DESC:CONTROLLED-RELEASE PHARMACEUTICAL COMPOSITIONS OF BUDESONIDE

Field of the Invention

The present invention relates to controlled-release pharmaceutical compositions comprising budesonide or pharmaceutically acceptable salts thereof and a matrix consisting essentially of hydrophobic and hydrophilic release-controlling agents. It further relates to processes for the preparation of said pharmaceutical compositions.

Background of the Invention

Budesonide is a glucocorticoid steroid indicated for the treatment of Crohn’s disease. In order to be effective for the treatment of inflammatory bowel disease, it is desirable to target the formulation to the specific site of action and provide drug release over an extended period of time.

U.S. Patent No. 8,029,823 discloses a controlled-release and taste-masking oral pharmaceutical composition comprising budesonide incorporated into a matrix structure consisting essentially of a lipophilic matrix, an amphiphilic matrix, an outer hydrophilic matrix, and a gastro-resistant coating.

U.S. Patent No. 5,932,249 describes budesonide pellets with a controlled-release pattern wherein sugar spheres are coated with an active layer followed by a first coating layer comprising a combination of polymers, out of which one is insoluble in gastric fluid and soluble in intestinal fluid and the other is insoluble in gastric and intestinal fluids, and a second coating layer consisting of at least one polymer which is insoluble in gastric and intestinal fluids.

U.S. Publication No. 2010/0209500 discloses controlled release minitablets comprising an extended-release core and an optional pH dependent delayed-release coating thereon, wherein the extended-release core comprises a mixture of budesonide, a carrier, at least one extended-release polymer, and an acid.

U.S. Patent No. 6,692,767 describes a solid solution beadlet (used synonymously with granule or particle) comprising a hydrophobic long chain fatty acid or ester material, a surfactant, and a therapeutic agent, which in admixture forms a solid solution at room temperature. The list of therapeutic agents also includes budesonide.

The present invention provides an alternative controlled-release pharmaceutical composition of budesonide for the treatment of inflammatory bowel disease which releases the drug directly into the intestinal lumen for effective action. The present invention provides the use of hydrophobic and hydrophilic release-controlling agents to achieve the desired release profile.

Summary of the Invention

Budesonide has poor aqueous solubility. Therefore, in order to achieve the required release rate from the controlled-release pharmaceutical composition, it is desirable to use a combination of both hydrophobic and hydrophilic release-controlling agents.

A first aspect of the present invention provides a controlled-release pharmaceutical composition comprising budesonide or pharmaceutically acceptable salts thereof, and a matrix consisting essentially of hydrophobic and hydrophilic release-controlling agents.

According to one embodiment of this aspect, there is provided a controlled-release pharmaceutical composition comprising budesonide or pharmaceutically acceptable salts thereof, wherein said pharmaceutical composition is coated with a pH dependent polymer.

A second aspect of the present invention provides a controlled-release pharmaceutical composition comprising budesonide or pharmaceutically acceptable salts thereof and a matrix consisting essentially of hydrophobic and hydrophilic release-controlling agents, wherein said composition is prepared by direct compression.

A third aspect of the present invention provides a controlled-release pharmaceutical composition comprising budesonide or pharmaceutically acceptable salts thereof and a matrix consisting essentially of hydrophobic and hydrophilic release-controlling agents, wherein said composition is prepared by melt granulation or melt extrusion.

A fourth aspect of the present invention provides a process for the preparation of a controlled-release pharmaceutical composition comprising budesonide or pharmaceutically acceptable salts thereof, and a matrix consisting essentially of hydrophobic and hydrophilic release-controlling agents, wherein the process comprises the steps of:
a) mixing budesonide with hydrophobic and hydrophilic release-controlling agents;
b) mixing the blend of step a) with other pharmaceutically acceptable excipients;
c) lubricating the blend of step b) and compressing into suitable size tablets or filling into capsules; and
d) optionally coating the tablets or capsules of step c) with a pH dependent polymer.

