WO2013098577A1 - Pharmaceutical compositions of bosentan - Google Patents
Pharmaceutical compositions of bosentan Download PDFInfo
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- WO2013098577A1 WO2013098577A1 PCT/IB2011/003200 IB2011003200W WO2013098577A1 WO 2013098577 A1 WO2013098577 A1 WO 2013098577A1 IB 2011003200 W IB2011003200 W IB 2011003200W WO 2013098577 A1 WO2013098577 A1 WO 2013098577A1
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- bosentan
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
Definitions
- the present invention relates to a pharmaceutical composition comprising bosentan. More particularly, it relates to a pharmaceutical composition comprising bosentan, a surfactant, and at least one pharmaceutically acceptable excipient.
- 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 I”.
- Bosentan and its preparation is disclosed in EP to 0526708 Al .
- Bosentan is a dual endothelin receptor antagonist with affinity for both endothelin ET A and ET B receptors thereby preventing the deleterious effects of ET-1.
- Bosentan is commercially available under the trade-name TracleerTM. It is indicated for oral treatment for pulmonary arterial hypertension (Class III and IV in the United States, Class III in Europe).
- the commercially available formulation has the following composition: bosentan (125 or 62.5 mg), starch, triacetin, magnesium stearate, talc, ferric oxide, povidone, titanium dioxide, ethylcellulose, glyceryl behenate, hypromellose and sodium starch glycollate.
- PCT Application 2006/123285 discloses dispersible tablets of bosentan which disperse in water in less than one minute.
- the formulations described therein are alleged to have better compliance, especially in pediatric patients.
- Bosentan is a compound which is practically insoluble in water. It is also known that bosentan has low oral bioavailability. There is a need for alternative compositions of bosentan which have good bioavailability.
- pharmaceutical compositions of bosentan having increased bioavailability may be formulated by modifying the particle size of bosentan and including a surfactant, such as poloxamer, in the composition.
- aspects of the invention relate to pharmaceutical composition of bosentan.
- composition comprising:
- composition comprising:
- bosentan has dgo in the range of 5 ⁇ to 40 ⁇ .
- a pharmaceutical composition comprising i) about 10% to about 90 % by weight bosentan; ii) about 0.1 % to about 5 % by weight poloxamer; iii) about 1 % to about 30 % by weight of a diluent; iv) about 1 % to about 10 % by weight of a binder; v) about 1 % to about 10 % by weight of a disintegrant; vi) about 0.1 to about 5 % by weight of a glidant, and vii) about 0.1 to about 5 % by weight of a lubricant, wherein the bosentan has d90 in the range of 5 ⁇ to 40 ⁇ .
- step (ii) granulating the mixture of step (i) with an aqueous poloxamer solution; iii) drying the granules of step (ii):
- step (iii) mixing the granules of step (iii) with at least one pharmaceutically acceptable excipient;
- step (iv) compressing the mixture of step (iv) into a tablet
- step (v) optionally coating the tablet of step (v).
- step (i) granulating the mixture of step (i) with an aqueous poloxamer solution
- step (iii) mixing the granules of step (iii) with at least one pharmaceutically acceptable excipient;
- step (iv) compressing the mixture of step (iv) into a tablet
- bosentan has d 0 in the range of 5 ⁇ to 40 ⁇ .
- bosentan as described herein is defined to mean bosentan free base or its pharmaceutically acceptable salts, or solvates, including hydrates, of bosentan.
- bosentan is in the monohydrate form.
- the amount of bosentan may vary from about 10 % to about 90 % by weight, preferably from about 40 % to about 80 % 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.
- d 90 value of 30 ⁇ means that 90 % particles are smaller than 30 ⁇ .
- the "d 90 " of bosentan as described herein may vary ranging from about 5 ⁇ to about 40 ⁇ .
- dso means that 50% the particles are smaller than the specified value.
- the “d 50 " of bosentan as described herein may vary ranging from about 1 ⁇ to about 20 ⁇ .
- the term “dio” as described herein means that 10 % the particles are smaller than the specified value.
- the "di 0 " of bosentan as described herein may vary ranging from about 1 ⁇ to about 5 ⁇ . Conventional procedures known to the skilled person, 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 to the skilled person such as Malvern ' Mastersizer.
- poly(propylene oxide) refers to a class of surfactants which are nonionic triblock co-polymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)).
- the poloxamer as described herein may be selected from the various grades available commercially under the trade name of PluronicTM or LutrolTM.
- the poloxamer as described herein may be present in a range varying from about 0.1 % to about 5 % by weight of the composition.
