| Title of Invention | TELMISARTAN AND HYDROCHLOROTHIAZIDE COMPOSITION |
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| Abstract | The invention disclosed herein is a solid oral pharmaceutical composition comprising telmisartan or a salt thereof, hydrochlorothiazide, an acidifier, basic agent(s) and pharmaceutically acceptable excipients in a single unit, wherein the composition does not include binder and surfactant. The invention further discloses process for preparation of such solid oral pharmaceutical composition. |
| Full Text | FORM 2 THE PATENTS ACT 1970 (39 of 1970) AND The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION: "TELMISARTAN AND HYDROCHLOROTHIAZIDE COMPOSITION" 2. APPLICANT (S): (a) NAME: FDC Limited (b)NATIONALITY: Indian company incorporated under the Companies Act 1956 (c) ADDRESS: 142-48, S.V. Road, Jogeshwari (West), Mumbai - 400 102, Maharashtra, India. 3. PREAMBLE TO THE DESCRIPTION: The following specification particularly describes the invention and the manner in which it is to be performed. Field of the invention: The present invention is directed to a solid oral pharmaceutical composition comprising of angiotensin II receptor antagonist telmisartan or a salt thereof and thiazide diuretic hydrochlorothiazide. The invention further provides a method of producing such compositions. Background and prior art: Telmisartan is a non-peptide angiotensin II receptor antagonist. Its chemical name is 4'-[2-n-propyl-4-methyl-6-(l-methyLbenzimidazol-2-yl)-benzimida2ol-l-ylmethyl]-biphenyl-2-carboxylic acid. The molecular structure of Telmisartan is represented as: Angiotensin II receptor blockers, which cause blood vessels to relax, has proven to be effective in lowering both systolic and diastolic blood pressure. Telmisartan is a type of angiotensin II receptor blocker that is prescribed for the treatment of high blood pressure. Telmisartan is manufactured and supplied in its free acid form. It is characterized by very poor solubility in aqueous systems at the physiological pH range of the gastro-intestinal tract between pH 1 to 7. Hydrochlorothiazide (HCTZ) is a first-line and widely prescribed diuretic, representative of the benzothiadiazine class sulfonamide derivatives, commonly known as thiazides. The thiazide class acts by inhibiting the kidneys' ability to retain water, which inturn decreases blood return to the heart and cardiac output, and by other mechanisms, is believed to lower peripheral vascular resistance. The chemical name of hydrochlorothiazide is 6-chloro-1,1 -dioxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide. The molecular structure of Hydrochlorothiazide is represented as Hypertension is a multifactorial disease. The increased blood pressure can be reduced in several ways, and one of the commonest ways is by blocking the actions of angiotensin-U. Telmisartan is an angiotensin recentor blocker. The drug, acts by blocking the Angiotensin-Il receptor. Several clinical studies have shown Telmisartan to be safe and effective in the treatment of hypertension. However, over a period of time the controlled blood pressure starts showing 'escape' due to other compensatory mechanisms coming into play. At this point of time the physician has two options-either to increase the dose of antihypertensive or to use the combination. Increasing the dose of any antihypertensive including Telmisartan would lead to increased incidence of adverse effects, morbidity and mortality which would result into treatment failure. Combination of two antihypertensives acting by different mechanisms would obviate the need of increasing the dose, thus achieving blood pressure control using lower doses of the drug. Hydrochlorothiazide is a time tested diuretic. Clinical experience has shown hydrochlorothiazide to be highly effective in the treatment of hypertension. Both Telmisartan and Hydrochlorothiazide reduce blood pressure by different mechanisms. Several clinical trials have shown benefit of combination of Telmisartan and Hydrochlorothiazide. Telmisartan and hydrochlorothiazide combination has complementary mechanism like reduction of peripheral resistance with angiotensin receptor blocker (ARB) and reduction of fluid volume with diuretics. ARB counteracts reactive increase in blood pressure related to diuretic induced rennin secretion; and ameliorates diuretic induced potassium depletion. This combination is well tolerated and has fewer metabolic disturbances. WO2003059327 describes bilayer pharmaceutical tablet