Classifications

• • 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
  • A61K9/4808—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
  • A61K9/5026—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
  • A61K9/48—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
  • 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
  • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
• • 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 invention relates to new pharmaceutical formulations with opioid antagonistic activity and their use in opioid-induced constipation.
• the invention relates to pellet, granule or microtablet formulations which contain the active ingredients naloxone, N-methylnaloxone or N-methylnaltrexone as active ingredients with opioid antagonistic activity.
• opioids morphine was usually chosen as the model substance
• opioids have a direct effect on the smooth muscles of the intestine, thus increasing muscle tone in the intestinal segments.
• segmental tone and a simultaneous decrease in the propulsive motility of the intestine lead to a significant increase in the gastrointestinal passage time [Cameron J.C. "Constipation related to narcotic therapy", Cancer Nurs. 15, 372, 377 (1992)].
• the aim of therapy is to eliminate this peripheral side effect of morphine and related substances, since opioid-induced constipation can be very painful and ultimately jeopardize the success of treatment [Glare P., Lickiss J.N. "Unrecognized constipation in patients with advanced cancer: a recipe for therapeutic disaster", J. Pain Symptom Manage. 7, 369-371 (1992)].
• opioid-induced constipation can be very painful and ultimately jeopardize the success of treatment
• opioid antagonists Since it is assumed in the case of opioid-induced constipation that the actual effect takes place directly and locally over the entire intestine through the occupation of the opioid receptors, this effect should be able to be eliminated by the use of opioid antagonists.
• opioid antagonists only makes sense if the antagonistic effect is limited to the intestine and the central analgesic effect is not eliminated. Therefore, only a few opioid antagonists such as naloxone, N-methylnaloxone or N-methylnaltrexone come into question under certain conditions act peripherally and not in the CNS.
• Naloxone is a pure opioid antagonist, which is usually administered intravenously as an antidote in the event of poisoning with opioids. After oral administration, naloxone is rapidly and completely absorbed. Since the substance is subject to a very pronounced first-pass metabolism, only small amounts of the unchanged substance are available systemically. The majority of the applied substance is present in the blood in the form of the inactive or only weakly active metabolites naloxone-3-glucuronide, ⁇ -naloxol-3-glucuronide and ⁇ -naloxol [Vollmer K.O. "Pharmacokinetic basis of the Valoron-N principle", Fortsch. Med. 106, 593-596 (1988)].
• naloxone in an appropriate dose is an ideal candidate for remedying opioid-induced constipation: it is present in the intestine as an active substance and can thus cancel out the debilitating effect of the opioid on the gastrointestinal tract; after absorption, it becomes severely unwell after the first passage through the liver changes and becomes ineffective. Thus, the pain-relieving effect of the opioids is not affected.
• naloxone was administered intravenously (40 ⁇ g / kg / hour in 3 hours) [Basilisco G., Bozzani A., Camboni G., Recchia M., Quatrini M., Conte D., Penagini R., Bianchi PA "Effect of loperamide and naloxone on mouth-to-caecum transit time evaluated by lactulose hydrogen breath test", Gut 26, 700-703 (1985)] and the constipating also after oral administration of relatively high doses of 16 or 32 mg Effect of loperamide could cancel [Basilisco G., Camboni G., Bozzani A., Paravicini M., Bianchi PA "Oral naloxone antagonizes loperamide-induced delay of orocecal transit", Dig.
• Culpepper-Morgan et al. report on a pilot study in which 3 patients with opioid-induced constipation were treated with orally administered naloxone. Two of the three patients responded to treatment after doses up to 16 mg (withdrawal of constipation). In the other patient, constipation could not be abolished by increasing the dose up to 24 mg naloxone (within 3 hours). Plasma level determinations showed that dose-dependent maximum naloxone concentrations up to 7.9 ng / ml were measured.