- compositions as described herein may comprise at least one pharmaceutically acceptable excipient selected from a group comprising diluent, binder, disintegrant, glidant, lubricant, flavoring agent and sweetening agent.
- Diluent as described herein may be selected from a group comprising lactose, sucrose, dextrose, microcrystalline cellulose, dibasic calcium phosphate, calcium sulphate, mannitol, erythritol, lactilol, maltitol, xylitol, sorbitol, starch, and mixtures thereof.
- the diluents may be present in an amount ranging from about 1% to about 30 % by weight of the composition.
- Binder as described herein may be selected from a group comprising polyvinyl pyrrolidone, hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, starch, and mixtures thereof.
- the binder may be present in an amount ranging from about 1 % to about 10 % by weight of the composition.
- Disintegrant as described herein may be selected from one or more of sodium starch glycolate, crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, pregelatinized starch, alginic acid, sodium alginate, and mixtures thereof.
- the disintegrant may be present in an amount ranging from about 1% to about 10 % by weight of the composition.
- Glidant as described herein may be selected from a group comprising colloidal silicon dioxide, talc, and mixtures thereof.
- the glidant may be present in an amount ranging from about 0.1 % to about 5 % by weight, more preferably from about 0.1 % to about 2 % by weight of the composition.
- Lubricant as described herein may be selected from a group comprising magnesium stearate, stearic acid, talc, sodium stearyl fumarate, glyceryl dibehenate, polyethylene glycol, hydrogenated castor oil, and mixtures thereof.
- the lubricant may be present in an amount ranging from about 0.1 % to about 5 % by weight, more preferably from about 0.1 % to about 2 % by weight of the composition.
- Flavoring agent as described herein may be selected from a group comprising cinnamon, cherry, strawberry, raspberry, apple, bubblegum, vanilla, chocolate, mint, apricot, and the like, and mixtures thereof.
- the flavoring agent may be present in an amount ranging from 0.1% to 2 % by weight of the composition.
- Sweetening agent as described herein may be selected from a group comprising xylose, rebose, glucose, mannose, galactose, fructose, sucrose, maltose, invert sugar, partially hydrolyzed starch, glycyrrhizin, sorbitol, xylitol, mannitol, maltitol, saccharin acid, saccharin salts, acesulfame potassium, sucralose, and mixtures thereof.
- the sweetening agent may be present in an amount ranging from 0.1 % to 2 % by weight of the composition.
- compositions as described herein may be prepared by techniques such as direct compression, dry granulation or wet granulation.
- compositions as described herein may be prepared by direct compression.
- bosentan may be mixed with a diluent, disintegrant, binder, surfactant, flavoring agent and sweetening agent, in a mixer and the mixture may be compressed into a tablet.
- the surfactant is poloxamer.
- compositions as described herein may be prepared by dry granulation.
- bosentan may be mixed with a diluent, disintegrant, binder, and surfactant and the mixture may be passed through a roller compactor or a slugger, and processed to form compacts or slugs.
- the compacts may be mixed with excipients such as lubricant , glidant and optionally a diluent, disintegrant, flavoring agent or sweetening agent, and the mixture may be compressed into a tablet.
- compositions as described herein may be prepared by wet granulation.
- bosentan may be mixed with a diluent, disintegrant and a binder, and the mixture may be granulated with an aqueous solution of the surfactant, in a conventional high shear mixer granulator or in fluid bed granulator equipment, such as GlattTM or WursterTM.
- a binder may be included in the aqueous surfactant solution and the mixture of bosentan, diluent and disintegrant may be granulated.
- the surfactant is poloxamer.
- the granules may be dried, sieved and mixed with extragranular excipients such as lubricant, glidant and optionally a diluent,
- disintegrant, flavoring agent or sweetening agent, and the mixture may be processed into suitable composition such as tablet.
- suitable composition such as tablet.
- the tablet may be coated with suitable coating composition such as the one
- Such a coating composition may comprise a film-forming polymer, plasticizer, detackifying agent, coloring agent and an opacifying agent.
- the film-forming agent as described herein include, but not limited to, polyvinyl alcohol, ethylcellulose, hydroxypropyl methylcellulose, and the like.
- the plasticizer as described herein include, but not limited to, diethyl phthalate, diethyl sebacate, dibutyl sebacate, , triethyl citrate, dibutyl phthalate, acetyl triethyl citrate, glyceryl monostearate, glyceryl triacetate, polyethylene glycol, propylene glycol, and the like.
- the detackifying agent as described herein include, but not limited to,talc, finely divided silicon dioxide, glyceryl monostearate. and the like.
