Solid oral composition of telmisartan sodium and preparation thereof

Abstract

The present invention relates to a solid oral pharmaceutical composition of telmisartan sodium as an active ingredient and its preparation thereof. More specifically, the present invention provides a stable pharmaceutical composition of telmisartan sodium having minimal weight and reduced size.

Description

[0001] SOLID ORAL COMPOSITION OF TELMISARTAN SODIUM

[0002] AND PREPARATION THEREOF

[0003] CROSS REFERENCE

[0004] This application claims the benefit of priority of our Indian patent application IN202411058309 filed on 01 August 2024, which is incorporated herein by reference.

[0005] FIELD OF THE INVENTION

[0006] The present invention relates to a solid oral pharmaceutical composition of telmisartan sodium as an active ingredient and its preparation thereof. More specifically, the present invention provides a stable pharmaceutical composition of telmisartan sodium having minimal weight and reduced size.

[0007] BACKGROUND OF THE INVENTION

[0008] Telmisartan is chemically described as 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazol]-T- yl)methyl]-[l,l'-biphenyl]-2-carboxylic acid, and has the following structure as shown below

[0009] Telmisartan is a white to off-white, crystalline powder. It is a biopharmaceutical classification system (BCS) class II drug that has extremely low water solubility but sparingly soluble in strong acid except hydrochloric acid, soluble in strong base.

[0010] Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Telmisartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the ATI receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis. The stable crystalline form of telmisartan sodium is first described in US Patent. 6,737,432. The patent generically discloses pharmaceutical compositions comprising said crystalline form with one or more pharmaceutical acceptable excipients.

[0011] Another US patent 9,029,363 discloses pharmaceutical compositions containing the telmisartan sodium salt and one or more pharmaceutical acceptable excipients.

[0012] One another US patent publication 2006 / 0293377 (US’ 377) discloses an amorphous form of telmisartan sodium and process for preparing said amorphous form. Further US’ 377 unveils different polymorphic forms of telmisartan sodium and process thereof wherein said patent publication also discloses pharmaceutical compositions having active pharmaceutical ingredient in different polymorphic forms along with amorphous form of telmisartan sodium.

[0013] US patent publication 2009 / 0012140 describes pharmaceutical composition comprising amorphous telmisartan or sodium or magnesium or calcium or potassium salt of telmisartan alone or in combination with another active ingredient.

[0014] US patent publication 2010 / 0234411 (refer as US’411) discloses telmisartan in the form of suitable pharmacologically acceptable salts like sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. US’411 also discloses the pharmaceutical composition of telmisartan sodium salt.

[0015] In most of the prior arts, the tablet containing telmisartan sodium as active ingredient is disclosed to have substantially bulky and a large size whereas large-sized tablet may affect the transit of the tablet through the pharynx and esophagus, which may directly affect a patient's ability to swallow a particular drug product. In addition, the above-mentioned prior art also discloses the use of excessive amounts of diluents in the telmisartan sodium tablet, which add bulk to the weight of the tablets. The excessive amounts of diluents may cause hardness of tablet and forms caking of tablet. Larger size reduces the willingness of patients to take tablets on a regular basis, which is of more concern in the case of chronic treatments where medicines are required to be taken for months. To overcome the aforementioned drawbacks, there is an urgent need to develop a stable pharmaceutical composition for oral administration of effective amount of telmisartan sodium by using minimum amounts of excipients. Therefore, a stable pharmaceutical composition for oral administration is desired which should result in enhanced technical formulation attributes such as dissolution profile, stability, bioequivalence which is simple, reproducible and commercially viable at industrial scale.

[0016] OBJECT OF THE INVENTION

[0017] The principal object of the present invention is to provide a stable solid oral pharmaceutical composition of telmisartan sodium having minimal weight and reduced size.

[0018] Another object of the present invention is to provide a stable solid oral pharmaceutical composition comprising telmisartan sodium with one or more pharmaceutically acceptable excipients wherein minimum excipients are used for the preparation of pharmaceutical composition and the impurity profile and stability comply with the regulatory / ICH guidelines.

[0019] One another object of the present invention is to provide a stable solid oral pharmaceutical composition of telmisartan sodium having good dissolution properties.

[0020] Yet another object of the present invention is to provide an efficient, industrially feasible and economical process for the preparation of pharmaceutical composition of telmisartan sodium.

[0021] SUMMARY OF THE INVENTION

[0022] Accordingly, the present invention provides a stable solid oral pharmaceutical composition of telmisartan sodium and its preparation thereof. More specifically, the present invention provides an industrially advantageous pharmaceutical composition of telmisartan sodium having minimal weight and reduced size and further complies for the impurity profile as well as stability as per regulatory / ICH guidelines. In one embodiment, the present invention provides a stable solid orally administrable pharmaceutical composition comprising telmisartan sodium and one or more pharmaceutically acceptable excipients selected from the group comprising of diluent, binder, disintegrant, glidant and lubricant.