• the naloxone dose was based on the daily opioid dose. Naloxone was given in doses of 0.5%, 1%, 2%, 5%, 10%, 20% and 40% based on the opioid dose. No effect was found up to the 10% naloxone dose. Only in the very high dose range (20% to 40%) is an increase in constipation reported.
• the absolute doses of naloxone administered could be up to 72 mg naloxone [Sykes N.P. "Oral naloxone in opioid-associated constipation", The Lancet 337, 1475 (1991)].
• naloxone works especially when it is applied in high doses. In this dose range, withdrawal symptoms already occur in isolated patients.
• conventional, simple formulations e.g. capsules or drops
• the active ingredient is released quickly and without modification.
• naloxone is rapidly and completely absorbed in the upper part of the gastrointestinal tract. The resulting, relatively high blood concentrations can lead to undesirable side effects.
• Therapeutic applications of such naloxone formulations are e.g. in EP 0 103 636 (AI) and EP 0 352 361 (AI).
• DE 4325465 (AI) proposes a combination preparation of an opioid and an opioid antagonist for oral administration, the opioid being retarded, the opioid antagonist being released rapidly, ie with little or no retardation. Based on the naloxone content, this preparation corresponds to an unmodified quick-release formulation with the disadvantages mentioned above. This route increases the risk of an undesirable systemic naloxone effect, which cancels the pain-relieving effect of the opioid. Therefore, if the teaching of DE 4325465 (AI) is used, complete elimination of the side effects cannot be achieved or withdrawal symptoms can occur again in the patient in the selected dose ranges.
• the invention is therefore based on the object of providing an oral galenical formulation with opioid antagonistic activity which, on account of its pharmaceutical technological properties, is able to abolish the opioid-induced constipation without leading to any noteworthy systemic availability of naloxone and thus the opioid effect to antagonize in the CNS.
• the invention is based on the knowledge that an effective antagonization of the opioid effect on the upper and lower parts of the gastrointestinal tract while avoiding the systemic antagonization of the opioid effect can only occur if the active substance is released in a modified manner over the entire gastrointestinal tract.
• the release is controlled site-specifically via the different ambient pH in the respective gastric or intestinal sections, which is not a retardation in the sense of a slowed release.
• the intestinal passage of the formulation is lengthened and the active ingredient is released prematurely in the upper sections of the gastrointestinal tract, while the lower sections are not supplied.
• naloxone N-methylnaloxone and / or N-methylnaltrexone, or a pharmaceutically acceptable salt thereof as the active ingredient, the release of the active ingredient being thereby achieved over the entire gastrointestinal tract that the particles contained in the composition release the active ingredient initially and depending on the ambient pH.
• naloxone applies equally to N-methylnaloxone, N-methylnaltrexone, pharmaceutically acceptable salts of these compounds and mixtures thereof.
• the naloxone formulation according to the invention is characterized by targeted and controlled release of active ingredient as uniformly as possible over the entire gastrointestinal tract, i.e. from the stomach to the colon, with rapid drug release locally in individual sections of the gastrointestinal tract. Since the release of the active substance, in contrast to time-dependent controlled release systems, is not controlled by the slowed release, but by the varying pH ratios in the gastrointestinal tract, the opioid-induced constipation and the associated delayed gastrointestinal transit of the active substance carriers (pellets or the like) do not result to an uncontrolled release of the drug in parts of the intestine where should not be released. This has the advantage in the formulation according to the invention that a lower single dose can be used.
• the active ingredient-containing particles are provided with a coating which is soluble as a function of the ambient pH.
• Conventional film-forming substances with a different solubility depending on the ambient pH can be used for such a coating.
• the employed in pharmaceutical technology and known acrylic polymers of the Eudragit ® series, in particular Eudragit ® L100-55, Eudragit ® L100 and Eudragit ® S100 are preferred.
• the desired release pH can be set in a targeted manner by appropriately mixing these substances or the active substance particles coated with these substances. Another advantage is the possible reduction of the systemic load and the dose applied by the principle of 'drug targeting'.