comprising first layer formulated for immediate release of telmisartan from a dissolving tablet matrix which contains telmisartan in substantially amorphous form and a second layer formulated for immediate release of a diuretic hydrochlorothiazide from a fast disintegrating tablet matrix. However, tablets with fast disintegrating matrix tend to be hygroscopic and therefore, need to be packaged using moisture proof packaging materials. CN101134032 describes compounded tablets for treating hypertension, which is composed of core layer and outer layer. The outer layer comprises (wt. parts): telmisartan (5-15), filler (18-50), pH regulator (0.5-5), surfactant (2-12), adhesive (3.5-10) and lubricant (1-3). The core layer comprises (wt. parts): diuretic (15-20), filler (15-20), disintegrant (1-3), adhesive (1-3), lubricant (0.5-2) and coating (0.3-1). WO2009/115301 discloses the combination therapy of a non-peptide angiotensin II receptor antagonist such as telmisartan or a pharmaceutically acceptable salt thereof with a diuretic such as HCTZ. US20090202636 discloses a formulation of telmisartan and hydrochlorothiazide having both substances in separate units. Both the units are either compressed into tablets or filled in capsules. The said US application also discloses the first telmisartan unit consisting of granules, pellets and tablets, to which coating of hydrochlorothiazide with appropriate polymer is applied. Indian Patent Application No. 1928/DELNP/2004 discloses bilayer pharmaceutical tablet comprising a first layer for immediate release of the angiotensin II receptor antagonist (Telmisartan) from a dissolving tablet matrix which contains telmisartan in substantially amorphous form, and a second layer formulated for immediate release of a diuretic like Hydrochlorothiazide from a fast disintegrating tablet matrix. A method of producing the bilayer tablet is also disclosed. Indian Patent Application No. 4579/DELNP/2007 relates to a pharmaceutical composition for the treatment of hypertension comprising as active ingredients about 80 mg of the angiotensin II receptor antagonist telmisartan and about 25 mg of the diuretic hydrochlorothiazide and the method of manufacture of the said bilayer tablet. It is known from the literature that telmisartan has very poor aqueous solubility in the physiological pH range of the gastrointestinal tract between pH I and 7; and is soluble in strong base. On the other hand, hydrochlorothiazide degrades in alkaline conditions. It is advantageous to administer both telmisartan and hydrochlorothiazide to treat hypertension, either concomitantly or even better to administer a composition comprising both. Difficulty results from the fact that both active substances need to be released from the composition simultaneously. In the aforementioned prior arts, it is provided that the formulation of telmisartan and hydrochlorothiazide is either in bilayer or in two separate units to keep the two APIs well separated from each other, to prevent degradation of hydrochlorothiazide. The prior arts processes require either complex processes like separate granulation of the two drugs or coating of one drug over the core of other, or a process of preparing bilayer tablets, which need to have special machine and critical control of process parameters. Hence, the aforementioned prior arts suffer from one or more drawbacks. It was surprisingly found in the present invention that formulation of telmisartan and hydrochlorothiazide can be prepared in a single unit or a single layer tablet by simple and cost effective process which will overcome the drawbacks of the aforementioned prior arts. Thus, the present invention provides a solid oral pharmaceutical composition of telmisartan or a salt thereof and hydrochlorothiazide, having good disintegration and dissolution properties which would further provide rapid and complete drug release. Object of the invention: The main objective of the present invention is to provide composition comprising telmisartan or a salt thereof and hydrochlorothiazide, free of binder and surfactant. Another objective of the present invention is to provide a solid oral pharmaceutical composition of telmisartan or a salt thereof and hydrochlorothiazide, having good disintegration and dissolution properties which would further provide rapid and complete drug release. Yet another objective of the invention is to provide a process for preparing solid oral pharmaceutical composition of Telmisartan or a salt thereof and