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WO2016193456A2 - Antagoniste de récepteur d'opioïde destiné à être utilisé dans le traitement de patients souffrant de constipation sévère - Google Patents

Antagoniste de récepteur d'opioïde destiné à être utilisé dans le traitement de patients souffrant de constipation sévère Download PDF

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Publication number
WO2016193456A2
WO2016193456A2 PCT/EP2016/062692 EP2016062692W WO2016193456A2 WO 2016193456 A2 WO2016193456 A2 WO 2016193456A2 EP 2016062692 W EP2016062692 W EP 2016062692W WO 2016193456 A2 WO2016193456 A2 WO 2016193456A2
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Prior art keywords
composition
receptor antagonist
opioid
composition according
opioid receptor
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WO2016193456A3 (fr
Inventor
Hélène Rey
Olaf MUNDSZINGER
Isabelle GOLFIER
Silvia JAKOB
Oliver RUSCH
Marc Fischer
Christian Holl
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Develco Pharma Schweiz AG
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Develco Pharma Schweiz AG
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Priority to EP16730722.2A priority Critical patent/EP3302476A2/fr
Publication of WO2016193456A2 publication Critical patent/WO2016193456A2/fr
Publication of WO2016193456A3 publication Critical patent/WO2016193456A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • 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
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • 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

Definitions

  • the present invention is in the field of medicine, particularly in the field of treatment of constipation.
  • the invention relates to a composition comprising an opioid receptor antagonist for use in treating a patient with severe constipation, in particular opioid-induced constipation, wherein the dosage of said opioid is equivalent to at least 80 mg morphine per day.
  • Constipation is a major symptom of bowel malfunction. Long-term consequences of constipation can increase morbidity and mortality as well as deterioration of quality of life. Chronic constipation can result in haemorrhoid formation, rectal pain and burning, bowel obstruction and potential bowel rupture and death.
  • constipation can be opioid induced.
  • Opioid-induced constipation is predominantly due to the activity of gastrointestinal ⁇ -opioid receptors. Selective inhibition of these peripheral receptors can relieve constipation without compromising centrally mediated effects of opioid analgesia or precipitating withdrawal.
  • Opioids are the most effective analgesics widely used in patients with severe chronic pain. Their clinical efficacy is often burdened by adverse drug reactions that may influence drug adherence associated with early discontinuation, under-dosing, inadequate analgesia and reduced quality of life. One major health concern is constipation occurring in 80-90 % of the patients on long-term opioid treatment. To avoid efficacy problems and specific signs and symptoms of the bowel dysfunction as haemorrhoid formation, rectal pain, burning or bowel obstruction, non-specific laxatives are frequently prescribed as stool softeners, bowel stimulant, or osmotic agents. Their clinical efficacy, however, is not undisputed and they may produce new problems.
  • a more specific approach to avoid opioid-induced constipation in patients with chronic pain is combination therapy with opioid antagonists that may prevent the undesired ⁇ -opioid receptor activation along the large intestine without compromising the centrally mediated analgesia or precipitating withdrawal effects.
  • opioid antagonists that may prevent the undesired ⁇ -opioid receptor activation along the large intestine without compromising the centrally mediated analgesia or precipitating withdrawal effects.
  • Suitable compounds are methylnaltrexone and naloxone that are either not absorbed from the gut lumen, do not pass the blood-brain barrier or are being inactivated along the "first-pass" absorption route.
  • Subcutaneous methylnaltrexone (MNTX-SC) is approved in palliative care for the acute treatment of opioid induced constipation.
  • the quaternary ammonium compound does not cross the blood-brain-barrier; consequently, it does not antagonize the central effects and acts only in the periphery. After subcutaneous administration, it induces predominantly a short-term laxative effect on constipation rather than the desired prevention of opioid-induced bowel dysfunction.
  • methylnaltrexone as immediate-release formulation (MNTX-I ) provided lower efficacy compared to the extended- release formulation (MNTX-ER).
  • MNTX-I immediate-release formulation
  • MNTX-ER extended- release formulation
  • the pharmacodynamics results with oral methylnaltrexone formulations are preliminary and may be misleading as the changes in intestinal motility were evaluated using the lactulose hydrogen breath test which is a measure for small intestinal transit (oro- cecal transit time, OCT). It has to be considered that 10 g of the osmotic active lactulose may exert own laxative effects and may accelerate OCT.
  • Opioid-induced constipation can be uncomfortable and very painful, and often leads to the discontinuation of the opioid-based therapy, and thus endangers the success of the treatment with the opioids especially in high doses. Since it can be assumed that the opioid-induced constipation is caused directly and locally over the entire intestine through binding to the opioid receptors, this side effect should be eliminated through the use of opioid antagonists. However, the use of opioid antagonists only makes sense if the antagonistic effect is limited to the intestine and does not cancel the main analgesic effect.
  • Naloxone is a suitable opioid antagonist for the treatment of opioid-induced constipation. Naloxone is rapidly and completely absorbed after oral administration and because the substance is subject to extensive first-pass metabolism, only small amounts of unmetabolised naloxone are available to the system.
