EP3229785A2 - Monopréparation de naloxone et comprimé multicouche - Google Patents

Monopréparation de naloxone et comprimé multicouche

Info

Publication number
EP3229785A2
EP3229785A2 EP15817094.4A EP15817094A EP3229785A2 EP 3229785 A2 EP3229785 A2 EP 3229785A2 EP 15817094 A EP15817094 A EP 15817094A EP 3229785 A2 EP3229785 A2 EP 3229785A2
Authority
EP
European Patent Office
Prior art keywords
composition
active ingredient
naloxone
matrix
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP15817094.4A
Other languages
German (de)
English (en)
Inventor
Hélène Rey
Olaf MUNDSZINGER
Isabelle GOLFIER
Silvia JAKOB
Oliver RUSCH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Algobate AG
Original Assignee
Develco Pharma Schweiz AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Develco Pharma Schweiz AG filed Critical Develco Pharma Schweiz AG
Publication of EP3229785A2 publication Critical patent/EP3229785A2/fr
Ceased legal-status Critical Current

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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
    • A61K9/20—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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • 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
    • A61K9/20—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
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • Constipation is a major side effect in the treatment of painkillers of the opioid type. It is one of the most common side effects and is an undesirable concomitant in over 85% of patients, especially in long-term opioid therapy. In contrast to other opioid-induced side effects, opioid-induced constipation is a chronic condition that does not lose its intensity during treatment. The effect of opioids on gut motility is presumably based on the binding of opioids to opioid receptors of the gastrointestinal tract, which are found there in relatively high density.
  • the aim of a suitable therapy is to eliminate this peripheral side effect of the opioids, since the opioid-induced constipation can be uncomfortable and very painful, often leads to the discontinuation of opioid therapy, and thus endangers the treatment success of the opioids. Since opioid-induced constipation is believed to be directly and locally effected throughout the intestine by the occupancy of opioid receptors, this side effect should be reversed by the use of opioid antagonists. However, the use of opioid antagonists only makes sense if the antagonistic effect on the intestine is limited and the central analgesic effect is not abolished.
  • a suitable opioid antagonist for the treatment of opioid-induced constipation is naloxone.
  • naloxone is absorbed rapidly and completely, and since the substance is subject to very pronounced first-pass metabolism, only small amounts of unaltered naloxone are systemically available.
  • the majority of the administered substance is present in the blood in the form of non or only weakly effective metabolites such as naloxone-3-glucuronide or beta-6-naloxol.
  • Naloxone in an appropriate dose is an ideal candidate for the treatment of opioid-induced constipation: it is an active substance in the intestine and can thus neutralize the paralytic activity of the opioid on the gastrointestinal tract, whereas it is highly metabolised after absorption at the first passage through the liver and becomes ineffective.
  • the analgesic effect of opioids is not affected.
  • Opioid-induced constipation can not be successfully treated with a fast-release naloxone formulation because it paralyzes the entire gastrointestinal tract and not just
  • WO 2011/117306 discloses a
  • Naloxone combination preparations are available in the market, in which naloxone and opiate in a fixed ratio side by side.
  • a naloxone Monogarparat since this can be administered independently of the nature of the opiate and on the other in a variable amount, whereby the desired amount of naloxone administered exactly and so optimal Treatment success can be achieved.
  • naloxone Monogarparate described as in WO 98/25613 A2.
  • these preparations release the naloxone specifically depending on the ambient pH of the gastrointestinal tract, which is why a locally uniform supply over the entire gastrointestinal tract away with naloxone and thus optimal treatment success is not possible.
  • It is an object of the present invention to provide a solid oral pharmaceutical composition comprising as active ingredient naloxone or a pharmaceutically acceptable salt thereof, wherein the composition releases the active ingredient naloxone in a sustained release and thus is suitable for at least twelve hours administration for the treatment of opioid-indicated constipation.
  • a solid oral pharmaceutical composition comprising as active ingredient naloxone or a pharmaceutically acceptable salt thereof, wherein the composition releases the active ingredient naloxone in a sustained release and an in vitro release rate of the active ingredient naloxone, measured using the paddle stirrer method according to Eur. Ph. at 75 rpm in 500 ml 0.1 N
  • composition according to the invention having said release profile is suitable for at least twelve hours administration for the treatment of opioid-indicated constipation and accordingly has a relatively high patient compliance.
