WO2013057741A2 - Pharmaceutical compositions of ursodeoxycholic acid - Google Patents
Pharmaceutical compositions of ursodeoxycholic acid Download PDFInfo
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- WO2013057741A2 WO2013057741A2 PCT/IN2012/000667 IN2012000667W WO2013057741A2 WO 2013057741 A2 WO2013057741 A2 WO 2013057741A2 IN 2012000667 W IN2012000667 W IN 2012000667W WO 2013057741 A2 WO2013057741 A2 WO 2013057741A2
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- ursodeoxycholic acid
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
Definitions
- the present invention relates to pharmaceutical compositions of Ursodeoxycholic acid (Ursodiol). Particularly, the present invention relates to pharmaceutical compositions of Ursodeoxycholic acid containing micronized Ursodeoxycholic acid.
- Ursodeoxycholic acid is 3a, 7P-dihydroxy-5P-cholan-24-oic acid with a molecular formula C 24 H 40 O 4 . Ursodeoxycholic acid has a molecular weight of 392.56. Its structure is shown belo
- Ursodeoxycholic acid is especially suitable for the treatment of cholesterol metabolic disorders.
- Ursodeoxycholic acid is a naturally occurring bile acid found in small quantities in normal human bile and in larger quantities in the biles of certain species of bears. It is a bitter-tasting white powder consisting of crystalline particles freely soluble in ethanol and glacial acetic acid, slightly soluble in chloroform, sparingly soluble in ether, and practically insoluble in water. Ursodeoxycholic acid is normally present as a minor fraction of the total bile acids in humans (about 5%). Following oral administration, the majority of Ursodeoxycholic acid is absorbed by passive diffusion and its absorption is incomplete. Once absorbed, Ursodeoxycholic acid undergoes hepatic extraction to the extent of about 50% in the absence of liver disease.
- Ursodeoxycholic acid is conjugated with glycine or taurine, then secreted into bile, These conjugates of Ursodeoxycholic acid are absorbed in the small intestine by passive and active mechanisms. The conjugates can also be deconjugated in the ileum by intestinal enzymes, leading to the formation of free ursodiol that can be reabsorbed and reconjugated in the liver. Nonabsorbed ursodiol passes into the colon where it is mostly 7-dehydroxylated to lithocholic acid. Some Ursodeoxycholic acid is epimerized to chenodiol (CDCA) via a 7-oxo intermediate.
- DCA chenodiol
- Chenodiol also undergoes 7-dehydroxylation to form lithocholic acid. These metabolites are poorly soluble and excreted in the feces. A small portion of lithocholic acid is reabsorbed, conjugated in the liver with glycine, or taurine and sulfated at the 3 position. The resulting sulfated lithocholic acid conjugates are excreted in bile and then lost in feces.
- Ursodeoxycholic acid is marketed in France as DELURSAN ® 250mg tablets ' or as RUSOLVAN® 200mg capsules.
- EP0599282 patent discloses controlled release pharmaceutical compositions for Ursodeoxycholic acid containing microgranules, wherein microgranules are prepared by extrusion-spheronization technique.
- WO2008130234 patent discloses high dose pharmaceutical formulation containing 400 to 3000 mg of Ursodeoxycholic acid.
- the formulation is prepared by using multiparticulate technology.
- EP1317925 patent discloses taste masked microgranules for the oral administration of Ursodeoxycholic acid, which consists of plasticiser and copolymer of (meth)acrylic acid having a molecular weight ranging between 100,000 and 850,000.
- EP0524395 patent discloses sustained release pharmaceutical compositions of Ursodeoxycholic acid containing agar, one or more substances suitable for gel formation and a basic buffer.
- EP0625353 patent discloses slow-release pharmaceutical composition containing a bile acid as active ingredient and comprising at least one bioadhesive substance and at least one high specific gravity substance, and provided in the form of 0.5-2 mm dia. coated particles or of tablets, characterized by having an aliquot enteric coated with gastro-resistant substances and the remainder non-enteric coated.