A fifth aspect of the present invention provides a process for the preparation of a controlled-release pharmaceutical composition comprising budesonide or pharmaceutically acceptable salts thereof, and a matrix consisting essentially of hydrophobic and hydrophilic release-controlling agents, wherein the process comprises the steps of:
a) mixing budesonide with hydrophobic and hydrophilic release-controlling agents;
b) heating the blend of step a) followed by cooling;
c) milling or extruding the cooled mass of step b) to obtain granules;
d) optionally blending the granules of step c) with other pharmaceutically acceptable excipients;
e) lubricating the granules of step c) or the blend of step d) and compressing into suitable size tablets or filling into capsules; and
f) optionally coating the tablets or capsules of step e) with a pH dependent polymer.

Detailed Description of the Invention

The term ‘controlled-release’ as used herein refers to the release of an active ingredient from a pharmaceutical composition in which the active ingredient is released according to a desired profile over an extended period of time and encompasses sustained release, modified release, prolonged release, and delayed release.

The term ‘pharmaceutical composition’ as used herein refers to physically discrete units to be administered in single or multiple dosages, each unit containing a predetermined quantity of active material in association with the required pharmaceutically acceptable excipients. The pharmaceutical composition used herein may be selected from tablets, minitablets, or capsules.

The pharmaceutical composition may be coated with a coating layer comprising a pH dependent polymer for colon targeted delivery. The presence of an outer pH dependent polymer layer which provides release at a pH greater than 6 prevents the release of budesonide in the acidic gastric environment and upper duodenum, thereby targeting the drug at the actual site of action, i.e., in the colon. Upon reaching the colon, the drug is released over a prolonged period of time.

The term ‘budesonide’ as used herein includes budesonide free base and pharmaceutically acceptable salts, solvates, hydrates, or mixtures thereof.

The ratio of hydrophobic release-controlling agents to hydrophilic release-controlling agents may be selected from the range 4:1 to 1:4, particularly from 2:1 to 1:3. In particular, a ratio of 1:1 may be used.

The hydrophobic release-controlling agents as used herein are selected from the group consisting of waxes, hydrogenated oils, saturated or unsaturated fatty acids, fatty acid esters with glycerols or polyethylene glycols, ceramides, cholesterol derivatives, or combinations thereof. The melting point of such hydrophobic agents ranges from 40°C to 150°C and particularly from 60°C to 100°C. Polymers like ethyl cellulose may also be used as hydrophobic release-controlling agents.

Waxes are selected from the group comprising waxes of animal origin, waxes from vegetable fat, synthetic waxes, or semi-synthetic waxes. Specific examples include paraffin, micro crystalline wax, ceresin, Japan wax, cocoa butter, carnauba wax, or beeswax.

Hydrogenated oils used may be selected from hydrogenated castor oil, hydrogenated cottonseed oil, hydrogenated peanut oil, hydrogenated corn oil, hydrogenated soyabean oil, hydrogenated rapeseed oil, other vegetable oils, or beef tallow.

Fatty acids include both saturated and unsaturated fatty acids, selected from myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, linoleic acid, linolenic acid, lauric acid, ricinoleic acid, caprylic acid, or capric acid.

Glycerine fatty acid esters are monoesters, diesters, and triesters of glycerin and various fatty acids. Examples of glycerine fatty acid esters are C6-22 fatty acids, such as stearic acids, behenic acids, palmitic acids, oleic acids, linoleic acids, linolenic acids, myristic acids, lauric acids, ricinoleic acids, caprylic acids, and capric acids.

Polyglycerol fatty acid esters refer to esters in which one or more fatty acids are bonded to polyglycerol in which two or more glycerols are polymerized. Such polyglycerol fatty acid esters include polyglycerol full esters of fatty acid in which the fatty acid is linked via an ester bond to all of the hydroxyl groups of polyglycerol and polyglycerol half esters of fatty acid in which the fatty acid is linked via an ester bond to half of the hydroxyl groups of polyglycerol. Fatty acids of polyglycerol fatty acid esters are, for example, C6-22 fatty acids, and specific examples of such fatty acids are stearic acids, behenic acids, palmitic acids, oleic acids, linoleic acids, linolenic acids, myristic acids, lauric acids, ricinoleic acids, caprylic acids, and capric acids.