  • the in-vitro release rate is determined using the blade stirrer apparatus (Apparatus 2) and the blade stirrer method according to Eur.Ph. (European Pharmacopoeia, 7th edition, 3rd supplement, 2.9.3 "Release of active ingredient from solid dosage forms", pp 5519-5526) at 75 rev / min in 500 ml of 0.1 N hydrochloric acid at 37 ° C.
  • the amount of Released active ingredient is preferably determined by UV detection at 220 nm.
  • the active ingredient is released in a sustained release, and the in vitro release rate of the active ingredient naloxone, measured using the paddle stirrer method according to Eur. Ph.
  • the paddle stirrer method according to Eur. Ph.
  • 75 rev / min in 500 ml of 0.1 N hydrochloric acid at 37 ° C 0% to 75% in 2 h, from 3% to 95% in 4 h, from 20% to 100% in 10 h, from 30% to 100% in 16 h, from 50% to 100% in 24 h and more than 80% in 36 h.
  • the opioid-induced constipation that may be treated by the composition of the present invention may be derived from any opioid analgesics or opioid analogues analgesics, their salts, and mixtures thereof.
  • corresponding analgesics are: alfentanil, allylprodin, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, besomorphine, dextromoramide, decocin, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, Dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl,
  • the composition has an in vitro release rate of the active ingredient from 0% to 50% in 2 h, from 5% to 95% in 4 h, from 20% to 90% in 10 h of more than 70% in 18 hours and more than 80% in 24 hours.
  • the composition has an in vitro release rate of the active ingredient of 0% to 38% in 2 h, of 5% to 55% in 4 h and of 20% to 75% in 10 h.
  • the composition has an in vitro release rate of the active ingredient of 0% to 50% in 1 h, 10% to 95% in 4 h, 35% to 100% in 8 h, from 55% to 100% in 12 h, from 70% to 100% in 16 h and of more than 90% in 24 h.
  • the composition has an in vitro release rate of the active ingredient of 0% to 30% in 1 h, 0% to 40% in 2 h, 3% to 55% in 4 h, from 10% to 65% in 8 h, from 20% to 75% in 12 h, from 30% to 88% in 16 h, from 50% to 100% in 24 h and of more than 80% in 36 h having.
  • the composition has an in vitro release rate of the active ingredient of 10% to 30% in 1 h, 17% to 37% in 2 h, 27% to 47% in 4 h, from 40% to 60% in 8 h, from 50% to 70% in 12 h, from 60% to 80% in 16 h, from 80% to 100% in 24 h.
  • the composition releases the active ingredient naloxone regardless of the ambient pH of the gastrointestinal tract.
  • the pH-independent release of active ingredient of the composition according to the invention can be known to the person skilled in the art by selection pharmaceutical excipients are obtained, wherein in the gastrointestinal tract local pH values of about 1.2 (stomach) prevail to about 6.8 colon.
  • a release of the active ingredient of the composition according to the invention independent of the ambient pH of the gastrointestinal tract is preferably understood according to the invention as meaning that the similarity factor f2 of a first in vitro release is 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 greater than 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. Namely, the similarity factor f2 (English, similarity factor) is calculated according to the following formula:
  • Rt and Tt represent the amounts of drug released at time t at the first pH and at the second pH, respectively.
  • N is the number of times.
  • the f2 factor is determined under the following conditions: a) the minimum number of times for release is 3 (time 0 is excluded), b) the times for the first and second pH should be the same; (c) for the released quantities for each time point, an average value of 12 measurements is given for each pH; (d) not more than an average measured above a release of 85% may be included in the calculation, (e) the relative standard deviation or Coefficient of variation of release at one pH should be less than 20% for the first time and less than 10% for the second and any further time.
  • the in vitro release profiles are determined using the paddle stirrer apparatus (Apparatus 2) and the paddle stirrer method according to Eur.Ph. (European Pharmacopoeia, 7th edition, 3rd supplement, 2.9.3 "release of active ingredient from solid dosage forms", pp 5519-5526) at 75 rev / min in 500 ml buffer (according to European Pharmacopoeia, 7th edition, 7th supplement, 4.1.3 "Buffer Solutions", p. 7671-7679) at 37 ° C. The amount of drug released is determined by UV detection at 220 nm. According to a further preferred embodiment of the composition according to the invention, it is provided that the composition comprises a matrix which releases the active ingredient in a retarded manner.
  • the active ingredient can be released in a delayed-release manner if it is contained in a sustained release matrix.
  • composition of the invention may comprise a matrix which releases the naloxone or the pharmaceutically acceptable salt thereof retarded.
  • the matrix may preferably be a so-called scaffold matrix, which may be swellable or non-swellable, or a so-called eroding matrix.