- EP0508312 patent discloses controlled release pharmaceutical formulations for oral use coated by an entero-soluble gastro-resistant film containing therapeu tical ly effective amounts of a mixture of bile acids and their salts with alkali metals or organic bases.
- WO2008062475 patent discloses ursodiol composition containing micronized and unmicronized ursodiol in the ratio about 5:95 to about 95:5. Nevertheless, such proposal suffers from the limitation of uniform distribution of two heterogeneous particle size grades in intended ratio in each tablet and thereby it is difficult to obtain reproducible dissolution profile from batch to batch in commercial scale. Further, from regulatory and quality control point of view, it will also be difficult to establish uniform distribution of active by a validated analytical method. As Ursodeoxycholic acid is very less soluble and bioavailability is highly depend on particle size. The present inventors developed formulation containing micronized Ursodeoxycholic acid, having a particle size of d 90 less than 25 microns, which is bio-equivalent to reference product (DELURSAN ® 250rng tablets),
- the main embodiment of the present invention provides Ursodeoxycholic acid composition comprising Ursodeoxycholic acid and one or more pharmaceutically acceptable excipients, wherein Ursodeoxycholic acid is present in the form of micronized particles having a particle size of d 90 less than 25 microns.
- composition w r herein ursodeoxycholic acid is present in the form of micronized particles having a particle size of d.) 0 less than 25 microns has the sought dissolution profile and is bio-equivalent to re ference product (DELURSAN ® 250mg tablets), which means that the composition has C nui and AUCo-t values matching the reference product.
- particle size of d 90 means that at least 90% of the particles of micronized ursodeoxycholic acid have a size less than 25 microns.
- Ursodeoxycholic acid is measured by Malvern master-sizer.
- Micronization of ursodeoxycholic acid is carried out using conventionally known mills, such as a ball mill, colloid mill, grinding mill, air jet mill, roller mill, impact mill, etc.
- Air jet milling is particularly well suited as it is a well proven technique that consistently produces particles of a size less than 25 microns.
- 100% of ursodeoxycholic acid is present in the form of micronized particles having a particle size of d 90 less than 25 microns.
- the ursodeoxycholic acid content in the composition preferably ranges from 40% to 80% by weight, advantageously from 50% to 70% by weight, in respect of the total weight of the composition.
- the one or more pharmaceutically acceptable excipients are selected from the group consisting of diluents, binders, disintegrants, wetting agents, lubricants, glidants and combinations thereof.
- Diluents are inactive excipients which are generally used to increase the bulk of the tablet, thus facilitating easy of tablet or capsule preparations.
- Suitable diluents used according to the present invention may be selected from the group consisting of microcrystalline cellulose, mannitol, lactose, maize starch, calcium hydrogen phosphate, sorbitol, sucrose, dicalcium phosphate and combinations thereof. Maize starch is preferred.
- Binders are used in the formulation of solid oral dosage forms to hold the active pharmaceutical ingredient and inactive ingredients together in a cohesive mix.
- Suitable binders used according to the present invention may be selected from the group consisting of povidone, potato starch, wheat starch, corn starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin and combinations thereof ⁇ av0done_is_preferred.—
- Disintegrants are excipients causing a quick breaking of the tablet in contact of aqueous medium and also a quick disintegration of the granules, such that the ursodeoxycholic acid is more rapidly dispersed or dissolved.
- Suitable disintegrants used according to the present invention may be selected from the group consisting of sodium starch glycolate, crospovidone, microcrystalline cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium, carmellose calcium, croscarmellose potassium, Silicified microcrystalline cellulose and combinations thereof.
- Wetting agents are excipients used to aid in attaining intimate contact between solid particles and liquids.
- Suitable wetting agents used to the present invention ma y be selected from the group consisting of sodium lauryl sulfate, polysorbates. Poloxamers, Sorbiton, povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin and combinations thereof. Povidone, sodium lauryl sulfate and combinations thereof are preferred.