- the coloring agent may be selected form permitted FD&C dyes.
- the opacifying agent as described herein includes, but not limited to, titanium dioxide, iron oxides, and the like.
- any excipient as described herein may serve more than one function e.g. diluent, disintegrant, binder, glidant, and/or lubricant.
- composition comprising bosentan may be prepared by i) mixing bosentan, a diluent, a disintegrant and a binder;
- step (i) granulating the mixture of step (i) with an aqueous poloxamer solution
- step (iii) mixing the granules of step (iii) with a glidant and a lubricant;
- step (iv) compressing the mixture of step (iv) into a tablet
- PROCEDURE Bosentan monohydrate, maize starch, povidone, pregelatinized starch and sodium starch glycollate are sifted and mixed in a blender. The mixture is granulated with an aqueous solution of poloxamer in a high shear granulator. The granules are dried and sieved. The dried granules are lubricated by addition of glycerol dibehenate and magnesium stearate, and the mixture is compressed into tablets using appropriate tooling. The tablets are coated by spraying Opadry coating composition.
- PROCEDURE Bosentan mono hydrate, maize starch, povidone, pregelatinized starch, and sodium starch glycollate are sifted and mixed in a blender. The mixture is granulated with an aqueous solution of poloxamer in a high shear granulator. The granules are dried and sieved. The dried granules are mixed with colloidal silicon dioxide and lubricated by addition of glyceryl dibehenate and magnesium stearate, and the mixture is compressed into tablets using appropriate tooling. The tablets are coated by spraying Opadry coating composition.
- PROCEDURE Bosentan monohydrate, maize starch, povidone, pregelatinized starch and sodium starch glycollate are sifted and mixed in a blender. The mixture is granulated with an aqueous solution of poloxamer in a high shear granulator. The granules are dried and sieved. The dried granules are mixed with colloidal silicon dioxide and lubricated by addition of glyceryl dibehenate and magnesium stearate, and the mixture is compressed into tablets using appropriate tooling. The tablets are coated by spraying Opadry coating composition.
- PROCEDURE Bosentan monohydrate, maize starch, povidone, pregelatinized starch, and sodium starch glycollate are sifted and mixed in a blender. The mixture is granulated with an aqueous solution of poloxamer in a high shear granulator. The granules are dried and sieved. The dried granules are lubricated by addition of glyceryl dibehenate and magnesium stearate, and the mixture is compressed into tablets using appropriate tooling. The tablets are coated by spraying OpadryTM coating composition.
- PROCEDURE Bosentan monohydrate, maize starch, povidone, pregelatinized starch, and sodium starch glycollate are sifted and mixed in a blender. The mixture is granulated with an aqueous solution of poloxamer in a high shear granulator. The granules are dried and sieved. The dried granules are lubricated by addition of glyceryl dibehenate and magnesium stearate, and the mixture is compressed into tablets using appropriate tooling. The tablets are coated by spraying OpadryTM coating composition.
- Example 5 demonstrates the criticality of poloxamer in the compositions as described herein. Tablets comprising poloxamer showed increased bioavailability (in terms of increased C ma and AUCo-oo under fasting conditions) in comparison to a composition devoid of poloxamer, even when the particle size were similar.
- compositions of Example 2 were bioequivalent to reference product TracleerTM (125 mg) whereas the compositions of Comparative Example 2 were not bio-equivalent.
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Abstract
The present invention relates to pharmaceutical compositions comprising bosentan. More particularly, it relates to a pharmaceutical composition comprising bosentan, a surfactant, and at least one pharmaceutically acceptable excipient.
Description
PHARMACEUTICAL COMPOSITIONS OF BOSENTAN
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising bosentan. More particularly, it relates to a pharmaceutical composition comprising bosentan, a surfactant, and at least one pharmaceutically acceptable excipient.
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 I".
Bosentan and its preparation is disclosed in EP to 0526708 Al . 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 (Class III and IV in the United States, Class III in Europe). The commercially available formulation has the following composition: bosentan (125 or 62.5 mg), starch, triacetin, magnesium stearate, talc, ferric oxide, povidone, titanium dioxide, ethylcellulose, glyceryl behenate, hypromellose and sodium starch glycollate.
PCT Application 2006/123285 discloses dispersible tablets of bosentan which disperse in water in less than one minute. The formulations described therein are alleged to have better compliance, especially in pediatric patients.
Bosentan is a compound which is practically insoluble in water. It is also known that bosentan has low oral bioavailability. There is a need for alternative compositions of bosentan which have good bioavailability. We have surprisingly found that pharmaceutical compositions of bosentan having increased bioavailability may be formulated by modifying the particle size of bosentan and including a surfactant, such as poloxamer, in the composition.
