Modified-release therapeutic systems for oral administration of curcumin in the treatment of intestinal disorders

Abstract

Disclosed are colon-specific delayed-release pharmaceutical compositions comprising: a) a matrix consisting of hydrophilic substances wherein curcumin is dispersed; b) a gastroresistant or acid-resistant pH-independent coating with a lag time of matrix a).

Claims

1. Monolithic colon-specific delayed-release pharmaceutical compositions comprising: a) a core with a monolithic matrix comprising hydroxypropylmethylcellulose wherein curcumin is dispersed; b) a gastroresistant coating of core a) selected from: i) coating comprising shellac, hydroxypropylmethylcellulose and glycerin, or ii) a coating comprising ethylcellulose, sodium alginate, titanium dioxide and stearic acid; wherein the core with a monolithic matrix slows the release of the active ingredient within 8-24 hours, and wherein the gastrointestinal coating provides for a lag time of at least 2-4hours, and wherein the curcumin to hydroxypropylmethylcellulose weight ratio in the core ranges from 4:1 to 2:1.

2. Compositions according to claim 1 wherein the hydroxypropylmethylcellulose in core a) has an apparent viscosity at 20 C. in 2% aqueous solution ranging from 3 to 200,000 mPas.

3. Compositions according to claim 1 wherein the core comprises a mixture of two hydroxypropylmethylcelluloses having different viscosity values.

4. Compositions according to claim 3 wherein the mixture consists of one hydroxypropylmethylcellulose having an apparent viscosity ranging from 80 to 120 mPas, and one hydroxypropylmethylcellulose having a viscosity ranging from 3000 to 5600 mPas, at 20 C. in 2% aqueous solution.

5. Compositions according to claim 1 comprising 50 to 1200 mg of curcumin.

6. Compositions according to claim 1 further comprising excipients selected from wetting agents, ionic surfactants, non-ionic surfactants, water-soluble diluents, water-dispersible diluents, water-insoluble diluents, disintegrants, lubricants, glidants, and colouring agents.

7. Compositions according to claim 6 wherein said excipients are selected from phosphatides, lecithins, sodium lauryl sulphate, sorbitan esters, sucrose palmitate, sodium laurylsarcosinate, cholic acids, poloxamer, cyclodextrins, starches, sodium starch glycolate, croscarmellose, crosslinked polyvinylpyrrolidones, polyols, microcrystalline celluloses, dibasic calcium phosphate, calcium salts, and magnesium salts.

8. Compositions according to claim 1 further comprising one or more ingredients selected from probiotics, digestive enzymes, prebiotics, fibres, antispastics, anti-inflammatories, inflammatory bowel discease (IBD) active medicaments, irritable bowel syndrome (IBS) active medicaments, extracts of plant origin, active ingredients of plant origin, and antibiotics with a local topical action.

9. Method of treating inflammatory bowel disease in subjects in need thereof, said method comprising administering to said subjects an effective amount of the compositions according to claim 1; and thereby treating said subjects of said inflammatory bowel disease.

Description

EXAMPLE 1

(1) 500 g of curcumin is loaded into a mixer/granulator with 100 g of dibasic calcium phosphate. 2 g of crospovidone, 5 g of lecithin and 200 g of hydrophilic matrix, consisting of hydroxypropylmethylcellulose (HPMC K100 lv) (100 g) and hydroxypropyl methylcellulose (HPMC K4M) (100 g), are added to the same system in sequence.

(2) The ingredients are mixed until a homogenous dispersion of the matrices is obtained, and 10 g of magnesium stearate and 10 g of colloidal silicon dioxide are then added in sequence.

(3) The final mixture is compressed to a unit weight of 827 mg/tablet in order to administer 500 mg of active ingredient per tablet.

(4) The resulting tablets are then film-coated with a gastroresistant solution/suspension based on 28 g of shellac (25%), 12 g of hydroxypropylmethylcellulose and 5 g of glycerin, so that a tablet with a mean weight of 872 mg is obtained.

(5) The tablets remain intact for at least 2 hours when subjected to a disintegration test at pH 1.2. When subjected to a dissolution test at pH 7.2 and to 2% sodium lauryl sulphate, they present the following release profile: not more than 20% after 60 minutes and not more than 40% after 480 minutes; in any event, the value must be >70% after 24 hours.

EXAMPLE 2

(6) 500 g of curcumin is loaded into a mixer/granulator with 100 g of microcrystalline cellulose. 2 g of croscarmellose, 5 g of lecithin and 200 g of hydroxypropylmethylcellulose (HPMC K100 lv) are added in sequence to the same system.

