Formulations for parenteral delivery of compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-2023414490-A1
Application number	US-202318244446-A
Country	US
Kind code	A1
Filing date	Sep 11, 2023
Priority date	Aug 4, 2006
Publication date	Dec 28, 2023
Grant date	—

Abstract

The present invention provides formulations that achieve effective delivery of methylnaltrexone compositions. The provided formulations are useful for preventing, treating delaying, diminishing or reducing the severity of side effects resulting from use of analgesic opioids.

First claim

We claim:

1 . A pharmaceutical composition comprising an effective amount of methylnaltrexone or a pharmaceutically acceptable salt thereof, about 0.2 mg/mL to about 0.8 mg/mL of calcium ethylenediaminetriacetic acid (EDTA) or a calcium salt EDTA derivative, and about 0.1 mg/mL to about 0.8 mg/mL of glycine in an aqueous solution, wherein the solution has a pH of about 3 to 4.

2 . The pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable salt of methylnaltrexone comprises methylnaltrexone bromide.

3 . The pharmaceutical composition of claim 1 , wherein the composition comprises about 5 mg to about 40 mg of methylnaltrexone or a pharmaceutically acceptable salt thereof.

4 . The pharmaceutical composition of claim 1 , wherein the calcium salt EDTA derivative comprises calcium EDTA disodium.

5 . The pharmaceutical composition of claim 1 , wherein the glycine comprises glycine HCl.

6 . The pharmaceutical composition of claim 1 , wherein the solution has a pH of about 3.4 to about 3.6.

7 . The pharmaceutical composition of claim 1 , wherein the solution has a pH of about 3.5.

8 . The pharmaceutical composition of claim 1 , further comprising sodium chloride.

9 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is a unit dose contained in a vial, ampoule, or syringe for subcutaneous administration to a subject.

10 . The pharmaceutical composition of claim 1 , wherein the concentration of degradation products in the composition following six months of room temperature storage conditions is characterized by one or more of the following:
a. the concentration of total degradation products does not exceed about 1.25% of methylnaltrexone or the pharmaceutically acceptable salt thereof; b. the concentration of 2,2′ bis-methylnaltrexone degradant product (RRT 1.55) does not exceed about 0.2% of methylnaltrexone or the pharmaceutically acceptable salt thereof; c. the concentration of 7-dihydroxymethylnaltrexone degradant product (RRT 0.67) does not exceed about 0.2% of methylnaltrexone or the pharmaceutically acceptable salt thereof; d. the concentration of the ring contracted methylnaltrexone degradant product (RRT does not exceed about 0.2% of methylnaltrexone or the pharmaceutically acceptable salt thereof; e. the concentration of aldol dimer methylnaltrexone degradant product (RRT 1.77) does not exceed about 0.2% of methylnaltrexone or the pharmaceutically acceptable salt thereof; f. the concentration of Hoffman elimination methylnaltrexone degradant product (RRT 2.26) does not exceed about 0.2% of methylnaltrexone or the pharmaceutically acceptable salt thereof; and g. the concentration of O-methyl methylnaltrexone (RRT 1.66) does not exceed about of methylnaltrexone or the pharmaceutically acceptable salt thereof.

11 . A method of preparing a methylnaltrexone formulation for parenteral administration, the method comprising the steps of:
mixing calcium EDTA, or a calcium salt EDTA derivative, and glycine with a solution of methylnaltrexone, or a pharmaceutically acceptable salt thereof; adjusting the pH to about 3.0 to about 4.0; and sterilizing the resulting solution, thereby preparing the methylnaltrexone formulation, wherein the formulation comprises about 0.2 mg/mL to about 0.8 mg/mL of calcium EDTA, or a calcium EDTA derivative, and about 0.1 mg/mL to about 0.8 mg/mL of glycine.

12 . The method of claim 11 , wherein the salt of methylnaltrexone comprises methylnaltrexone bromide.

13 . The method of claim 11 , wherein the calcium salt EDTA derivative comprises calcium EDTA disodium.

14 . The method of claim 11 , wherein the glycine comprises glycine HCl.

15 . The method of claim 11 , wherein the pH is adjusted to about 3.4 to about 3.6.

16 . The method of claim 11 , further comprising adding sodium chloride to the solution of methylnaltrexone, or a pharmaceutically acceptable salt thereof.

17 . A method for reducing a side effect of opioid treatment in a subject receiving opioid treatment, comprising administering the pharmaceutical composition of claim 1 to the subject.

18 . The pharmaceutical composition of claim 1 in a sealed container.

19 . The pharmaceutical composition of claim 18 , wherein the container is selected from the group consisting of a vial, an ampoule, a bag, a bottle, a syringe, and a dispenser package.

20 . The method of claim 17 , wherein the side effect is opioid induced constipation.

Assignees

• Wyeth Llc

Inventors

• Shah Syed M
• Ofslager Christian
• Fawzi Mahdi B
• Bazhina Nataliya

Classifications

• A61K9/0019 Primary

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61K47/183

  Amino acids, e.g. glycine, EDTA or aspartame · CPC title

• A61K31/485

  Morphinan derivatives, e.g. morphine, codeine · CPC title

• A61K47/02

  Inorganic compounds · CPC title

• A61K9/08 Primary

  Solutions {(composition of solutions A61K47/00)} · CPC title