Pharmaceutical formulations of desmopressin

Abstract

Described herein are orodispersible pharmaceutical dosage forms of desmopressin comprising desmopressin free base or a pharmaceutically acceptable salt thereof, and one or more carriers, wherein at least one carrier is hydrolyzed gelatin in an open matrix network structure. Also described are methods of making and using such desmopressin orodispersible pharmaceutical dosage forms.

Claims

1. A method of treating a disease or condition selected from the group consisting of voiding postponement, incontinence, primary nocturnal enuresis (PNE), nocturia, and central diabetes insipidus, said method comprising administering to a subject an orodispersible pharmaceutical dosage form comprising desmopressin in a form selected from one or more of the free base of desmopressin and a pharmaceutically acceptable salt thereof; and one or more carriers, wherein at least one carrier is hydrolyzed gelatin in an open matrix network structure, wherein the amount of desmopressin in the dosage form is selected from 25 g and 50 g, measured as the free base, and wherein the method achieves a maximum plasma concentration of desmopressin in about 0.5 to 2 hours after administration.

2. The method according to claim 1, wherein the disease or condition is primary nocturnal enuresis (PNE).

3. The method according to claim 1, wherein the disease or condition is nocturia.

4. The method according to claim 1, wherein the method results in a desmopressin bioavailability of from greater than 0.1% to 0.38%.

5. The method according to claim 1, wherein the method results in a desmopressin bioavailability of from 0.23% to 0.38%.

6. The method according to claim 1, wherein the method results in a desmopressin bioavailability of 0.30%.

7. A method of treating a disease or condition selected from the group consisting of voiding postponement, incontinence, primary nocturnal enuresis (PNE), nocturia, and central diabetes insipidus, said method comprising administering to a subject an orodispersible pharmaceutical dosage form comprising desmopressin in a form selected from one or more of the free base of desmopressin and a pharmaceutically acceptable salt thereof; and one or more carriers, wherein at least one carrier is hydrolyzed gelatin in an open matrix network structure, wherein the amount of desmopressin in the dosage form is selected from 25 g and 50 g, measured as the free base, and wherein the method achieves a mean elimination half-life of desmopressin of about 2.8 to 3 hours after the maximum plasma concentration is reached.

8. The method according to claim 7, wherein the disease or condition is primary nocturnal enuresis (PNE).

9. The method according to claim 7, wherein the disease or condition is nocturia.

10. The method according to claim 7, wherein the method results in a desmopressin bioavailability of from greater than 0.1% to 0.38%.

11. The method according to claim 7, wherein the method results in a desmopressin bioavailability of from 0.23% to 0.38%.

12. A method of treating a disease or condition selected from the group consisting of voiding postponement, incontinence, primary nocturnal enuresis (PNE), nocturia, and central diabetes insipidus, said method comprising administering to a subject an orodispersible pharmaceutical dosage form comprising desmopressin in a form selected from one or more of the free base of desmopressin and a pharmaceutically acceptable salt thereof; and one or more carriers, wherein at least one carrier is hydrolyzed gelatin in an open matrix network structure, wherein the amount of desmopressin in the dosage form is selected from 25 g and 50 g, measured as the free base, and wherein the method results in a desmopressin bioavailability of from greater than 0.1% to 0.38%.

13. The method according to claim 12, wherein the method achieves a maximum plasma concentration of desmopressin in 0.5 to 2 hours after administration.

14. The method according to claim 12, wherein the disease or condition is primary nocturnal enuresis (PNE).

15. The method according to claim 12, wherein the disease or condition is nocturia.

16. The method according to claim 12, wherein the method achieves a maximum plasma concentration of desmopressin in about 2.8 to 3 hours after administration.

17. A method of treating a disease or condition selected from the group consisting of voiding postponement, incontinence, primary nocturnal enuresis (PNE), nocturia, and central diabetes insipidus, said method comprising administering to a subject an orodispersible pharmaceutical dosage form comprising desmopressin in a form selected from one or more of the free base of desmopressin and a pharmaceutically acceptable salt thereof; and one or more carriers, wherein at least one carrier is hydrolyzed gelatin in an open matrix network structure, wherein the amount of desmopressin in the dosage form is selected from 25 g and 50 g, measured as the free base, and wherein the method results in a desmopressin bioavailability of from 0.23% to 0.38%.