hydrochlorothiazide in a single unit using simple granulation process, thereby offering cost effective technology. Summary of the invention: In accordance with the above objectives, the present invention is directed to a solid oral pharmaceutical composition of Telmisartan or a salt thereof and hydrochlorothiazide, without the use of binder and surfactant, and yet having good disintegration and dissolution properties. The present invention further provides a solid oral pharmaceutical composition comprising telmisartan or a salt thereof, hydrochlorothiazide, an acidifier, basic agent (s) and pharmaceutically acceptable excipients. The present invention also provides process for manufacturing such composition, wherein both the drugs are in a single unit. Brief Description of Drawings: Fig. 1: Graph depicting dissolution profile of Example 1 in pH 7.5 Phosphate buffer, 900 ml, 75 rpm, paddle. Fig. 2: Graph depicting dissolution profile of Example 2 in pH 7.5 Phosphate buffer, 900 ml, 75 rpm, paddle. Detailed description of the invention: The invention will now be described in detail so that various aspects thereof may be more fully understood and appreciated. The present invention provides a solid oral pharmaceutical composition comprising telmisartan or a salt thereof hydrochlorothiazide, an acidifier, basic agent(s) and pharmaceutically acceptable excipients in a single unit, wherein the composition does not include binder and surfactant. The said composition has good disintegration and dissolution properties, and gives faster drug release from the dosage form. Telmisartan is an angiotensin-II receptor blocker that has demonstrated efficacy in the reduction of blood pressure in patients with hypertension. Telmisartan is a white to slightly yellowish, odorless crystalline powder. It is practically insoluble in water and in the pH range of 1 to 7. Telmisartan is soluble in a strong base. The amount of Telmisartan in the formulation is 9% to 15% by weight of total formulation. A basic agent is added to the pharmaceutical composition of the present invention to solublize Telmisartan and use of this solution for granulation in the manufacturing process is disclosed. Basic agent used in the formulation is selected from group consisting of but not limited to alkali metal hydroxides, alkaline hydroxide, alkaline phosphates, alkaline carbonates, meglumine, veegum and basic amino acids such as arginine. The amount of basic agent used in the formulation is 3.5% to 9.0% by weight of the total formulation. Hydrochlorothiazide is first line diuretic drug of the thiazide class that acts by inhibiting the kidneys ability to retain water. Hydrochlorothiazide is used in combination with many drugs for oral administration in the treatment of edema and hypertension. Hydrochlorothiazide is a white powder which is slightly soluble in water, but freely soluble in strong alkali. The amount of hydrochlorothiazide used in the formulation is 1.5% to 5.0% by weight of total formulation. The basic agents used to dissolve Telmisartan, increase the overall pH of the composition; however, at high pH hydrochlorothiazide degrades. The acidifier helps in protecting hydrochlorothiazide from getting degraded In preferred embodiment the present invention provides a solid oral pharmaceutical composition comprising telmisartan or a salt thereof and hydrochlorothiazide in a single layer tablet dosage form wherein an acidifier is use to prevent degradation of Hydrochlorothiazide within the composition, thus providing stability to the composition. The acidifier used in the formulation is selected from a group consisting of but not limited to phosphates such as monobasic sodium phosphate and monobasic potassium phosphate preferably monobasic sodium phosphate. Total acidifier used in the composition is 0.5% to 10% by weight of total formulation. The compositions of the present invention further comprise excipients such as diluent, disintegrants, lubricants and optionally colorants. The term 'Diluent(s)' herein below refers to water-soluble and water insluble diluents. Suitable water soluble diluent used in the pharmaceutical composition of the present invention is selected from a group consisting of sugars including lactose, sucrose, glucose, lactulose and dextrose and polyols including mannitol, xylitol, erythritol, dulcitol, ribitol, lactitol and sorbitol, and is in the range of less than 25% weight of the total composition. Suitable water insoluble diluent is selected from group consisting