  • naloxone is an ideal candidate for remedying opioid-induced constipation: in the intestine it is present as an active substance and can thus counter the paralysing effect of the opioid on the gastrointestinal tract, while after absorption it is largely metabolised during the first passage in the liver, and thereby becomes inactive. The analgesic effect of the opioids is thus not affected.
  • WO 2011/117306 discloses a two-layer tablet, which in one layer contains an opioid agonist, and in another layer an opioid antagonist, wherein the tablet quickly releases both active substances.
  • the advantage of this double-layer is to suppress the side effects of the opioid agonist, but it does not focus on suppression of the opioid- induced constipation.
  • the combined preparation Targin ® is available on the market and comprises a mixture of the opioid agonist oxycodone in the form of a hydrochloric salt, and the opioid antagonist naloxone also in the form of a hydrochloric salt.
  • the active substances are released in a prolonged manner. It is therefore suitable for the parallel treatment of pain and opioid-induced constipation.
  • this monolithic formulation has the disadvantage that the release rates of the two active substances are fixed. Individualised treatments are therefore difficult to optimise.
  • naloxone single agent preparations are described in the patent literature, such as in WO 98/25613 A2.
  • release of naloxone from these compositions is dependent on the ambient pH in the gastrointestinal tract. A uniform application of naloxone to the entire gastrointestinal tract, and therefore an optimal treatment, are thus not possible with such products.
  • Prophylaxis can be considered when starting opioid therapy, although common constipation prophylaxis (e.g., fiber, fluids, exercise) may not be sufficient for patients receiving palliative care.
  • fiber-based laxatives may be dangerous in those with fecal impaction and may result in impaction without adequate water intake.
  • first line treatments as for example with stool softeners and peristaltic stimulants fail.
  • the above products do not address the need of severely constipated patients. Such patients may for example be defined by their colon transit times (CTT). Such patients may have CTTs of 50 hours and more. This is a severe constipation.
  • CTT colon transit times
  • Colon transit time is defined as the Whole gut transit (WGT) time minus the Oro-cecal transit time.
  • the WGT time can be determined by any suitable method. However, in a preferred embodiment, the WGT time is determined using radio-opaque markers.
  • OCT time can be determined by any suitable method. Preferably, OCT time is determined by the sulfasalazine/sulfapyridine method (Gramatte, T. et al.; 1991, Int. J. Clin. Pharmacol. Ther. Toxicol. ;29(4), 147-150). DESCRIPTION OF THE INVENTION
  • composition comprising an opioid receptor antagonist, or a pharmaceutically acceptable salt thereof, for use in treating a patient with severe constipation, wherein
  • the antagonist in the composition is prepared in an oral extended release formulation
  • the patient is characterized by a severe opioid-induced constipation
  • Severe constipation is characterized by a WGT of 65 to 180 h, preferably 65 to 150 h, more preferably of 70 to 140 h, even more preferably of 70 to 130 h, yet more preferably of 70 to 120 h, and most preferably of 70 to 110 h.
  • severe constipation is characterized by a WGT of 65 hours or more, preferably 70 h or more and most preferably a WGT of 75 h or more.
  • the WGT time can be determined by any suitable method. However, in a preferred embodiment, the WGT time is determined using radio-opaque markers.
  • the antagonist in the composition is prepared in an oral extended release formulation
  • the composition is an oral composition that releases the antagonist in a prolonged manner.
  • the patient is receiving an opiate treatment with a dosage equivalent to at least 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 200, 240, 250, 300, 320, 400, or 500 mg of morphine per day.
  • the patient is receiving an opiate treatment with a dosage equivalent to 70 to 300 mg morphine, preferably equivalent to 75 to 270 mg morphine, more preferably 85 to 260 mg morphine and most preferably a dosage equivalent to 80 to 250 mg morphine per day.
  • the opioid receptor antagonist is a ⁇ -receptor antagonist.
  • the daily dosage of a ⁇ -receptor antagonist in the composition can be expressed as naloxone- equivalent dosage. This relation is likely due to the fact that naloxone also belongs to the class of ⁇ - receptor antagonists.
  • the composition comprises the opioid receptor antagonist, or the pharmaceutically acceptable salt thereof, in a dose equivalent to 8 to 60 mg of naloxone, more preferably a dose equivalent to 10 to 56 mg of naloxone, even more preferably a dose equivalent to 12 to 48 mg of naloxone, and most preferably a dose equivalent to 12, 24, 36 or 48 mg of naloxone.
  • the daily dosage is equivalent to 24 or 48 mg of naloxone.
  • the daily dosage is equivalent to 24 mg naloxone.
  • the daily dosage is equivalent to 48 mg of naloxone.
  • the composition comprises an opioid receptor antagonist, or the pharmaceutically acceptable salt thereof, in a dose equivalent to 3 to 60 mg of naloxone hydrochloride, more preferably a dose equivalent to 8 to 48 mg of naloxone HCI, even more preferably a dose equivalent to 12 to 48 mg of naloxone HCI.
  • the composition comprises methylnaltrexone bromide at a dosage of 150 mg, in an alternative embodiment the dosage of methylnaltrexone bromide is 500 mg.
