WO2023107066A2

WO2023107066A2 - Bosentan pharmaceutical compositions

Info

Publication number: WO2023107066A2
Application number: PCT/TR2022/051418
Authority: WO
Inventors: Udaya Kumar DUDE; Muzeyyen Ozge SAHIN; Ali Osman Sarikaya
Original assignee: Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date: 2021-12-07
Filing date: 2022-12-06
Publication date: 2023-06-15
Also published as: WO2023107066A3

Abstract

The present invention relates to a dispersible tablet formulation containing bosentan. More particularly, it relates to a dispersible tablet formulation comprising bosentan, polaxamer, acidifier and at least one pharmaceutically acceptable excipient and the manufacturing process thereof.

Description

BOSENTAN PHARMACEUTICAL COMPOSITIONS

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a dispersible tablet composition comprising bosentan. More particularly, it relates to a dispersible tablet composition comprising bosentan, polaxamer, acidifier and at least one pharmaceutically acceptable excipient; and a manufacturing process thereof.

BACKGROUND OF THE INVENTION

Bosentan is chemically known as 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy- phenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl]-benzenesulfonamide. The structure of bosentan is depicted in the following “Formula 1”.

Bosentan and its preparation is disclosed in EP 0526708 A1. Bosentan is a dual endothelin receptor antagonist with affinity for both endothelin ETA and ETB receptors thereby preventing the deleterious effects of ET-1 .

Bosentan is commercially available under the trade name Tracleer™. It is indicated for oral treatment for pulmonary arterial hypertension. The commercially available formulations are Bosentan 62.5 and 125 mg film coated tablets, and Bosentan 32 mg dispersible tablet. Bosentan 32 mg dispersible tablet has a composition of microcrystalline cellulose, calcium hydrogen phosphate anhydrous, croscarmellose sodium, colloidal silica anhydrous, tartaric acid, tutti frutti flavor, aspartame (E951 ), acesulfame potassium and magnesium stearate.

WO 2006/123285 discloses dispersible tablets of bosentan which disperse in water in less than five minute. The formulations described therein are alleged to have better compliance, especially in pediatric patients. The patent document discloses that the composition is obtained by direct compression.

Bosentan is a practically water-insoluble compound. Further, since bosentan is a BCS Class II molecule, that has low solubility and high permeability, it is difficult to obtain a product with suitable bioavailability. It is known to the person skilled in the art that different compositions of the same active ingredient of this class with same dissolution profile may not exhibits same bioavailability. It requires judicious experimentation, to prepare such composition that exhibits desired bioavailability.

Therefore, there is still exist a need in the art to prepare a bosentan dispersible tablet compositions using different excipients that exhibits desired bioavailability i.e. bioequivalence composition compared to Tracleer™.

OBJECT OF THE INVENTION

The main object of the invention is to provide a dispersible tablet composition comprising bosentan.

Another object of the invention is to provide a dispersible tablet composition comprising bosentan, poloxamer, acidifier and at least one pharmaceutically acceptable excipient.

Another object of the invention is to provide dispersible tablet composition comprising granules containing bosentan, poloxamer, acidifier and at least one pharmaceutically acceptable excipient, and at least one pharmaceutically acceptable extragranular excipient.

Another object of the invention is to prepare the dispersible tablet formulation by wet granulation method.

Another object of the invention is to provide a dispersible tablet composition comprising bosentan, which overcomes the problems in the prior art.

Another object of the invention is to provide a commercially scalable, cost effective, environmentally friendly and robust process for the manufacture of the bosentan composition. SUMMARY OF THE INVENTION

In one aspect, present invention relates to a dispersible tablet composition comprising bosentan.

In another aspect, the present invention provides a dispersible tablet composition comprises: i) bosentan; ii) poloxamer; iii) acidifier; and iv) at least one pharmaceutically acceptable excipient.

In another aspect, the present invention provides dispersible tablet composition comprises: i) a granule containing bosentan, poloxamer, acidifier and at least one pharmaceutically acceptable excipient, and ii) at least one pharmaceutically acceptable extragranular excipient.

In another aspect, the present invention provides a dispersible tablet composition comprises: i) bosentan; ii) poloxamer; iii) acidifier; and iv) at least one pharmaceutically acceptable excipient, and wherein tablet comprises bosentan particles having d90 in the range of 5 pm to 40 pm. In another aspect, the present invention provides a dispersible tablet composition comprises: i) about 5 wt % - 30 wt % of bosentan, ii) about 0.01 wt % - 5 wt % of poloxamer, iii) about 1 wt % - 85 wt % of a filler, iv) about 1 wt % - 10 wt % of a binder, v) about 1 wt % - 10 wt % of a disintegrant, vi) about 0.1 wt % - 5 wt % of a glidant, vii) about 0.1 wt % - 5 wt % of a lubricant, viii) about 0.01 wt % - 3 wt % of a sweetener, ix) about 0.01 wt % - 2 wt% of a flavoring agent, x) about 0.5% - 5% of an acidifier and wherein tablet comprises bosentan particles having d90 in the range of 5 pm to 40 pm.