  • the matrix may also have properties of both skeleton matrix and eroding matrix.
  • the active ingredient is incorporated in a matrix scaffold.
  • the active ingredient is gradually leached out of the matrix scaffold by the digestive juices. After this is done, the matrix framework is eliminated in a more or less unchanged or swollen form.
  • the matrix is degraded or eroded, as a result of which active ingredient particles reach the surface and dissolve. The release rate depends on the extent of the matrix degradation or its erosion.
  • the matrix comprises one or more water-insoluble matrix formers.
  • the matrix comprises one or more water-soluble matrix formers.
  • the matrix is water-insoluble.
  • the matrix comprises as matrix former one or more compounds selected from the group consisting of cellulose esters, cellulose ethers, polyethylene oxide, polyvinylpyrrolidone / polyvinyl acetate mixtures, methacrylate-acrylate copolymers, waxes, fats such as for example, glycerol esters and fatty alcohols.
  • the substance classes mentioned are particularly suitable as matrix formers for the composition according to the invention, wherein, according to the invention, preference is given in particular to polyvinyl acetate mixed with a polyvinylpyrrolidone and / or a glycerol-di-behenic acid ester as matrix former.
  • the solid oral pharmaceutical composition include a glycerol di-behenic acid ester matrix as one of the matrix formers.
  • the preferred mass ratio of naloxone to the matrix image (s) comprises values between 1: 1 and 1:10.
  • the composition includes glycerol di-behenic acid ester as a matrix former in an amount of 10-50% by weight. More preferably, the composition includes glycerol di-behenic acid ester in an amount of 10-50% by weight, preferably in an amount of 15-45% by weight, more preferably 20-35%, and most preferably 25-30% by weight.
  • Preferred is glycerol di-behenic acid ester in an amount of 29.4% by weight relative to the naloxone matrix.
  • the composition is free of film-coated, naloxone-containing particles, wherein the filming causes the sustained release of the naloxone.
  • composition is directly tabletted, since this is particularly cost-effective.
  • the composition is in the form of a tablet, capsule, granules, a microtablet, extruded particles or granules compressed into a tablet.
  • the composition is in the form of a once-a-day (once-a-day-formulation) or a twice-a-day-formulation.
  • the active ingredient is naloxone or a pharmaceutically acceptable salt thereof, with naloxone hydrochloride being particularly preferred because of its solubility and stability.
  • One or more further active ingredients may be present in the composition.
  • the naloxone or the pharmaceutically acceptable salt thereof is preferably contained in the composition of the present invention in an amount of 0.1 to 500 mg, more preferably in an amount of 1 mg to 50 mg, and most preferably in an amount of 3 mg, 6 mg , 12 mg, 24 mg, 36 mg or 48 mg.
  • the present invention further relates to the use of the composition of the invention for the treatment of opioid-induced constipation.
  • the present invention further relates to a solid oral pharmaceutical composition
  • a solid oral pharmaceutical composition comprising as active ingredient naloxone or a pharmaceutically acceptable salt thereof, wherein the composition releases the active ingredient in a retarded manner and an in vitro Release rate of the active ingredient, measured using the paddle stirrer method according to Eur. Ph.
  • Eur. Ph. At 75 rpm in 500 ml of 0.1 N hydrochloric acid at 37 ° C., from 5% to 50% in 1 h, from 10% to 75% in 2 h, from 20% to 95% in 4 h, from 40% to 100% in 8 h, of more than 50% in 12 h, of more than 70% in 18 h and of more than 80% in 24 h having.
  • the present invention further relates to a solid oral pharmaceutical composition
  • a solid oral pharmaceutical composition comprising as active ingredient naloxone or a pharmaceutically acceptable salt thereof, wherein the composition releases the active ingredient in a retarded manner and an in vitro Release rate of the active ingredient, measured using the paddle stirrer method according to Eur. Ph.
  • Eur. Ph. At 75 rpm in 500 ml of 0.1 N hydrochloric acid at 37 ° C., from 20% to 50% in 1 h, from 40% to 75% in 2 h, from 60% to 95% in 4 h, from 80% to 100% in 8 h and from 90% to 100% in 12 h.
  • the present invention further relates to a solid oral pharmaceutical composition comprising as active ingredient naloxone or a pharmaceutically acceptable salt thereof, wherein the composition releases the active ingredient in a retarded manner and an in vitro Release rate of the active ingredient, measured using the paddle stirrer method according to Eur. Ph.