Glycerol organic acid fatty acid esters refer to esters in which organic acids and fatty acids are bonded to glycerol. Specific examples of glycerol organic acid fatty acid esters are glycerol citric acid fatty acid esters, glycerol acetic acid fatty acid esters, glycerol lactic acid fatty acid esters, glycerol succinic acid fatty acid esters, glycerol fumaric acid fatty acid esters, glycerol tartaric acid fatty acid esters, glycerol diacetyl tartaric acid fatty acid esters, polyglycerol citric acid fatty acid esters, polyglycerol acetic acid fatty acid esters, polyglycerol lactic acid fatty acid esters, polyglycerol succinic acid fatty acid esters, polyglycerol fumaric acid fatty acid esters, polyglycerol tartaric acid fatty acid esters, and polyglycerol diacetyl tartaric acid fatty acid esters.

In particular, hydrogenated vegetable oils are used as hydrophobic release controlling agents.

The amount of hydrophobic release-controlling agents may be from 10% to 50% by weight of the total weight of the pharmaceutical composition. Particularly, from 20% to 40% by weight of the total weight of the pharmaceutical composition may be used.

The hydrophilic release-controlling agents may be selected from polyethylene glycol (PEG) of various molecular weights, e.g. 1,000 to 20,000, preferably 3,000 to 10,000, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, pullulan, inulin, pectin, dextran, or combinations thereof.

The amount of hydrophilic release controlling agent(s) may be from 10% to 50% by weight of the total weight of the pharmaceutical composition. Particularly, from 25% to 50% by weight of the total weight of the pharmaceutical composition may be used.

According to a particular embodiment of the present invention, the hydrophobic release-controlling agent is hydrogenated vegetable oil and the hydrophilic release-controlling agent is polyethylene glycol.

The pharmaceutical composition of the present invention may be prepared by direct compression or by granulation techniques.

The term ‘granules’ as used herein refers to blend of drug and hydrophobic and hydrophilic release-controlling agents formed by hot-melt granulation or hot-melt extrusion.

The granules so obtained may be milled or extruded, optionally mixed with other pharmaceutically acceptable excipients, and then compressed into tablets or minitablets or filled into capsules. Alternatively, the minitablets so formed may be filled into capsule shells.

The other pharmaceutically acceptable excipients may be selected from diluents, binders, lubricants, combinations thereof, and other excipients known to a person skilled in the art.

Binders may be selected from pregelatinized starch, polyvinyl pyrrolidone, copovidone, shellac, zein, gelatin, synthetic resins, and cellulose polymers like hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, or combinations thereof.

Diluents may be selected from lactose, microcrystalline cellulose, calcium hydrogen phosphate (dihydrate), calcium hydrogen phosphate (anhydrous), tribasic calcium phosphate, calcium carbonate, kaolin, magnesium carbonate, magnesium oxide, or combinations thereof.

Lubricants may be selected from stearic acid, polyethylene glycol, magnesium stearate, calcium stearate, zinc stearate, talc, sodium stearyl fumarate, or combinations thereof.

According to an embodiment of the present invention, there is provided a process for the preparation of a controlled-release pharmaceutical composition of budesonide, wherein the process comprises the steps of:
a) mixing budesonide with hydrophobic and hydrophilic release-controlling agents;
b) mixing the blend of step a) with other pharmaceutically acceptable excipients; and
c) lubricating the blend of step b) and compressing into suitable size tablets or filling into capsules.

According to another embodiment of the present invention, there is provided a process for the preparation of a controlled-release pharmaceutical composition of budesonide, wherein the process comprises the steps of:
a) mixing budesonide with hydrophobic and hydrophilic release-controlling agents;
b) mixing the blend of step a) with other pharmaceutically acceptable excipients;
c) lubricating the blend of step b) and compressing into suitable size tablets or filling into capsules; and
d) coating the tablets or capsules of step c) with a pH dependent polymer.

