WO2010146551A2

WO2010146551A2 - Orally disintegrating compositions comprising antihypertensive agents

Info

Publication number: WO2010146551A2
Application number: PCT/IB2010/052718
Authority: WO
Inventors: Sumit Madan; Venkateshwaran Rathinasabapathy; Vinod Kumar Arora
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2009-06-16
Filing date: 2010-06-16
Publication date: 2010-12-23
Also published as: WO2010146551A3

Abstract

The present invention relates to orally disintegrating compositions comprising angiotensin II receptor antagonists. It also relates to orally disintegrating compositions comprising combination of angiotensin II receptor antagonists and other antihypertensive drugs. It further relates to processes for preparing such compositions. It also relates to method of treating hypertension and congestive heart failure using the compositions of the present invention.

Description

ORALLY DISINTEGRATING COMPOSITIONS COMPRISING ANTIHYPERTENSIVE AGENTS

Field of the Invention

The present invention relates to orally disintegrating compositions comprising angiotensin II receptor antagonists. It also relates to orally disintegrating compositions comprising combination of angiotensin II receptor antagonists and other antihypertensive drugs. It further relates to processes for preparing such compositions. It also relates to method of treating hypertension and congestive heart failure using the compositions of the present invention. Background of the Invention

Hypertensive crisis is one of the most important clinical concerns in patients with hypertension and comprises a spectrum of conditions; hypertensive urgency is a sudden and severe increase in blood pressure with mild or no acute damage to vital target organs including the heart, kidney, eye and brain. If this critical increase in blood pressure is accompanied by damage to vital organs, it is called hypertensive emergency.

Hypertensive emergency is severe hypertension with acute impairment of an organ system (especially the central nervous system, cardiovascular system and/or the renal system) and the possibility of irreversible organ-damage. In case of a hypertensive emergency, the blood pressure should be lowered aggressively over minutes to hours with intravenous medication.

Management of a hypertensive emergency requires administration of parenteral antihypertensive agents. Patients need to be shifted into an intensive care unit and presence of a registered medical practitioner is required for administering the injection. But in many cases parenteral antihypertensives are not readily available and it may take time to shift the patient to a medical facility.

In patients with hypertensive urgency, blood pressure is lowered gradually, usually with oral or sublingual medications that possess a rapid onset of action with few side effects. Mean arterial pressure should be reduced by no more than 25% within the first 24 hours using conventional oral therapy. Therefore there is a need for an oral dosage form which is readily available and provides immediate relief in case of a hypertensive crisis.

Early angiotensin II receptor antagonists to be developed included peptide analogues like sarlasin, but poor oral bioavailability of these peptide analogues lead to the development of non-peptide angiotensin receptor antagonists. These are more commonly known as "ARBs", i.e., "Angiotensin Receptor Blockers". Drugs in this class include losartan, irbesartan, candesartan, olmesartan, valsartan, telmisartan, and eprosartan.

Presently non-peptide angiotensin II receptor antagonists (or ARBs) as well as their combinations with other antihypertensive agents are marketed as immediate release tablets. For example, losartan, the first non-peptide angiotensin II antagonist to be developed, is being marketed as immediate release tablet under the brand name COZAAR^® and its combination with hydrochlorothiazide is marketed under the brand name HYZAAR^® by Merck. Candesartan is marketed under the brand name ATACAND^® by Astra-Zeneca, eprosartan is marketed as TEVETEN^® by Abbott, irbesartan is marketed as AVAPRO^® by Sanofi Aventis, olmesartan is available as immediate release tablets under the brand name BENICAR^® marketed by Daiichi-Sankyo, telmisartan is marketed as MICARDIS^® by Boehringer Ingelheim and valsartan is marketed as DIOV AN^® by Novartis.

ARBs have outcome data in patients with hypertension showing long-term reduction in progression of target-organ damage. These agents have also been found to exhibit the lowest incidence of side-effects when compared to other antihypertensives. Further, their effects have been found to be superior to other antihypertensives in patients with type-2 diabetic nephropathy. These agents reduce the rate of stroke in hypertensive patients better than the other classes and are effective in patients with congestive heart failure.