[0023] Another embodiment of the present invention provides a stable solid oral pharmaceutical composition comprising: telmisartan sodium in an amount of 10% to 55% w / w, diluent ranging from 10% to 90% w / w, binder ranging from 0% to 40% w / w, disintegrant ranging from 0.5% to 15% w / w, glidant ranging from 0.1% to 10% w / w, and lubricant ranging from 0.25% to 5% w / w, relative to the total weight of the pharmaceutical dosage form.

[0024] According to an embodiment, the present invention provides an efficient process for the preparation of stable solid oral pharmaceutical composition of telmisartan sodium, which comprises steps of: i. mixing telmisartan sodium with one or more pharmaceutical acceptable excipients, ii. lubricating the mixture obtain in step (i) with suitable excipients to obtain a final blend, iii. compressing the final blend of step (ii) into final dosage form.

[0025] In another embodiment, the pharmaceutical composition according to the present invention, the ratio of disintegrant to telmisartan sodium in the pharmaceutical composition ranges from 1 :2 to 1: 100 and the ratio of glidant to telmisartan sodium in the pharmaceutical composition ranges from 1 : 5 to 1 :300.

[0026] Yet another embodiment of the present invention provides stable solid oral pharmaceutical composition of telmisartan sodium wherein the total weight of the composition is in the range from 35 mg to 200 mg. DETAILED DESCRIPTION OF THE INVENTION

[0027] The present invention relates to a stable solid oral pharmaceutical composition of telmisartan sodium along with one or more pharmaceutically acceptable excipients and a process for the preparation of said oral pharmaceutical composition thereof.

[0028] As used herein, the term “solid oral pharmaceutical composition” refers to tablet, capsule, powder, disc, caplet, granules, pellets, tablet in tablet, tablet in capsule, pellets in capsule, powder in capsule and granules in capsule and other like dosage forms suitable for oral administration.

[0029] As used herein, the term “direct compression” refers to the process by which tablets are compressed directly from powder mixture of telmisartan sodium and suitable excipients.

[0030] As used herein, the term “stable” refers to the chemical stability of telmisartan sodium in solid dosage forms wherein there is no significant change in assay, dissolution and related impurities when the dosage form is kept at 40°C / 75% RH for 6 months.

[0031] In the first aspect, the present invention provides a stable solid oral pharmaceutical composition comprising telmisartan sodium and one or more pharmaceutically acceptable excipients. The excipients for pharmaceutical composition can be selected from binders, diluents, disintegrants, glidant and lubricants and / or combination thereof. The stable solid oral pharmaceutical composition of telmisartan sodium may be in the form of a tablet, a capsule and stock of the granules.

[0032] The telmisartan sodium used in the stable solid oral pharmaceutical composition may be selected from crystalline or amorphous form.

[0033] In accordance with the first aspect of the present invention the pharmaceutical composition comprising telmisartan sodium in an amount from 10% to 55% w / w of the total weight of the pharmaceutical dosage form, more preferably from 25% to 55% w / w of the total weight of the pharmaceutical dosage form.

[0034] In the pharmaceutical composition of the present invention suitable “diluent” may be selected from but not limited to starch, corn starch, potato starch, pregelatinized starch, dry starch, disaccharides, lactose, cellulose, maltodextrins, cellulose derivatives, such as silicified microcrystalline cellulose, microcrystalline cellulose, mannitol, sorbitol, xylitol, trehalose, colloidal silica, sucrose or other sugars or sugar derivatives, calcium hydrogen phosphate and dicalcium phosphate. Preferably the diluent is selected from dicalcium phosphate, mannitol, sorbitol, xylitol. More preferably, the diluent is dicalcium phosphate and mannitol and combination thereof. The total amount of the diluent can be within the range from 10% to 90%, relative to the total weight of the pharmaceutical dosage form.

[0035] In the pharmaceutical composition of the present invention suitable “binder” may be selected from but not limited to potato starch, wheat starch, corn starch, microcrystalline cellulose; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hypromellose, ethyl cellulose, sodium carboxymethylcellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinylpyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth and combination thereof. The total amount of the binder can be within the range from 0% to 40% w / w, more preferably the range from 20% to 40%, relative to the total weight of the pharmaceutical dosage form.

[0036] In the pharmaceutical composition of the present invention suitable “disintegrant” may be selected from but not limited to croscarmellose sodium, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone; cross-linked sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose, sodium — carboxymethylcellulose, calcium carboxymethylcellulose, microcrystalline cellulose; sodium starch glycolate; ion-exchange resins including polacrilin potassium (Kyron T 314); starch and modified starches including pregelatinized starch; formalin- casein; alginates, gums; and combination thereof. The total amount of the disintegrant can be within the range from 0.5% to 15% w / w, more preferably the range from 2% to 12% w / w, relative to the total weight of the pharmaceutical dosage form.

