Crystal forms of (r)-n-methylnaltrexone bromide and uses thereof

Abstract

The present invention provides a new forms of (R)—N-methylnaltrexone, and compositions thereof, useful as a peripheral mu opioid receptor antagonist.

Description

BACKGROUND OF THE INVENTION[0001]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 and producing constipation. 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.[0002]In addition to analgesic opioid induced side effects, studies have suggested that endogenous opioid compounds and receptors may also affect ac...

AI Technical Summary

Benefits of technology

where the compound is in the (R) configuration with respect to the nitrogen. The present invention also provides pharmaceutical compositions and formulations comprising such solid forms. Compound 1, and inventive solid forms thereof, is useful for the treatment, prevention, amelioration, delay or reduction of severity and / or incidence of side effects associated with opioid administration, such as, for example, gastrointestinal dysfunction (e.g., inhibition of intestinal motility, constipation, GI sphincter constriction, nausea, emesis (vomiting), biliary spasm, opioid bowel dysfunction, colic), dysphoria, pruritus, urinary retention, depression of respiration, papillary constriction, cardiovascular effects, chest wall rigidity and cough suppression, depression of stress response, and immune suppression associated with administration of narcotic analgesia, etc, or combinations thereof. Other uses of Compound 1, and inventive solid forms thereof as described herein, are set forth infra.

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.

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.

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