18. The method according to claim 17, wherein the disease or condition is primary nocturnal enuresis (PNE).

19. The method according to claim 17, wherein the disease or condition is nocturia.

20. The method according to claim 17, wherein the method achieves a maximum plasma concentration of desmopressin in 0.5 to 2 hours after administration.

21. The method according to claim 17, wherein the method achieves a maximum plasma concentration of desmopressin in about 2.8 to 3 hours after administration.

Description

EXAMPLE 1 200 g DESMOPRESSIN ORODISPERSIBLE DOSAGE FORM

(1) Spray-dried fish gelatin (4 g) and mannitol (3 g) are added to a glass beaker. Purified water (93 g) is then added and solution effected by stirring using a magnetic follower. The pH is checked and adjusted to 4.8 with citric acid as necessary.

(2) A Gilson pipette can then be used to deliver 500 mg of this solution into each one of a series of pre-formed blister pockets having a pocket diameter of about 16 mm. The blister laminate may comprise PVC coated with PVdC. The dosed units are then frozen at a temperature of 110 C. in a freeze tunnel with a residence time of 3.2 minutes and the frozen units are then held in an upright freezer for a time greater than 1.5 hours at a temperature of 25 C. (5 C.). The units are then freeze-dried overnight with an initial shelf temperature of 10 C. rising to +20 C. at a pressure of 0.5 mbar. The units can be checked for moisture prior to unloading by the drying trace and by the pressurised moisture check.

(3) In this way, following the general procedure given in Example 1 of WO-A-0061117, a desmopressin orodispersible dosage form is prepared using the following ingredients per unit dosage form:

(4) TABLE-US-00001 Desmopressin (PolyPeptide 200 g Laboratories, Sweden) Mannitol EP/USP (Roquette, 15 mg Mannitol 35) Fish gelatin USNF/EP 20 mg Citric acid (if necessary) q.s. to pH 4.8 [pH adjusting agent] Purified water [Removed during processing]

EXAMPLE 2 400 g DESMOPRESSIN ORODISPERSIBLE DOSAGE FORM

(5) The procedure of Example 1 herein is followed, except that the amount of desmopressin per unit dosage form was 400 g.

EXAMPLE 3 800 g DESMOPRESSIN ORODISPERSIBLE DOSAGE FORM

(6) The procedure of Example 1 herein is followed, except that the amount of desmopressin per unit dosage form was 800 g.

EXAMPLE 4 200 g DESMOPRESSIN ORODISPERSIBLE DOSAGE FORM

(7) Following the general procedure given in Example 1 of WO-A-00611117, a desmopressin dosage form orodispersible dosage form was prepared using the following ingredients per unit dosage form:

(8) TABLE-US-00002 Desmopressin (PolyPeptide 200 g Laboratories, Sweden) Mannitol EP/USP 6 mg (Roquette, Mannitol 35) Fish gelatin USNF/EP 10 mg Citric acid (if necessary) q.s. to pH 4.8 [pH adjusting agent] Purified water [Removed during processing]

EXAMPLE 5 400 g DESMOPRESSIN ORODISPERSIBLE DOSAGE FORM

(9) The procedure of Example 4 herein was followed, except that the amount of desmopressin per unit dosage form was 400 g.

EXAMPLE 6 80 g DESMOPRESSIN ORODISPERSIBLE DOSAGE FORM

(10) The procedure of Example 4 herein was followed, except that the amount of desmopressin per unit dosage form was 800 g.

COMPARATIVE EXAMPLE 1 DESMOPRESSIN I.V. SOLUTION

(11) An injectable preparation of desmopressin was conventionally prepared using the following ingredients:

(12) TABLE-US-00003 Desmopressin (PolyPeptide 4 mg Laboratories, Sweden) Sodium chloride 9 mg (National Corporation of Swedish Pharmacies, Sweden) Hydrochloric acid (1N) q.s. to pH 4 (Merck, Germany) Water for injection q.s. to 1 ml

COMPARATIVE EXAMPLE 2 200 g DESMOPRESSIN CONVENTIONAL TABLET

(13) Using a conventional wet granulation process, tablets containing the following ingredients were prepared:

(14) TABLE-US-00004 Desmopressin (PolyPeptide 200 g Laboratories, Sweden) Lactose (Pharmatose 150M, 120 mg DMV, The Netherlands) Potato starch (Lyckeby AB, 77 mg Sweden) PVP (Kollidon 25, BASF, 1.8 mg Germany) Magnesium stearate (Peter 1 mg Greven, Germany) Granulation Liquid (water, [Removed during ethanol) processing]

COMPARATIVE EXAMPLE 3 100 g DESMOPRESSIN CONVENTIONAL TABLET

(15) The procedure of Comparative Example 2 was followed, except that the amount of desmopressin was 100 g per tablet.