  • an amount of an opioid or of an opioid antagonist is to be understood as the indicated amount ⁇ 10 %, ⁇ 8 %, ⁇ 5 %, ⁇ 3 %, or more preferably ⁇ 1 %.
  • the opioid receptor antagonist is naloxone, methylnaloxone, naloxonesulfonate, methylnaltrexone, naltrexone or any derivative, in particular esthers or sulfonates, or pharmaceutically acceptable salts thereof. More preferably, the opioid receptor antagonist is naloxone or methylnaltrexone, or any derivative or pharmaceutically acceptable salt thereof.
  • the opioid receptor antagonist is naloxone hydrochloride.
  • the opioid receptor antagonist is methylnaltrexone, or even more preferably methylnaltrexone bromide.
  • N-methylnaltrexone bromide is a quaternary derivative of the pure opioid antagonist naltrexone that does not cross the human blood-brain barrier. Following subcutaneous administration, methylnaltrexone is rapidly absorbed, with peak concentrations achieved at approximately 0.5 hours after administration. The steady-state volume of distribution is 1.1 l/kg. The proportion of methylnaltrexone that binds to plasma proteins is 11-15 % and its terminal half-life was found to be about 8 hours. Accumulation has not been observed with intravenous administration every 6 hours. Methylnaltrexone is primarily eliminated without being metabolised (85% of the administered dose).
  • composition according to the present invention is in particular suitable for patients, which do not respond to laxatives. Accordingly, in a preferred embodiment the patient is a laxative non-responder.
  • objective of the present invention is to provide a solid oral pharmaceutical composition comprising an opioid receptor antagonist, or a pharmaceutically acceptable salt or derivative thereof, as an active substance, wherein the composition releases the opioid receptor antagonist in an extended release formulation, for use in treating patients with severe constipation characterised by a highly increased WGT.
  • the present invention achieves those objectives by a composition comprising an opioid receptor antagonist, or any pharmaceutically acceptable salt or derivative thereof, for use in treating a patient with severe constipation, wherein:
  • the antagonist in the composition is prepared in an extended release formulation, and patient is characterized by severe constipation characterized by a WGT of at least
  • the composition is a composition that is administered orally.
  • the severe constipation is characterized by a WGT of 65 to 180 h, preferably 65 to 150 h, more preferably of 70 to 140 h, even more preferably of 70 to 130 h, yet more preferably of 70 to 120 h, and most preferably of 70 to 110 h.
  • severe constipation is characterized by a WGT of 65 hours or more, preferably 70 h or more and most preferably a WGT of 75 h or more.
  • An amount of time defined by a number of hours is to be understood as the indicated amount of time in hours ⁇ 10 h, ⁇ 8 h, ⁇ 5 h, ⁇ 3 h, more preferably ⁇ 1 h, and even more preferably ⁇ 0.5 h, but most preferably, the stated time in hours.
  • the severe constipation is not an opioid-induced constipation.
  • the severe constipation is an opioid-induced constipation.
  • Opioid-induced constipation can be caused by any opioid analgesic or opioid analgesic analogue, or by any of their salts or mixtures.
  • analgesics are the following: alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, besomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, Dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorph
  • the WGT time can be determined by any suitable method. However, in a preferred embodiment, the WGT time is determined using radio-opaque markers. Alternatively, the severe constipation can be characterized by the colon transit time. CTT is defined as the WGT time minus the OCT time. OCT time can be determined by any suitable method. Preferably, OCT time is determined by the sulfasalazine/sulfapyridine method (Gramatte, T. et al.; 1991, Int. J. Clin. Pharmacol. Ther. Toxicol. ;29(4), 147-150).
  • the severe constipation is characterized by a colon transit time of at least 55 h.
  • the severe constipation is characterized by a colon transit time of 56 to 130 h, more preferably of 60 to 120 h, even more preferably of 65 to 110 h, yet more preferably of 70 to 105 h, and most preferably of 75 to 100 h.
  • severe constipation is characterized by a colon transit time of 56 hours or more, preferably 60 h or more and most preferably a colon transit time of 65 h or more.
  • the opioid receptor antagonist is a ⁇ -receptor antagonist.
  • the opioid receptor antagonist is naloxone, methylnaloxone, naloxonesulfonate, methylnaltrexone, naltrexone or any derivative, in particular esthers or sulfonates, or pharmaceutically acceptable salts thereof. More preferably, the opioid receptor antagonist is naloxone or methylnaltrexone, or any derivative or pharmaceutically acceptable salt thereof. In one preferred embodiment, the opioid receptor antagonist is naloxone hydrochloride. In an alternative preferred embodiment, the opioid receptor antagonist is methylnaltrexone, or even more preferably methylnaltrexone bromide.
  • N-methylnaltrexone bromide is a quaternary derivative of the pure opioid antagonist naltrexone that does not cross the human blood-brain barrier. Following subcutaneous administration, methylnaltrexone is rapidly absorbed, with peak concentrations achieved at approximately 0.5 hours after administration. The steady-state volume of distribution is 1.1 l/kg. The proportion of methylnaltrexone that binds to plasma proteins is 11-15 % and its terminal half-life was found to be about 8 hours. Accumulation has not been observed with intravenous administration every 6 hours. Methylnaltrexone is primarily eliminated without being metabolised (85% of the administered dose). Approximately half of the dose is excreted in urine and less in faeces. A smaller part of the dose is metabolized to five distinct metabolites; N-demethylation to naltrexone is not a significantly used route.