• the pharmaceutical form according to the invention as a monopreparation also enables use in constipation by means of a wide variety of opioids, but it can also be used as a combination preparation with a certain opioid, in particular morphine, or one or more substances of the morphine type.
• a selection of such opioids includes, for example, codeine, dihydrocodeine, hydromorphone, levomethadone, oxycodone, pethidine and propoxyphene and / or their salts.
• the dosage of the opioid depends on the age, gender and the severity of the patient's illness, and can be easily adjusted by the attending physician based on his specialist knowledge.
• Preferred pharmaceutical dosage forms contain naloxone-containing particles (pellets, microtablets or granules) with different varnish coatings.
• the particles should preferably be dimensioned such that they pass the pylorus largely independently of the motility of the gastrointestinal tract. A maximum size of approx. 2 mm is favorable for this.
• the pellets usually have a diameter of approx. 1 mm, the described microtablets of approx. 2 mm.
• the average grain size of the granules is smaller than approximately 1 mm, preferably approximately 300 to approximately 600 ⁇ m.
• the varnishes on the particles differ in their different solubility characteristics.
• the solubility of the paints and the associated release of the drug depends on the local pH of the gastrointestinal tract. A mixture of different particles with different release behavior takes advantage of the strongly varying pH ratios in the gastrointestinal tract (stomach approx. PH 1.2 colon approx. PH 7.0).
• the pharmaceutical composition according to the invention preferably contains at least two types of particles, each of which contains the active ingredient at a different ambient pH release. Since opioid-induced constipation in humans arises to about 50% from delayed gastric emptying and approx. 25% each from sluggish propulsive peristalsis in the small and large intestine [Manara L., Bianchetti A. "The central and peripheral influenced of opiods on gastrointestinal propulsion ", Ann. Rev. Pharmacol. Toxicol. 25, 249-273 (1985)], an initial release of a certain amount of active ingredient is recommended as soon as the formulation reaches the stomach.
• the first type of particles can be designed so that the active ingredient is released at the ambient pH of the stomach.
• the second particle type then releases the active substance at the ambient pH of the lower intestinal tract, ie a pH of approx. 7.0.
• the first type of particles can release the active substance independently of the pH upon contact with an aqueous medium. This initial release can be achieved in that the first type of particles having a methylhydroxypropylcellulose and optionally polyethylene glycol (for example, Macrogol ® 6000; average molecular weight 6000) is provided coating as an adjuvant-containing, which is in an aqueous medium regardless of the pH soluble.
• the ratio of the particles of the first type to the particles of the second type is 1:10 to 10: 1, particularly preferably approximately 1: 1.
• further types of particles can be contained which release the active substance at an ambient pH of approximately 5.5 to approximately 6.5.
• the pharmaceutical composition contains a first type of particles which are pH-independent of the active ingredient when in contact with an aqueous medium, and a second or more types of particles which contain the active ingredient at an ambient pH of approximately 5. Release 5 to 7.0.
• the finished pharmaceutical form eg hard gelatin capsule
• the composition of the invention can be administered to treat an existing opioid-induced constipation. However, it can also be given as a precaution to prevent constipation from occurring from the outset during opioid analgesic treatment.
• Example 1 Naloxone pellets type A (pH-independent release in the upper gastrointestinal (GI) tract)
• Example 2 Naloxone pellets type B (release in intestinal sections with a pH environment of approx. 5.5)
• Example 3 Naloxone pellets type C (release in intestinal sections with a pH environment of approx. 6.0)
• Example 4 Naloxone pellets type D (release in intestinal sections with a pH environment of approx. 6.5)
• Example 5 Naloxone pellets type E (release in intestinal sections with a pH environment of approx. 7.0)
• the pellet cores are produced by a known method (e.g. extrusion and subsequent rounding, drawing the active ingredient onto starter cores in the fluidized bed) and then filmed.
• the pellets are filled in hard gelatin capsules.
• pellet combination contains pellet types A and E in a ratio of 1:10 and 10: 1, but preferably 1: 1.