Based on their efficacy in controlling hypertension and their wider health benefits, together with minimal side effects, ARBs are now considered as first-line agents for the treatment of hypertension, particularly in patients with other cardiovascular risk factors. These are effective in lower doses and once daily administration provides the blood pressure control for 24 hours. Therefore, administration of ARBs in orally disintegrating forms is advantageous in the hypertensive crisis, wherein the ARBs will bring about reduction in the blood pressure without causing damage to the vital organs.

Oral administration in the form of a conventional tablet, pill or capsule constitutes a preferred route of administration. But such compositions are associated with certain disadvantages, particularly in the treatment of patients having dysphagia, i.e., who have difficulty in swallowing, thereby leading to patient incompliance.

In these patients liquid dosage forms like suspensions and solutions are generally preferred to improve the patient compliance. But these dosage forms have other drawbacks like certain suspensions have to be reconstituted prior to administration and, sometimes, stored under refrigerated conditions to prevent them from deterioration. Liquid dosage forms are also inconvenient to carry while travelling and also involve the risk of inaccurate measurement and dosing.

Orally disintegrating compositions offer all the advantages of the liquid dosage forms in addition to convenience of handling as that of solid dosage forms. These compositions disperse readily when placed on tongue to form a suspension or solution of the drug after mixing with the saliva, which is easily swallowed by the patients. Further, these compositions do not require water to disperse before taking. Therefore, these constitute a preferred dosage form for administration to patients who have difficulty in swallowing solid oral dosage forms like tablets and capsules and can have restricted water intake.

Orally disintegrating compositions of angiotensin II receptor antagonists are useful not only in those patients who have difficulty in using conventional dosage forms but also treating hypertension in the pediatric and geriatric patients as well. Moreover, these dosage forms exhibit ease or convenience as these are free from spillage, breakage, difficulty of carrying around, etc.

Different types of technologies have been applied for preparing orally disintegrating tablets in prior art for example freeze-drying, spray drying, and sublimation. ZYDIS^® is the first orally disintegrating dosage form marketed by Cardinal Healthcare markets. It is a unique freeze-dried tablet having an oral dissolution time of 2 to 5 seconds. U.S. Patent Nos. 4,642,903; 5,188,825; 5,631,023; 5,827,541 and 5,976,577 describe this technology. Cima labs markets ORASOLV^® (U.S. Patent No. 5,178,878) and DURASOL V^®

(U.S. Patent Nos. 6,221,392 and 6,024,981) where ORASOLV^® is an effervescent direct compression tablet, that disperses in mouth's saliva with the aid of almost hardly noticeable effervescence and dissolves in less than one minute, leaving the coated drug powder. The unpleasant flavor of the drug is addressed by coating of the drug powder and effervescence. The major disadvantage of ORASOLV^® is its mechanical strength due to light compression. DURASOLV^® is a recently introduced direct compression tablet having higher mechanical strength than ORASOLV^® due to the use of higher compaction pressures during tabletting.

U.S. Patent Nos. 4,855,326; 5,587,172; 5,622,719; 5,866,163 and 5,869,098 assigned to Fuisz use a precision-engineered, rapidly spinning machine to convert a unique mixture of a spinnable carrier agent such as sugar and other processing aids into candy floss. U. S. Patent No. 5,576,014 describes a fluidized-bed granulation technology for WOWTAB^® quick-dissolving, without water tablets.

Spray drying technique described in U. S. Patent Nos. 5,587,180; 5,595,761, 5,635,210 and 5,807,576 is another technique used to prepare fast dissolving tablets.

Processes employed for preparing orally disintegrating tablets in prior art involve costly and time consuming manufacturing operations. Therefore, a need exists for a cost effective, rapid operation process for producing orally disintegrating compositions comprising angiotensin II antagonists, which provide for ease of oral administration. The present inventors have prepared orally disintegrating compositions of angiotensin II antagonists having more stability and lesser friability using simpler and cost effective manufacturing processes.