(7) The ingredients are mixed until a homogenous dispersion of the matrices is obtained, and 10 g of magnesium stearate and 15 g of colloidal silicon dioxide are then added in sequence.

(8) The final mixture is compressed to a unit weight of 842 mg/tablet in order to administer 500 mg of active ingredient per tablet.

(9) The resulting tablets are then film-coated with a gastroresistant solution/suspension based on 30 g of shellac (25%), 10 g of hydroxypropyl-methylcellulose and 5 g of glycerin, so that a tablet with a mean weight of 887 mg is obtained.

(10) The tablets remain intact for at least 2 hours when subjected to a disintegration test at pH 1.2. When subjected to a dissolution test at pH 7.2 and to 2% sodium lauryl sulphate, they present the following release profile: not more than 30% after 60 minutes, not more than 60% after 480 minutes; in any event, the value must be >80% after 24 hours.

EXAMPLE 3

(11) 500 g of curcumin is loaded into a mixer/granulator with 200 g of mannitol. 2 g of sodium starch glycolate, 5 g of lecithin and 200 g of hydrophilic matrix, consisting of hydroxypropylmethylcellulose (HPMC K 15M), are added to the same system in sequence.

(12) The ingredients are mixed until a homogenous dispersion of the matrices is obtained, and 15 g of magnesium stearate and 10 g of colloidal silicon dioxide are then added in sequence.

(13) The final mixture is compressed to a unit weight of 932 mg/tablet in order to administer 500 mg of active ingredient per tablet.

(14) The resulting tablets are then film-coated with a gastroresistant solution/suspension based on 40 g of shellac (25%), 8 g of hydroxypropyl-methylcellulose and 5 g of glycerin, so that a tablet with a mean weight of 985 mg is obtained.

(15) The tablets remain intact for at least 2 hours when subjected to a disintegration test at pH 1.2. When subjected to a dissolution test at pH 7.2 and to 2% sodium lauryl sulphate, they present the following release profile: not more than 15% after 60 minutes, not more than 65% after 480 minutes; in any event, the value must be >80% after 24 hours.

EXAMPLE 4

(16) 800 g of curcumin is loaded into a granulator/homogeniser, and 200 g of hydroxypropylmethylcellulose (HPMC K100 lv), 200 g of polyoxyethylene oxide (PEO-20NF), 480 g of mannitol and 252 g of microcrystalline cellulose are added.

(17) The ingredients are mixed for at least 15 minutes to obtain a homogenous mixture.

(18) 3 g of croscarmellose, 25 g of lecithin, 50 g of colloidal silicon dioxide and 30 g of magnesium stearate are then added in sequence.

(19) The final mixture is compressed to a unit weight of 510 mg/tablet in order to administer 200 mg of active ingredient per tablet.

(20) The cores obtained are coated with an aqueous dispersion containing 80 g of ethylcellulose, 16 g of sodium alginate, 2 g of titanium dioxide and 2 g of stearic acid. A film-coating with about 25 mg of coating per tablet is obtained.

(21) When subjected to a dissolution test, the tablets exhibit the following release profile: 0% after 120 minutes in gastric juice; not more than 25% after 60 minutes, not more than 60% after 180 minutes, and not more than 80% after 8 hours; >80% after 24 hours.

EXAMPLE 5

(22) 250 g of curcumin is loaded into a mixer/granulator with 175 g of dibasic calcium phosphate.

(23) 1 g of crospovidone and 75 g of hydrophilic matrix hydroxypropyl-methylcellulose (HPMC K15M) are added in sequence to the same system.

(24) The ingredients are mixed until a homogenous dispersion of the matrices is obtained, and 2.5 g of magnesium stearate, 2.5 g of colloidal silicon dioxide and 4 g of glyceryl behenate are then added in sequence.

(25) The final mixture is compressed to a unit weight of 547.5 mg/tablet in order to administer 250 mg of active ingredient per tablet.

(26) The resulting tablets are then film-coated with a gastroresistant solution/suspension based on 80 g of shellac (25%), 10 g of hydroxypropyl-methylcellulose and 4 g of glycerin.

(27) The tablets remain intact for at least 2 hours when subjected to a disintegration test at pH 1.2. When subjected to a dissolution test at pH 7.2 they exhibit the following release profile: not more than 30% after 60 minutes, not more than 60% after 240 minutes, and not more than 70% after 480 minutes; in any event, the value must be >70% after 24 hours.