oral administration.
Further, as xanthan gum has a faster hydration rate and is highly pseudoplastic and viscoelastic as compared to cellulose, hence, less xanthan gum is required and the dosage form weight and thereby size is kept relatively small with less matrix forming ingredient, making the oral dosage form of the formulation economical and easy to swallow.
The lipophilic ingredient is selected from a fatty acid ester such as glyceryl behenate, hydrogenated castor oil, hydrogenated vegetable oil, wax and cetyl alcohol either alone or in combination with the fatty acid ester.
The preferred carriers are lactose, mannose, etc. The ratio of the active agent to the carrier is in the range of 4:1 to 2:1.
Examples of water soluble active pharmaceutical ingredients are isosorbide -5- mononitrate, isosorbide dinitrate, venlafaxine hydrochloride, propranolol hydrochloride, metformin hydrochloride, diltiazem hydrochloride their combinations and other pharmaceutically acceptable water soluble active ingredients thereof.
-8-

Lubricants such as stearic acid, magnesium stearate, etc may be used.
Colorants such as pigments, lakes, iron oxide, etc may by used.
The formulation thus prepared may be compressed alone as a tablet or may be compressed as bilayered tablet along with a second active ingredient. One of the suitable second active ingredients is Aspirin. Aspirin in the form of "Encapsulated Aspirin"(available under the brand name "Gattaprine" from Gattafosse) may also be used which minimizes the side effect such as gastric irritation associated with Aspirin. It also enhances the stability of Aspirin.
The following examples are included by way of illustration and do not in any way restrict the scope of the invention. EXAMPLES Example 1
Ingredients mg/tablet
isosorbide-5-mononitrate 75 mg
Lactose Premix (4:1)
Compritol 888 ATO (glyceryl behenate) 75 mg
Xanthan Gum 40 mg
Aerosil 5 mg
The ingredients are mixed in a planetary mixer for 30 minutes. Heated to 70 to 100°C and mixed for 30 minutes. The hot mass is cooled and milled to get a particle size of #16 mesh (about 1190 microns).
-9-

This granulate was further blended as follows:
Granulate 195 mg
Xanthan Gum 45 mg
Talc 2 mg
Aerosil 5 mg
Yellow oxide of Iron 0.2 mg
The tablet was compressed at 247.2 mg using 8.7 mm round punches. The hardness may be in the range of 50 to 150 N, preferably between 75 to 110 N.
The in vitro drug release of the tablets was studied by employing standard dissolution techniques in a USP Apparatus (type 1) at 75 rpm with 1000 ml of distilled water at 37.5°C. The results are as follows:
Time(Hour) % Dissolved
1 13.88
2 27.72 4 50.90 8 79.65 10 85.96 12 89.99 15 95.20 24 100.02
The results indicate that the tablets made according to the invention, reduce dose dumping during the initial hour as well as provide drug release over 10 to 15 hours.
The dissolution studies compared the properties of the hot melt blend tablets of the present invention to the isosorbide -5- mononitrate controlled release tablets prepared using Hydroxypropylmethylcellulose as controlled
-10-

release agent.
The isosorbide-5-mononitrate controlled release tablets using Hydroxypropylmethylcellulose as controlled release agent were prepared as per formulation given below :
Ingredients mg/tablets
lsosorbide-5-mononitrate : 75 mg
Lactose premix (4:1)
Lactose 175 mg
Methocel - K4M (Hydroxypropylmethylcellulose K4M) 85 mg
Methocel E15LV (Hydroxypropylmethylcellulose E15LV) 15 mg
Magnesium Stearate 6 mg
Talc 4 mg
The isosorbide - 5 - mononitrate controlled release tablets using hydroxypropylmethylcellulose as controlled release agent were prepred as given below : -1. Sift isosorbide -5- mononitrate, lactose and Methocel K4M (Hydroxypropyl methylcellulose K4M) through # 40 mesh (about 400 microns) and mix in a planetary mixer.
-2. Dissolve Methocel E 15VL (Hydroxypropyl methylcellulose E15LV) in suitable solvent (isopropyl alcohol : methylene chloride 1 : 1) and granulate the powder mix in step 1 with the resulting solution.
-3. Mill the resulting wet mass through 12.6 mm sieves and dry. -4. Size the dried granule to get # 20 mesh (about 841 microns) granules. Lubricate the granules with magnesium stearate and talcum.
-11-

5. Compress the granulate on a rotary tablet compression machine using 10.3 mm round punches at 360 mg/ tablet weight.
The in vitro release profile of the hot melt blend
tablets of the present invention was compared to the
isosorbide -5- mononitrate controlled release tablets
prepared using hydroxypropylmethylcellulose as controlled
release agent (as per formulation given above).
The results are as given below:
Hour Invention HPMC Tablet
1 13.88 31.23
2 27.72 45.32
4 50.90 65.26
8 79.65 89.02
10 85.96 95.12
12 89.99 98.55
15 95.20
24 100.02
From the result it is apparent that the invention
reduces the drug release during the first hour, sustains drug
release upto 24 hours and provides for a smaller size.
Example 2
The granulate from Example 1 may be compressed as a
bilayered tablet with a second active pharmaceutical
ingredient such as Aspirin.
I. Isosorbide - 5- mononitrate fraction:
-12-