- Lubricants are excipients reducing tensions between particles, favoring the formation of the tablets and preventing the adhesion of the particles.
- Suitable lubricants used according to the present invention may be selected from the group consisting of sodium stearyl fumarate, magnesium stearate, calcium stearate, hydrpgenated vegetable oil,, stearic acid, glyceryl behenate, tale and the like, magnesium stearate is preferred.
- Glidants are used to promote powder flow by reducing interparticle friction and cohesion.
- Suitable glidants used according to the present invention may be selected from the group consisting of calcium phosphate tribasic, powdered cellulose, colloidal silicon dioxide, magnesium oxide, magnesium silicate, mag iesjurn_ trisilicate, starch, talc and combinations thereof. Colloidal silicon dioxide is preferred.
- a preferred composition according to the invention, comprises:
- diluent in particular maize starch
- At least one wetting agent in particular selected from the group consisting of Povidone, sodium lauryl sulfate and combinations thereof;
- At least one lubricant in particular magnesium stearate
- glidant in particular colloidal silicon dioxide
- each ingredient is adapted by the skilled person on the basis o f his common general knowledge and the usual handbooks and reference books i n pharmaceutical technology.
- Ursodeoxycholic acid composition of the present invention may be in the form of tablets, capsules, granules, sachets, preferably tablets.
- Ursodeoxycholic acid composition of the present, invention may be prepared by wet granulation, dry granulation or direct compression process.
- the composition is prepared by wet granulatiori ⁇ rocess ⁇
- Suitable solvents used according to the present invention may be selected from water, ethanol, isopropyl alcohol, and combinations thereof.
- Example 1 Example 1 composition is prepared using Ursodeoxycholic acid having particle size of d 90 less than 25 microns
- Example 2 composition is prepared using Ursodeoxycholic acid having particle size of d 90 less than 80 microns
- Binder solution preparation Dispersed maize starch in purified water under stirring to form slurry. Dissolved Povidone and sodium lauryl sulfate in purified water heated up to 70-80°C. Added starch slurry to the hot solution under continuous stirring to form smooth transparent paste.
- Granulation Loaded sifted Ursodeoxycholic acid, colloidal anhydrous silica and maize starch in rapid mixing granulator and mix for 20 minutes. Added binder solution slowly and granulated to get consistent mass. The granules are dried in Fluid bed drier at 60°.
- Blending Loaded the above dried granules and magnesium stearate in a blender and blended for 5 minutes.
- the above blend is compressed into tablets.
- Dissolution profile was conducted for both the tablets of Example 1 & 2 in pH 8.0 phosphate buffer, 1000 ml using USP 1 apparatus at 100 rpm.
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Abstract
The present invention is directed to pharmaceutical compositions of Ursodeoxycholic acid, wherein the composition comprises micronized Ursodeoxycholic acid having a particle size of d90 less than 25 microns and one or more pharmaceutically acceptable excipients.
Description
DESCRIPTION
FILED OF INVENTION
The present invention relates to pharmaceutical compositions of Ursodeoxycholic acid (Ursodiol). Particularly, the present invention relates to pharmaceutical compositions of Ursodeoxycholic acid containing micronized Ursodeoxycholic acid.
BACKGROUND OF THE INVENTION
Ursodeoxycholic acid is 3a, 7P-dihydroxy-5P-cholan-24-oic acid with a molecular formula C24 H40 O4. Ursodeoxycholic acid has a molecular weight of 392.56. Its structure is shown belo
Ursodeoxycholic acid is especially suitable for the treatment of cholesterol metabolic disorders.
Ursodeoxycholic acid is a naturally occurring bile acid found in small quantities in normal human bile and in larger quantities in the biles of certain species of bears. It is a bitter-tasting white powder consisting of crystalline particles freely soluble in ethanol and glacial acetic acid, slightly soluble in chloroform, sparingly soluble in ether, and practically insoluble in water.