According to yet another embodiment of the present invention, there is provided a process for the preparation of a controlled-release pharmaceutical composition of budesonide, wherein the process comprises the steps of:
a) mixing budesonide with hydrophobic and hydrophilic release-controlling agents;
b) heating the blend of step a) followed by cooling;
c) milling or extruding the cooled mass of step b) to obtain granules;
d) mixing the granules of step c) with pharmaceutically acceptable excipients; and
e) lubricating the blend of step d) and compressing into suitable size tablets or filling into capsules.

According to another embodiment of the present invention, there is provided a process for the preparation of a controlled release pharmaceutical composition of budesonide, wherein the process comprises the steps of:
a) mixing budesonide with hydrophobic and hydophillic release controlling agents;
b) heating the blend of step a) followed by cooling;
c) milling or extruding the cooled mass of step b) to obtain granules;
d) mixing the granules of step c) with pharmaceutically acceptable excipients;
e) lubricating the blend of step d) and compressing into suitable size tablets or filling into capsules; and
f) coating the tablets or capsules of step e) with a pH dependent polymer.

According to yet another embodiment of the present invention, there is provided a process for the preparation of a controlled-release pharmaceutical composition of budesonide, wherein the process comprises the steps of:
a) mixing budesonide with hydrophobic and hydrophilic release-controlling agents;
b) heating the blend of step a) followed by cooling;
c) milling or extruding the cooled mass of step b) to obtain granules;
d) mixing the granules of step c) with pharmaceutically acceptable excipients;
e) lubricating the blend of step d) and compressing into minitablets;
f) filling the minitablets of step e) into capsules; and
g) coating the capsules of step f) with a pH dependent polymer for colon targeted delivery.

The pharmaceutical composition prepared using the process described herein may be provided with a coating layer for colon targeted delivery. The pH dependent polymers may be selected from poly(methacrylic acid, methyl methacrylate) 1:2 (Eudragit® S), poly(methacrylic acid, methyl methacrylate) 1:1 (Eudragit® L), and an anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid in a ratio of 7:3:1 (Eudragit® FS 30 D). In particular, Eudragit® S 100 or Eudragit® L 100 may be used.

Eudragit® L, is an anionic copolymer derived from methacrylic acid and methyl methacrylate, with a ratio of free carboxyl groups to the ester groups of approximately 1:1, and a mean molecular weight of approximately 135,000; Eudragit® S is an anionic copolymer derived from methacrylic acid and methyl methacrylate, with a ratio of free carboxyl groups to the ester groups of approximately 1:2, and a mean molecular weight of approximately 135,000; Eudragit® FS 30 D is an anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid in a ratio of 7:3:1, and a mean molecular weight of approximately 280,000.

Organic or aqueous solvents may be used during the coating process. Solvents like water, acetone, isopropyl alcohol, ethanol, methylene chloride, or combinations thereof are used.

Appropriate plasticizers used during coating may be selected from polyethylene glycol, propylene glycol, dibutyl phthalate, diethyl phthalate, triethyl citrate, tributyl citrate, tributyrin, triacetin, castor oil, citric acid esters, or combinations thereof. In particular, the plasitcizer is dibutyl phthalate or triethyl citrate. These plasticizers are present in an amount to facilitate the coating process and to obtain an even coating film with enhanced physical stability. Generally, the coating material comprises from about 0% to about 50% of a plasticizer, particularly from about 0% to about 25% by weight, more particularly from about 10% to about 20% by weight of the enteric polymer.

In addition, the coating material may also comprise inert solid particulates. In particular, talc and titanium dioxide are used as opacifiers. Lakes and dyes are also used to impart color to the coating. These include iron oxide (red or yellow), aluminium lakes, natural coloring materials like anthocyanins, and carotenoids.

The selection of optional plasticizer, optional inert solid particulate, and levels thereof, coating formulation type (solvent, ammoniated aqueous solution, or aqueous dispersion), and process are based upon the specific enteric polymer used and the type of dosage form used according to criteria known to those skilled in the art.

The invention is further illustrated by the following non-limiting examples.

