Orodispersible tablet containing burlulipase and pharmaceutical composition produced therefrom

Abstract

The present invention relates to an orodispersible tablet characterized in that it includes burlulipase. It also relates to liquid pharmaceutical compositions that contain solutions of such orodispersible tablets in water or other beverages. It relates to drugs that contain or consist of such orodispersible tablets or solutions. In particular, it relates to such drugs that are suitable for treating digestive problems, in particular exocrine pancreatic insufficiency used to treat digestive problems. In particular, they are for the treatment of exocrine pancreatic insufficiency in cystic fibrosis patients and for treatment of exocrine pancreatic insufficiency in pediatric patients.

Claims

1. An orodispersible tablet comprising amorphous burlulipase.

2. The orodispersible tablet according to claim 1, wherein said tablet comprises a lyophilizate.

3. The orodispersible tablet according to claim 1, wherein said tablet comprises a lyophilizate of a composition comprising burlulipase.

4. The orodispersible tablet according to claim 3, wherein said lyophilizate is a lyophilizate of an aqueous solution comprising burlulipase.

5. The orodispersible tablet according to claim 4, wherein said lyophilizate of an aqueous solution comprising burlulipase has been freeze-dried at a temperature of 0° C. or less.

6. The orodispersible tablet according to claim 1, wherein the tablet contains no effervescent additive and no disintegrants.

7. The orodispersible tablet according to claim 1, further comprising at least one excipient selected from the group consisting of binders and structure-forming excipients.

8. The orodispersible tablet according to claim 7, further comprising an acid or base for adjusting the pH and/or a surfactant for improving the disintegration or the dissolution behavior.

9. The orodispersible tablet according to claim 7, wherein said at least one binder comprises fish gelatin, and said at least one structure-forming excipient comprises mannitol, and further comprising sodium hydroxide.

10. The orodispersible tablet according to claim 1, wherein the tablet consists of burlulipase, fish gelatin, mannitol, sodium hydroxide and residual water.

11. The orodispersible tablet according to claim 1, wherein the tablet comprises 0.1 to 25 mg of burlulipase protein.

12. A method of preparing a liquid pharmaceutical composition comprising burlulipase, comprising the step of introducing an orodispersible tablet according to claim 1 into a liquid.

13. The method of claim 12, wherein the liquid is a beverage.

14. The method according to claim 12, wherein the composition is in the form of a solution, a suspension or an emulsion.

15. A process for producing an orodispersible tablet according to claim 4, comprising the steps of: providing an aqueous solution comprising the burlulipase and excipients, filling the aqueous solution into a mold, freezing the aqueous solution in the mold, freeze-drying the aqueous solution in the mold.

16. The orodispersible tablet according to claim 1, wherein the burlulipase activity upon solubilization is ninety-percent or greater of the activity of the solution, emulsion or suspension used to prepare the lyophilizate.

Description

EXAMPLES

(1) Reagents/Excipients

(2) Avicel® PH-101: microcrystalline cellulose of the company FMC;

(3) Emcompress: calcium hydrogen phosphate dihydrate of the company JRS Pharma, Rosenberg, Germany;

(4) Kollidon® CL: polyvinylpyrrolidone of the company BASF SE, Ludwigshafen, Germany;

(5) Aerosil®: pyrogenic silicic acid of the company Evonik Industries AG, Essen, Germany.

(6) Method of Analysis

(7) Unless indicated otherwise, the analytical determination of the lipolytic activity is undertaken by the so-called tributyrin assay according to Erlanson, Ch. & Borgström, 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 indication of the lipolytic activity determined by the so-called tributyrin assay is undertaken synonymously in TBU units (TBU u., sometimes abbreviated to TBU), wherein the notations (with/without abbreviation point, with/without hyphen as well as with/without space) sometimes vary greatly in the scientific literature. In that, an enzymatic activity of 1 unit (1 enzyme unit) corresponds to a substance conversion of 1 μmol of substrate per minute.

(8) The values given are normalized values, which are based on the protein content of burlulipase. The residual water content is determined according to Karl Fischer. Here, formamide is optionally used as solubilizer.

(9) The analytical determination of the breaking strength is carried out in accordance with the relevant method of the European Pharmacopoeia—Ph. Eur. “2.9.8 Breaking strength of tablets”—with a breaking strength tester of the Schleuniger 6D type.

Example 1

Preparation of an Orodispersible Tablet

(10) Preparation of a Solution for Freeze-Drying

(11) 26.11 parts of water, 5 parts of fish gelatin and 4 parts of mannitol are combined and heated to 60° C.±2° C. with stirring. The solution is cooled to 8° C.±2° C. and the pH value of the resulting solution is adjusted to 7.75±0.25 by adding a 3% by weight solution of sodium hydroxide in water. For that, 1.44 parts of soda lye are required. Then 63.45 parts of a burlulipase solution are added and mixed well. The burlulipase solution has a burlulipase concentration of 23.64 mg of protein/ml.