  • the daily dosage of a ⁇ -receptor antagonist in the composition can be expressed as naloxone- equivalent dosage. This relation is likely due to the fact that naloxone also belongs to the class of ⁇ - receptor antagonists.
  • the composition comprises the opioid receptor antagonist, or the pharmaceutically acceptable salt thereof, in a dose equivalent to 8 to 60 mg of naloxone, more preferably a dose equivalent to 10 to 56 mg of naloxone, even more preferably a dose equivalent to 12 to 48 mg of naloxone, and most preferably a dose equivalent to 12, 24, 36 or 48 mg of naloxone. Most preferably the daily dosage is equivalent to 24 or 48 mg of naloxone.
  • the daily dosage is equivalent to 24 mg naloxone. In a second most preferred embodiment the daily dosage is equivalent to 48 mg of naloxone.
  • One aim of the present invention is to provides a solid oral pharmaceutical composition comprising an opioid receptor antagonist, or a pharmaceutically acceptable salt thereof, as an active substance, wherein the composition releases the active substance in a prolonged manner, and is suitable for an administration period of at least twelve-hours, for the treatment of severe opioid-induced constipation, wherein the dosage of said opioid is equivalent to at least 80 mg of morphine per day.
  • the severe constipation is characterized by a WGT of 65 to 180 h, preferably 65 to 150 h, more preferably of 70 to 140 h, even more preferably of 70 to 130 h, yet more preferably of 70 to 120 h, and most preferably of 70 to 110 h.
  • An amount of time defined by a number of hours is to be understood as the indicated amount of time in hours ⁇ 10 h, ⁇ 8 h, ⁇ 5 h, ⁇ 3 h, more preferably ⁇ 1 h, and even more preferably ⁇ 0.5 h, but most preferably, the stated time in hours.
  • the in vitro release rate is determined using the paddle stirrer apparatus (apparatus 2) with the paddle stirrer method according to Ph. Eur. (European Pharmacopoeia, 7th edition, 3rd supplement, 2.9.3 StammDissolution test for solid dosage forms", pages 3797-3803) at 75 rpm in 500 ml 0.1 N hydrochloric acid at 37 °C.
  • the amount of released active substance is preferably determined by UV-detection at 220 nm.
  • the opioid receptor antagonist is provided in an extended release formulation.
  • the release rate of the opioid receptor antagonist is measured using the paddle stirrer method according to Ph. Eur. at 75 rpm in 500 ml 0.1 N hydrochloric acid at 37 °C.
  • the release rate is 0 % to 75 % in 2 h, 3 % to 95 % in 4 h, 20 % to 100 % in 10 h, 30 % to 100 % in 16 h, 50 % to 100 % in 24 h, and of more than 80 % in 36 h.
  • the pharmaceutical composition comprises an opioid receptor antagonist such as naloxone, or a pharmaceutically acceptable salt thereof, as an active substance, wherein the composition releases the active substance in a prolonged manner, and the in vitro release rate of the active substance, measured using the paddle stirrer method according to Ph. Eur.
  • composition according to the invention with its release profile, was suitable for an administration period of at least 12 h for the treatment of opioid-induced constipation. Accordingly, it possesses a relatively high level of patient compliance.
  • composition according to the present invention is in particular suitable for patients, which do not respond to laxatives. Accordingly, in a preferred embodiment the patient is a laxative non-responder.
  • the opioid-induced constipation which can be treated by the composition according to the invention can be caused by any opioid analgesic or opioid analgesic analogue, or by any of their salts or mixtures.
  • analgesics are the following: alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, besomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, Dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin
  • the composition releases the active substance independently of the ambient pH of the gastrointestinal tract. This ensures that the entire gastrointestinal tract can be evenly and continuously supplied with the opioid receptor antagonist, or an acceptable salt thereof. A further optimisation of the treatment is thereby achieved.
  • the pH- independent release of the active substance from the composition of the invention can be achieved through the choice of suitable pharmaceutical excipients that will be known to the person skilled in the art. Local pH values in the gastrointestinal tract are from about 1.2 (in the stomach), to about 6.8 in the colon.
  • the release of the active substance from the composition of the invention that is independent from the pH of the gastrointestinal tract is preferably understood to mean that the similarity factor f2 between a first in vitro release at a pH of 1.2 to 6.8 and a second in vitro release at any other pH of 1.2 to 6.8 is larger or equal to 50.
  • the similarity factor f2 is determined according to SHAH V.P., TSONG Y., SATHE P., & LIU J. P. (1998), "In vitro dissolution profile comparison-statistics and analysis of the similarity factor, f2", Pharmaceutical Research, 15, 889-896. Specifically, the similarity factor f2 is calculated by the following formula:
  • Rt and Tt represent the released quantities of active substance at time point t at the first and second pH.
  • n is the number of time points.