  • a solid oral pharmaceutical composition comprising as active ingredient naloxone or a pharmaceutically acceptable salt thereof, wherein the composition releases the active ingredient in a retarded manner and an in vitro Release rate of the active ingredient, measured using the paddle stirrer method according to Eur. Ph.
  • the present invention further relates to a solid oral pharmaceutical composition comprising as active ingredient naloxone or a pharmaceutically acceptable salt thereof, wherein the
  • Composition releases the drug retarded and an in vitro release rate of
  • Active ingredient measured using the paddle stirrer method according to Eur. Ph. At 75 rpm in
  • the present invention further relates to a solid oral pharmaceutical composition
  • a solid oral pharmaceutical composition comprising as active ingredient naloxone or a pharmaceutically acceptable salt thereof, wherein the composition releases the active ingredient in a retarded manner and an in vitro Release rate of the active ingredient, measured using the paddle stirrer method according to Eur. Ph.
  • Eur. Ph. At 75 rpm in 500 ml of 0.1 N hydrochloric acid at 37 ° C., from 10% to 30% in 1 h, from 17% to 37% in 2 h, from 27% to 47% in 4 h, from 40% to 60% in 8 h, from 50% to 70% in 12 h, from 60% to 80% in 16 h, from 80% to 100% in 24 hours.
  • the composition preferably a tablet or a capsule, a in wiro-release rate of the active ingredient, measured using the Blattrlocher method according to Eur.
  • Ph In 500 ml of 0.1 N hydrochloric acid at 37 ° C, from 0% to 75% in 2 h, from 3% to 95% in 4 h, from 20% to 100% in 10 h, from 30% to 100% in 16 h, from 50% to 100% in 24 h and more than 80% in 36 h.
  • the composition is intended to have an in vitro release rate of the active ingredient of 0% to 50% % in 2 h, from 5% to 95% in 4 h, from 20% to 90% in 10 h, of more than 70% in 18 h and of more than 80% in 24 h.
  • the rate of release is regulated by adjusting the mass ratio of naloxone to matrix former.
  • the mass ratio of naloxone to matrix images is 1: 1, more preferably 1: 2, even more preferably 1: 3, even more preferably 1: 4, more preferably 1: 5, more preferably 1: 6, even more preferably 1: 7, even more preferably 1: 8, more preferably 1: 9 and most preferably 1:10.
  • the composition according to the invention is characterized in that the concentration of naloxone in the plasma is extremely low due to the retardation. Compared with a non-sustained-release composition, the maximum plasma concentration (C max ) over the course of action is about 20 times lower and 100 times lower compared to an intravenous composition.
  • the inhibition of the receptors is better overall over the course of action.
  • the low bioavailability in the system therefore ensures, in addition to the anti-obstruction effects of naloxone, a reduced probability and / or severity of side effects.
  • the composition has an IC 50 / C max of at least 30. In a more preferred embodiment, the composition has an IC 50 / Cmax of at least 35. In a more preferred embodiment, the composition has an IC 50 / C max of at least 40. In the most preferred embodiment, the composition has an IC 50 / C max of at least 50.
  • T max is a classic parameter in pharmacokinetics and describes the time to maximum plasma concentration of a substance.
  • Antagonists are lower.
  • the reduction of the opioid effect is lower and also the
  • composition comprises a t max (naloxone) / t max (naloxone-3-glucuronoid) value of at least 5.
  • the composition additionally comprises at least one stabilizer which protects the active ingredient.
  • this is at least one stabilizer selected from the list comprising sulfur dioxide, sodium sulfite, sodium bisulfite, ascorbic acid and derivatives thereof and tocopherol and its water and fat soluble derivatives such.
  • tocopherol acetate As tocopherol acetate, sulfites, bisulfites and hydrogen sulfites of alkali earth alkaline and other metals, PHB esters, BHA, BHT, gallates and lower fatty acids, fruit acids, phosphoric acids, sorbic and benzoic acid and their salts, esters, derivatives and isomeric compounds, ascorbyl palmitate , Lecithins, mono- and polyhydroxylated benzene derivatives, ethylenediaminetetraacetic acid and its salts, citraconic acid, cysteine, L-cystine, conidendrines, diethyl carbonates, methylenedioxyphenols, cephalins, ⁇ , ⁇ '-dithiopropionic acid, biphenyl and other phenyl derivatives.
  • the composition additionally comprises at least one stabilizer which protects the matrix.
  • this is at least one stabilizer selected from the list comprising butylhydroxytoluene, sulfur dioxide, sodium sulfite, sodium bisulfite, ascorbic acid and derivatives thereof and tocopherol and its water and fat soluble derivatives such.
