PHARMACEUTICAL COMPOSITION COMPRISING PANCREATIN AND A LIPASE-CONTAINING COATING

Abstract

The present invention relates to a pharmaceutical composition comprising pancreatin, which has a coating that contains a least one lipase. Preferably the at least one lipase is burlulipase. It also relates to a medicinal product comprising such a pharmaceutical composition. A method of producing such a pharmaceutical composition also forms part of the present invention.

Claims

1. Pharmaceutical composition comprising pancreatin, having a coating that contains at least one lipase, wherein the pharmaceutical composition comprises a core which contains pancreatin onto which the coating is applied, characterised in that the at least one lipase used in the coating is a lipase different from the lipases present in the pancreatin.

2. Pharmaceutical composition according to claim 1, characterised in that the activity of the at least one lipase is stable against the in vitro simulated effect of gastric acid.

3. Pharmaceutical composition according to any one of claim 1 or 2, characterised in that the at least one lipase is a bacterial lipase.

4. Pharmaceutical composition according to any one of claim 1, 2 or 3, characterised in that the at least one lipase is burlulipase.

5. Pharmaceutical composition according to any one of claims 1 to 4, more particularly according to claim 4, characterised in that it does not have a gastric juice-resistant coating.

6. Pharmaceutical composition according to any one of claims 1 to 5, characterised in that it comprises a core that is selected from the group consisting of tablets, micro-tablets, fast disintegrating micro-tablets, granulates, pellets and powders.

7. Pharmaceutical composition according to any one of claims 1 to 6, characterised in that it comprises a core that is a fast disintegrating micro-tablet.

8. Pharmaceutical composition according to any one of claims 1 to 7, characterised in that the coating comprises burlulipase and a binding agent.

9. Pharmaceutical composition according to any one of claims 1 to 8, characterised in that the coating comprises burlulipase and hydroxypropyl methylcellulose

10. Pharmaceutical composition according to any one of claims 1 to 9, characterised in that in its coating it exhibits a lipolytic activity in the range from 10,000 to 500,000 TBU/g.

11. Medicinal product comprising a composition according to any one of claims 1 to 10.

12. Medicinal product according to claim 11 for the prevention and/or treatment of digestive disorders.

13. Medicinal product according to any one of claim 11 or 12 for the prevention and/or treatment of exocrine pancreatic insufficiency in patients with cystic fibrosis.

14. Method of manufacturing a pharmaceutical composition according to any one of claims 1 to 10, comprising the steps: Provision of pancreatin, Provision of a coating composition for the coating containing at least one lipase, Coating of the pancreatin with the coating composition for the coating.

15. Method according to claim 14, characterised in that the pancreatin is provided in the form of a pancreatin-containing fast disintegrating micro-tablet and the coating composition for the coating is a solution of burlulipase, hydroxypropyl methylcellulose and possibly other auxiliary substances in water.

Description

EXAMPLES

Analysis Methods:

[0041] The analytical determination of the lipolytic activity takes place by way of the so-called tributyrine assay according to Erlanson, Ch. & Borgstrom, B.: Tributyrine as a Substrate for Determination of Lipase Activity of Pancreatic Juice and Small Intestinal Content; Scand. J. Gastroent. 5, 293-295 (1970). The lipolytic activity determined by the so-called tributyrine assay is synonymously indicated in TBU units (TBU u., sometimes abbreviated to TBU) wherein the spellings (with/without abbreviation full stop, with/without hyphen as well as with/without a space) sometimes vary greatly in the scientific literature. An enzymatic activity of 1 unit (1 enzyme unit) corresponds to a material conversion of 1 mol substrate per minute.

Example

Production of a Pharmaceutical Composition According to the Invention

[0042] Into 24.8 parts by weight of a 10.5% solution of hydroxypropyl methylcellulose (type C606 from the company HARKE Germany Services GmbH & Co. KG, in Mlheim an der Ruhr,Germany) in water, are stirred 75.2 parts by weight of a solution of burlulipase in water with a TBU activity of 64650 TBU/ml. The pH value is adjusted to 7.5 with 3% sodium hydroxide solution.

[0043] 450 g of spherical pancreatin micro-pellets consisting of pancreatin produced by the method according to claim 1 of EP 2 295 039 B1 with a mean particle diameter of around 0.6 mm are coated in a Wurster spray coating system of type Glatt-GPCG-5 with a Wurster column with 4,500 g of the solution of burlulipase. The following parameters are used: atomiser air pressure 1.5 bars, air quantity 50-55 m3/h, inlet air temperature 47.3-49.7 C., product temperature 30.6-31.8 C., spray rate 4.9-6.0 g/min, spray duration 160 mins. The yield is 96.7%.

[0044] The loss of activity (in TBU) of burlulipase in the coated micro-pellets through the spraying process is 22.2%. This includes the loss through the enzyme adhering to the apparatus. The corrected loss of activity through inactivation of the burlulipase is 20.8%. After storage at 25 C. over 8 months in polyethylene bags no further changes in the activity can be detected. A repeat of the experiment with pancreatin micro-pellets produced in accordance with example 2 of EP 0 436 110 A1 produces very similar results. If pure solutions of burlulipase in water (76,000 TBU/ml) are used for coating, the losses of activity are 17.4% through the spraying process and 13.2% corrected loss through inactivation of the burlulipase. These results are reproducible and the products are suitable for use as medicinal products.

Comparative Example

[0045] 5,000 g magnesium stearate are added via a 0.25 mm sieve to 495.0 g of a microcrystalline cellulose (proprietary name: Avicel PH101 available from FMC Corporation, Philadelphia, USA) and mixed in a Zoller gravity mixer for 10 minutes at 25 rpm. 300 mg of the thus produced carrier mixture are mixed with 150 ul of a solution of burlulipase in water with an activity of 50,050 TBU/ml and worked in with a spatula until the solution is fully incorporated. The resulting mixture is dried in a vacuum drying oven at room temperature (<25 C.) and 50 mbar for 1.5 hours. The thus obtained mixture is pressed into tablets by means of a Korsch EKO eccentric press and stamping tool with a diameter of 10 mm, drage-convex with a pressing force of 21.0 kN. The finished tablets are placed in water and the TBU activity is determined. The burlulipase activity loss (TBU) is 41.5%. The present pharmaceutical composition is thus superior to normal tabletting. If the burlulipase is added to the carrier mixture in the form of a solid lyophilisate, similar losses of activity are obtained.