  • the f2 factor is determined under the following conditions: a) the minimal number of time points for one release is 3 (time point 0 is excluded); b) the time points for the first and the second pH should be equal; c) for each time point, and for each pH, the released quantity is indicated as the mean value of 12 measurements; d) no more than one mean value measured above a release of 85 % can be taken into account for the calculation; e) the relative standard deviation or coefficient of variation of the release at a given pH should be smaller than 20 % for the first time point and smaller than 10 % for the second, and every subsequent time point.
  • the composition comprises a matrix, which releases the active ingredient in a prolonged manner.
  • the active substance can be released in a prolonged manner inexpensively, particularly when it is contained in a matrix that prolongs its release.
  • composition according to the invention may comprise a matrix, which releases an opioid receptor antagonist such as naloxone, or a pharmaceutically acceptable salt thereof, in a prolonged manner.
  • the matrix according to the invention is preferably a so-called scaffold matrix, which can be swelling or non-swelling, or can be a so-called eroding matrix.
  • the matrix can also have properties of both scaffold and eroding matrixes.
  • the active substance is incorporated into the matrix structure.
  • the active substance is gradually dissolved by the digestive juices from the loaded scaffold matrix during the transport through the gastrointestinal tract.
  • the matrix scaffold is excreted in more or less unchanged form, or in a swollen form.
  • the matrix is degraded, or eroded, which leads to active substance particles being exposed at the surface, and dissolved.
  • the release rate therefore depends on the matrix degradation or erosion rate.
  • a further preferred embodiment of the invention is a composition with a matrix that comprises one or several water-insoluble matrix-forming agents.
  • Another embodiment of the invention is a composition with a matrix that comprises one or several water-soluble matrix-forming agents.
  • the matrix of the composition is water- insoluble.
  • the matrix of the composition is water-soluble.
  • the matrix of the composition comprises one or several matrix-forming agents selected from the group consisting of cellulose esters, polyethylene oxide, polyvinylpyrrolidone/polyvinyl acetate mixtures, methacrylate-acrylate copolymers, waxes, fats such as glycerol esters, and fatty alcohols.
  • the substance classes mentioned here are particularly suitable as matrix-forming agents for the composition of the invention. However, particularly preferred is the use of a mixture of polyvinyl acetate and polyvinylpyrrolidone, and/or a glycerol dibehenic acid ester as matrix-forming agent.
  • the composition is free of film-coated, opioid receptor antagonist-containing particles, wherein the coating causes the prolonged release of the opioid receptor antagonist.
  • the composition can be formed by direct compression, since this is particularly inexpensive.
  • the composition is in the form of a tablet, capsule, granule, a micro tablet, extruded particles or granules compressed into a tablet.
  • the composition is designed as a once-a-day formulation, or a twice-a-day formulation.
  • the present invention further relates to a solid oral pharmaceutical composition comprising an opioid receptor antagonist, or a pharmaceutically acceptable salt thereof, as an active substance, wherein the composition releases the active substance in a prolonged manner, and the in vitro release rate of the active substance, measured using the paddle stirrer method according to Ph. Eur.
  • the present invention further relates to a solid oral pharmaceutical composition comprising an opioid receptor antagonist, or a pharmaceutically acceptable salt thereof, as an active substance, wherein the composition releases the active substance in a prolonged manner, and the in vitro release rate of the active substance, measured using the paddle stirrer method according to Ph. Eur.
  • the present invention further relates to a solid oral pharmaceutical composition comprising an opioid receptor antagonist, or a pharmaceutically acceptable salt thereof, as an active substance, wherein the composition releases the active substance in a prolonged manner, and the in vitro release rate of the active substance, measured using the paddle stirrer method according to Ph. Eur.
  • hydrochloric acid at 37 °C is of 0 % to 30 % in 1 h, of 0 % to 40 % in 2 h, of 3 % to 55 % in 4 h, of 10 % to 60 % in 8 h, of 20 % to 75 % in 12 h, of 30 % to 88 % in 16 h, of 50 % to 100 % in 24 h, and of more than 80 % in 36h.
  • the present invention further relates to a solid oral pharmaceutical composition comprising an opioid receptor antagonist, or a pharmaceutically acceptable salt thereof, as an active substance, wherein the composition releases the active substance in a prolonged manner, and the in vitro release rate of the active substance, measured using the paddle stirrer method according to Ph. Eur.
  • a further preferred embodiment of the invention is a composition, wherein the composition is preferably a tablet or a capsule, which has an in vitro release rate of the active substance, measured using the paddle stirrer method according to Ph. Eur.
  • a further preferred embodiment of the invention is providing a composition that is suitable for the treatment of opioid-induced constipation for at least 12 h, provided that the composition has an in vitro release rate of the active substance of 0 % to 50 % in 2 h, of 5 % to 95 % in 4 h, of 20 % to 90 % in 10 h, of more than 70 % in 18 h, and of more than 80 % in 24 h.
  • the release rate is, in accordance with the invention, controlled by adjusting the mass ratio of opioid receptor antagonist to matrix-forming agent.
  • the mass ratio of opioid receptor antagonist to matrix-forming agent is 1:1, more preferably 1:2, more preferably 1:5, more preferably 1:10, more preferably 1:20, even more preferably 1:50, yet more preferably 1:75 and most preferably 1:100.