Ursodeoxycholic acid is normally present as a minor fraction of the total bile acids in humans (about 5%). Following oral administration, the majority of Ursodeoxycholic acid is absorbed by passive diffusion and its absorption is incomplete. Once absorbed, Ursodeoxycholic acid undergoes hepatic extraction to the extent of about 50% in the absence of liver disease. As the severity of liver disease increases, the extent of extraction decreases. In the liver, Ursodeoxycholic acid is conjugated with glycine or taurine, then secreted into bile, These conjugates of Ursodeoxycholic acid are absorbed in the small intestine by passive and active mechanisms. The conjugates can also be deconjugated in the ileum by intestinal enzymes, leading to the formation of free ursodiol that can be reabsorbed and reconjugated in the liver. Nonabsorbed ursodiol passes into the colon where it is mostly 7-dehydroxylated to lithocholic acid. Some Ursodeoxycholic acid is epimerized to chenodiol (CDCA) via a 7-oxo intermediate. Chenodiol also undergoes 7-dehydroxylation to form lithocholic acid. These metabolites are poorly soluble and excreted in the feces. A small portion of lithocholic acid is reabsorbed, conjugated in the liver with glycine, or taurine and sulfated at the 3 position. The resulting sulfated lithocholic acid conjugates are excreted in bile and then lost in feces.
Ursodeoxycholic acid is marketed in France as DELURSAN ® 250mg tablets' or as RUSOLVAN® 200mg capsules.
EP0599282 patent discloses controlled release pharmaceutical compositions for Ursodeoxycholic acid containing microgranules, wherein microgranules are prepared by extrusion-spheronization technique.
WO2008130234 patent discloses high dose pharmaceutical formulation containing 400 to 3000 mg of Ursodeoxycholic acid. The formulation is prepared by using multiparticulate technology.
EP1317925 patent discloses taste masked microgranules for the oral administration of Ursodeoxycholic acid, which consists of plasticiser and copolymer of (meth)acrylic acid having a molecular weight ranging between 100,000 and 850,000. EP0524395 patent discloses sustained release pharmaceutical compositions of Ursodeoxycholic acid containing agar, one or more substances suitable for gel formation and a basic buffer.
EP0625353 patent discloses slow-release pharmaceutical composition containing a bile acid as active ingredient and comprising at least one bioadhesive substance and at least one high specific gravity substance, and provided in the form of 0.5-2 mm dia. coated particles or of tablets, characterized by having an aliquot enteric coated with gastro-resistant substances and the remainder non-enteric coated.
EP0508312 patent discloses controlled release pharmaceutical formulations for oral use coated by an entero-soluble gastro-resistant film containing therapeu tical ly effective amounts of a mixture of bile acids and their salts with alkali metals or organic bases.
WO2008062475 patent discloses ursodiol composition containing micronized and unmicronized ursodiol in the ratio about 5:95 to about 95:5. Nevertheless, such proposal suffers from the limitation of uniform distribution of two heterogeneous particle size grades in intended ratio in each tablet and thereby it is difficult to obtain reproducible dissolution profile from batch to batch in commercial scale. Further, from regulatory and quality control point of view, it will also be difficult to establish uniform distribution of active by a validated analytical method.
As Ursodeoxycholic acid is very less soluble and bioavailability is highly depend on particle size. The present inventors developed formulation containing micronized Ursodeoxycholic acid, having a particle size of d90 less than 25 microns, which is bio-equivalent to reference product (DELURSAN ® 250rng tablets),
BRIEF DESCRIPTION OF THE INVENTION
The main embodiment of the present invention provides Ursodeoxycholic acid composition comprising Ursodeoxycholic acid and one or more pharmaceutically acceptable excipients, wherein Ursodeoxycholic acid is present in the form of micronized particles having a particle size of d90 less than 25 microns.
DETAILED DESCRIPTION OF THE INVENTION
It has been surprisingly discovered that a composition wrherein ursodeoxycholic acid is present in the form of micronized particles having a particle size of d.)0 less than 25 microns has the sought dissolution profile and is bio-equivalent to re ference product (DELURSAN ® 250mg tablets), which means that the composition has Cnui and AUCo-t values matching the reference product.