• pellet types B, C and / or D can be mixed with the above-mentioned mixture.
• the total dose of naloxone HCl in a capsule can be between about 1 mg mg un d about 30, preferably about 1 mg and about 10 mg.
• Example 6 Naloxone micro-tablets type A (pH-independent release in the upper GI tract)
• Example 7 Naloxone microtablets type B (release in intestinal segments with a pH environment of approx. 5.5)
• Example 8 Naloxone Microtablets Type C (release in intestinal sections with a pH environment of approx. 6.0)
• Example 9 Naloxone microtablets type D (release in intestinal segments with a pH environment of approx. 6.5)
• Example 10 Naloxone microtablets type E (release in intestinal sections with a pH environment of approx. 7.0) Core (diameter: 2 mm)
• the constituents of the tablet core are sieved and in a suitable free-fall mixer for 15 min. mixed. After adding the magnesium stearate, the mixture is mixed for a further 10 minutes. The mass is then pressed into microtablets on a tablet press with a special stamp (diameter 2 mm). The microtablets obtained are filmed in a suitable device and filled into hard gelatin capsules.
• microtablets contains types A and E in a ratio of 1:10 and 10: 1, but preferably 1: 1.
• the micro-tablets B, C and / or D can be mixed with the above-mentioned mixture.
• the total dose of naloxone HCl in a capsule can be between approximately 1 mg and approximately 30 mg, preferably approximately 1 mg and approximately 10 mg.
• Example 11 Naloxone granules type A (pH-independent release in the upper GI tract) Basic granulate
• Example 12 Naloxone granules type B (release in intestinal sections with a pH environment of approx. 5.5)
• Example 13 Naloxone granules type C (release in intestinal sections with a pH environment of approx. 6.0)
• Example 14 Naloxone granules type D (release in intestinal sections with a pH environment of approx. 6.5)
• Example 15 Naloxone granules type E (release in intestinal sections with a pH environment of approx. 7.0)
• the constituents of the basic granulate according to Examples 11 to 15 are sieved and moistened with granulating liquid in a suitable mixer and granulated.
• the granules are then dried in the fluidized bed and sieved so that a granulate with an average grain size of preferably 300 to 600 microns is obtained.
• the granules are filmed in a suitable device.
• the total dose of the active ingredient in a granular formulation can be between approximately 1 mg and approximately 30 mg, preferably approximately 1 mg and approximately 10 mg.
• the filmed granules can be processed further as follows:
• tablette • Compression into tablets after admixing suitable tabletting aids (e.g. microcrystalline cellulose, magnesium stearate)
• suitable tabletting aids e.g. microcrystalline cellulose, magnesium stearate

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• Animal Behavior & Ethology (AREA)
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• Emergency Medicine (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
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Priority Applications (7)

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• 1996
  • 1996-12-11 DE DE19651551A patent/DE19651551C2/de not_active Expired - Fee Related
• 1997
  • 1997-12-04 PT PT97954355T patent/PT938316E/pt unknown
  • 1997-12-04 AT AT97954355T patent/ATE220907T1/de active
  • 1997-12-04 ES ES97954355T patent/ES2181055T3/es not_active Expired - Lifetime
  • 1997-12-04 DE DE59707812T patent/DE59707812D1/de not_active Expired - Lifetime
  • 1997-12-04 WO PCT/EP1997/006789 patent/WO1998025613A2/de not_active Ceased
  • 1997-12-04 DK DK97954355T patent/DK0938316T3/da active
  • 1997-12-04 JP JP52618398A patent/JP5065548B2/ja not_active Expired - Fee Related
  • 1997-12-04 US US09/319,818 patent/US6419959B1/en not_active Expired - Fee Related
  • 1997-12-04 CA CA2273353A patent/CA2273353C/en not_active Expired - Fee Related
  • 1997-12-04 EP EP97954355A patent/EP0938316B1/de not_active Expired - Lifetime

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