In another aspect, the present invention provides a process for the preparation of the dispersible tablet composition comprises the following steps: i) mixing bosentan with an acidifier and at least one pharmaceutically acceptable excipient, ii) granulating the mixture of step (i) with the aqueous solution comprising poloxamer, iii) drying the granules of step (ii), iv) mixing the granules of step (iii) with at least one pharmaceutically acceptable extragranular excipient; and v) compressing the mixture of step (iv) into a tablet. In another aspect, the present invention provides a process for the preparation of dispersible tablet composition comprises the following steps: i) mixing bosentan with an acidif ier and at least one pharmaceutically acceptable excipient, ii) granulating the mixture of step (i) with the aqueous solution comprising poloxamer and binder, iii) drying the granules of step (ii), iv) mixing the granules of step (iii) with at least one pharmaceutically acceptable extragranular excipient; and v) compressing the mixture of step (iv) into a tablet.

The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION

Terms used herein are intended to have their usual meanings in the art, unless otherwise stipulated.

The term "about" indicates a difference of 10%of the value specified.

The term "dispersible tablet" as used in the present invention means uncoated or film- coated tablets that are intended to be dispersed in water prior to administration to give a homogeneous dispersion.

The term "wet granulation" as used in the present invention refers to a process known in the pharmaceutical prior art that involves forming granules by adding a liquid such as purified water, alcohol or a binder solution.

The term "bosentan" means bosentan free base or its solvates, including pharmaceutically acceptable salts or hydrates. In the invention, preferably, bosentan is in the form of monohydrate. The amount of bosentan is in the range of about 5% to about 30%, preferably about 10% to about 15%, by weight of the composition. The term “dgo” as described herein denotes particle size of bosentan used in the composition, and it means that 90% the particles are smaller than the specified value. For example, dgo value of 30 pm means that 90% particles are smaller than 30 pm. The “dgo” of bosentan as described herein may vary ranging from about 5 pm to about 40 pm. The term “dso” as described herein means that 50% the particles are smaller than the specified value. The “dso” of bosentan as described herein may vary ranging from about 1 pm to about 20 pm. The term “dio” as described herein means that 10 % the particles are smaller than the specified value. The “dio” of bosentan as described herein may vary ranging from about 1 pm to about 5 pm. Conventional procedures known by skilled person in the art, such as milling, may be employed to obtain particle size of bosentan in the specified range. The particle size may be measured using equipments known by skilled person such as Malvern™ Mastersizer.

The term formulation and composition mentioned herein is used interchangeably.

The term "granule" refers to bosentan, poloxamer, acidifier and at least one pharmaceutically acceptable excipient. The granules mentioned herein can be obtained by wet granulation or dry granulation.

The dispersible tablet comprising bosentan can be produced by conventional methods such as direct compression, direct mixing, wet granulation, dry granulation, fluid bed granulation, spray granulation. Preferably, wet granulation is used in the invention.

Here, the term 'poloxamer' represents a class of surfactants which are nonionic triple block co-polymers consisting of a central hydrophobic polyoxypropylene (polypropylene oxide)) chain surrounded by two hydrophilic polyoxyethylene (poly(ethylene oxide) chains. The poloxamer described can be selected from a variety of grades available under the trade name PluronicTM or LutrolTM. As described herein, the amount of poloxamer can vary from about 0.01 % to about 5% by weight of the composition.

The compositions as described herein can comprise at least one pharmaceutically acceptable excipient. Pharmaceutically acceptable excipient comprises at least one filler, at least one binder, at least one disintegrant, at least one glidant, at least one lubricant, at least one acidifier, at least one flavoring agent, at least one sweetener or combinations thereof.

The filler as described herein refers to, but is not limited to, at least one of lactose, sucrose, dextrose, microcrystalline cellulose, dibasic calcium phosphate, calcium sulfate, mannitol, erythritol, lactilol, maltitol, xylitol, sorbitol, starch, or mixtures thereof. The amount of the filler may range from about 1 % to about 85% by weight of the composition.

The binder as described herein refers to, but is not limited to, at least one of polyvinyl pyrrolidone (povidone), hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, starch or mixtures thereof. The amount of binder may range from about 1 % to about 10% by weight of the composition.