As used herein, "particle size of d90" means that at least 90% of the particles of micronized ursodeoxycholic acid have a size less than 25 microns.
The particle size of Ursodeoxycholic acid is measured by Malvern master-sizer. Micronization of ursodeoxycholic acid is carried out using conventionally known mills, such as a ball mill, colloid mill, grinding mill, air jet mill, roller mill, impact mill, etc. Air jet milling is particularly well suited as it is a well proven technique that consistently produces particles of a size less than 25 microns.
In a preferred embodiment of the invention 100% of ursodeoxycholic acid is present in the form of micronized particles having a particle size of d90 less than 25 microns.
The ursodeoxycholic acid content in the composition preferably ranges from 40% to 80% by weight, advantageously from 50% to 70% by weight, in respect of the total weight of the composition.
The selection of additional excipients represents routine work for the skilled person, taking into account his common general knowledge and the usual handbooks and reference books in pharmaceutical technology such as the Handbook of Pharmaceutical excipients, Sixth edition edited by Raymond C Rowe, Paul J Sheskey and Marian E Quinn.
The one or more pharmaceutically acceptable excipients are selected from the group consisting of diluents, binders, disintegrants, wetting agents, lubricants, glidants and combinations thereof.
Diluents are inactive excipients which are generally used to increase the bulk of the tablet, thus facilitating easy of tablet or capsule preparations. Suitable diluents used according to the present invention may be selected from the group consisting of microcrystalline cellulose, mannitol, lactose, maize starch, calcium hydrogen phosphate, sorbitol, sucrose, dicalcium phosphate and combinations thereof. Maize starch is preferred.
Binders are used in the formulation of solid oral dosage forms to hold the active pharmaceutical ingredient and inactive ingredients together in a cohesive mix. Suitable binders used according to the present invention may be selected from the group consisting of povidone, potato starch, wheat starch, corn starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin and combinations thereof^^av0done_is_preferred.—
Disintegrants are excipients causing a quick breaking of the tablet in contact of aqueous medium and also a quick disintegration of the granules, such that the ursodeoxycholic acid is more rapidly dispersed or dissolved. Suitable disintegrants used according to the present invention may be selected from the group consisting of sodium starch glycolate, crospovidone, microcrystalline cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium, carmellose calcium, croscarmellose potassium, Silicified microcrystalline cellulose and combinations thereof. Wetting agents are excipients used to aid in attaining intimate contact between solid particles and liquids. Suitable wetting agents used to the present invention ma y be selected from the group consisting of sodium lauryl sulfate, polysorbates. Poloxamers, Sorbiton, povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin and combinations thereof. Povidone, sodium lauryl sulfate and combinations thereof are preferred.
Lubricants are excipients reducing tensions between particles, favoring the formation of the tablets and preventing the adhesion of the particles. Suitable lubricants used according to the present invention may be selected from the group consisting of sodium stearyl fumarate, magnesium stearate, calcium stearate, hydrpgenated vegetable oil,, stearic acid, glyceryl behenate, tale and the like, magnesium stearate is preferred.
Glidants are used to promote powder flow by reducing interparticle friction and cohesion. Suitable glidants used according to the present invention may be selected from the group consisting of calcium phosphate tribasic, powdered cellulose, colloidal silicon dioxide, magnesium oxide, magnesium silicate, mag iesjurn_
trisilicate, starch, talc and combinations thereof. Colloidal silicon dioxide is preferred.
A preferred composition, according to the invention, comprises:
- Ursodeoxycholic acid 100% present in the form of micronized particles having a particle size of d90 less than 25 microns;
- at least one diluent, in particular maize starch;
- at least one binder, in particular povidone;
- at least one wetting agent, in particular selected from the group consisting of Povidone, sodium lauryl sulfate and combinations thereof;
- at least one lubricant, in particular magnesium stearate;
- at least one glidant, in particular colloidal silicon dioxide;
- optionally water. The content in each ingredient is adapted by the skilled person on the basis o f his common general knowledge and the usual handbooks and reference books i n pharmaceutical technology.