Summary of the Invention

The present invention relates to orally disintegrating compositions of angiotensin II receptor antagonists and processes for preparing such compositions. One of the aspects of the present invention relates to orally disintegrating compositions comprising a angiotensin II receptor antagonists or pharmaceutically acceptable salts or esters thereof.

According to one of the embodiments angiotensin II receptor antagonists include losartan, irbesartan, candesartan, olmesartan, valsartan, telmisartan, eprosartan or pharmaceutically acceptable salts or esters thereof.

Another aspect of the present invention relates to orally disintegrating compositions comprising a combination of a angiotensin II receptor antagonists and another antihypertensive drug. According to one of the embodiments another antihypertensive drug includes thiazide diuretics, β-blockers, calcium channel blockers, rennin inhibitor, and ACE inhibitors.

According to another aspect the orally dispersible compositions of the present invention are in the form of tablets, wafers, granules, pills, lozenges or sachets. Most particularly the compositions of the present invention are in the form of tablets.

According to yet another aspect the orally dispersible compositions of the present invention comprise one or more pharmaceutically acceptable excipients selected from the group comprising of diluents, binders, disintegrants, surfactants, lubricants, glidants, sweeteners colors or flavors. Yet another aspect of the present invention relates to the processes of preparing orally dispersible compositions comprising a angiotensin II receptor antagonists.

According to one of the embodiments the orally dispersible compositions of the present invention are prepared by wet granulation, dry granulation or direct compression. Most particularly the compositions of the present invention are prepared by direct compression.

Another aspect of the present invention relates to a method of treating hypertension, hypertensive crisis and congestive heart failure using orally disintegrating compositions comprising angiotensin II receptor antagonists. According to yet another aspect the present invention relates to a method of treating hypertension, hypertensive crisis and congestive heart failure using orally disintegrating compositions comprising a combination of angiotensin II receptor antagonists and another antihypertensive drug. Detailed Description of the Invention

The present invention is directed to orally disintegrating compositions comprising angiotensin II receptor antagonists and processes for preparing such compositions.

The term "orally disintegrating" as used herein refers to the composition, which when placed in the mouth disperse within about 60 seconds or less, preferably within about 30 seconds or less.

The phrase "pharmaceutically-acceptable salts or esters thereof as used herein include salts of ARBs with mineral or organic acids which permit separation or suitable crystallization of the compounds such as trifluoroacetic acid, picric acid, oxalic acid or an optically active acid, for example a mandelic acid or a camphosulfonic acid, and acids which form pharmaceutically acceptable salts such as the hydrochloride, the hydrobromide, the sulfate, the hydrogensulfate, the dihydrogenphosphate, the methanesulfonate, the methylsulfate, the maleate, the fumarate and the naphthalene-2- sulfonate.

These also include the salts with organic or mineral bases, for example, the salts of alkali or alkaline earth metals, such as the sodium, potassium and calcium salts, the sodium and potassium salts being preferred, or with a tertiary amine such as trometamol, or else the salts of arginine, lysine or any physiologically acceptable amine. Preferred ester residues for forming pharmaceutically acceptable esters include pivaloyloxy methyl, ethoxy carbonyloxymethyl, 1 -(ethoxycarbonyloxy)ethyl, isopropoxycarbonyloxymethyl, (l-isopropoxycarbonyloxy)ethyl, (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl and phthalidyl groups.

Angiotensin II is an oligopeptide that causes vasoconstriction and increased blood pressure. Angiotensin II receptor antagonists work by antagonizing the activation of angiotensin receptors by angiotensin II and constitute one of the most important class of drugs for the treatment of high blood pressure. According to one of the embodiments orally disintegrating compositions of the present invention comprise angiotensin II receptor antagonists, for example, losartan, irbesartan, candesartan, olmesartan, valsartan, telmisartan, or eprosartan.

Further the orally disintegrating compositions of the present invention comprise a angiotensin II receptor antagonist in combination with another antihypertensive drug, for example, thiazide diuretics, β-blockers, calcium channel blockers, rennin inhibitor, and ACE inhibitors.