EXAMPLES

Example 1 2 3 4 5 6
Ingredients mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab
Core tablet
Budesonide 9.00 9.00 9.00 9.00 9.00 9.00
Hydrogenated vegetable oil 25.00 12.50 12.50 20.50 20.50 25.00
PEG 3350 25.00 50.00 50.00 48.00 48.00 25.00
Ethyl cellulose (Ethocel TM cps) - - 26.50 20.50 - 39.00
Microcrystalline cellulose 39.00 26.50 - - 20.50 -
Colloidal silicon dioxide 1.00 1.00 1.00 1.00 1.00 1.00
Magnesium stearate 1.00 1.00 1.00 1.00 1.00 1.00
Tablet weight 100.00 100.00 100.00 100.00 100.00 100.00
Coating
Eudragit® L100 7.75 - 7.75 7.75 7.75 7.75
Eudragit® S 100 - 7.75 - - - -
Triethyl citrate 1.00 1.00 1.00 1.00 1.00 1.00
Titanium dioxide 0.20 0.20 0.20 0.20 0.20 0.20
Talc 1.00 1.00 1.00 1.00 1.00 1.00
Iron oxide 0.05 0.05 0.05 0.05 0.05 0.05
Acetone q.s. q.s. q.s. q.s. q.s. q.s.
Isopropyl alcohol q.s. q.s. q.s. q.s. q.s. q.s.
Total Weight 110.00 110.00 110.00 110.00 110.00 110.00

Process:
Core tablet
1. All ingredients except magnesium stearate were sifted and blended together.
2. The blend of step 1 was lubricated with magnesium stearate.
3. The lubricated blend of step 2 was compressed into tablets using suitable tooling.
Coating
4. Acetone and isopropyl alcohol were mixed together.
5. In case of example 2, Eudragit® S 100 and in all other examples 1, 3, 4, 5, 6, Eudragit® L 100, was dissolved in the solvent mixture of step 4.
6. Triethyl citrate was added to the solution of step 5.
7. Talc, titanium dioxide and iron oxide were dispersed in the solution of step 6.
8. The coating solution of step 7 was used to coat the tablets of step 3.
Dissolution Studies
Dissolution was carried out using USP type 2 method with sinker, at 75 rpm; using 900 mL 0.1 N HCl for 2 hours followed by pH 6.8 phosphate buffer up to 14 hours. The percentage of drug released at various time points is provided in Table 1.

Table 1: Dissolution data for examples 1 to 6
Example 1 2 3 4 5 6
Dissolution Time (hours) Acid Stage (% drug release)
1 0 0 0 0 0 0
2 0 0 0 0 0 0
Buffer Stage (% drug release)
2 28.60 51.90 39.40 38.60 48.60 22.20
6 47.60 62.00 53.80 45.60 58.10 40.40
10 76.20 76.10 69.80 66.80 72.10 64.10
14 96.10 86.50 81.40 81.20 93.70 77.40

Example
7 8 9 10 11 12
Ingredients mg/tab mg/tab mg/tab mg/tab mg/tab mg/tab
Core tablet
Intragranular
Budesonide 9.00 9.00 9.00 9.00 9.00 9.00
Hydrogenated vegetable oil 25.00 12.50 12.50 25.00 25.00 12.50
PEG 3350 25.00 37.50 50.00 25.00 25.00 37.50
Extragranular
Lactose monohydrate - - - 39.00 - 39.00
Microcrystalline cellulose 39.00 39.00 26.50 - 39.00 -
Colloidal silicon dioxide 1.00 1.00 1.00 1.00 1.00 1.00
Magnesium stearate 1.00 1.00 1.00 1.00 1.00 1.00
Tablet weight 100.00 100.00 100.00 100.00 100.00 100.00
Coating
Eudragit® L100 7.75 - - - 7.75 7.75
Eudragit® S 100 - 7.75 7.75 7.75 - -
Triethyl citrate 1.00 1.00 1.00 1.00 1.00 1.00
Titanium dioxide 0.20 0.20 0.20 0.20 0.20 0.20
Talc 1.00 1.00 1.00 1.00 1.00 1.00
Iron oxide 0.05 0.05 0.05 0.05 0.05 0.05
Acetone q.s. q.s. q.s. q.s. q.s. q.s.
Isopropyl alcohol q.s. q.s. q.s. q.s. q.s. q.s.
Total Weight 110.00 110.00 110.00 110.00 110.00 110.00
Process:
Core tablet
1. All intragranular ingredients were sifted and mixed together.
2. The blend of step 1 was heated at 100oC to form a melt.
3. The melt of step 2 was cooled and milled through Quadro Comil to obtain granules.
4. Extragranular ingredients (except magnesium stearate) were sifted and mixed with the granules of step 3.
5. The blend of step 4 was lubricated with magnesium stearate.
6. The lubricated blend of step 5 was compressed into tablets using suitable tooling.