Ursodeoxycholic acid composition of the present invention may be in the form of tablets, capsules, granules, sachets, preferably tablets.
In another embodiment of the present invention provides process for preparing Ursodeoxycholic acid composition.
Ursodeoxycholic acid composition of the present, invention may be prepared by wet granulation, dry granulation or direct compression process. Preferably the composition is prepared by wet granulatiori^rocess^
Suitable solvents used according to the present invention may be selected from water, ethanol, isopropyl alcohol, and combinations thereof.
The invention is illustrated by the following non limiting examples: Example 1: Example 1 composition is prepared using Ursodeoxycholic acid having particle size of d90 less than 25 microns
Example 2: Example 2 composition is prepared using Ursodeoxycholic acid having particle size of d90 less than 80 microns
Table 1
Process:
Example 1 & 2:
Sifting: Sifted Ursodeoxycholic acid, maize starch, and magnesium stearate separately through #30 mesh and Colloidal anhydrous silicon dioxide through #40 mesh.
Binder solution preparation: Dispersed maize starch in purified water under stirring to form slurry. Dissolved Povidone and sodium lauryl sulfate in purified water heated up to 70-80°C. Added starch slurry to the hot solution under continuous stirring to form smooth transparent paste.
Granulation: Loaded sifted Ursodeoxycholic acid, colloidal anhydrous silica and maize starch in rapid mixing granulator and mix for 20 minutes. Added binder solution slowly and granulated to get consistent mass. The granules are dried in Fluid bed drier at 60°.
Blending: Loaded the above dried granules and magnesium stearate in a blender and blended for 5 minutes.
The above blend is compressed into tablets.
In-vitro dissolution studies: Dissolution profile was conducted for both the tablets of Example 1 & 2 in pH 8.0 phosphate buffer, 1000 ml using USP 1 apparatus at 100 rpm.
Table 2. Cumulative % of drug release The above dissolution data revealed that composition with both the particle size have similar dissolution profile and matching with reference product.
Bio-equivalency study:
A three way cross-over study was conducted for studying the Bio-equivalency of two compositions.
The summary of the Bio-equivalency study results are as follows:
90% confidence interval of Geometric mean Pharmacokinetic arameters
* Free (unconjugated) Ursodeoxycholic acid.
** Total (conjugated and unconjugated) Ursodeoxycholic acid.
Table 3 From the above data, it is evident that only composition having ursodeoxYcholic* acid particle size d90 less than 25 microns is bio-equivalent to the reference product irrespective of similar in- vitro dissolution for both compositions.
Claims
1. Pharmaceutical composition of Ursodeoxycholic acid, wherein the composition comprises micronized Ursodeoxycholic acid having a particle size of d90 less than 25 microns and one or more pharmaceutically acceptable excipients.
2. Pharmaceutical composition of Ursodeoxycholic acid any one of the preceding claims, wherein one or more pharmaceutically acceptable excipients are selected from the group consisting of diluents, binders, disintegrants, wetting agents, lubricants, glidants and combinations thereof.