According to another embodiment orally disintegrating compositions of the present invention comprise drug particles having do.s between 1 μm to 200 μm. Particularly it comprises drug particles having do.s between 2 μm to 100 μm.

Orally disintegrating compositions of the present invention further comprise a composite of a water soluble and water-swellable or water-insoluble excipient in a ratio of 1 :50 to 50: 1. More particularly in a ratio of 1 :20 to 20: 1.

The water-soluble excipients include water-soluble carbohydrates, salt or a polyhydric alcohol or its derivative. The water-soluble carbohydrates can be a monosaccharide, disaccharide, oligosaccharide or polysaccharide. Examples include, but are not limited to, monosaccharides such as glyceraldehyde, erythrose, threose, ribose, arabinose, xylose, allose, altrose, glucose, mannose, fructose, gulose, idose, galactose, talose and sorbitol; disaccharides such as maltose, lactose, cellobiose, sucrose, mannitol and trehalose; oligosaccharides such as raffϊnose, stachyose, and dextrates; or polysaccharides such as maltodextrins, starch, glycogen, cellulose, chitin, callose, galactomannan, xylan and laminarin.

The water swellable or water insoluble excipients include, but are not limited to, inorganic salts such as calcium silicate-ortho, meta and alpha triclinic forms thereof, magnesium trisilicate -ortho and meta forms thereof or light anhydrous silicic acid, mica, synthetic aluminum silicate, silicon dioxide, magnesium aluminum silicate, magnesium metasilicate aluminate, celluloses such as microcrystalline cellulose, crystalline cellulose, cellulose derivatives, vinylpyrolidone derivatives, colloidal silicon dioxide, etc. Orally disintegrating compositions of the present invention further comprise one or more pharmaceutically acceptable excipients selected from the group comprising of diluents, binders, disintegrants, surfactants, lubricants, glidants, sweeteners colors or flavors. Suitable diluents include those excipients, which facilitate compression and provide strength. These may be selected from the group comprising of lactose, starch, sugar alcohols such as mannitol, sucrose, sorbitol, xylitol, lactitol, erythritol or maltitol, hydroxylpropyl cellulose, microcrystalline cellulose, calcium carbonate, dicalcium phosphate and mixtures thereof. Examples of disintegrants include sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinized starch, starch and starch derivatives, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, swellable clays, smectite, attapulgite, montmorillonite, bentonite, magnesium aluminium silicate and combinations thereof. Disintegrants may constitute from 1 % to 15% w/w of the tablet.

Surfactants/wetting agents include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical compositions. These include polyethoxylated fatty acid esters, polyethylene glycol fatty acid esters, alcohol-oil transesterification products, polyglycerized fatty acids, polyethylene glycol sorbitan fatty acid esters, sugar esters, polyoxyethylene-polyoxypropylene block copolymers, ionic surfactants, derivatives of fat soluble vitamins, and mixtures thereof. Suitable examples include sodium lauryl sulphate, sodium dodecyl sulphate, polyoxyethylene castor oil derivatives, for example, Tweens, polyoxyethylene-polyoxypropylene block copolymers, for example, Poloxamer, or mixtures thereof.

Suitable examples of binding agents include, either individually or in combination, acacia; tragacanth; sucrose; gelatin; glucose; starch; cellulose materials such as, methylcellulose and sodium carboxymethylcellulose {e.g., TYLOSE^®); alginic acid and salts of alginic acid; magnesium aluminum silicate; polyethylene glycol; guar gum; polysaccharide acids; bentonites; polyvinylpyrrolidone; polymethacrylates; hydroxypropylmethylcellulose (HPMC); hydroxypropylcellulose (KLUCEL^®); ethylcellulose (ETHOCEL^®); pregelatinized starch (such as National 1511 and Starch 1500).