EXAMPLE 7 BIOAVAILABILITY OF DESMOPRESSIN ADMINISTERED IN ACCORDANCE WITH EXAMPLES 4 TO 6

(16) Study Design

(17) Twenty-four healthy non-smoking male volunteers were enrolled in the present study. The study was designed as a one-centre, open-labelled, randomised, balanced, 4-way cross-over phase I study. Each subject was, in a randomised order, administered sublingually desmopressin as a 200 g, 400 g and 800 g orodispersible dosage form (Examples 4, 5 and 6, respectively) and 2 g as an i.v. bolus dose (Comparative Example 1). Between the doses there was a washout period of 72 hours. In order to standardise the buccal mucosa before administration of the orodispersible tablet, the subjects were asked to avoid foods, chewing gum etc. Subjects were allowed to brush their teeth in the morning before dosing, but without toothpaste.

(18) Blood Samples

(19) Blood samples for plasma concentration of desmopressin were collected according to the following schedule: pre-dose and 15, 30 and 45 min and at 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dosing. After intravenous administration additional blood samples were collected 5 and 10 minutes post-dosing.

(20) Assay

(21) The concentration of desmopressin in plasma was determined by a validated RIA method.

(22) Pharmacokinetic Analysis

(23) The concentration of desmopressin in plasma was analysed for the individual volunteer in each administration group, by use of non-compartmental methods using the commercially available software WinNonlin Pro, ver. 3.2 (Pharsight Corporation, US). A plasma concentration value below limit of quantitation (LOQ) followed by values above LOQ was set at LOQ/2 for the NCA analysis and for the descriptive statistics on concentrations. Values below LOQ not followed by values above the LOQ are excluded from the NCA analysis, and set to zero in the descriptive statistics on concentrations.

(24) Results of Pharmacokinetic Analysis After i.v. administration the mean volume of distribution at steady state (Vss) was 29.7 dm.sup.3. The mean clearance was calculated to be 8.5 dm.sup.3/hr and the mean elimination half-life was determined to be 2.8 hours. After oral administration of desmopressin maximum plasma concentrations were observed at 0.5-2.0 hours after dosing. The maximum plasma concentration was 14.25, 30.21 and 65.25 g/ml after an oral dose of 200, 400 and 800 g, respectively. After reaching the maximum value desmopressin was eliminated with a mean elimination half-life in the range of 2.8-3.0 hours. The bioavailability was determined to be 0.30% with at 95% confidence interval of 0.23-0.31%.

(25) The pharmacokinetics of desmopressin is linear, when administered as the orodispersible dosage form of Example 4, 5 or 6.

COMPARATIVE EXAMPLE 4 BIOAVAILABILITY OF DESMOPRESSIN ADMINISTERED IN ACCORDANCE WITH COMPARATIVE EXAMPLES 2 AND 3

(26) Thirty six healthy male volunteers (Caucasian, Black and Hispanic) were enrolled in this study, which was designed as an open label, single dose, 3-way crossover study. Each subject was, in a randomised order, administered 200 g desmopressin as a single 200 g tablet (Comparative Example 2), 200 g desmopressin as two 100 g tablets (Comparative Example 3) and 2 g as an i.v. bolus dose (Comparative Example 1).

(27) After i.v. administration the mean elimination half-life was determined to be 2.24 hours. After oral administration of desmopressin maximum plasma concentrations were observed at 1.06 hours (2100 g) or 1.05 hours (1200 g) after dosing. The maximum plasma concentration was 13.2 and 15.0 g/ml after an oral dose of 2100 g and 1200 g, respectively. The bioavailability was determined to be 0.13% (2100 g) or 0.16% (1200 g).