Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/10—Laxatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents

Definitions

• composition for Treatment of Constipation and Irritable Bowel Syndrome
• 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 .
• an opioid antagonist especially naloxone and naltrexone
• Opioids including codeine phosphate and morphine
• Opioids 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.
• 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 lh after parenteral administration. It is absorbed from the gastrointestinal tract and subject to considerable first- pass metabolism.
• Naltrexone (17- (cyclopropylmethyl) -4 , 5 ⁇ -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.
• coatings such as polyacrylates or cellulose acetate phthalates .
• US-A-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.
• opioid antagonists such as naloxone or naltrexone.
• 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.
• 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.
• 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.
• 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.
• 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 .
• 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.
• initial release of the antagonist is targeted to the distal ileum and/or ascending colon and subsequent sustained release occurs along the colon.
• the presently preferred opioid antagonist is naloxone. This substance is particularly suited to administration by the oral route since it is known to be efficiently metabolised by the liver, which minimises its absorption into the blood circulatory system thus limiting the risk of systemic side effects, such as negation of systemic pain relief for which certain opioids are administered.
• a suitable unit dose for the treatment of constipation by opioid antagonists is in the range of 0.5 to 30 mg naloxone or the equivalent thereof .
• a delayed, sustained release oral formulation was prepared as follows. Naloxone hydrochloride (10 mg) was suspended in 400 to 450 mg of a matrix of GelucireTM 50/13 and GelucireTM 42/12 (a polyglycolised glyceride supplied by Gattefosse, France) in the ratio 82.5:17.5 and the resulting suspension filled into a size No. 2 hard gelatin capsule.
• Formulations were also prepared with naloxone suspended in the following polyglycolised glycerides : a) GelucireTM 42/12, b) GelucireTM 44/14, c) GelucireTM 46/07, d) GelucireTM 48/09, e) GelucireTM 50/13, f) GelucireTM 53/10, g) GelucireTM 54/02, h) GelucireTM 62/05, i) GelucireTM 64/02, j) GelucireTM 54/02 & GelucireTM 46/07 50:50, k) GelucireTM 62/05 S GelucireTM 46/07 50:50, 1) GelucireTM 64/02 & GelucireTM 46/07 50:50, m) GelucireTM 54/02 & GelucireTM 46/07 75:25, n) GelucireTM 64/07 & GelucireTM 46/07 75:25, o) GelucireTM 54/02 & GelucireTM
• the capsules were then enteric coated using a 3% w/w acrylic resin (EudragitTM S) dissolved in an organic solvent mixture (methanol 10% v/v in acetone 90% v/v) . Diethyl phthalate was included as the plasticiser and dimethicone 20 as a lubricant. 75 cm 3 of this mixture was used to coat 100 capsules.
• the study consisted of four 10-day study periods, with at least two weeks between each, which were in a randomised order and the capsules being administered daily in a double blind manner.
• the capsules in each case were A (codeine phosphate 30 mg or placebo) and B (naloxone 10 mg or placebo) and the study conducted such that all four combinations of treatments were given, that is to say placebo only, codeine with placebo, placebo with naloxone and codeine with naloxone.
• the capsules were administered twice a day ("bd") .
• the naloxone formulation used was that in a matrix of GelucireTM 50/13 and GelucireTM 42/12 in the ratio 82.5:17.5.
• the study protocol was as follows: On day 0, subjects were given capsule B and on days 1 to 9, were given capsules A and B. On days 3 to 6, the subjects took transit markers; packaged in distinctly coloured capsules, each containing 20 different shaped radio opaque marker pellets (Dunn Clinical Nutrition) . From day 7, the subjects' next two bowel motions were collected. A normal diet was adhered to throughout the study period and recorded on days 3 to 6.
• Table 1 shows the gut transit time of all 12 patients in the study for the control period and for the periods of treatment with codeine, naloxone and the combined treatment.
• Table 2 shows gut transit times for only those patients whose gut transit time was increased when taking codeine.
• naloxone alone and naloxone with codeine both produced reduced gut transit time. This indicates that the naloxone preparation accelerates gut transit by blocking opioid receptors and hence is effective in both opioid induced constipation and idiopathic constipation.
• Example 1 the procedure of Example 1 was substantially followed using GelucireTM 53/10 & GelucireTM 42/12 95:5 as the polyglycolised glyceride matrix.
• the capsule was enterically coated with a mixture of acrylic resin materials (EudragitTM LS) which caused the capsule to remain intact until the mid small intestine.
• the glyceride provided a harder melt than GelucireTM 50/13 & GelucireTM 42/12 82.5:17.5 and released the naloxone over a 12 hour period.
• naloxone in all three doses was shown to accelerate gut transit time by " blocking the opioid effect, with the 10 and 20 mg bd doses being more reliable.
• a 38 year old female patient with Irritable Bowel Syndrome having been subject to abdominal distension, pain and constipation for approximately ten years was treated with a naloxone hydrochloride formulation as used in Example 1, administered twice daily for one year. The treatment kept the patient almost symptom free for the duration of the treatment.

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• Animal Behavior & Ethology (AREA)
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• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Emergency Medicine (AREA)
• Nutrition Science (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines Containing Plant Substances (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)
• Medicinal Preparation (AREA)
• Coloring Foods And Improving Nutritive Qualities (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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Cited By (50)

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• 2000
  • 2000-10-30 AU AU10447/01A patent/AU776567B2/en not_active Ceased
  • 2000-10-30 JP JP2001534385A patent/JP2003513045A/ja active Pending
  • 2000-10-30 PT PT00971617T patent/PT1225897E/pt unknown
  • 2000-10-30 ES ES00971617T patent/ES2226933T3/es not_active Expired - Lifetime
  • 2000-10-30 IL IL14937800A patent/IL149378A0/xx active IP Right Grant
  • 2000-10-30 WO PCT/GB2000/004167 patent/WO2001032180A2/en not_active Ceased
  • 2000-10-30 AT AT00971617T patent/ATE275402T1/de active
  • 2000-10-30 US US10/111,850 patent/US6734188B1/en not_active Expired - Fee Related
  • 2000-10-30 DK DK00971617T patent/DK1225897T3/da active
  • 2000-10-30 CA CA002389650A patent/CA2389650C/en not_active Expired - Fee Related
  • 2000-10-30 DE DE60013630T patent/DE60013630T2/de not_active Expired - Lifetime
  • 2000-10-30 EP EP00971617A patent/EP1225897B1/en not_active Expired - Lifetime
  • 2000-10-30 CZ CZ20021536A patent/CZ299726B6/cs not_active IP Right Cessation
• 2002
  • 2002-04-28 IL IL149378A patent/IL149378A/en not_active IP Right Cessation

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