Dosage Forms of Palonosetron Hydrochloride Having Improved Stability and Bioavailability

• US 20080152704A1
• Filed: 10/24/2007
• Published: 06/26/2008
• Est. Priority Date: 10/24/2006
• Status: Abandoned Application

• Current Assignee: Helsinn Healthcare SA
• Original Assignee: Helsinn Healthcare SA
• Inventors: Braglia, Enrico, Bonadeo, Daniele, Calderari, Giorgio, Braglia, Riccardo
• Application Number:
  US11/877,722
• Publication Number:
  US 20080152704A1
• Time in Patent Office: Days
• US Class Current: 424/452
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/4825 Proteins, e.g. gelatin gelatin capsule shells with substantial amounts of other macromolecular substances A61K9/4816
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics

Abstract

Provided are solid oral dosage forms of palonosetron hydrochloride, methods of using the dosage forms to treat emesis, and methods of making the dosage forms. The dosage forms have improved stability and bioavailability, and are preferably in the form of liquid filled capsules.

Claims

1. ) A soft gelatin capsule for oral administration comprising:

a) a soft gelatin outer shell having an oxygen permeability of less than about 1.0×

10<sup>−

3</sup> ml·

cm/(cm²·

24 hr. atm); and

b) a lipophilic liquid inner fill composition comprising;

i) greater than about 50 wt. % of one or more lipophilic components;

ii) from about 1 to about 20 wt. % of water miscibilized or homogenized in said one or more lipophilic components;

iii) from about 0.05 to about 2.0 mg. of palonosetron as palonosetron hydrochloride solubilized or dispersed in said water; and

iv) a surfactant.

wherein said capsule exhibits pharmacokinetics when orally ingested in a fasted state that are bioequivalent to a formulation having greater than 95% absolute bioavailability, wherein bioequivalence is established by a 90% confidence interval for AUC which is between 80% and 125%.

2. ) The capsule of claim 1 wherein said inner fill composition comprises:

a) from 0.5 to 1.0 mg. of palonosetron as palonosetron hydrochloride; and

b) a solubilizing effective amount of a liquid comprising a lipophilic excipient and water.

3. ) The soft gelatin capsule of claim 1 comprising glycerin in said outer shell and said inner fill composition.

4. ) The soft gelatin capsule of claim 1, wherein:

a) said inner fill composition further comprises an antioxidant or a reducing agent;

b) said palonosetron comprises less than about 1 wt. % of Cpd1.

5. ) The capsule of claim 1 exhibiting pharmacokinetics when orally ingested in a fasted state that are bioequivalent to a formulation having greater than 95% absolute bioavailability, and a C_max of from 800 to 820 ng/L, wherein bioequivalence is established by:

a) a 90% confidence interval for AUC which is between 80% and 125%, and

b) a 90% confidence interval for C_max which is between 80% and 125%.

6. ) The capsule of claim 1 wherein said inner fill composition comprises oxygen in an amount that mediates no more than about 3.0 wt. % oxidative degradation when said dosage form is stored for three months at 40°

C. and 75% RH.

7. ) The capsule of claim 1 wherein no less than about 75% of said palonosetron or pharmaceutically acceptable salt thereof dissolves in 45 minutes when tested in a type II paddle dissolution apparatus according to the U.S. Pharmacopeia, at 75 rpm and 37°

C., in 500 ml. of 0.01N HCl.

8. ) The capsule of claim 1 wherein no less than about 75% of said palonosetron or pharmaceutically acceptable salt thereof dissolves in 30 minutes when tested in a type II paddle dissolution apparatus according to the U.S. Pharmacopeia, at 75 rpm and 37°

C., in 500 ml. of 0.01N HCl.

9. ) The capsule of claim 1 wherein said shell has an oxygen permeability of less than about 1.0×

1 ml·

cm/(cm²·

24 hr. atm).

10. ) The capsule of claim 1 wherein said inner fill comprises from 0.5 to 4 wt. % of a surfactant.