  • composition of the invention is characterised in that through the prolonged release the concentration of the opioid receptor antagonist in the plasma is low. Its maximum plasma concentration (C ma x) is about 20x lower during the active course compared to a composition without prolonged release, and about lOOx lower compared with an intravenously administered composition.
  • the inhibition of the receptors over the active course is advantageous.
  • the low bioavailability in the system also ensures a reduced likelihood and/or severity of the side effects.
  • the assessment of the risk factor of a tablet can be calculated with the ratio IC 5 o/C m ax.
  • the value of IC 5 o/C m ax for a tablet according to the invention with 48 mg of naloxone is 54.
  • all values relating to the IC 5 o are for the ⁇ receptor.
  • the composition has an IC 5 o/C m ax value of at least 30.
  • the composition has an IC 5 o/C m ax value of at least 35. In an even more preferred embodiment, the composition has an IC 5 o/C m ax value of at least 40. In the most preferred embodiment, the composition has an IC 5 o/C m ax value of at least 50.
  • the composition additionally comprises at least one stabilizer, which protects the active substance.
  • the at least one stabilizer is selected from the list comprising sulphur dioxide, sodium sulphite, sodium bisulphite, ascorbic acid and its derivatives and tocopherol, as well as its water- and fat-soluble derivatives, such as, for example, tocopherol acetate, sulphites, bisulphites and hydrogen sulphites of alkali, alkaline earth metals or other metals, paraben, BHA, BHT, gallates, as well as lower fatty acids, fruit acids, phosphoric acids, sorbic and benzoic acids as well as their salts, esters, derivatives and isomeric compounds, ascorbyl palmitate, lecithins, mono- and polyhydroxylated benzene derivatives, ethylenediaminetetraacetic acid and salts thereof, citraconic acid, cysteine, L-cysteine, conidendrin, diethyl
  • the composition additionally comprises at least one stabilizer, which protects the matrix.
  • the at least one stabilizer is selected from the list comprising butylated hydroxytoluol, sulphur dioxide, sodium sulphite, sodium bisulphite, ascorbic acid and its derivatives and tocopherol, as well as its water- and fat-soluble derivatives, such as, for example, tocopherol acetate, sulphites, bisulphites and hydrogen sulphites of alkali, alkaline earth metals and other metals, paraben, BHA, BHT, gallates as well as lower fatty acids, fruit acids, phosphoric acids, sorbic and benzoic acids and their salts, esters, derivatives and isomeric compounds, ascorbyl palmitate, lecithins, mono- and polyhydroxylated benzene derivatives, ethylenediaminetetraacetic acid and their salts, citraconic acid, cysteine, L-cysteine, con
  • the composition comprises at least one additive, wherein the additive is an emetic or a pungent agent drug.
  • the composition comprises an additive, wherein this additive is a pungent agent, selected from the group comprising Allii sativi bulb, Asari rhizome cum herba, Calami rhizoma, capsici fructus (capsicum ⁇ capsici fructus acer (cayenne pepper), hizoma Curcumae Longae, Curcumae xanthorrhizae rhizoma, Galangae rhizoma, Semen Myristicae, Piperis nigri fructus (pepper), Sinapis albae (Erucae) Semen, Sinapis nigrae semen, Zedoariae rhizoma and Zingiberis rhizoma, preferably from the group consisting of capsici fructus (capsicum), capsici fructus acer (cayenne pepper), hizoma Cur
  • the composition comprises at least one additive, wherein this additive is an emetic.
  • this additive is an emetic.
  • the emetic is based on one or several substances from radix ipecacuanha (ipecac).
  • the emetic is based on the substance emetine, in an alternative embodiment, the emetic is apomorphine.
  • the composition comprises a dye.
  • the dye is selected from a group comprising red iron oxide, black iron oxide and indigo carmine.
  • the composition additionally comprises at least one non-steroid antirheumatic or an antihistamine.
  • the composition additionally comprises at least one water-soluble lubricant.
  • the composition comprises at least one water-soluble lubricant selected from the group comprising adipic acid, fumaric acid, sodium benzoate and macrogol.
  • naloxone hydrochloride and glycerol dibehenic acid ester were sieved and mixed together. First the sieved Colloidal silicon dioxide and then the magnesium stearate were mixed into the resulting mixture. The thus obtained mixture was pressed into a tablet using a conventional tablet pressing tool.
  • Kollidon ® S consisting of 80 wt.-% polyvinyl acetate, 19 wt.-% povidone, 0.8 wt.-% sodium lauryl sulfate and 0.2 wt.-% Colloidal silicon dioxide.
  • naloxone layer that is, naloxone hydrochloride, Kollidon ® S , glycerol dibehenic acid ester, colloidal silicon dioxide and magnesium stearate were sieved and blended together to form a first powdery mixture.
  • the components of the placebo layer sugar pellets, hypromellose, microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate were sieved and mixed together to form a second powdery mixture.
  • the first and the second mixture were pressed with a conventional two-layer tablet press to obtain the two-layer tablet core.