The disintegrant as described herein refers to, but is not limited to, at least one of sodium starch glycolate, crospovidone, croscarmellose sodium, low substituted hydroxypropyl cellulose, pregelatinized starch, alginic acid, sodium alginate or mixtures thereof. The amount of disintegrant may range from about 1 % to about 10% by weight of the composition.

The glidant as described herein refers to, but is not limited to, at least one of colloidal silicon dioxide, talc, stearic acid or mixtures thereof. The amount of glidant may range from about 0.1 % to about 5%, more preferably from about 0.1 % to about 2%, by weight of the composition.

The lubricant as described herein refers to, but is not limited to at least one of magnesium stearate, stearic acid, talc, sodium stearyl fumarate, glyceryl dibehenate, polyethylene glycol, hydrogenated castor oil or mixtures thereof. The amount of lubricant may range from about 0.1 % to about 5%, more preferably from about 0.1 % to about 2%, by weight of the composition. The acidifier as described herein refers to, but are not limited to, at least one of tartaric acid, citric acid, lactic acid, acetic acid, fumaric acid or mixtures thereof. The amount of acidifier may range from about 0.5% to about 5%, more preferably from about 1 % to about 3%, by weight of the composition.

The flavoring agent as described herein refers to, but are not limited to, at least one of cinnamon, cherry, strawberry, raspberry, apple, bubble gum, vanilla, chocolate, mint, apricot, tutti frutti, and the like or mixtures thereof. The flavor may range from about 0.01 % to about 2% by weight of the composition.

The sweetener as described herein refers to, but are not limited to, xylose, ribose, glucose, mannose, galactose, fructose, sucrose, maltose, invert sugar, partially hydrolyzed starch, glycyrrhizin, sorbitol, xylitol, mannitol, maltitol, saccharic acids, saccharin salts, acesulfame potassium, sucrose, aspartame or mixtures thereof. The amount of sweetener may range from about 0.01 % to about 3% by weight of the composition.

The pharmaceutical compositions used herein can be prepared by techniques such as direct compression, dry granulation or wet granulation. The wet granulation method is the preferred production method to improve the cohesiveness of powders in tablet compression and turn them into granules with suitable flow and cohesion for compression. The composition described herein is prepared by the wet granulation method.

The granules used herein may be prepared by techniques as dry granulation or wet granulation. The wet granulation method is the preferred production method to improve the cohesiveness of powders in tablet compression and turn them into granules with suitable flow and cohesion for compression. The granules described herein is prepared by the wet granulation method.

Suitable solvent for the wet granulation includes water, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, methyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, or mixtures thereof. Preferred solvent for the granulation is water. In one of the embodiments of the invention, the composition may be prepared by wet granulation. For example, bosentan may be mixed with at least one filler, at least one disintegrant, at least one binder, at least one acidifier, and this mixture may be granulated with an aqueous solution of the surfactant in a conventional high shear mixer granulator such as GlattTM or WursterTM or in a fluid bed granulator.

Alternatively, at least one binder and at least one surfactant may be incorporated into the aqueous solution to granulate a mixture of bosentan, at least one filler, at least one acidifier and at least one disintegrant. The granules may be dried, sieved and mixed with pharmaceutically acceptable extragranular excipients such as at least one lubricant, at least one glidant and optionally at least one filler, at least one flavoring agent or at least one sweetener, and the mixture may be compressed into tablets.

In one of the embodiments of the invention, the composition described herein can be prepared by dry granulation. For example, bosentan may be mixed with at least one filler, at least one disintegrant, at least one binder, at least one acidifier, at least one surfactant, and this mixture may be passed through a roller compactor or a filler machine to form compacts. The compact may be mixed with at least one lubricant, at least one glidant, or optionally, at least one filler, at least one disintegrant, at least one flavoring agent, or at least one sweetener and the mixture may be compressed into tablets.

The person skilled in the art knows that excipients such as filler, disintegrant, binder, glidant and/or lubricant described herein have multiple functions.

In one of the embodiments of the present invention, a process for the preparation of the dispersible tablet composition comprises the following steps: i) mixing bosentan with an acidifier and at least one pharmaceutically acceptable excipient, ii) granulating the mixture of step (i) with the aqueous solution comprising poloxamer iii) drying the granules of step (ii), iv) mixing the granules of step (iii) with at least one pharmaceutically acceptable extragranular excipient; and v) compressing the mixture of step (iv) into a tablet.

In one of the embodiments of the present invention, a process for the preparation of the dispersible tablet composition comprises the following steps: i) mixing bosentan with an acidifier and at least one pharmaceutically acceptable excipient, ii) granulating the mixture of step (i) with the aqueous solution comprising poloxamer and binder, iii) drying the granules of step (ii), iv) mixing the granules of step (iii) with at least one pharmaceutically acceptable extragranular excipient; and v) compressing the mixture of step (iv) into a tablet.