  • tocopherol acetate As tocopherol acetate, sulfites, bisulfites and hydrogen sulfites of alkali earth alkaline and other metals, PHB esters, BHA, BHT, gallates and lower fatty acids, fruit acids, phosphoric acids, sorbic and benzoic acid and their salts, esters, derivatives and isomeric compounds, ascorbyl palmitate , Lecithins, mono- and polyhydroxylated benzene derivatives, ethylenediaminetetraacetic acid and its salts, citraconic acid, cysteine, L-cystine, conidendrines, diethyl carbonates, methylenedioxyphenols, cephalins, ⁇ , ⁇ '-dithiopropionic acid, biphenyl and other phenyl derivatives.
  • the composition comprises at least one additive, wherein the additive is an emetic or a Scharf substance drug.
  • the composition comprises an additive, which is a drug substance selected from the group comprising Allii sativi Bulbus, Asari Rhizoma c. Herba, Calami Rhizoma, Capsici Fructus (Paprika), Capsici Fructus acer (Cayenne pepper), Curcumae longae Rhizoma, Curcumae xanthorrhizae Rhizoma, Galangae Rhizoma, Myristicae Semen, Piperis nigri Fructus (pepper), Sinapis albae (Erucae)
  • Semen Sinapis nigri Semen, Zedoariae Rhizoma and Zingiberis Rhizoma, more preferably from the group consisting of Capsici Fructus (paprika), Capsici Fructus acer (cayenne pepper) and
  • the composition comprises at least one additive, which is an emetic.
  • the emetic is based on one or more ingredients of Radix Ipecacuanhae (vomiting root).
  • the emetic is based on the ingredient emetine, in an alternative embodiment, the emetic is apomorphine.
  • the composition comprises a dye.
  • this dye is selected from the group comprising red iron oxide, black iron oxide and indigo carmine.
  • the composition additionally comprises at least one non-steroidal anti-inflammatory or 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 macrogols.
  • a multi-layer tablet comprising at least
  • a first drug layer containing as active ingredient an opioid agonist or a pharmaceutically acceptable salt thereof;
  • a second active ingredient layer containing as active ingredient an opioid antagonist or a
  • Embodiment put the first and the second drug layer releases the drug retarded.
  • Multi-layer tablet may also comprise other active ingredients.
  • the multilayer tablet according to the invention is suitable for the parallel treatment of pain and opioid-induced constipation, wherein a variable release kinetics for each active ingredient can be easily realized and therefore an individual treatment success can be easily optimized.
  • the multilayer tablet according to the invention also has the advantage that in each layer a different etard istssystem, e.g. can be used with a sustained-release layer coated pellets or a retarded releasing matrix. As a result, a specific release kinetics for each active ingredient and a variable ratio of the active ingredients individually adapted to a specific patient can be realized particularly easily.
  • the multilayer tablet according to the invention has the advantage that much more precise dosages of the two active substances are possible by means of the same. This comes into play especially for small doses.
  • the tablet according to the invention is advantageous if the two active ingredients are incompatible with one another.
  • the multilayer tablet is a two-layer tablet.
  • the multilayer tablet according to the invention can be realized in the form of a two-layer tablet in terms of process technology, simply and thus cost-effectively.
  • the second active substance layer comprises a matrix which retards the release of the opioid antagonist or the pharmaceutically acceptable salt thereof.
  • a retardant-acting matrix can be produced in terms of process technology simply and thus inexpensively.
  • the matrix may preferably be a so-called scaffold matrix, which may be swellable or non-swellable, or a so-called eroding matrix.
  • the matrix may also have properties of both skeleton matrix and eroding matrix.
  • the active ingredient is incorporated in a matrix scaffold.
  • the drug is gradually dissolved out of the digestive juices from the matrix framework. After this is done, the matrix framework is eliminated in a more or less unchanged or swollen form.
  • the matrix is degraded or eroded, as a result of which active ingredient particles reach the surface and dissolve. It is the
  • Rate of release depends on the extent of the matrix degradation or its erosion.
  • the matrix contains one or more water-insoluble matrix formers. In an alternative embodiment it is provided that the matrix contains one or more water-soluble matrix formers.
  • the matrix comprises as matrix former one or more constituents selected from the group consisting of cellulose esters, cellulose ethers, polyvinylpyrrolidone / polyvinyl acetate mixtures, methacrylate-acrylate copolymers, polyethylene oxide waxes, fats such as glycerol esters , and fatty alcohols.