SUMMARY OF THE INVENTION
Aspects of the invention relate to pharmaceutical composition of bosentan.
In one aspect, it discloses a pharmaceutical composition comprising:
i) bosentan;
ii) poloxamer; and
iii) at least one pharmaceutical acceptable excipient.
In one embodiment of the aspect, it discloses a pharmaceutical composition comprising:
i) bosentan;
ii) poloxamer; and
iii) at least one pharmaceutical acceptable excipient,
wherein the bosentan has dgo in the range of 5 μτη to 40 μπι.
In another embodiment of the aspect, it discloses a pharmaceutical composition comprising i) about 10% to about 90 % by weight bosentan; ii) about 0.1 % to about 5 % by weight poloxamer; iii) about 1 % to about 30 % by weight of a diluent; iv) about 1 % to about 10 % by weight of a binder; v) about 1 % to about 10 % by weight of a disintegrant; vi) about 0.1 to about 5 % by weight of a glidant, and vii) about 0.1 to about 5 % by weight of a lubricant, wherein the bosentan has d90 in the range of 5 μηι to 40 μπι.
In another aspect, it discloses a process for the preparation of a pharmaceutical composition, wherein the process comprises:
i) mixing bosentan and at least one pharmaceutically acceptable excipient;
ii) granulating the mixture of step (i) with an aqueous poloxamer solution;
iii) drying the granules of step (ii):
iv) mixing the granules of step (iii) with at least one pharmaceutically acceptable excipient;
v) compressing the mixture of step (iv) into a tablet; and
vi) optionally coating the tablet of step (v).
In one embodiment of the aspect, it discloses a process for the preparation of a pharmaceutical composition, wherein the process comprises:
i) mixing bosentan and at least one pharmaceutically acceptable excipient;
ii) granulating the mixture of step (i) with an aqueous poloxamer solution;
iii) drying the granules of step (ii);
iv) mixing the granules of step (iii) with at least one pharmaceutically acceptable excipient;
v) compressing the mixture of step (iv) into a tablet; and
vi) optionally coating the tablet of step (v),
wherein the bosentan has d 0 in the range of 5 μηι to 40 μιη.
DETAILED DESCRIPTION OF THE INVENTION
The term "bosentan" as described herein is defined to mean bosentan free base or its pharmaceutically acceptable salts, or solvates, including hydrates, of bosentan. In one preferred embodiment of the invention bosentan is in the monohydrate form. The amount of bosentan may vary from about 10 % to about 90 % by weight, preferably from about 40 % to about 80 % 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, d90 value of 30 μπι means that 90 % particles are smaller than 30 μιτι. The "d90" of bosentan as described herein may vary ranging from about 5 μιη to about 40 μηι. The term "dso" as described herein means that 50% the particles are smaller than the specified value. The "d50" of bosentan as described herein may vary ranging from about 1 μιη to about 20 μπι. The term "dio" as described herein means that 10 % the particles are smaller than the specified value. The "di0" of bosentan as described herein may vary ranging from about 1 μπ to about 5 μιη. Conventional procedures known to the skilled person, 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 to the skilled person such as Malvern ' Mastersizer.
The term "poloxamer" as described herein refers to a class of surfactants which are nonionic triblock co-polymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)). The poloxamer as described herein may be selected from the various grades available commercially under the trade name of Pluronic™ or Lutrol™. The poloxamer as described herein may be present in a range varying from about 0.1 % to about 5 % by weight of the composition.
The compositions as described herein may comprise at least one pharmaceutically acceptable excipient selected from a group comprising diluent, binder, disintegrant, glidant, lubricant, flavoring agent and sweetening agent.
Diluent as described herein may be selected from a group comprising lactose, sucrose, dextrose, microcrystalline cellulose, dibasic calcium phosphate, calcium sulphate, mannitol, erythritol, lactilol, maltitol, xylitol, sorbitol, starch, and mixtures thereof. The diluents may be present in an amount ranging from about 1% to about 30 % by weight of the composition.
Binder as described herein may be selected from a group comprising polyvinyl pyrrolidone, hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, starch, and mixtures thereof. The binder may be present in an amount ranging from about 1 % to about 10 % by weight of the composition.
Disintegrant as described herein may be selected from one or more of sodium starch glycolate, crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, pregelatinized starch, alginic acid, sodium alginate, and mixtures thereof. The disintegrant may be present in an amount ranging from about 1% to about 10 % by weight of the composition.