3. Pharmaceutical composition of Ursodeoxycholic acid any one of the preceding claims, wherein the composition is prepared by direct compression, wet granulation and dry granulation, most preferably by wet granulation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN3612CH2011 | 2011-10-21 | ||
| IN3612/CHE/2011 | 2011-10-21 |
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| Publication Number | Publication Date |
|---|---|
| WO2013057741A2 true WO2013057741A2 (en) | 2013-04-25 |
| WO2013057741A3 WO2013057741A3 (en) | 2013-06-20 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2012/000667 WO2013057741A2 (en) | 2011-10-21 | 2012-10-09 | Pharmaceutical compositions of ursodeoxycholic acid |
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|---|---|
| FR (1) | FR2981572B1 (en) |
| WO (1) | WO2013057741A2 (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015198258A1 (en) * | 2014-06-28 | 2015-12-30 | Shilpa Medicare Limited | Dispersible tablet comprising ursodeoxycholic acid or its salts |
| USRE48286E1 (en) | 2001-03-12 | 2020-10-27 | Intercept Pharmaceuticals, Inc. | Steroids as agonists for FXR |
| WO2021099973A1 (en) * | 2019-11-22 | 2021-05-27 | Shilpa Medicare Limited | Injectable compositions of ursodeoxycholic acid |
| CN113975233A (en) * | 2021-10-22 | 2022-01-28 | 北京汇诚益健医药科技有限责任公司 | Preparation method of enteric stable ursodeoxycholic acid nanosuspension |
| CN114504580A (en) * | 2021-12-28 | 2022-05-17 | 湖南醇健制药科技有限公司 | Method for preparing ursodeoxycholic acid preparation in large scale |
| CN115671073A (en) * | 2021-07-22 | 2023-02-03 | 华益泰康药业股份有限公司 | Ursodeoxycholic acid capsule and preparation method thereof |
| WO2024043843A1 (en) * | 2022-08-22 | 2024-02-29 | Pharmactive Ilac Sanayi Ve Ticaret A.S. | Pharmaceutical compositions comprising cdca as active ingredient and relevant excipients |
| CN115671073B (en) * | 2021-07-22 | 2024-07-09 | 华益泰康药业股份有限公司 | Ursodeoxycholic acid capsule and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US5352460A (en) * | 1992-06-22 | 1994-10-04 | Digestive Care Inc. | Compositions of gastric acid-resistant microspheres containing salts of bile acids |
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- 2012-01-17 FR FR1250462A patent/FR2981572B1/en active Active
- 2012-10-09 WO PCT/IN2012/000667 patent/WO2013057741A2/en active Application Filing
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| US5352460A (en) * | 1992-06-22 | 1994-10-04 | Digestive Care Inc. | Compositions of gastric acid-resistant microspheres containing salts of bile acids |
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| WO2008062475A2 (en) * | 2006-10-26 | 2008-05-29 | Cadila Healthcare Limited | Pharmaceutical compositions of ursodiol |
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| USRE48286E1 (en) | 2001-03-12 | 2020-10-27 | Intercept Pharmaceuticals, Inc. | Steroids as agonists for FXR |
| WO2015198258A1 (en) * | 2014-06-28 | 2015-12-30 | Shilpa Medicare Limited | Dispersible tablet comprising ursodeoxycholic acid or its salts |
| WO2021099973A1 (en) * | 2019-11-22 | 2021-05-27 | Shilpa Medicare Limited | Injectable compositions of ursodeoxycholic acid |
| CN115671073A (en) * | 2021-07-22 | 2023-02-03 | 华益泰康药业股份有限公司 | Ursodeoxycholic acid capsule and preparation method thereof |
| CN115671073B (en) * | 2021-07-22 | 2024-07-09 | 华益泰康药业股份有限公司 | Ursodeoxycholic acid capsule and preparation method thereof |
| CN113975233A (en) * | 2021-10-22 | 2022-01-28 | 北京汇诚益健医药科技有限责任公司 | Preparation method of enteric stable ursodeoxycholic acid nanosuspension |
| CN114504580A (en) * | 2021-12-28 | 2022-05-17 | 湖南醇健制药科技有限公司 | Method for preparing ursodeoxycholic acid preparation in large scale |
| CN114504580B (en) * | 2021-12-28 | 2024-04-16 | 湖南醇健制药科技有限公司 | Method for preparing ursodeoxycholic acid preparation in large scale |
| WO2024043843A1 (en) * | 2022-08-22 | 2024-02-29 | Pharmactive Ilac Sanayi Ve Ticaret A.S. | Pharmaceutical compositions comprising cdca as active ingredient and relevant excipients |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2981572A1 (en) | 2013-04-26 |
| FR2981572B1 (en) | 2018-01-19 |
| WO2013057741A3 (en) | 2013-06-20 |
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