  • Said constituents are particularly suitable as matrix formers for the tablet according to the invention, wherein according to the invention it is preferred in particular to use polyvinyl acetate mixed with a polyvinylpyrrolidone and / or a glycerol-di-behenic acid ester as matrix former.
  • the rate of release is regulated by adjusting the mass ratio of naloxone to matrix former.
  • the mass ratio of naloxone to matrix images is 1: 1, more preferably 1: 2, even more preferably 1: 3, even more preferably 1: 4, more preferably 1: 5, more preferably 1: 6, even more preferably 1: 7, even more preferred 1: 8, more preferably 1: 9 and most preferably 1:10.
  • the multilayer tablet contains glycerol di-behenic acid ester as a matrix former in an amount of 10-50% by weight. More preferably, the multi-layer tablet contains glycerol di-behenic acid ester in an amount of 15-45% by weight, more preferably 20-35%, and most preferably 25-30% by weight.
  • the second active substance layer releases the active ingredient, ie the opioid antagonist or the pharmaceutically acceptable salt thereof, independently of the ambient pH of the gastrointestinal tract. This ensures that the entire gastrointestinal tract is supplied with the opioid antagonist or a salt thereof, regardless of the particular local pH environment, so that a further optimization of the treatment success can be achieved.
  • the pH-independent release of active ingredient of the composition according to the invention can be achieved by selecting suitable components, with local pH values in the gastrointestinal tract of about 1.2 (stomach) to about 7.0 colon.
  • the opioid antagonist is selected from the group consisting of naloxone, N-methylnaloxone and N-methylnaltrexone and pharmaceutically acceptable salts thereof, wherein naloxone hydrochloride is particularly preferred according to the invention.
  • the opioid agonist or the pharmaceutically acceptable salt thereof is contained in the first active ingredient layer in the form of pellets containing the opioid agonist and to which the release of the opioid agonist Agonist retarding layer is applied.
  • the multilayer tablet has an IC 5 o / C value for naloxone of at least 30. In a preferred embodiment, the multilayer tablet has an IC 50 / C max value of at least 35. In a more preferred embodiment, the multilayer tablet has an IC 50 / C max value of at least 40. In the most preferred embodiment, the multilayer tablet has an IC 50 / C ma) ⁇ value of at least 50.
  • the multi-layer tablet comprises a t max (naloxone) / t max (naloxone-3-glucuronoid) value of at least 5.
  • opioid agonist is selected from the group comprising: alfentanil, allylprodin, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, besomorphine, dextromoramide, decocin, Diampromid, diamorphone, Dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,
  • Etonitazen fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone,
  • Pentazocine phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodin, piritramide,
  • Buprenorphine codeine, fentanyl, levorphanol, meperidine, methadone, levomethadone and
  • Dextromethadone and their pharmaceutically acceptable salts are particularly preferred according to the invention.
  • the second active ingredient layer is directly tabletted, since this is so particularly inexpensive to produce.
  • the multilayer tablet additionally comprises at least one stabilizer which protects the active ingredient naloxone.
  • this is at least one stabilizer selected from the list comprising sulfur dioxide, sodium sulfite, sodium bisulfite, ascorbic acid and derivatives thereof and tocopherol and its water and fat soluble derivatives such.
  • tocopherol acetate As tocopherol acetate, sulfites, bisulfites and hydrogen sulfites of alkali earth alkaline and other metals, PHB esters, BHA, BHT, gallates and lower fatty acids, fruit acids, phosphoric acids, sorbic and benzoic acid and their salts, esters, derivatives and isomeric compounds, ascorbyl palmitate , Lecithins, mono- and polyhydroxylated benzene derivatives, ethylenediaminetetraacetic acid and its salts, citraconic acid, cysteine, L-cyctin, conidendrins, diethyl carbonates, methylenedioxyphenols, cephalins, ß, ß'-dithiopropionic acid, biphenyl and other phenyl derivatives.
  • the multilayer tablet additionally comprises at least one stabilizer which protects the matrix.
  • this is at least one stabilizer selected from the list comprising butylhydroxytoluene, sulfur dioxide, sodium sulfite, sodium bisulfite, ascorbic acid and derivatives thereof and tocopherol and its water and fat soluble derivatives such.
  • tocopherol acetate As tocopherol acetate, sulfites, bisulfites and hydrogen sulfites of alkali earth alkaline and other metals, PHB esters, BHA, BHT, gallates and lower fatty acids, fruit acids, phosphoric acids, sorbic and benzoic acid and their salts, esters, derivatives and isomeric compounds, ascorbyl palmitate, lecithins, mono- and polyhydroxylated
  • Benzene derivatives ethylenediaminetetraacetic acid and its salts, citraconic acid, cysteine, L-cystine,
  • the multilayer tablet comprises at least one additive, wherein the additive is an emetic or a Scharf substance drug.