Glidant as described herein may be selected from a group comprising colloidal silicon dioxide, talc, and mixtures thereof. The glidant may be present in an amount ranging from about 0.1 % to about 5 % by weight, more preferably from about 0.1 % to about 2 % by weight of the composition.
Lubricant as described herein may be selected from a group comprising magnesium stearate, stearic acid, talc, sodium stearyl fumarate, glyceryl dibehenate, polyethylene glycol, hydrogenated castor oil, and mixtures thereof. The lubricant may be present in an
amount ranging from about 0.1 % to about 5 % by weight, more preferably from about 0.1 % to about 2 % by weight of the composition.
Flavoring agent as described herein may be selected from a group comprising cinnamon, cherry, strawberry, raspberry, apple, bubblegum, vanilla, chocolate, mint, apricot, and the like, and mixtures thereof. The flavoring agent may be present in an amount ranging from 0.1% to 2 % by weight of the composition.
Sweetening agent as described herein may be selected from a group comprising xylose, rebose, glucose, mannose, galactose, fructose, sucrose, maltose, invert sugar, partially hydrolyzed starch, glycyrrhizin, sorbitol, xylitol, mannitol, maltitol, saccharin acid, saccharin salts, acesulfame potassium, sucralose, and mixtures thereof. The sweetening agent may be present in an amount ranging from 0.1 % to 2 % by weight of the composition.
The pharmaceutical compositions as described herein may be prepared by techniques such as direct compression, dry granulation or wet granulation.
In one embodiment, the compositions as described herein may be prepared by direct compression. For example, bosentan may be mixed with a diluent, disintegrant, binder, surfactant, flavoring agent and sweetening agent, in a mixer and the mixture may be compressed into a tablet. In one embodiment, the surfactant is poloxamer.
In another embodiment, the compositions as described herein may be prepared by dry granulation. For example, bosentan may be mixed with a diluent, disintegrant, binder, and surfactant and the mixture may be passed through a roller compactor or a slugger, and processed to form compacts or slugs. The compacts may be mixed with excipients such as lubricant , glidant and optionally a diluent, disintegrant, flavoring agent or sweetening agent, and the mixture may be compressed into a tablet.
In another embodiment, the compositions as described herein may be prepared by wet granulation. For example, bosentan may be mixed with a diluent, disintegrant and a binder, and the mixture may be granulated with an aqueous solution of the surfactant, in a conventional high shear mixer granulator or in fluid bed granulator equipment, such as Glatt™ or Wurster™. Alternatively, a binder may be included in the aqueous surfactant solution and the mixture of bosentan, diluent and disintegrant may be granulated. In one embodiment the surfactant is poloxamer. The granules may be dried, sieved and mixed with extragranular excipients such as lubricant, glidant and optionally a diluent,
disintegrant, flavoring agent or sweetening agent, and the mixture may be processed into suitable composition such as tablet.
The tablet may be coated with suitable coating composition such as the one
T"Vl · · commercially available under the trade name Opadry . Such a coating composition may comprise a film-forming polymer, plasticizer, detackifying agent, coloring agent and an opacifying agent. The film-forming agent as described herein include, but not limited to, polyvinyl alcohol, ethylcellulose, hydroxypropyl methylcellulose, and the like. The plasticizer as described herein include, but not limited to, diethyl phthalate, diethyl sebacate, dibutyl sebacate, , triethyl citrate, dibutyl phthalate, acetyl triethyl citrate, glyceryl monostearate, glyceryl triacetate, polyethylene glycol, propylene glycol, and the like. The detackifying agent as described herein include, but not limited to,talc, finely divided silicon dioxide, glyceryl monostearate. and the like. The coloring agent may be selected form permitted FD&C dyes. The opacifying agent as described herein includes, but not limited to, titanium dioxide, iron oxides, and the like.
The skilled person is in cognizance of the fact that any excipient as described herein may serve more than one function e.g. diluent, disintegrant, binder, glidant, and/or lubricant.
In one embodiment a composition comprising bosentan may be prepared by i) mixing bosentan, a diluent, a disintegrant and a binder;
ii) granulating the mixture of step (i) with an aqueous poloxamer solution;
iii) drying the granules of step (ii);
iv) mixing the granules of step (iii) with a glidant and a lubricant;
v) compressing the mixture of step (iv) into a tablet; and
vi) coating the tablet of step (v).
Certain specific aspects and embodiments of this invention are described in further detail by the examples below, where such examples are provided only for the purpose of illustration and are not intended to scope of the appended claims in any manner.
EXAMPLE 1
Amount
Ingredients (in mg)
CORE
Intragranular
Bosentan monohydrate* (equivalent to
130.3
125 mg Bosentan)
Maize starch 26.3
Povidone 1.8
Pregelatinized starch 9.0
Sodium starch glycollate 7.2
Poloxamer 1.8
Purified water q.s.
Extragranular
Glycerol dibehenate 0.9
Magnesium stearate 2.7
COATING
Opadry™ 4.5
TOTAL 184.50
*d90 = 29 μιτι; d50 = 8 μηι (as measured my Malvern™ Mastersizer)
PROCEDURE: Bosentan monohydrate, maize starch, povidone, pregelatinized starch and sodium starch glycollate are sifted and mixed in a blender. The mixture is granulated with an aqueous solution of poloxamer in a high shear granulator. The granules are dried and sieved. The dried granules are lubricated by addition of glycerol dibehenate and magnesium stearate, and the mixture is compressed into tablets using appropriate tooling. The tablets are coated by spraying Opadry coating composition.
EXAMPLE 2
Amount
Ingredients (in mg)
CORE
Intragranular
Bosentan monohydrate* (equivalent to
129.1
125 mg Bosentan)
; Maize starch 26.6
Povidone 1.8
Pregelatinized starch 9.0
Sodium starch glycollate 7.2
Colloidal silicon dioxide 1.8
Poloxamer 0.9
Purified water q.s.
Extragranular
Glyceryl dibehenate 0.9
Magnesium stearate 2.7
COATING
Opadry™ 4.5
TOTAL 184.5
*d90 < 30 μηι; d50 < 10 μηι (as measured my Malvern Mastersizer)
PROCEDURE: Bosentan mono hydrate, maize starch, povidone, pregelatinized starch, and sodium starch glycollate are sifted and mixed in a blender. The mixture is granulated with an aqueous solution of poloxamer in a high shear granulator. The granules are dried and sieved. The dried granules are mixed with colloidal silicon dioxide and lubricated by addition of glyceryl dibehenate and magnesium stearate, and the mixture is compressed into tablets using appropriate tooling. The tablets are coated by spraying Opadry coating composition.
EXAMPLE 3
Amount
Ingredients (in mg)
CORE
Intragranular
Bosentan monohydrate* (equivalent to
64.54
62.5 mg Bosentan)
Maize starch 13.31
Povidone 0.90
Pregelatinized starch 4.50
Sodium starch glycollate 3.60
Colloidal silicon dioxide 0.90
Poloxamer 0.45
Purified water q.s.
Extragranular
Glyceryl dibehenate 0.45
Magnesium stearate 1.35
COATING
Opadry™ 2.25
TOTAL 92.25
*d90 < 30 μπι; d50 < 10 μπι (as measured my Malvern Mastersizer)
PROCEDURE: Bosentan monohydrate, maize starch, povidone, pregelatinized starch and sodium starch glycollate are sifted and mixed in a blender. The mixture is granulated with an aqueous solution of poloxamer in a high shear granulator. The granules are dried and sieved. The dried granules are mixed with colloidal silicon dioxide and lubricated by addition of glyceryl dibehenate and magnesium stearate, and the mixture is compressed into tablets using appropriate tooling. The tablets are coated by spraying Opadry coating composition.
COMPARATIVE EXAMPLE 1
Amount
Ingredients (in mg)
CORE
Intragranular
Bosentan monohydrate (equivalent to
129.3
125 mg Bosentan)
Maize starch 21.0
Povidone 1.8
Pregelatinized starch 18.0
Sodium starch glycollate 7.2
Purified water q.s.
Extragranular
Glyceryl dibehenate 0.9
Magnesium stearate 1.8
COATING
Opadry1 M 4.5
TOTAL 184.5
*d90 = 50 μίτι; d5o = 15 μιτι (as measured my Malvern Mastersizer)
PROCEDURE: Bosentan monohydrate, maize starch, povidone, pregelatinized starch, and sodium starch glycollate are sifted and mixed in a blender. The mixture is granulated with an aqueous solution of poloxamer in a high shear granulator. The granules are dried and sieved. The dried granules are lubricated by addition of glyceryl dibehenate and magnesium stearate, and the mixture is compressed into tablets using appropriate tooling. The tablets are coated by spraying Opadry™ coating composition.
COMPARATIVE EXAMPLE 2
Amount
Ingredients (in mg)
CORE
Intragranular
Bosentan monohydrate (equivalent to
130.3
125 mg Bosentan)
Maize starch 28.1
Povidone 1.8
Pregelatinized starch 9.0
Sodium starch glycollate 7 Ί
Purified water q.s.
Extragranular
Glyceryl dibehenate 0.9
Magnesium stearate 2.7
COATING
Opadry™ 4.5
TOTAL 184.5
*dgo < 30 μηι; d50 < 10 μπι (as measured my Malvern Mastersizer)
PROCEDURE: Bosentan monohydrate, maize starch, povidone, pregelatinized starch, and sodium starch glycollate are sifted and mixed in a blender. The mixture is granulated with an aqueous solution of poloxamer in a high shear granulator. The granules are dried and sieved. The dried granules are lubricated by addition of glyceryl dibehenate and magnesium stearate, and the mixture is compressed into tablets using appropriate tooling. The tablets are coated by spraying Opadry™ coating composition.
EXAMPLE 4
Dissolution of Bosentan from compositions of Example 1 and Comparative Example in USP Type-II Apparatus (pedal), 50 rpm, in 900 ml water (containing 1 % SLS)
EXAMPLE 5
Pharmacokinetic Parameters of Compositions of Example 1 and Comparative Example 2
A single dose, crossover study was done on 21 subjects under fasting conditions. The mean values are as below:
Moreover, compositions of Example 2 were bioequivalent to reference product Tracleer™ (125 mg) whereas the compositions of Comparative Example 2 were not bio-equivalent.
Having thus described the invention with reference to particular embodiments and illustrative examples, those in the art may appreciate that modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as recited in the appended claims.
Claims
1 ) A pharmaceutical composition comprising:
i) bosentan;
ii) poloxamer; and
iii) at least one pharmaceutical acceptable excipient.
2) The composition of claim 1, wherein bosentan has d90 in the range of 5 μιη to 40 μπι.
3) The composition of claim 1, wherein bosentan has d50 in the range of 1 μηι to 20 μηι.
4) The composition of claim 1, wherein bosentan is present in an amount ranging from about 10 % to about 80 % by weight of the composition.
5) The composition of claim 1, wherein poloxamer is present in an amount ranging from about 0.1 % to about 5 % by weight of the composition.
6) The composition of claim 1, wherein the pharmaceutically acceptable excipient is selected from a group consisting of diluent, binder, disintegrant, glidant, lubricant, flavoring agent and sweetening agent.
7) The composition of claim 6, wherein the diluent is selected from a group consisting of lactose, sucrose, dextrose, microcrystalline cellulose, dibasic calcium phosphate, calcium sulphate, mannitol, erythritol, lactilol, xylitol, sorbitol, starch, and mixtures thereof.
8) The composition of claim 6, wherein the diluent is present in an amount ranging from about 1% to about 30 % by weight of the composition.
9) The composition of claim 6, wherein the binder is selected from a group consisting of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, starch, and mixtures thereof.
10) The composition of claim 6, wherein the binder is present in an amount ranging from about 1% to about 10 % by weight of the composition. 1 1) The composition of claim 6, wherein the disintegrant is selected from a group consisting of sodium starch glycolate, crospovidone, croscarmellose sodium, low- substituted hydroxypropyl cellulose, pregelatinized starch, alginic acid, sodium alginate, and mixtures thereof.
12) The composition of claim 6, wherein the disintegrant is present in an amount ranging from about 1% to about 10 % by weight of the composition.
13 ) The composition of claim 6, wherein the glidant is selected from a group consisting of colloidal silicon dioxide, talc, stearic acid, and mixtures thereof.
14) The composition of claim 6, wherein the glidant is present in an amount ranging from about 0.1 % to about 5 % by weight of the composition.
15) The composition of claim 6, wherein the lubricant is selected from a group consisting of magnesium stearate, stearic acid, talc, sodium stearyl fumarate, glyceryl dibehenate, polyethylene glycol, hydrogenated castor oil, and mixtures thereof.
16) The composition of claim 6, wherein the lubricant is present in an amount ranging from about 0.1 % to about 5 % by weight of the composition.
17) The composition of claim 1 , wherein the composition is a tablet. 18) A tablet composition comprising i) about 10% to about 80 % by weight bosentan; ii) about 0.1 % to about 5 % by weight poloxamer; iii) about 1 % to about 30 % by weight of a diluent selected from a group consisting of lactose, microcrystalline cellulose, starch, and mixtures thereof; iv) about 1 % to about 10 % by weight of a binder selected from a group consisting of polyvinyl pyrrolidone, starch, and mixtures thereof; v) about 1 % to about 10 % by weight of a disintegrant selected from a group consisting of sodium starch glycolate, crospovidone, croscarmellose sodium and pregelatinized starch; and vi) about 0.1 to about 5 % by weight of a glidant selected from a group consisting of colloidal silicon dioxide, talc, and mixtures thereof; and vii) about 0.1 to about 5 % by weight of a lubricant selected from magnesium stearate, stearic acid, talc, sodium stearyl fumarate, glyceryl dibehenate, polyethylene glycol, hydrogenated castor oil, and mixtures thereof, wherein the bosentan has dgo in the range of 5 μηι to 40 μιη.