  • the thus obtained two-layer tablet core was coated to obtain the two-layer tablet.
  • the components of the oxycodone layer that is, sustained release oxycodone pellets, microcrystalline cellulose, colloidal silicon dioxide and magnesium stearate were sieved and blended together to form a first powdery mixture.
  • naloxone hydrochloride naloxone hydrochloride
  • Kollidon ® SR colloidal silicon dioxide and magnesium stearate were sieved and mixed together to form a second powdery mixture.
  • the first and the second mixture were pressed with a conventional two-layer tablet press to obtain the two-layer tablet core.
  • the thus obtained two-layer tablet core was coated with the coating material Opadry II ® that had been dissolved in water at a temperature of 30°C to 50 °C to obtain the two-layer tablet.
  • the sustained-release oxycodone pellets had the following composition and were prepared as known in the art:
  • Kollidon ® SR consists of 80 wt.-% polyvinyl acetate, 19 wt.-% povidone, 0.8 wt.-% sodium lauryl sulfate and 0.2 wt.-% Colloidal silicon dioxide.
  • Opadry II ® consists of polyvinyl alcohol, iron oxide or titanium dioxide, Macrogol and talc.
  • Capsules containing micro tablets of 2mm in diameter were produced as follow:
  • methylnaltrexone bromide, povidone, colloidal silicon dioxide and magnesium stearate were mixed togethter and compressed on a rotary machine.
  • Micro tablets were further coated with a solution of ethylcellulose, povidone and propylene glycol in a fluid bed processor in order to obtain a sustained release coating.
  • the clinical study was performed in 15 German white subjects (11 males, 4 females, age 20-34 years, body mass index 20.3-27.0 kg/ m 2 ). All subjects were in good health as confirmed by medical histories, physical examination, routine clinical-chemical and hematologic screenings and 12-lead ECG. Three female subjects took hormonal contraceptives regularly and one subject took 300 mg ibuprofen to treat headache 4 days before the administration of study medication. Three subjects were smokers of less than 10 cigarettes per day. 14 subjects drank alcohol occasionally. All were negative in the pre- study screenings for alcohol, drugs, hepatitis-B-virus (HBV) and hepatitis-C-virus (HCV) and human immunodeficiency virus (HIV).
  • HBV hepatitis-B-virus
  • HCV hepatitis-C-virus
  • HCV human immunodeficiency virus
  • Loperamide is an agonist of ⁇ -opioid receptors in the myenteric plexus without central nervous opioid effects which is known to delay OCT of radiolabeled lactulose that can be reversed by the opioid antagonist naloxone.
  • the time of methylnaltrexone administration was defined to be time zero.
  • 200 ml of pure apple juice and a methylnaltrexone placebo capsule were given at the respective times (Control).
  • Methylnaltrexone placebo capsules were identical in color and shape to MNTX-IR and MNTX-ER which all were swallowed using 200 ml table water; i.e., the clinical study has been performed double-blinded with exception of the MNTX-SC study period.
  • Oro-cecal transit time (OCT) was assessed using the sulfasalazine/sulfapyridine method.
  • sulfasalazine 500 mg immediate-release sulfasalazine (Azulfidine ® , Pharmacia, Germany) were swallowed with 200 ml table water 2 h after administration of the respective methylnaltrexone study medication to avoid competitive interactions during absorption.
  • the time of first appearance of sulfapyridine in serum was defined to be the OCT (cut-off: 100 ⁇ g/ml serum).
  • Whole gut transit time (WGT) was evaluated using a radio-opaque marker method.
  • Colon TransitTM capsules (Medical Instruments Corporation GmbH, Herford, Germany) were swallowed 24, 12 and 1 h before time zero using the 200 ml apple juice for loperamide dosing.
  • Each capsule contains 10 radio-opaque markers of identical shape (e.g. triangles).
  • a Colon TransitTM batch consists of capsules with markers of different shape (e.g. triangles, circles, rings etc.).
  • Our subjects were willing and compliant for sampling stool in single portions immediately after feeling urge without suppressing defecation using tightly closable containers. Then, the number of radio-opaque markers with identical shape was counted in the stool portions after X-ray imaging (Philips Optimus, Philips Healthcare, Hamburg, Germany) using the Agfa PACS Workstation Impact-Version 5.2 (Agfa-Healthcare, Cologne, Germany).
  • Colon transit time was derived from the difference of WGT and OCT.
  • CCT Colon transit time
  • Colon TransitTM After overnight fasting, Colon TransitTM, loperamide, the methylnaltrexone study medication or placebo and sulfasalazine were administered as described above. Bed rest lasted from 1.5 h before to 4.5 h after methylnaltrexone administration. Standard meals were served 5, 8 and 13 h after methylnaltrexone administration. The subjects had to eat and drink the same individual amount of food and table water on all study days.
  • venous blood was sampled via an indwelling cannula placed in a forearm vein or by individual vein punctures 1.5 h before and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12, 16, 24 h after administration of the study medication (Smonovette ® , Sarstedt, Nurnbrecht, Germany).
  • Urine was collected at 24 h-intervals for 3 days and stool was collected as described above. Serum and urine aliquots were stored at least at -20 °C until quantitative analysis of methylnaltrexone and sulfapyridine, respectively.
