Formulations for parenteral delivery of compounds and uses thereof

a technology of parenteral delivery and compound, which is applied in the field of formulations for parenteral delivery of compounds, can solve the problems of limited pain relief effect of opioids, inability to administer opioids, and inability to meet the needs of patients, so as to reduce the secretion of bile, increase gastroesophageal reflux, and reduce the secretion of pancreatic acid

Inactive Publication Date: 2008-03-20
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Opioids, however, also react with receptors outside of the central nervous system, resulting in side effects including constipation, nausea, vomiting, urinary retention and severe itching.
The effectiveness of opioids for pain is often limited due to resultant side effects, which can be debilitating and often cause patients to cease use of opioid analgesics.
Thus, an abnormal physiological level of endogenous compounds and / or receptor activity may lead to bowel dysfunction.
For example, patients who have undergone surgical procedures, especially surgery of the abdomen, often suffer from bowel dysfunction, such as post-operative (or post-surgical) ileus, that may be caused by fluctuations in natural opioid levels.
Administration of opioid analgesics to a patient after surgery, which is now an almost universal practice, may exacerbate bowel dysfunction, thereby delaying recovery of normal bowel function, prolonging hospital stays, and increasing medical care costs.
However, these agents act not only on peripheral opioid receptors, but also on central nervous system sites, so that they sometimes reverse the beneficial analgesic effects of opioids, or cause symptoms of opioid withdrawal.

Method used

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  • Formulations for parenteral delivery of compounds and uses thereof
  • Formulations for parenteral delivery of compounds and uses thereof
  • Formulations for parenteral delivery of compounds and uses thereof

Examples

Experimental program
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Effect test

example 1

Identification and Characterization of Degradants of Methylnaltrexone Formulations

[0114] Previously, at least three degradation products were demonstrated from HPLC analysis in 20 mg / mL isotonic saline solution (identified as RRT peaks at about 0.72, 0.89, and 1.48 when products were analyzed by HPLC). See, e.g., US Patent Application Publication No. 20040266806A1, published Dec. 30, 2004. We examined 20 mg / mL saline methylnaltrexone solutions for production of degradants, and identification of degradants, as well as identification of inhibitors of formation of different degradant products. We have identified and characterized degradants which accumulate in certain methylnaltrexone solutions. In these degradation experiments, and in the formulations prepared in the examples, R—N-methylnaltrexone was used having less than 0.15 weight percent S—N-methylnaltrexone based on the total weight of methylnaltrexone.

[0115] For HPLC analysis, two (2) different methods were utilized to obtain...

example 2

Inhibition of Metal and Calcium Mediated Degradation of Methylnaltrexone Formulations

[0123] Inhibition of metal-catalyzed formation of 2,2′bis methylnaltrexone. We have found Fe3+ facilitates degradation of methylnaltrexone bromide in solution, resulting in formation of a 2,2′bis methylnaltrexone degradant. We have found by HPLC analysis (Method B) the 2,2′bis methylnaltrexone degradant results in a peak having an RRT about 1.55. Fe3+ is an ion that can get into the liquid formulation from several sources. For example, it can be leached from stainless steel process equipment, syringe needles, stoppers and amber vials. EDTA, as a metal chelating agent sequesters the available Fe3+ in the solution, thereby preventing catalysis of the undesirable metal-catalyzed reactions. Methylnaltrexone solutions were prepared in 0.9% NaCl, in the presence of iron and various concentrations of sodium EDTA and calcium EDTA. Used throughout the experiments sodium EDTA is EDTA disodium dihydrate, and ...

example 3

Inhibition of pH Dependent Degradation of Methylnaltrexone Formulations

[0128] Inhibition of pH influenced formation of methylnaltrexone degradants. We have found in the presence of Ca2+ and EDTA, degradation of methylnaltrexone bromide in solution occurs under some stability conditions, resulting in formation of a third-methylnaltrexone degradant. We have found by HPLC analysis (Method B) the degradant results in a peak having an RRT about 0.79. Identification and production of the 0.79 degradant is described in U.S. provisional patent application 60 / 835,687, filed Aug. 4, 2006, filed concurrently with the present application, the contents of which are incorporated herein in their entirety by reference.

[0129] Formation of the 0.79 methylnaltrexone degradant was lower at room temperature in the CaEDTA formulation described in Example 2 above as compared to refrigerated methylnaltrexone in saline solution. Methylnaltrexone solution as described in Example 2 containing CaEDTA was com...

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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.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present invention claims priority to U.S. provisional patent application Ser. No. 60 / 835,574, filed Aug. 4, 2006, the entirety of which is hereby incorporated herein by reference.BACKGROUND OF THE INVENTION [0002] Opioids are widely used in patients with advanced cancers and other terminal diseases to lessen suffering. Opioids are narcotic medications that activate opioid receptors located in the central nervous system to relieve pain. Opioids, however, also react with receptors outside of the central nervous system, resulting in side effects including constipation, nausea, vomiting, urinary retention and severe itching. Most notable are the effects in the gastrointestinal tract (GI) where opioids inhibit gastric emptying and propulsive motor activity of the intestine, thereby decreasing the rate of intestinal transit which can produce constipation. The effectiveness of opioids for pain is often limited due to resultant side effects...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/34A61P43/00B65D1/09B65D83/04
CPCA61K9/0019A61K47/183A61K31/485A61P1/00A61P1/04A61P1/10A61P1/14A61P1/16A61P1/18A61P13/00A61P17/00A61P25/04A61P25/36A61P27/02A61P29/00A61P35/00A61P37/02A61P39/00A61P41/00A61P43/00A61P7/06A61P9/10A61K9/08A61K47/02A61K47/18
Inventor SHAH, SYED M.OFSLAGER, CHRISTIANFAWZI, MAHDI B.BAZHINA, NATALYIA
Owner WYETH LLC
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