Ingredients mg/tablet
Granulate from Example 1 247.2 mg
II Aspirin Fraction
Ingredients mg/tablet
Granular Aspirin/ Encapsulated Aspirin 50.0 mg
Microcrystalline cellulose 13.0 mg
Sodium Starch Glycolate 8.0 mg
Talc 4.0 mg
Colloidal Silicon Dioxide 5.0 mg
All ingredients of the Aspirin fraction are sifted and blended together. Isosorbide -5- mononitrate fraction (Average weight: 247,2 rag) and Aspirin fraction (Average weight: 180.0 mg) are compressed as bilayered tablet using 9.56 mm round punches on a Press Kota cadmach machine.
-13-

WE CLAIM :
1. A controlled release formulation for water soluble drug comprising, a water soluble active pharmaceutical ingredient, a polysaccharide gum, a lipophillic ingredient, and inert carrier and pharmaceutically acceptable excipients, diluents and additives optionally in association with a second active ingredient.. 2. The controlled released formulation as claimed in claim 1, wherein, the percentage range by weight of composition for water soluble active pharmaceutical ingredient is 5 to 50%;polysaccharide gum is 5 to 50% and lilophilic ingredient is 5 to 50 %.
3. The controlled release formulation as claimed in claim 2, wherein the percentage range by weight of composition for the water soluble active pharmaceutical ingredient is 20 to 40%.
4. The controlled release formulation as claimed in claim 2, wherein the percentage range by weight of composition tor the polysaccharide gum is 10 to 40%.
5. The controlled release formulation as claimed in claim2, wherein the
percentage range by weight of composition for the lilophilic ingredient is 10 to
40%.
6. The controlled release formulation as claimed in any of claims 1 and 2,
wherein the preferred active pharmaceutical ingredient is selected from the group
consisting of isosorbide-5-mononitrate, isosorbide dinitrate, venlafaxine
hydrochloride, propranolol hydrochloride, metformin hydrochloride and
diltiazem hydrochloride.
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7. The controlled release formulation as claimed in claims 1 and 2, wherein the polysaccharide gum is selected from the group consisting of xanthan gum, gellan gum, locust bean gum and gum caraya.
8. The controlled release formulation as claimed in any of claims 1 and 2, wherein the lipophilic ingredient is selected from the group consisting of a fatty acid ester, hydrogenated castor oil, hydrogenated vegetable oil, wax or cetyl alcohol either alone or in combination with the fatty acid ester.
9. The controlled release formulation as claimed in any of claims 1 and 2, wherein the lipophilic ingredient is the fatty acid ester glyceryl behenate.
10. A process for the preparation of a controlled release formulation for a water soluble drug comprising,

(a) mixing a water soluble active pharmaceutical ingredient, a lipophilic ingredient and part or all of the polysaccharide gum with diluents;
(b) hot melting of the mixture to form aggregates;
(c) cooling and granulating the aggregates;
(d) blending the granulates with the remaining polysaccharide gum and pharmaceutically acceptable excipients and additives; and
(e) compressing either alone or as a bilayer matrix formulation with a second active pharmaceutical ingredient or as a coated formulation or optionally as caplets, soft chews, gel capsules and microcapsules.
11. A process as claimed in claim 10, wherein the second
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active pharmaceutical ingredient is Aspirin.
12. A controlled release formulation for a water soluble drug substantially as
herein described particularly with reference to the examples.
13. A process for the preparation of a controlled release formulation for a water
soluble drug substantially as herein described particularly with reference to the
examples.
14. The controlled release formulation as claimed in any of the claims 1 to 9, wherein the formulation contains a second active ingredient.
15. The formulation as claimed in claim 14, wherein said second active ingredient is aspirin.
16. The formulation as claimed in claim 15, wherein the said formulation is in
the form of bi-layered tablet.
The present invention discloses a controlled release formulation for a water soluble drug comprising, a water soluble active pharmaceutical ingredient, a polysaccharide gum, a lipophilic ingredient, an inert carrier and pharmaceutically acceptable excipients, diluents and additives.

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Patent Number

207119

Indian Patent Application Number

00097/CAL/2001

PG Journal Number

21/2007

Publication Date

25-May-2007

Grant Date

23-May-2007

Date of Filing

20-Feb-2001

Name of Patentee

TORRENT PHARMACEUTICALS LTD

Applicant Address

CENTRAL PLAZA, 1ST FLOOR , ROOM # 106, 2/56 SARAT BOSE ROAD, CAL-20

Inventors:

#	Inventor's Name	Inventor's Address
1	VYAS SHARAD KUMAR	OF B/31 GOYAL PARK APPART, OPPO.LAD SOCIETY ,VASTRAPUR, AHMEDABAD 380015 GUJRAT INDIA

PCT International Classification Number

A 61 K 9/54

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA