Solid dispersions of Coenzyme Q.SUB.10

Abstract

The invention relates to a solid dispersion comprising Coenzyme Q.sub.10 and a phospholipid, in the presence of a cellulosic derivative and/or a polymeric material selected from the group consisting of polyvinylpyrrolidone, polyvinyl acetate, poly (methacrylic acid, methyl methacrylate), poloxamers, chitosan, alginates, hyaluronic acid, pectin, pullulan, cyclodextrins, starch polymers, D-alpha-tocopheryl polyethylene glycol 1000 succinate.

Claims

1. A solid dispersion comprising: a) Coenzyme Q10 b) a phospholipid, c) one or more a cellulosic derivative selected from the group consisting of carboxymethyl cellulose, methylcellulose, ethyl cellulose, hydroxypropylcellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, microcrystalline cellulose, cellulose acetate phthalate and hydroxypropylmethyl cellulose phthalate; wherein the Coenzyme Q10 to phospholipid ratio is 0.5 to 1, and the phospholipid is the only surfactant, said solid dispersion being obtained by a method comprising the steps of: i) preparing a suspension of the one or more cellulosic derivative, the phospholipid in an organic solvent; ii) preparing a solution of coenzyme Q10 in an organic solvent; iii) mixing the solution obtained in step ii) with the suspension obtained in step i); iv) stirring the suspension obtained in step iii) at a temperature between 40 C. and 70 C.; v) removing the solvent from the suspension obtained in step iv).

2. A pharmaceutical or nutraceutical formulation for oral administration containing the solid dispersion according to claim 1 and a pharmaceutically or food acceptable excipient.

3. The solid dispersion according to claim 1 wherein the phospholipid is selected from the group consisting of lecithins from soy, sunflower or egg, phosphatidyl choline, phosphatidyl serine and phosphatidyl ethanolamine.

4. The solid dispersion according to claim 1 wherein the Coenzyme Q10 to cellulosic derivative ratio is 0.2 to 2.

5. The solid dispersion according to claim 4 wherein the Coenzyme Q10 to cellulosic derivative ratio is 0.5 to 1.

6. The solid dispersion according to claim 1 comprising Coenzyme Q10, a phospholipid and one or more a cellulosic derivative selected from microcrystalline cellulose, hydroxypropylmethyl cellulose, methylcellulose.

7. The solid dispersion according to claim 6 wherein the phospholipid is a lecithin from soy, sunflower or egg.

8. The solid dispersion according to claim 1 wherein the organic solvent is selected from the group consisting of ethanol, acetone and ethyl acetate.

9. The solid dispersion according to claim 8 wherein the organic solvent is ethyl acetate.

Description

EXAMPLES

Example 1Preparation of the Solid Dispersion

(1) 1.5 Kg of microcrystalline cellulose, 2.0 Kg of sunflower lecithin and 0.5 Kg of cellulose ethers (methyl cellulose and hydroxypropylmethyl cellulose) were suspended in 50 liters of ethyl acetate and refluxed for one hour. The resulting suspension was cooled to 40 C.

(2) 1 Kg of Coenzyme Q.sub.10 was dissolved in 30 liters of ethyl acetate at 20-25 C. in the dark. The obtained solution was filtered and added to the suspension of microcrystalline cellulose, sunflower lecithin and cellulose ethers. The obtained suspension was stirred at 40 C. for about one hour.

(3) The solvent was then removed under reduced pressure until a soft mass was obtained. The latter was dried at 50 C. under vacuum for 16 hours, until a residual of Ethyl acetate lower than 5000 ppm.

(4) The resulting solid was calibrated through a 2 mm screen to obtain a yellow-orange solid

Example 2Characterization of the Solid Dispersion: Differential Scanning Calorimetry

(5) The solid dispersion of Coenzyme Q10 with phospholipid was analyzed by Differential Scanning calorimetry (DSC) in comparison with crystalline Coenzyme Q.sub.10.

(6) The analyses were performed using a Mettler DSC1 System. Heat flow was recorded from 30 to 300 C. with linear heating rate (10 C./min), using closed aluminium crucibles (40 l volume) with a pinhole, under a 50 ml/min nitrogen flow.

(7) About 5-10 mg of powder were used for each measurement. The thermal profiles were acquired and elaborated by a dedicated software.

(8) The degree of amorphization of Coenzyme Q.sub.10 in the solid dispersion was in the range 30-40% and it was calculated on the basis of the reduction of the enthalpy of fusion.

Example 3Pharmacokinetic Study in Rats

(9) Pharmacokinetic parameters (T.sub.max, C.sub.max, absolute bioavailability) were determined in rats after the oral administration of a single dose of Coenzyme Q.sub.10 as crystalline powder and as solid dispersion with phospholipids.

(10) Male Sprague-Dawley rats, weighting 300-350 g were used for the pharmacokinetic experiment. Rats were fasted 16 hours before administration with free access to water.

(11) Coenzyme Q.sub.10 as crystalline powder and as solid dispersion with phospholipids were suspended in 1% carboxymethyl cellulose water suspension and administered by intragastric gavage as a single dose of 50 mg of Coenzyme Q.sub.10/Kg.

(12) Blood samples were collected from tail vein after 0.5-1.0-2.0-4.0-8.0-12.0 and 24 hours after administration.

(13) Plasma was obtained from blood samples by centrifugation at 5.000g for 15 minutes and kept frozen (20 C.) until analysis. After protein sedimentation, Coenzyme Q.sub.10 was extracted by plasma samples with n-hexane; the extraction step with hexane was repeated for three times. The hexane phases, separated by centrifugation, were collected and the solvent was removed by evaporation under nitrogen. The residue was dissolved in 2-propanol for HPLC/MS analysis at 275 nm, using internal standard method for Coenzyme Q.sub.10 quantification.

(14) The following pharmacokinetic parameters were calculated:

(15) TABLE-US-00001 Crystalline Coenzyme Q.sub.10 solid dispersion Parameter Coenzyme Q.sub.10 with phospholipids T.sub.max (hours) 3.8 4.0 C.sub.max (g/ml) 0.23 1.35 AUC 0-24 (g .Math. h/ml) 4.1 29.2

Example 4Formulations Containing the Solid Dispersion of Coenzyme Q.SUB.10 .with Phospholipid Film-Coated Tablets

(16) TABLE-US-00002 Coenzyme Q.sub.10 solid dispersion 400.0 mg Microcrystalline cellulose 200.0 mg Dicalcium phosphate anhydrous 146.0 mg Sodium croscarmellose 30.0 mg Silicon dioxide 8.0 mg Talc 8.0 mg Magnesium stearate 8.0 mg Film-coating 20.0 mg

Example 5Formulation Containing the Solid Dispersion of Coenzyme Q.SUB.10 .with Phospholipids Soft Gelatin Capsules

(17) TABLE-US-00003 Coenzyme Q.sub.10 solid dispersion 250.0 mg Flaxseed oil 384.0 mg Glyceryl monostearate 10.0 mg Lecithin 6.0 mg