  • the composition comprises an additive, which is a drug substance selected from the group comprising Allii sativi Bulbus, Asari Rhizoma c.
  • the multilayer tablet comprises at least one additive, which is an emetic.
  • the emetic is based on one or more ingredients of Radix Ipecacuanhae (vomiting root).
  • the emetic is based on the ingredient emetine, in an alternative embodiment, the emetic is apomorphine.
  • the multilayer tablet comprises a dye.
  • this dye is selected from the group comprising red iron oxide, black iron oxide and indigo carmine.
  • the composition additionally comprises at least one non-steroidal anti-inflammatory or 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 macrogols. According to a further preferred embodiment of the invention
  • Multi-layer tablet it is provided that the tablet is designed for once-daily administration
  • the tablet is designed for twice-daily administration (twice-daily-formulation).
  • the multilayer tablet contains from 0.1 mg to 500 mg of the opioid agonist or a pharmaceutically acceptable salt thereof and from 0.1 mg to 500 mg of the opioid antagonist or of a pharmaceutically acceptable salt thereof, according to the invention particularly preferably in a ratio (agonist: antagonist) of 1:10 to 10: 1.
  • the present invention further relates to a first method for producing the multilayer tablet according to the invention, comprising the steps
  • Providing a first tableting composition comprising as active ingredient an opioid agonist or a pharmaceutically acceptable salt thereof, and optionally a doping agent;
  • Providing a second tableting composition comprising as active ingredient an opioid antagonist or a pharmaceutically acceptable salt thereof, and a
  • Tablettiermasse and a second filling shoe of the tablet press tool with the second Tablettiermasse are provided;
  • the present invention further relates to a second method for producing the multilayer tablet according to the invention, comprising the steps
  • Providing a first tableting composition comprising as active ingredient an opioid agonist or a pharmaceutically acceptable salt thereof, wherein the opioid agonist or the pharmaceutically acceptable salt thereof is contained in the first tabletting mass in the form of pellets containing and containing the opioid agonist a layer releasing the release of the opioid agonist is applied;
  • Providing a second tabletting composition comprising as active ingredient an opioid antagonist or a pharmaceutically acceptable salt thereof and a doping agent;
  • Tablettiermasse and a second filling shoe of the tablet press tool with the second Tablettiermasse are provided;
  • the second tabletting mass has an IC 50 / C max value of at least 30. In a more preferred embodiment, the second tabletting mass has an IC 5 o / C value of at least 35. In a further preferred embodiment, the second tabletting compound has an IC 50 / C max value of at least 40. In the most preferred embodiment, the second tabletting mass has an IC 50 / C ma) ⁇ value of at least 50.
  • the second tabletting mass comprises a matrix with at least one matrix former as retarding agent.
  • the preferred mass ratio of antagonist in the second tableting mass to the matrix image or images comprises values between 1: 1 and 1:10.
  • the second tableting mass contains glycerol di-behenic acid ester as a matrix former in an amount of 10-50% by weight.
  • the second tabletting mass comprises glycerol di-behenic acid ester in an amount of 15-45% by weight, more preferably 20-35%, and most preferably 25-30% by weight.
  • Preferred is glycerol di-behenic acid ester in an amount of 29.4% by weight relative to the naloxone matrix.
  • the multilayer tablet produced by one of the methods comprises a t max (naloxone) / t max (naloxone-3-glucuronoid) value of at least 5.
  • the present invention further relates to the use of the multilayer tablet according to the invention for the treatment of pain and for the simultaneous treatment of opioid-induced constipation.
  • the following embodiments serve to explain the invention.
  • Fig. 1 Release profiles of the tablets according to the embodiments 1 and 2.
  • Embodiment 2 The ingredients naloxone hydrochloride and glycerol di-benzenic acid ester were sieved and mixed together. To the resulting mixture was added first the colloidal silica in sieved form and then the magnesium stearate. The mixture thus obtained was compressed to tablets by means of a conventional tablet press.
  • Embodiment 2 The ingredients naloxone hydrochloride and glycerol di-benzenic acid ester were sieved and mixed together. To the resulting mixture was added first the colloidal silica in sieved form and then the magnesium stearate. The mixture thus obtained was compressed to tablets by means of a conventional tablet press.
