Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-08-05
2004-05-11
Henley, III, Raymond J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C424S456000, C424S457000, C424S463000
Reexamination Certificate
active
06734188
ABSTRACT:
The present invention relates to the use of an opioid antagonist, especially naloxone and naltrexone, for the treatment of opioid induced or idiopathic constipation or of Irritable Bowel Syndrome (IBS) by delayed and sustained release.
Opioids, including codeine phosphate and morphine, are widely used as analgesics and are known to cause constipation as a troublesome and often serious complication. The effect is particularly troublesome amongst in-patients requiring prolonged opioid therapy in high doses such as terminally ill patients with a malignant disease. Treatment of the constipation is usually by use of conventional laxatives, but it is often poorly controlled.
IBS is a functional bowel disorder consisting of abdominal pain and altered bowel habit. Pain is characteristically relieved by defecation and may be associated with increase or decrease in stool frequency, alterations in stool consistency, straining or urgency, a sensation of incomplete evacuation, passage of mucus or abdominal distention. The pathophysiology is poorly understood despite the fact that about a quarter of the population in the UK may exhibit the symptoms.
There has been no convincing evidence that any current drug regime is of proven benefit in the treatment of IBS. Primary treatment involves counselling and dietary modification. Drug therapy is considered to be beneficial if directed at individual symptoms. For diarrhoea predominant cases, anti-diarrhoeal drugs are used, particularly loperamide. For constipation predominant cases, ispaghula is often used to increase dietary fibre. Where patients have pain and distension as predominant symptoms, antispasmolytics are commonly used. Mebeverine and peppermint oil are often used in such cases. Other agents that have been tried, in treating IBS, include beta-blockers, naloxone, ondansetron, calcium channel blockers, simethicone, leuprorelin, octreotide and cholecystokinin antagonists, with variable results (Martindale The Extra Pharmacopoeia, 31st Edition (1996) p 1197).
Naloxone (17-allyl-6-deoxy-7,8-dihydro-14-hydroxy-6-oxonormorphine) is known to be a specific opioid antagonist and is given intravenously for the treatment of opioid-overdosage and to reverse therapeutic effects of opioids (for example postoperatively when opioids are used during surgery). It has a short plasma half-life of about 1 h after parenteral administration. It is absorbed from the gastrointestinal tract and subject to considerable first-pass metabolism.
Naltrexone (17-(cyclopropylmethyl)-4,5
&agr;
-epoxy-3,14-dihydroxymorphinan-6-one) is known to have opioid-blocking activity. It is given orally in the treatment of opioid dependence as an aid to maintaining abstinence following opioid withdrawal. Naltrexone is more potent than naloxone and has a longer duration of action. Naltrexone is also used as an adjunct in the management of alcohol withdrawal.
Strong opioids delay gastrointestinal transit and patients treated with them experience marked constipation. The delay is partly mediated by opioid receptors in the gut. Naloxone has been shown to produce a laxative effect in patients with advanced cancer that are being treated with an opioid analgesic, although there were a number of instances of withdrawal observed. It appeared that the dose regime of naloxone was dependent on the dose of the constipation-causing opioid administered, however it was observed that any clinical use of naloxone should not depend on the dose being estimated based on a measured plasma concentration. Indeed, the dose of the opioid was not the only consideration. Patients that have been on longer term treatment of opioids and are thus more physically dependent appear to be more sensitive to naloxone treatment and show more withdrawal symptoms (N. P. Sykes,
Palliative Medicine
, 1996, 10, 135).
It has been suggested (N. P. Sykes,
Palliative Medicine
, 1996, 10, 135) that oral naloxone might have a therapeutic role in treatment of opioid induced constipation and that a slow release formulation could offer 12 or 24 hour administration, although it has been conceded that this would increase the difficulty of reversing any withdrawal that occurred.
WO 99/22737 (Drell et al) discloses a method for treating or preventing a range of conditions, often side effects from the use of opioid analgesics, including both opioid induced and non opioid induced constipation by administering a quaternary derivative of noroxymorphine, especially methylnaltrexone. The noroxymorphine derivative may be enterically coated to delay the release of the drug. Systemic uptake is not totally avoided, but quarternary ammonium salts such as methylnaltrexone do not cross the blood-brain barrier to a significant extent thus minimising the reduction of any opioid induced analgesic effect.
U.S. Pat. No. 4,774,230 (Tuttle et al) relates to the intestine specific delivery of opioid antagonists including naloxone and naltrexone for treating opioid induced and idiopathic constipation and IBS. The drug is targeted to the intestine by virtue of an inactive glucoronic acid derivative which is enzymatically cleaved by glucoronidase, in the lower intestine and particularly the colon. The glucoronic acid derivative may be in the form of capsules or tablets for oral administration and may have enteric coatings such as polyacrylates or cellulose acetate phthalates.
U.S. Pat. No. 4,987,136 (Kreek et al) relates to the treatment of a range of gastrointestinal dysmotility conditions including constipation and IBS by administering opioid antagonists such as naloxone or naltrexone. Preferably, the opioid antagonist will be in an oral sustained release form allowing sustained release along the gastrointestinal tract, in a pH independent manner. The sustained release formulation may be administered in a hard gelatin capsule.
There is a need to provide a therapeutic treatment that will relieve (opioid induced) constipation and treat IBS. The desired therapy would relieve opioid induced constipation without reversing the analgesic effect for which the opioid was intended.
The inventors have now found that an opioid antagonist specifically released, initially, in the mid to distal small intestine, especially the distal ileum, and/or ascending colon is effective in treating IBS and both opioid induced and idiopathic constipation.
Accordingly, in a first aspect of the invention, there is provided an opioid antagonist for use in the manufacture of a medicament for the treatment of a condition selected from constipation and Irritable Bowel Syndrome by targeting initial release of said antagonist to the mid to distal small intestine and/or ascending colon and providing subsequent sustained release of said antagonist along any remaining part of the small intestine and along the colon.
Preferably, initial release of the antagonist is targeted to the distal ileum and/or ascending colon and subsequent sustained release occurs along the colon.
The invention has particular application to the treatment of idiopathic constipation and especially opioid induced constipation.
Preferred opioid antagonists for use in the invention are naloxone and naltrexone and pharmacologically acceptable salts, derivatives and metabolites thereof.
Other opioid antagonists include methyl naloxone, nalmefene, cypridime, beta funaltrexamine, naloxonazine, naltrindole, nor-binaltorphimine and any pharmacologically acceptable salts, derivatives and metabolites thereof.
References herein to pharmacologically acceptable derivative, include any derivative which has the same type of pharmacological activity as the relevant opioid antagonist.
In a second aspect of the invention, there is provided a composition comprising an opioid antagonist in an oral delayed and sustained release form which targets initial release of the opioid antagonist to the mid to distal small intestine and/or ascending colon and provides sustained release along any remaining part of the small intestine and along the colon.
Preferably, initial release of the antagonist is targeted to the distal ileum and/or ascending colon an
Evans Brian Kenneth
Rhodes John
Henley III Raymond J.
Rhodes John
LandOfFree
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