  • LC-MS/MS liquid chromatopraphy-tandem mass spectrometry
  • the method was validated for simultaneous determination of methylnaltrexone and sulfapyridine in serum for the ranges of 0.5 to 250 ng/ml and 0.5 to 500 ng/ml, respectively.
  • the calibration range for methylnaltrexone was 0.005-1.0 ⁇ g/ml.
  • the chromatograms were evaluated using the Analyst 1.4 software (AB Sciex, Darmstadt, Germany) with the internal standard method using peak-area-ratios for calculation. Between-day and within-day accuracy for the assays of methylnaltrexone in serum and urine and for sulfapyridine in serum was between +8.4 % and -6.9 % of the nominal values. Precision accounted for ⁇ 13.1 % of the respective means. Biometrical evaluation
  • Whole-gut transit time was assessed by counting the radio-opaque markers with different shapes (Colon TransitTM) in the feces according to formula (1) : with ⁇ -3 as derived by formula (2):
  • Xi number of markers type 1, 2, 3 counted at time ti
  • n total number of stools
  • the CTT was evaluated from the difference of WGT and OCT.
  • MNTX-SC was rapidly absorbed into the blood and reached maximum concentrations between 94.7 and 309 ng/ml after 0.25 to 0.75 hours.
  • the volume of distribution (Vss) ranged between 107 and 712 L and the terminal elimination half-life between 3.4 and 26 hours. 22-51 % of the dose was excreted unchanged into the urine. Renal clearance was between 233-707 ml/min and accounted for 40-51 % of the total body clearance.
  • Pharmacokinetic characteristics (means ⁇ SD) of methylnaltrexone after subcutaneous injection of 12 mg (MNTX-SC) and single oral administration of 500 mg in immediate-release capsules (MNTX-IR) and extended-release capsules (MNTX-ER) in 15 healthy subjects. T1 ⁇ 2 after administration of MNTX-ER was not assessed because of the too low number of data points along the terminal elimination slope that were above the limit of quantification.
  • MNTX-IR and MNTX-ER The absorption of MNTX-IR and MNTX-ER from the gastrointestinal tract was significantly delayed and rather incomplete. MNTX-ER was absorbed with significantly lower rate and was less bioavailable than MNTX-IR. Relative bioavailability of MNTX-IR and MNTX-ER was only 1.53-5.49 % and 0.11-1.24 %, respectively, compared to MNTX-SC. Therefore, systemic exposure (AUC) of MNTX-IR and MNTX-ER was substantially smaller compared to MNTX-SC despite the 42-fold difference in dose (500 mg vs. 12 mg). Systemic elimination of MNTX-IR was not different from MNTX-SC as confirmed by similar terminal elimination half lives and renal clearances. For MNTX-ER, terminal half-life was not assessed because of low bioavailability and impossibility to assess the terminal slope correctly with an adequate number of data points.
  • MNTX-ER significantly antagonized loperamide effects on OCT and CTT but, however, not to baseline levels; the transit along the small and large intestine was still significantly prolonged after single dose co- medication of MNTX-ER (Table 2).
  • Figure 1 Release profile of naloxone from the composition according to the invention; example example 2 (x).
  • Figure 2 Intestinal transit times in 15 subjects before and after pre-treatment with loperamide (LOP).
  • LOP loperamide
  • Figure 3 Effect of subcutaneous (SC), immediate-release (IR) and extended-release (ER) administration of methylnaltrexone (MNTX) on the oro-cecal transit time (OCT) and the colon transit time (CTT) in 15 subjects upon loperamide (LOP) treatment.
  • SC subcutaneous
  • IR immediate-release
  • ER extended-release
  • MNTX methylnaltrexone

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Abstract

La présente invention concerne une composition pharmaceutique comprenant un antagoniste de récepteur d'opioïde, ou un dérivé ou un sel pharmaceutiquement acceptable de celui-ci, en tant que substance active, laquelle composition libère la substance active de manière prolongée. La composition convient à une période d'administration d'au moins douze heures pour le traitement d'une constipation sévère induite par un opioïde chez des patients recevant une dose quotidienne d'opioïde équivalente à au moins 80 mg de morphine.
PCT/EP2016/062692 2015-06-03 2016-06-03 Antagoniste de récepteur d'opioïde destiné à être utilisé dans le traitement de patients souffrant de constipation sévère Ceased WO2016193456A2 (fr)

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WO1998025613A2 (fr) 1996-12-11 1998-06-18 Klinge Pharma Gmbh Composition galenique contenant des antagonistes des opioides
WO2011117306A1 (fr) 2010-03-24 2011-09-29 L. Molteni & C. Dei Fratelli Alitti Societa' Di Esercizio S.P.A. Préparations pharmaceutiques double-couche contenant des agonistes et des antagonistes des récepteurs opioïdes

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EP1617846A1 (fr) * 2003-04-08 2006-01-25 Progenics Pharmaceuticals, Inc. Utilisation d'antagonistes des opioides peripheriques, en particulier de methylnaltrexone, dans le traitement du syndrome du colon irritable
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