11. ) A liquid filled soft capsule dosage form for oral administration comprising:

a) an outer shell having a oxygen permeability of less than about 1.0×

10<sup>−

3</sup> ml·

cm/(cm²·

24 hr. atm); and

b) an inner fill composition comprising from about 0.05 to about 2.0 mg. of palonosetron or pharmaceutically acceptable salt thereof, wherein said palonosetron or pharmaceutically acceptable salt thereof comprises Cpd1 of a pharmaceutically acceptable salt thereof in an amount of less than 1.0 wt. % based on the weight of said palonosetron.

wherein said inner fill composition comprises oxygen in an amount that mediates no more than about 3.0 wt. % oxidative degradation of said palonosetron or pharmaceutically acceptable salt thereof when said dosage form is stored three months or greater at 40°

C. and 75% RH.

12. ) The capsule of claim 11 exhibiting pharmacokinetics when orally ingested in a fasted state that are bioequivalent to a formulation having greater than 90% absolute bioavailability wherein bioequivalence is established by a 90% confidence interval for AUC which is between 80% and 125%.

13. ) The capsule of claim 11 wherein said inner fill composition comprises from about 1 wt. % to about 20 wt. % water.

14. ) The capsule of claim 11 exhibiting pharmacokinetics when orally ingested in a fasted state that are bioequivalent to a formulation having greater than 95% absolute bioavailability, and a C_max of from 800 to 820 ng/L, wherein bioequivalence is established by:

a) a 90% confidence interval for AUC which is between 80% and 125%, and

b) a 90% confidence interval for C_max which is between 80% and 125%.

15. ) The capsule of claim 11 wherein no less than about 75% of said palonosetron or pharmaceutically acceptable salt thereof dissolves in 45 minutes when tested in a type II paddle dissolution apparatus according to the U.S. Pharmacopeia, at 75 rpm and 37°

C., in 500 ml. of 0.01N HCl.

16. ) The capsule of claim 11 wherein said shell has an oxygen permeability of less than about 1.0×

10<sup>−

4</sup> ml·

cm/(cm²·

24 hr. atm).

17. ) The capsule of claim 11 wherein:

a) said inner fill composition comprises glycerin;

an

b) said shell comprises glycerin.

18. ) The capsule of claim 11 wherein said shell comprises gelatin, cellulose, starch or HPMC.

19. ) A method of optimizing the bioavailability and stability of palonosetron in a palonosetron gelatin capsule comprising:

a) providing a soft gelatin outer shell having an oxygen permeability of less than about 1.0×

10<sup>−

3</sup> ml·

cm/(cm²·

24 hr. atm); and

b) preparing a fill composition by steps comprising;

i) providing from about 0.05 to about 2.0 mg. of palonosetron as palonosetron hydrochloride wherein said palonosetron comprises Cpd1 in an amount of less than 3.0 wt. %;

ii) dissolving or dispersing said palonosetron in water to form an aqueous premix;

iii) mixing said aqueous premix with one or more lipophilic excipients, at a weight ratio of aqueous premix to lipophilic excipients of less than 30;

70, to form a miscible or homogenous lipophilic fill composition;

iv) mixing a surfactant with said water, said aqueous premix, or said fill composition; and

v) balancing the quantities of surfactant and water in said fill composition to facilitate the bioavailability of palonosetron from said gelatin capsule when orally ingested, and to minimize the degree of palonosetron degradation; and

c) filling said outer shell with said fill composition.

20. ) The method of claim 19 wherein said fill composition comprises from about 0.1 to about 10.0 wt. % surfactant, and from about 0.1 to about 20 wt. % water.

21. ) The method of claim 19 wherein said fill composition comprises from about 0.5 to about 4 wt. % surfactant, and from about 1 to about 10 wt. % water.

22. ) The method of claim 19 wherein said outer shell further comprises glycerin, further comprising mixing said aqueous premix with glycerin, before or after the formation of said lipophilic fill composition.

23. ) A method of making a batch of palonosetron dosage forms having reduced quantities of impurities and oxygen mediated degradation products comprising:

a) mixing palonosetron hydrochloride and one or more pharmaceutically acceptable excipients to form a mixture;

b) processing said mixture into a plurality of final dosage forms; and

c) testing one or more of said final dosage forms for one or more palonosetron related compounds selected from Cpd1, Cpd2, and Cpd3, or the hydrochloride salt thereof.

24. ) The method of claim 23 comprising testing for Cpd1 or the hydrochloride salt thereof.

25. ) The method of claim 23 comprising testing for Cpd2 or the hydrochloride salt thereof.

26. ) The method of claim 23 comprising testing for Cpd3 or the hydrochloride salt thereof.

27. ) The method of claim 23, further comprising testing said palonosetron hydrochloride or said final dosage form for one or more compounds selected from Cpd4, Cpd5, Cpd6, or Cpd7, or the hydrochloride salt thereof.