19) The composition of claim 18. wherein the composition is bioequivalent to Tracleer™
20) A process for the preparation of a pharmaceutical composition, wherein the process comprises: i) mixing bosentan and at least one pharmaceutically acceptable excipient; ii) granulating the mixture of step (i) with an aqueous poloxamer solution; iii) drying the granules of step (ii);
iv) mixing the granules of step (iii) with at least one pharmaceutically acceptable excipient;
v) compressing the mixture of step (iv) into a tablet; and
vi) optionally coating the tablet of step (v).
21) The process of claim 20, wherein the bosentan has d 0 in the range of 5 μπι to 40 μπι.
22) The process of claim 20, wherein the process comprises
i) mixing bosentan, a diluent, a disintegrant and a binder;
ii) granulating the mixture of step (i) with an aqueous poloxamer solution; iii) drying the granules of step (ii);
iv) mixing the granules of step (iii) with a glidant and a lubricant;
v) compressing the mixture of step (iv) into a tablet; and
vi) coating the tablet of step (v).
23) The process of claim 20, wherein the pharmaceutically acceptable excipient is selected from a group consisting of diluent, binder, disintegrant, glidant, lubricant, flavoring agent and sweetening agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB2011/003200 WO2013098577A1 (en) | 2011-12-31 | 2011-12-31 | Pharmaceutical compositions of bosentan |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB2011/003200 WO2013098577A1 (en) | 2011-12-31 | 2011-12-31 | Pharmaceutical compositions of bosentan |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2013098577A1 true WO2013098577A1 (en) | 2013-07-04 |
Family
ID=45607293
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2011/003200 WO2013098577A1 (en) | 2011-12-31 | 2011-12-31 | Pharmaceutical compositions of bosentan |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2013098577A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104826120A (en) * | 2015-05-05 | 2015-08-12 | 重庆华邦制药有限公司 | Bosentan preparation |
| CN104840965A (en) * | 2015-05-05 | 2015-08-19 | 重庆华邦制药有限公司 | Bosentan preparation and stabilizer thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0526708A1 (en) | 1991-06-13 | 1993-02-10 | F. Hoffmann-La Roche Ag | Sulfonamide, preparation and use thereof as medicine and intermediate |
| WO2009047637A1 (en) * | 2007-10-11 | 2009-04-16 | Actavis Group Ptc Ehf | Novel polymorphs of bosentan |
| WO2009098517A1 (en) * | 2008-02-08 | 2009-08-13 | Generics [Uk] Limited | Process for preparing bosentan |
| WO2010015623A1 (en) * | 2008-08-05 | 2010-02-11 | Farmaprojects, S. A. | Process for the preparation of endothelin receptor antagonists |
| WO2010127198A1 (en) * | 2009-04-30 | 2010-11-04 | Abbott Laboratories | Formulation for oral administration of apoptosis promoter |
-
2011
- 2011-12-31 WO PCT/IB2011/003200 patent/WO2013098577A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0526708A1 (en) | 1991-06-13 | 1993-02-10 | F. Hoffmann-La Roche Ag | Sulfonamide, preparation and use thereof as medicine and intermediate |
| WO2009047637A1 (en) * | 2007-10-11 | 2009-04-16 | Actavis Group Ptc Ehf | Novel polymorphs of bosentan |
| WO2009098517A1 (en) * | 2008-02-08 | 2009-08-13 | Generics [Uk] Limited | Process for preparing bosentan |
| WO2010015623A1 (en) * | 2008-08-05 | 2010-02-11 | Farmaprojects, S. A. | Process for the preparation of endothelin receptor antagonists |
| WO2010127198A1 (en) * | 2009-04-30 | 2010-11-04 | Abbott Laboratories | Formulation for oral administration of apoptosis promoter |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104826120A (en) * | 2015-05-05 | 2015-08-12 | 重庆华邦制药有限公司 | Bosentan preparation |
| CN104840965A (en) * | 2015-05-05 | 2015-08-19 | 重庆华邦制药有限公司 | Bosentan preparation and stabilizer thereof |
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