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Pharmaceutical formulation

a technology of methylnaltrexone and pharmaceutical preparations, which is applied in the direction of inorganic non-active ingredients, immunological disorders, metabolism disorders, etc., can solve the problems of unusual instability of methylnaltrexone, not necessarily predictable stability of pharmaceutical composition in solution, etc., to reduce side effects of opioid treatment, reduce biliary secretion, and delay gastric emptying

Inactive Publication Date: 2010-10-21
PROGENICS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides a stable composition of methylnaltrexone or its salt that can be used as a pharmaceutical composition. The composition contains a solution of methylnaltrexone or its salt that has a low concentration of degradation products. The composition can also contain various additives such as a chelating agent, buffering agent, anti-oxidant, cryoprotecting agent, isotonicity agent, and opioid. The pH of the solution is preferably between 2.0 and 6.0. The stable composition can be stored for at least six months at room temperature without losing its effectiveness. The invention also provides a method for inhibiting degradation of methylnaltrexone by adding a degradation inhibiting agent to the composition.

Problems solved by technology

The stability of a pharmaceutical composition in solution, however, is not necessarily predictable either over time when stored at room temperature or when autoclaved.
Surprisingly, it has been discovered that methylnaltrexone is unusually unstable.

Method used

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Examples

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Effect test

example 1

Manufacturing Process for a Pharmaceutical Formulation of Methylnaltrexone

[0074]A manufacturing process can be outlined as follows:[0075]1. Add required amount of water for injection (˜80% or final volume) to a stainless steel tank.[0076]2. Add chelating agent to the tank and stir till dissolved.[0077]3. Add buffering agent to the tank and stir till dissolved.[0078]4. Add methylnaltrexone to the tank and stir till dissolved.[0079]5. Add isotonicity agent to the tank and stir till dissolved.[0080]6. Adjust the pH of the solution to pH 3.25.[0081]7. Add water for injection to increase the volume to the required amount.[0082]8. Transfer material to supply pressure vessel.[0083]9. Sterile filter into a sterile stainless steel pressure vessel.[0084]10. Fill into bottles / vials, purge with nitrogen and then stopper the bottles / vials.[0085]11. Sterilize the filled vials by autoclaving.

Exact Amount of Excipients to be Used:

[0086]

Disodium edetate = 0.75 mg / mlAdded in step 2Sodium Citrate = 0....

example 2

Preferred Manufacturing Process for a Pharmaceutical Formulation of Methylnaltrexone

[0090]A preferred manufacturing process is as follows:

[0091]100 ml of 20 mg / ml solution of methylnaltrexone solutions

1. Add 80 ml of water for injection (˜80% or final volume) to a stainless steel tank.

2. Add 75 mg of disodium edetate, a chelating agent, to the tank and stir till dissolved.

3. Add 19.9 mg of sodium citrate and 35 mg of citric acid (as buffering agents) to the tank and stir till dissolved.

4. Add 2000 mg of methylnaltrexone to the tank and stir till dissolved.

5. Add 850 mg of sodium chloride, an isotonicity agent, to the tank and stir till dissolved.

6. Adjust the pH of the solution if necessary.

7. Add water for injection to increase the volume to 100 ml.

8. Transfer the material to supply pressure vessel.

9. Sterile filter using a 0.22 micron filter into a sterile stainless steel pressure vessel.

10. Fill, purge with nitrogen and then stopper the bottles / vials.

11. Sterilize the filled vial...

example 3

12 Month Stability of Pharmaceutical Preparation Methylnaltrexone

[0092]Methylnaltrexone (bromide salt) and its degradation products in an isotonic saline solution were tested upon manufacture of the solution (no added stabilizers, sterile filtered, not autoclaved) and upon storage at room temperature for 12 months using a Hewlett-Packard HP1100 series, HPLC system equipped with quaternary gradient pump, programmable variable wavelength UV detector and a Millennium data acquisition system. Two mobile phases were prepared as follows:

[0093]The reagents, standards and media included naltrexone methobromide as a reference standard, trifluoroacetic acid (ACS grade), acetonitrile (HPLC grade), Milli-Q water (or equivalent), and methanol (HPLC grade). The solutions were prepared as follows. Mobile phase A (85:15:0.1) (water:methanol:trifluoroacetic acid):850 mL of Milli-Q water was added to a suitable container, to which 150 mL of methanol and 1.0 mL of trifluoroacetic acid were added. The ...

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Abstract

Stable pharmaceutical compositions useful for administering methylnaltrexone are described, as are methods for making the same. Kits, including these pharmaceutical compositions, also are provided.

Description

RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 10 / 821,811, filed Apr. 8, 2004, entitled “PHARMACEUTICAL FORMULATION,” which claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application Ser. No. 60 / 461,611, entitled “PHARMACEUTICAL FORMULATION,” filed on Apr. 8, 2003, the contents of which applications are incorporated herein by reference in their entirety.FIELD OF THE INVENTION[0002]This invention relates to methylnaltrexone pharmaceutical preparations, methylnaltrexone formulations, methylnaltrexone kits, and methods of making the same.BACKGROUND OF THE INVENTION[0003]Quaternary amine opioid antagonist derivatives have been shown to have utility in a number of contexts. They are considered peripherally acting only, and, therefore, find particular utility in reducing the side-effects of opioids without reducing the analgesic effect of opioids. Such side effects include nausea, emesis, dysphoria, pruritis, urinary retention...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/485A61P1/08A61P37/06A61K9/127A61K9/19A61K31/047A61K31/195A61K45/06A61K47/12A61K47/18
CPCA61K9/0019A61K47/02A61K31/047A61K31/195A61K31/485A61K45/06A61K47/12A61K47/18A61K47/183A61K9/19A61K2300/00A61P1/00A61P1/04A61P1/06A61P1/08A61P1/10A61P1/12A61P1/14A61P1/16A61P1/18A61P13/00A61P13/02A61P17/00A61P17/04A61P19/02A61P25/04A61P25/06A61P25/22A61P25/28A61P29/00A61P3/00A61P31/18A61P35/00A61P37/04A61P37/06A61P43/00A61P7/06A61P7/08A61P7/10A61P9/00A61P9/02
Inventor SANGHVI, SUKETU P.BOYD, THOMAS A.
Owner PROGENICS PHARMA INC
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