of but not limited to cellulose or cellulose derivatives such as microcrystalline cellulose, powdered cellulose, pregelatinized starch, starch, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium oxide and magnesium carbonate in the range of about 25% to 75% of the total weight of the composition. The disintegrant is at least one component selected from group consisting of but not limited to croscarmellose sodium, crospovidone, pregelatinized starch, sodium starch glycolate, powdered cellulose and starch, in the range of about 0.5% to 40% of the total weight of the composition. The lubricant is at least one component selected from a group consisting of magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearte, stearic acid, talc, zinc stearate, hydrogenated vegetable oil, glyceryl behenate, sodium stearyl fumarate and colloidal silicon dioxide, in the range of about 0.1% to 5% of the total weight of the composition. The pharmaceutical composition of the invention containing combination of Telmisartan or a salt thereof and hydrochlorothiazide is in conventional pharmaceutical dosages. According to the present invention the oral solid formulation of Telmisartan is prepared by simple granulation method. In another embodiment, the invention provides the process for manufacturing pharmaceutical compositions of the present invention which comprises the following steps: 1. dissolving telmisartan in aqueous solution of basic agent(s); 2. sifting hydrochlorothiazide, acidifier, diluent(s), disintegrants, and granulating this dry mix using drug solution in step 1; 3. drying the wet mass of step 2, sizing the dried granules; 4. sifting disintegrant, optionally a diluent and mixing with dried granules in step 3; and 5. sifting lubricant(s) and blending with the blend in step 4 to make it ready for compression. The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention. Examples: Example 1 Sr. No. Ingredients mg/tablet Dry mix 1 Hydrochlorothiazide 25.0 2 Mannitol 112.0 3 Microcrystalline cellulose 281.0 4 Crospovidone 70.0 5 Monobasic sodium phosphate 27.0 Granulating solution 6 Telmisartan 80.0 7 Meglumine 24.0 8 Sodium hydroxide 6.0 9 Purified water q.s. Extragranular ingredients 10 Crospovidone 50.0 11 Magnesium Stearate 5.0 Total 680.0 Brief manufacturing procedure: Telmisartan is dissolved in aqueous solution of sodium hydroxide and meglumine. Hydrochlorothiazide, monobasic sodium phosphate monohydrate, mannitol, microcrystalline cellulose and crospovidone are sifted through sieve no. 30 (ASTM) and the resulting dry mix is granulated using the telmisartan drug solution. The wet mass is dried and the dried granules are sifted through Sieve No. 25 ASTM. Crospovidone is sifted through sieve No. 30 ASTM and blended with the dried granuIes.Lubrication of blend is done with magnesium stearate previously sifted through sieve No. 40 ASTM. The tablets are compressed using suitable punches. Graph depicting dissolution profile of Example 1 in pH 7.5 Phosphate buffer, 900 ml, 75 rpm, paddle is shown in fig. 1 Example 2 Sr. No. Ingredients mg/tablet Dry mix 1 Hydrochlorothiazide 25.0 2 Mannitol 112.0 3 Microcrystalline cellulose 231.0 4 Crospovidone 70.0 5 Monobasic sodium phosphate 27.0 Granulating solution 6 Telmisartan 80.0 7 Meglumine 24.0 8 Sodium hydroxide 6.0 9 Purified water q.s. Extragranular ingredients 10 Crospovidone 50.0 Microcrystalline cellulose 50.0 11 Magnesium Stearate 5.0 Total 680.0 Brief manufacturing procedure: Telmisartan is dissolved in aqueous solution of sodium hydroxide and meglumine. Hydrochlorothiazide, monobasic sodium phosphate monohydrate, mannitol, microcrystailine cellulose and crospovidone are sifted through sieve no. 30 (ASTM) and the resulting dry mix is granulated using the telmisartan drug solution. The wet mass is dried and the dried granules are sifted through Sieve No. 25 ASTM. Crospovidone and microcrystailine cellulose are sifted through sieve No. 30 ASTM and blended with the dried granules. Lubrication of blend is done with magnesium stearate previously sifted through sieve No. 40 ASTM. The Tablets are compressed using suitable punches. Graph depicting dissolution profile of Example 2 in pH 7.5 Phosphate buffer, 900 ml, 75 rpm, paddle is shown in Fig. 2 Example 3 Sr. No. Ingredients mg/tablet Dry mix 1 Hydrochlorothiazide 25.0 2 Mannitol 112.0 3 Microcrystailine cellulose 257.0 4 Crospovidone 70.0 5 Monobasic sodium phosphate 27.0 Granulating solution 6 Telmisartan 80.0 7 Magnesium aluminum silicate 48.0 8 