Suitable lubricants and/or glidants include, either individually or in combination, glyceryl behapate (COMPRITOL^® 888); stearates (magnesium, calcium, and sodium); stearic acid; hydrogenated vegetable oils (e.g., STEROTEX^®); talc; waxes: Stear-O-Wet; boric acid; sodium benzoate; sodium acetate; sodium fiimarate; sodium chloride; DL- leucine; polyethylene glycols (e.g., CARBO WAX^® 4000 and 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. Magnesium stearate is a preferred lubricant being used in the compositions of the present invention. The coloring agents and flavoring agents of the present invention may be selected from any FDA approved colors and flavors for oral use.

Suitable sweetening agents may be selected from a wide range of materials such as water soluble sweetening agents, water-soluble artificial sweeteners, dipeptide based sweetening agents and mixtures thereof. Water soluble sweetening agents include monosaccharides, disaccharides and polysaccharides, such as xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, corn syrup and sugar alcohols such as sorbitol, mannitol, xylitol, and mixtures thereof.

Water soluble artificial sweetening agents include free acid form of saccharine and its soluble salts such as sodium or calcium saccharine salts, cyclamate salts, acesulfame, aspartame and mixtures thereof.

According to another embodiment orally disintegrating compositions of the present invention are in the form of tablets, wafers, granules, pills, or lozenges.

The orally disintegrating compositions of the present invention may be prepared by using the conventional techniques for example either by direct compression, or first slugging some of the ingredients, milling the slugs, blending with the remaining ingredients and then compressing as appropriate. These compositions may also be prepared using wet granulation techniques. According to another embodiment the orally disintegrating compositions of the present invention may comprise low dose of angiotensin II receptor antagonist than that used in the conventional dosage form.

The present invention further relates to a method of treating hypertension, hypertensive crisis and congestive heart failure using the orally disintegrating compositions of the present invention.

Further the compositions of the present invention may also be used to treat other disorders associated with increased levels of angiotensin in the human body for example prophylaxis or treatment of diseases like intraocular angiogenic disorder, bone metabolic disorder, diabetic complication, vascular inflammation, prostatic hypertrophy, myocardial infarction and neuropathic conditions.

The following examples represent various embodiments according to the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

EXAMPLE 1

Orally disintegrating tablet containing olmesartan medoxomil

Process

1. Olmesartan medoxomil, croscarmellose sodium, aspartame, microcrystalline cellulose and flavour were mixed geometrically and sifted through a sieve.

2. Equivalent quantity of mannitol was mixed with the blend of step 1 and passed through a sieve. 3. Remaining quantity of mannitol along with the blend of step 2 was sifted through a sieve.

4. Blend of step 3 was mixed thoroughly in a blender.

5. Then magnesium stearate was sifted through a sieve and mixed with the blend of step 4.

6. Finally blend of step 5 was compressed into a tablet.

EXAMPLE 2 Orally disintegrating tablet containing losartan potassium

Process

1. Losartan potassium, croscarmellose sodium, aspartame, microcrystalline cellulose, sodium chloride and mango flavour were mixed geometrically and sifted through a sieve.

2. Equivalent quantity of mannitol was mixed with the blend of step 1 and passed through a sieve.

3. Remaining quantity of mannitol along with the blend of step 2 was sifted through a sieve.

4. Blend of step 3 was mixed thoroughly in a blender.

5. Then magnesium stearate was sifted through a sieve and mixed with the blend of step 4. 6. Finally blend of step 5 was compressed into a tablet.

EXAMPLES 3, 4, and 5

Orally disintegrating tablet containing candesartan cilexetil

Process

1. Candesartan cilexetil, crospovidone, aspartame, starch and ferric oxide were mixed geometrically and sifted through a sieve. 2. Equivalent quantity of mannitol was mixed with the blend of step 1 and passed through a sieve.

4. Blend of step 3 was mixed thoroughly in a rapid mixer granulator. 5. Polyethylene glycol 4000 was dissolved in purified water.

6. Blend of step 4 was granulated using the solution of step 5.

7. Granules of step 6 were dried and passed through a sieve. 8. Extragranular mannitol, crospovidone, flavour, aspartame and colloidal anhydrous silica were sifted and mixed with granules of step 7.