(12) Freeze-Drying

(13) Respectively 200 mg of the solution thus prepared are introduced into one pocket each of a blister. The pockets have the shape of tablets with a diameter of 11.50 mm and a height of 2.50 mm. Then, the blister filled with the solution is cooled to −80° C. within 3 to 4 minutes. The frozen product is then dried at 0° C. over a period of about 9 hours down to a moisture content of less than 5% by weight. The tablet thus produced contains 3 mg of burlulipase protein. After dissolution of the tablet in water, the rate of recovery of the burlulipase activity was 98.7% of the activity of the burlulipase solution originally used. At this rate of recovery, it can essentially be assumed that the losses only occur by burlulipase adhering to the devices used and that the burlulipase is practically not decomposed or deactivated. The orodispersible tablet gives an acceptable visual impression. It dissolves in 100 ml of water at 18.8° C. with stirring within 10 seconds without residue.

Example 2

Storage Stability Test

(14) The blisters of the orodispersible tablets produced were stored at 40° C. and 75% of atmospheric humidity for 3 months. After dissolution of the tablet in water, the rate of recovery of the burlulipase activity was 96.1% of the activity of the burlulipase solution originally used. Storage at room temperature in excess of 36 months showed no change in the activity of burlulipase. These values suggest that the orodispersible tablets produced are sufficiently stable in storage for use as pharmaceutical products.

Example 3

Preparation of a Liquid Pharmaceutical Product

(15) The tablet from a pocket of the blister is placed in 100 ml of Evian® water. The tablet dissolves without residue within 2 seconds while stirring.

Example 4

Comparative Example

(16) Production of a tablet containing burlulipase (freeze-dried lyophilizate from in-house production) by classical tableting

(17) In this example, the analytical determination of the lipolytic activity was carried out by the relevant method of the International Pharmaceutical Federation (Fédération International Pharmaceutique, FIP) according to Demeester, J. et al.: “XI. Microbial Lipases (F.I.P)”; Drugs and the pharmaceutical sciences: 84, Pharmaceutical enzymes, 379-382 (1997). The indication of the lipolytic activity determined by this method is given in FIP units (FIP u.), wherein the notations (with/without abbreviation point, with/without hyphen as well as with/without space) sometimes vary greatly in the scientific literature.

(18) The components 1) to 6) were mixed for 10 minutes in a Zoller free-fall mixer. After component 7) had been added, the mixture was finally mixed for another 5 minutes.

(19) TABLE-US-00001 1) Burlulipase lyophilizate  11.02 g (lipolytic activity: 3660 FIP u./mg) 2) Avicel ® PH-101  38.77 g 3) Emcompress ®  42.01 g 4) Talcum Ph. Eur.  4.67 g 5) Kollidon ® CL  1.75 g 6) Aerosil ®  0.78 g 7) Magnesium stearate Ph. Eur.  1.00 g Total mass: 100.00 g

(20) The resulting mass, ready to be pressed, was compressed into tablets with an average mass of 135.6 mg. For this purpose, an eccentric tablet press of type Korsch EK 0 (available from KORSCH AG, Berlin, Germany), fitted with a 7.0 mm punch (dragée-shaped), was used. The pressing pressure was 21 kN. The height of the tablets was 3.46 mm on average, the breaking strength of the tablets was 157 N on average.

(21) The burlulipase lyophilizate (active ingredient) used has a specific lipolytic activity of 3660 FIP u./mg. Since 11.02 g are used, a total amount of burlulipase with a total lipolytic activity of approx. 40.33 million FIP u. is used. Since the total mass of the components used is 100 g, a specific activity of 403.3 FIP u./mg is thus calculated for the total mass of the components of the mixture intended for compression. After mixing, a specific lipolytic activity of 335 FIP u./mg is measured in the mass ready for pressing. Thus, a loss of lipolytic activity of 16.9% results from mixing alone. The final product, i.e. the compressed tablet, only has a specific lipolytic activity of 244 FIP u./mg. Thus, there is a further loss of the lipolytic activity of 27.2% (compared to the specific lipolytic activity of the mass ready for pressing of 335 FIP u./mg) as a result of the pressing. Accordingly, the total loss of lipolytic activity by processing a lyophilizate of burlulipase to give a tablet is 39.5% (a reduction from 403.3 FIP u./mg to 244 FIP u./mg). Since burlulipase usually is initially obtained as a liquid solution during production, there is an additional loss of activity due to lyophilization.

(22) Thus, the rate of recovery of the burlulipase activity in the classical production of tablets by mixing and pressing is only 60.5% of the activity of the burlulipase lyophilizate originally used. In comparison to this, the rate of recovery of the burlulipase activity in the production of the orodispersible tablet according to the invention is 98.7% of the activity of the burlulipase solution initially used.