[0037] In the pharmaceutical composition of the present invention suitable “glidanf ’ may be selected from but not limited to silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and combination thereof. The total amount of the glidant can be within the range from 0.1% to 10% w / w, relative to the total weight of the pharmaceutical dosage form. In the pharmaceutical composition of the present invention suitable “lubricant” may be selected from but not limited to calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, fumaric acid, sodium benzoate, sodium stearyl fumarate, stearic acid, calcium stearate, glyceryl monostearate, talc, vegetable oil, zinc stearate, castor wax and combination thereof. The total amount of the lubricant can be within the range from 0.25% to 5% w / w, relative to the total weight of the pharmaceutical dosage form.

[0038] In the second aspect, the present invention provides a process for the preparation of stable solid oral pharmaceutical composition of telmisartan sodium, wherein the composition may be prepared by mixing telmisartan sodium with one or more pharmaceutical acceptable excipients to form a blend. Thereafter, lubricating the blend with suitable lubricant to obtain a final blend, which may be converted into solid oral dosage forms.

[0039] The components used in the process according to the second aspect of the present invention, as defined above, can be sieved prior to the blending / mixing steps. The specific components used in the process for the preparation of the stable solid oral pharmaceutical composition of telmisartan sodium, as well as their properties and amounts, are as described above for the first aspect of the invention.

[0040] Usually, excipients are added to the composition to achieve the desired quality of the product. In prior art, excipients are added in pharmaceutical composition of telmisartan sodium in the bulk amount specifically to improve disintegration, dissolution and bioavailability of the finished product. However, the present inventors have achieved the same quality of the product by using lesser amount of excipients which results in reduced tablet size, and consequently reduced cost for the patient.

[0041] The process for the preparation of a stable solid oral pharmaceutical composition of telmisartan sodium may be performed by using direct compression method.

[0042] In third aspect, the present invention provides the ratio of disintegrant to telmisartan sodium in the pharmaceutical composition ranges from 1:2 to 1:100 and the ratio of glidant to telmisartan sodium in the pharmaceutical composition ranges from 1 : 5 to 1 :300. Nevertheless, the present invention provides results which suggest that a telmisartan sodium composition by using direct compression method wherein specific ratio of telmisartan sodium and a disintegrant could effectively improve the drug’s solubility / oral bioavailability.

[0043] In a further aspect, of the present invention, the total weight of the stable pharmaceutical composition of telmisartan sodium is in the range from 35 mg to 200 mg, and more preferably 35 mg to 180 mg. The weight of the tablets in accordance with the invention is relatively less. The invention further relates to a tablet having a diameter as determined by the longest enveloping circle in the range of 1 -8 mm.

[0044] It is an advantage of the present invention that flowability is good also at high drug load into a die of small dimensions. Moreover, dwell time sensitivity is relatively low, allowing tableting by direct compression at high speed.

[0045] In a preferred embodiment of the present invention, a pharmaceutical composition is provided that is stable at 40°C and 75% relative humidity.

[0046] In another embodiment, pharmaceutical composition of the present invention exhibits more than 90% of drug release within 30 minutes in 500 ml of 0.1 N HC1 (Office of Generic Drugs dissolution database) using a USP I apparatus (basket) at a temperature of 37±0.5° C and a rotation speed of 100 revolutions per minute.

[0047] The stable pharmaceutical compositions of telmisartan sodium suitable for oral administration to humans must have desirable chemical and physical properties, disintegration, dissolution, stability and bioequivalence complying with demanding requirements and regulations of health and medicine regulatory agencies across the world.

[0048] It has been found that all dosage forms are stable, and the level of all impurities have been found to be below the detection limit and drug assay within the range, after 6 months during stability studies. The dosage forms of different strength prepared as per the present invention have been kept at stability conditions of 40°C / 75% RH, wherein all the impurities are below detection limit and drug assay within the range of 90% to 110% in the composition.

[0049] The invention is further defined by reference to the following examples describing in detail methods for the preparation and testing of telmisartan sodium pharmaceutical composition. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. The following examples are set out to illustrate the invention and do not limit the scope of the present invention.

[0050] Examples:

[0051] Example 1:

[0052] Procedure:

[0053] 1. Telmisartan sodium was mixed with all above mentioned excipients except magnesium stearate to form a blend.

[0054] 2. Magnesium stearate was sifted through an appropriate sieve and blended with the mixture obtained in step (1) to obtain a lubricated blend.

[0055] 3. The lubricated blend of step (2) was compressed into tablets. Example 2:

[0056] Procedure:

[0057] 1. Telmisartan sodium was mixed with all above mentioned excipients except magnesium stearate to form a blend.