Sodium hydroxide 6.0 9 Purified water q.s. Extragranular ingredients 10 Crospovidone 50.0 11 Magnesium Stearate 5.0 Total 680.0 Brief manufacturing procedure: Telmisartan is dissolved in aqueous solution of sodium hydroxide and Magnesium aluminum silicate. Hydrochlorothiazide, monobasic sodium phosphate monohydrate, mannitol, microcrystailine cellulose and crospovidone are sifted through sieve no. 30 (ASTM) and the resulting dry mix is granulated using the telmisartan drug solution. The wet mass is dried and the dried granules are sifted through Sieve No. 25 ASTM. Crospovidone and microcrystalline cellulose are sifted through sieve No. 30 ASTM and blended with the dried granules. Lubrication of blend is done with magnesium stearate previously sifted through sieve No. 40 ASTM. The Tablets are compressed using suitable punches. We claim: 1. A solid oral pharmaceutical composition comprising telmisartan or a salt thereof, hydrochlorothiazide, an acidifier, basic agent(s) and pharmaceutically acceptable excipients in a single unit, wherein the composition does not include binder and surfactant. 2. The solid oral pharmaceutical composition as claimed in claim 1, wherein the amount of Telmisartan in the formulation is 9% to 15% by weight of total formulation. 3. The solid oral pharmaceutical composition as claimed in claim 1, wherein the amount of hydrochlorothiazide used in the formulation is 1.5% to 5.0% by weight of total formulation. 4. The solid oral pharmaceutical composition as claimed in claim 1, wherein the basic agent is selected from a group consisting of alkali metal hydroxides, alkaline hydroxide, alkaline phosphates, alkaline carbonates, meglumine, veegum or basic amino acids including arginine, in the range of 3.5% to 9.0% by weight of the total formulation. 5. The solid oral pharmaceutical composition as claimed in claim I, wherein the acidifier used in the formulation is selected from a group consisting of phosphates including monobasic sodium phosphate or monobasic potassium phosphate, in the range of 0.5% to 10% by weight of total formulation. 6. The solid oral pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected from diluent, disintegrants, lubricants or colorants. 7. The solid oral pharmaceutical composition as claimed in claim 1, wherein the diluent(s) is water-soluble and/or water-insoluble diluents. 8. The solid oral pharmaceutical composition as claimed in claim 7, wherein the water soluble diluent is selected from a group consisting of sugars including lactose, sucrose, glucose, lactulose and dextrose and polyols including mannitol, xylitol, erythritol, dulcitol, ribitol, lactitol and sorbitol, and is in the range of less than 25% weight of the total composition. 9. The solid oral pharmaceutical composition as claimed in claim 7, wherein the water insoluble diluent is selected from a group consisting of cellulose or cellulose derivatives such as microcrystalline cellulose, powdered cellulose, pregelatinized starch, starch, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium oxide and magnesium carbonate, in the range of about 25% to 75% of the total weight of the composition. 10. The process for preparation of the pharmaceutical composition as claimed in claim I comprising the following steps: 1. dissolving telm isartan in aqueous solution of basic agent(s); 2. sifting hydrochlorothiazide, acidifier, diluent(s), disintegrants, and granulating the dry mix using drug solution in step 1; 3. drying the wet mass of step 2, sizing the dried granules; 4. sifting disintegrant, optionally a diluent and mixing with dried granules in step 3; and 5. sifting lubricant(s) and blending with the blend in step 4 to make it ready for compression. |
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| Patent Number | 279229 | ||||||||||||
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| Indian Patent Application Number | 1861/MUM/2010 | ||||||||||||
| PG Journal Number | 03/2017 | ||||||||||||
| Publication Date | 20-Jan-2017 | ||||||||||||
| Grant Date | 16-Jan-2017 | ||||||||||||
| Date of Filing | 23-Jun-2010 | ||||||||||||
| Name of Patentee | FDC LIMITED | ||||||||||||
| Applicant Address | 142-48, S.V. ROAD, JOGESHWARI (W), MUMBAI - 400 102, MAHARASHTRA, INDIA. | ||||||||||||
Inventors:
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| PCT International Classification Number | A61K31/4184 | ||||||||||||
| PCT International Application Number | N/A | ||||||||||||
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