9. Then magnesium stearate was sifted through a sieve and mixed with the blend of step 8. 10. Finally blend of step 9 was compressed into a tablet.

While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention. Accordingly, it is not intended that the invention be limited, except as by the appended claims.

Claims

Claims: 1. An orally disintegrating composition comprising angiotensin II receptor antagonist or pharmaceutically acceptable salt or ester thereof.

2. The orally disintegrating composition of claim 1 wherein the angiotensin II receptor antagonist is selected from the group losartan, irbesartan, candesartan, olmesartan, valsartan, telmisartan, eprosartan or pharmaceutically acceptable salts or esters thereof.

3. The orally disintegrating composition of claim 1 further comprising one or more pharmaceutically acceptable excipients selected from the group comprising diluents, binders, disintegrants, surfactants, lubricants, glidants, sweeteners colors or flavors.

4. The orally disintegrating composition of claim 3 wherein the diluents are selected from the group comprising lactose, starch, sugar alcohols such as mannitol, sucrose, sorbitol, xylitol, lactitol, erythritol or maltitol, hydroxylpropyl cellulose, microcrystalline cellulose, calcium carbonate, dicalcium phosphate and mixtures thereof.

5. The orally disintegrating composition of claim 3 wherein the binders are selected from the group comprising acacia; tragacanth; sucrose; gelatin; glucose; starch; cellulose materials such as, methylcellulose and sodium carboxymethylcellulose (e.g., TYLOSE^®); alginic acid and salts of alginic acid; magnesium aluminum silicate; polyethylene glycol; guar gum; polysaccharide acids; bentonites; polyvinylpyrrolidone; polymethacrylates; hydroxypropylmethylcellulose; hydroxypropylcellulose; ethylcellulose; pregelatinized starch or mixtures thereof.

6. The orally disintegrating composition of claim 3 wherein the disintegrants are selected from the group comprising sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinized starch, starch and starch derivatives, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, swellable clays, smectite, attapulgite, montmorillonite, bentonite, magnesium aluminium silicate and combinations thereof.

7. The orally disintegrating composition of claim 3 wherein the surfactants are selected from the group comprising polyethoxylated fatty acid esters, polyethylene glycol fatty acid esters, alcohol-oil transesterification products, polyglycerized fatty acids, polyethylene glycol sorbitan fatty acid esters, sugar esters, polyoxyethylene- polyoxypropylene block copolymers, ionic surfactants, derivatives of fat soluble vitamins, and mixtures thereof.

8. The orally disintegrating composition of claim 3 wherein the lubricants and glidants are selected from the group comprising glyceryl behapate (COMPRITOL^® 888); stearates (magnesium, calcium, and sodium); stearic acid; hydrogenated vegetable oils (e.g., STEROTEX^®); talc; waxes: Stear-O-Wet; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; polyethylene glycols (e.g., CARBOWAX^® 4000 and 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate.

9. The orally disintegrating composition of claim 1 wherein the said composition is in the form of tablets, wafers, granules, pills, or lozenges.

10. The orally disintegrating composition of claim 9 wherein the said composition is in the form of tablets.

11. The orally disintegrating composition of clam 10 wherein said composition is prepared by wet granulating angiotensin II receptor antagonist with one or more excipients.

12. The orally disintegrating composition of clam 10 wherein said composition is prepared by dry granulating angiotensin II receptor antagonist with one or more excipients.

13. The orally disintegrating composition of clam 10 wherein said composition is prepared by directly compressing angiotensin II receptor antagonist with one or more excipients.

14. The orally disintegrating composition of claim 1 further comprising another antihypertensive drug.

15. The orally disintegrating composition of claim 14 wherein another antihypertensive drug is selected from the group comprising thiazide diuretics, β-blockers, calcium channel blockers, rennin inhibitor, and ACE inhibitors.

16. The orally disintegrating composition of claim 1 and claim 14 wherein said composition is used for the treatment of hypertension, hypertensive crisis and congestive heart failure.