The following examples described in more details are intended to illustrate the scope of the present invention and embodiments but not to limit it thereto.

Example 1. Dispersible tablet composition comprising Bosentan with poloxamer

Manufacturing method: Bosentan monohydrate (dgo = 25 pm; dso = 8 pm (measured with Malvern™ Mastersizer.), calcium hydrogen phosphate (anhydrous), microcrystalline cellulose (type 101 ), croscarmellose sodium, tartaric acid, aspartame and acesulfame potassium were sieved and mixed in a mixer. This mixture was granulated with an aqueous solution of poloxamer and povidone. The granules were dried and sieved. Tutti frutti, microcrystalline cellulose (type 102), croscarmellose sodium and colloidal silicon dioxide (anhydrous) were added to the dried granules, and then magnesium stearate was added to obtain the final mixture. The final mixture was compressed to tablets. Example 2 Dispersible tablet composition comprising Bosentan without poloxamer

Manufacturing method: Bosentan monohydrate (dgo = 25 pm; dso = 8 pm (measured with Malvern™ Mastersizer.), calcium hydrogen phosphate (anhydrous), microcrystalline cellulose (type 101 ), croscarmellose sodium, tartaric acid, aspartame and acesulfame potassium were sieved and mixed in a mixer. This mixture was granulated with an aqueous solution of povidone. The granules were dried and sieved. Tutti frutti, microcrystalline cellulose (type 102), croscarmellose sodium and colloidal silicon dioxide (anhydrous) were added to dried granules, and then magnesium stearate was added to obtain the final mixture. The final mixture was compressed to tablets.

Example 3 In-vitro dissolution test

Dissolution test were performed in 4 different media for example 1 and 2, and the results are given in Table 1 -4.

Table 1. Dissolution results in 0.1 N HCI + 0.1% SLS (75 RPM, 900 ml, Pedal) for Example 1 and 2

Table 2. Dissolution results in pH 4.5 + 0.2% SLS (75 RPM. 900 ml. Pedal) for Example 1 and 2

Table 3. Dissolution results in pH 6.8 Phosphate (75 RPM. 900 ml. Pedal) for Example 1 and 2

Table 4. Dissolution results in Fassif (75 RPM. 900 ml. Pedal) for

Example 1 and 2

Example 4 In-vivo analysis

Example 1 and 2 are compared with the reference product Tracleer™ (32 mg Dispersible Tablet) in terms of Pharmacokinetic Parameters, and the bioequivalence results are given in Table 5 and 6.

Table 5. Bioequivalence evaluation of Example 1 and reference product Tracleer™

Table 6. Bioequivalence evaluation of Example 2 and reference product Tracleer™

According to the results from the bioequivalence study of Example 1 and 2, with almost identical dissolution results, only the Example 1 formulation was observed to be bioequivalent to the reference product Tracleer™.

It has been observed that tablets comprising poloxamer show increased bioavailability with similar particle size compared to the composition without poloxamer.

Claims

1 . A dispersible tablet comprising: a. bosentan; b. poloxamer; c. acidif ier and d. at least one pharmaceutically acceptable excipient.

2. The dispersible tablet according to claim 1 , wherein the tablet comprises: i. granule containing bosentan. poloxamer, acidifier and at least one pharmaceutically acceptable excipient; and ii. at least one pharmaceutically acceptable extragranular excipient.

3. The dispersible tablet according to claim 2, wherein the said granules are prepared by wet granulation method.

4. The dispersible tablet according to claim 1 , wherein the tablet comprises bosentan particles having dgo in the range of 5 pm to 40 pm.

5. The dispersible tablet according to claim 1 , wherein the amount of bosentan is in the range of about 5% to about 30% by weight of the composition.

6. The dispersible tablet according to claim 1 , wherein the amount of poloxamer is in the range of about 0.01 % to about 5% by weight of the composition.

7. The dispersible tablet according to claim 1 , wherein the amount of acidifier is in the range of about 0.5% and about 5% by weight of the composition.

8. The dispersible tablet according to claim 1 , wherein the pharmaceutically acceptable excipient comprises at least one filler, at least one binder, at least one disintegrant, at least one glidant, at least one lubricant, and optionally at least one flavoring agent or at least one sweetener.

9. A process for the preparation of the dispersible tablet according to claim 1 , wherein the process comprises the steps of: i. mixing bosentan with an acidifier and at least one pharmaceutically acceptable excipient, ii. granulating the mixture of step (i) with the aqueous solution comprising binder and poloxamer, iii. drying the granules of step (ii), iv. mixing the granules of step (iii) with at least one pharmaceutically acceptable extragranular excipient; and v.compressing the mixture of step (iv) in to a tablet.