Coating
7. Acetone and isopropyl alcohol were mixed together.
8. In case of examples 7, 11 and 12, Eudragit® L100, and for examples 8 to 10, Eudragit® S100 was dissolved in the solvent mixture of step 7.
9. Triethyl citrate was added to the solution of step 8.
10. Talc, titanium dioxide and iron oxide were dispersed in the solution of step 9.
11. The coating solution of step 10 was used to coat the tablets of step 6.
,CLAIMS:WE CLAIM:

1. A controlled release pharmaceutical composition comprising budesonide or pharmaceutically acceptable salts thereof, and a matrix consisting essentially of hydrophobic and hydrophilic release controlling agents.

2. The controlled release pharmaceutical composition of claim 1, wherein said composition is prepared by direct compression.

3. The controlled release pharmaceutical composition of claim 1, wherein said composition is prepared by melt granulation or melt extrusion.

4. The controlled release pharmaceutical composition of claim 1, wherein the hydrophobic release controlling agent is selected from the group consisting of ethyl cellulose, waxes, hydrogenated oils, saturated or unsaturated fatty acids, fatty acid esters with glycerols or polyethylene glycols, ceramides, cholesterol derivatives, or combinations thereof.

5. The controlled release pharmaceutical composition of claim 1, wherein the hydrophilic release controlling agent is selected from the group consisting of polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, hydroxylpropyl cellulose, hydroxyethyl cellulose, pullulan, inulin, pectin, dextran, or combinations thereof.

6. The controlled release pharmaceutical composition of claim 1, wherein the hydrophobic release controlling agent is hydrogenated vegetable oil and the hydrophilic release controlling agent is polyethylene glycol.

7. The controlled release pharmaceutical composition of claim 1, wherein said pharmaceutical composition is further coated with a pH dependent polymer.

8. The controlled release pharmaceutical composition of claim 7, wherein the pH dependent polymer releases at a pH greater than 6 and is selected from poly(methacrylic acid, methyl methacrylate) in a ratio of 1:2, poly(methacrylic acid, methyl methacrylate) in a ratio of 1:1 and anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid in a ratio of 7:3:1.

9. A process for the preparation of a controlled release pharmaceutical composition comprising budesonide or pharmaceutically acceptable salts thereof, and a matrix consisting essentially of hydrophobic and hydrophilic release controlling agents, wherein the process comprises the steps of:
a) mixing budesonide with hydrophobic and hydrophilic release controlling agents;
b) mixing the blend of step a) with other pharmaceutically acceptable excipients;
c) lubricating the blend of step b) and compressing into suitable size tablets or filling into capsules;
d) optionally coating the tablets or capsules of step c) with a pH dependent polymer.

10. A process for the preparation of a controlled release pharmaceutical composition comprising budesonide or pharmaceutically acceptable salts thereof, and a matrix consisting essentially of hydrophobic and hydrophilic release controlling agents, wherein the process comprises the steps of:
a) mixing budesonide with hydrophobic and hydrophilic release controlling agents;
b) heating the blend of step a) followed by cooling;
c) milling or extruding the cooled mass of step b) to obtain granules;
d) optionally blending the granules of step c) with other pharmaceutically acceptable excipients;
e) lubricating the granules of step c) or the blend of step d) and compressing into suitable size tablets or filling into capsules;
f) optionally coating the tablets or capsules of step e) with a pH dependent polymer.