  • Embodiment 2 Embodiment 2:
  • Kollidon ® SR consisting of 80% by weight of polyvinyl acetate, 19% by weight of povidone, 0.8% by weight of sodium lauryl sulfate and 0.2% by weight of colloidal silica.
  • naloxone-layer ie, naloxone hydrochloride, Kollidon ® SR, glycerol-di- behenic acid, colloidal silica and magnesium stearate were sieved and mixed together to form a first powdery mixture.
  • ingredients of the placebo layer ie, sugar pellets, hypromellose, microcrystalline cellulose, colloidal silica and magnesium stearate were sieved and mixed together to form a second powdered mixture.
  • the first and second mixtures were compressed by means of a conventional two-layer tablet press into two-layer tablet cores.
  • the two-layer tablet cores thus obtained were dissolved in a coater using Opadry ® film-coated in water at a temperature of 30 ° C to 50 ° C to give two-layer tablets.
  • the in vitro release profiles of the tablets according to embodiments 1 and 2 were determined using the paddle stirrer apparatus (apparatus 2) and the Blattrüh rer method according to Eur.Ph. (European Pharmacopoeia, Seventh Edition, 3rd Amendment, 2.9.3 "Release of Active Substance from Solid Pharmaceutical Forms", pp. 5519-5526) at 75 rpm in 500 ml of 0.1 N hydrochloric acid at 37 ° C. The amount released drug was determined by UV detection at 220 nm.
  • the in vitro release profiles of the tablets according to the embodiments 1 ( ⁇ ) and 2 (x) are shown in FIG.
  • the components of the oxycodone layer ie the retarded oxycodone pellets, microcrystalline
  • Cellulose, colloidal silica and magnesium stearate were screened and mixed together to a first mixture.
  • naloxone layer ie naloxone hydrochloride, Kollidon ® SR, colloidal silicon dioxide and magnesium stearate sieved and mixed together to form a second powdery mixture.
  • the first and second mixtures were compressed to two-layer tablet cores using a conventional two-layer tablet press.
  • the two-layer tablet cores thus obtained were dissolved in a coater using Opadry II ® film-coated in water at a temperature of 30 ° C to 50 ° C.
  • the retarded oxycodone pellets had the following composition and were prepared as known in the art.
  • Kollidon ® SR consisting of 80% by weight of polyvinyl acetate, 19% by weight of povidone, 0.8% by weight of sodium lauryl sulfate and 0.2% by weight of colloidal silica.
  • Opadry II ® consists of polyvinyl alcohol, iron oxide or titanium dioxide, macrogol and talc.
  • Embodiment 2 is a description of the structure of the invention.
  • Figure 1 Release profile of naloxone from a composition according to the invention.

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Abstract

La présente invention concerne une composition pharmaceutique solide à usage oral, comprenant comme principe actif de la naloxone ou un de ses sels pharmaceutiquement acceptables, ladite composition libérant le principe actif de façon retardée. Cette composition peut comprendre une matrice comportant comme agent de formation de matrice un ester d'acide dibéhénique glycérique, avec un rapport massique naloxone/agent(s) de formation de matrice compris entre 1:1 et 1:10, le principe actif naloxone étant ainsi libéré de façon retardée. Selon l'invention, pour obtenir une composition adaptée en vue d'une administration pendant au moins douze heures pour traiter la constipation due aux opiacés, la composition présente une vitesse de libération in vitro du principe actif, mesurée par la méthode de l'agitateur à pales selon la Ph. Eur. à 75 tr/min dans 500 ml d'acide chlorhydrique 0,1 N à 37 °C, allant de 0 % à 75 % en 2 h, de 3 % à 95 % en 4 h, de 20 % à 100 % en 10 h, de 30 % à 100 % en 16 h, de 50 % à 100 % en 24 h et de plus de 80 % en 36 h, la composition présentant une valeur IC50/Cmax d'au moins 40. La composition présente de préférence une valeur de rapport tmax (naloxone) / tmax (naloxone-3-glucuronide) d'au moins 5. Dans un autre mode de réalisation, la composition peut se présenter sous la forme d'un comprimé multicouche.
EP15817094.4A 2014-12-08 2015-12-07 Monopréparation de naloxone et comprimé multicouche Ceased EP3229785A2 (fr)

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PCT/EP2015/078827 WO2016091805A2 (fr) 2014-12-08 2015-12-07 Monopréparation de naloxone et comprimé multicouche

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CN115252583B (zh) * 2022-07-11 2023-08-08 河北奥星集团药业有限公司 复方盐酸替利定缓释制剂及其制备方法

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