[0058] 2. Magnesium stearate was sifted through an appropriate sieve and blended with the mixture obtained in step (1) to obtain a lubricated blend.

[0059] 3. The lubricated blend of step (2) was compressed into tablets.

[0060] Example 3:

[0061] Procedure:

[0062] 1. Telmisartan sodium was mixed with all above mentioned excipients except magnesium stearate to form a blend. 2. Magnesium stearate was sifted through an appropriate sieve and blended with the mixture obtained in step (1) to obtain a lubricated blend.

[0063] 3. The lubricated blend of step (2) was compressed into tablets.

[0064] Example 4:

[0065] Procedure:

[0066] 1. Telmisartan sodium was mixed with all above mentioned excipients except magnesium stearate to form a blend.

[0067] 2. Magnesium stearate was sifted through an appropriate sieve and blended with the mixture obtained in step (1) to obtain a lubricated blend.

[0068] 3. The lubricated blend of step (2) was compressed into tablets.

[0069] Stability Studies at 40° C / 75% RH

[0070] The proposed compositions were stored at 40° C / 75% RH and were tested for drug assay. The results are tabulated in Table 1.

[0071] TABLE 1: Tablets Dissolution Studies at 40° C / 75% RH

[0072] Dissolution studies of compositions were conducted in 500 ml of 0.1 N HC1 (Office of Generic Drugs dissolution database) using a USP I apparatus (basket) at a temperature of 37±0.5° C and a rotation speed of 100 revolutions per minute. The release of telmisartan at time point of 30 minutes on stability at 40° C / 75% RH as follows in Table 2.

[0073] TABLE 2: Tablets

[0074] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.

Claims

CLAIMS1. A pharmaceutical composition of telmisartan sodium, comprising telmisartan sodium and one or more pharmaceutically acceptable excipients selected from the group of a diluent, a binder, a disintegrant, a glidant and lubricant.

2. A pharmaceutical composition of telmisartan sodium, comprising telmisartan sodium ranging from 10% to 55% w / w; diluent ranging from 10% to 90% w / w; binder ranging from 0% to 40% w / w; disintegrant ranging from 0.5% to 15% w / w; glidant ranging from 0.1% to 10% w / w; and lubricant ranging from 0.25% to 5% w / w, relative to the total weight of the pharmaceutical dosage form.

3. The pharmaceutical composition as claimed in claim 2, wherein diluent is selected from starch, corn starch, potato starch, pregelatinized starch, dry starch, disaccharides, lactose, cellulose, maltodextrins, cellulose derivatives, such as silicified microcrystalline cellulose, microcrystalline cellulose, mannitol, sorbitol, xylitol, trehalose, colloidal silica, sucrose or other sugars or sugar derivatives, calcium hydrogen phosphate and dicalcium phosphate and combination thereof.

4. The pharmaceutical composition as claimed in claim 2, wherein binder is selected from potato starch, wheat starch, corn starch, microcrystalline cellulose; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hypromellose, ethyl cellulose, sodium carboxymethylcellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinylpyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth and combination thereof; lubricant is selected from calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, fumaric acid, sodium benzoate, sodium stearyl fumarate, stearic acid, calcium stearate, glyceryl monostearate, talc, vegetable oil, zinc stearate, castor wax and combination thereof.

5. The pharmaceutical composition as claimed in claim 2, wherein disintegrant is selected from croscarmellose sodium, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone; cross-linked sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose; sodium starch glycolate; ion-exchange resins including polacrilin potassium (Kyron T 314); starch and modified starches including pregelatinized starch; formalin-casein; alginates, gums; and combination thereof.

6. The pharmaceutical composition as claimed in claim 2, wherein glidant is selected from silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and combination thereof.

7. A process for the preparation of pharmaceutical composition of telmisartan sodium, which comprises the steps of: i. mixing telmisartan sodium with one or more pharmaceutical acceptable excipients, ii. lubricating the mixture obtain in step (i) with suitable excipients to obtain a final blend, iii. compressing the final blend of step (ii) into final dosage form.

8. A pharmaceutical composition comprising telmisartan sodium, disintegrant and a glidant, wherein the ratio of disintegrant to telmisartan sodium in the pharmaceutical composition ranges from 1 :2 to 1:100 and the ratio of glidant to telmisartan sodium in the pharmaceutical composition ranges from 1: 5 to 1 : 300.

9. The pharmaceutical composition as claimed in claim 8, wherein disintegrant is present in an amount within the range from 0.5% to 15% w / w and glidant is present in an amount within the range from 0.1% to 10% w / w.

10. A pharmaceutical composition of telmisartan sodium, wherein total weight of the composition is ranging from 35 mg to 200 mg.

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