EP3229785A2 - Naloxone monopreparation and multi-layer tablet - Google Patents

Naloxone monopreparation and multi-layer tablet

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Publication number
EP3229785A2
EP3229785A2 EP20150817094 EP15817094A EP3229785A2 EP 3229785 A2 EP3229785 A2 EP 3229785A2 EP 20150817094 EP20150817094 EP 20150817094 EP 15817094 A EP15817094 A EP 15817094A EP 3229785 A2 EP3229785 A2 EP 3229785A2
Authority
EP
Grant status
Application
Patent type
Prior art keywords
composition
tablet
according
active
embodiment
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.)
Pending
Application number
EP20150817094
Other languages
German (de)
French (fr)
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.)
Develco Pharma Schweiz AG
Original Assignee
DEVELCO PHARMA SCHWEIZ AG
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Filing date
Publication date

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/485Morphinan derivatives, e.g. morphine, codeine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, 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
    • A61K9/2086Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, 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
    • A61K9/2086Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209Layered 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

Abstract

The present invention relates to a solid, oral pharmaceutical composition comprising naloxone, or a pharmaceutically acceptable salt thereof as the active ingredient, the composition having a delayed release of said active ingredient. The composition can comprise a matrix containing glycerol di-behenic acid esters as matrix formers, with a mass ratio of naloxone to matrix former(s) of between 1:1 and 1:10, whereby the active ingredient naloxone has a delayed release. According to the invention, in order to provide a composition suitable for a dosage covering at least twelve hours for treating opioid-induced obstipation, the composition has an in-vitro release rate of the active ingredient, measured using a vane stirrer method according to Eur. Ph. at 75 U/min in 500 ml of 0.1 N hydrochloric acid at 37 °C, of 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 more than 80 % in 36 h, said composition having an IC50/Cmax value of at least 40. Preferably, the composition comprises a value for tmax (naloxone) / tmax (naloxone-3-glucuronoid) of at least 5. In an alternative embodiment, the composition can take the form of a multi-layer tablet.

Description

Naloxone MONO PREPARATION AND MULTI-LAYER TABLET

BACKGROUND OF THE INVENTION

In the medication of painkillers of the opioid type, provides the constipation is a significant side effect. It is considered one of the most common side effects and is particularly in opioid maintenance therapy an unwanted side effect, which occurs in about 85% of patients. Unlike other opioid-induced side effects are in the opioid-induced constipation is a chronic phenomenon which does not lose its intensity with continued treatment. The effect of opioids on the gut motility presumably due to the binding of the opioid to opioid receptors of the gastrointestinal tract that are to be found there in a relatively high density.

The aim of such therapy is to reverse this peripheral side effect of opioids as the opioid-induced constipation can be uncomfortable and very painful, often leads to discontinuation of opioid therapy, and so endanger the success of treatment of opioids. Since one assumes in the opioid-induced constipation in that it is effected directly and locally over the entire intestine by the occupation of the opioid receptors, these side effects should be able to be canceled by the use of opioid antagonists. However, the use of opioid antagonists is only useful when the antagonistic effect limited to the intestine and not the central analgesic effect is canceled.

A suitable opioid antagonist for the treatment of opioid-induced constipation is naloxone. Following oral administration, naloxone is rapidly and completely absorbed and because the drug is subject to extensive first pass metabolism, only small amounts of unchanged naloxone are systemically available. The major part of the applied substance is in the form of not or only weakly active metabolite as something that naloxone-3-glucuronide or the beta-6-naloxol in the blood. Naloxone in a suitable dose is an ideal candidate to remedy the opioid-induced constipation: in the intestine, it is as active Su bstanz before and can thus remove the paralyzing effect of the opioid on the gastrointestinal tract, while it greatly metabolized after absorption in the first liver passage and is so ineffective. Thus, the analgesic effects of opioids is not affected. The opioid-induced constipation can not be successfully treated with a rapid-release naloxone formulation since the paralysis throughout the gastrointestinal tract and not only

relates to the duodenum and upper parts of the small intestine. WO 2011/117306 discloses a

Zweischichtta blette, in the one layer contains an opioid agonist and the other layer an opioid antagonist, wherein the tablet releases both drugs quickly. Advantage of this two-layer tablet is indeed the suppression of opioid agonists caused

Side effects, but in this case the opioid-induced constipation is not a priority.

Although the combination product Targin ® present in the market, the opioid agonist oxycodone also be in the form of the hydrochloride salt and the opioid antagonist naloxone in the form of its hydrochloride salt in a mixture sets, the active ingredients slow-release and thus for the parallel treatment of pain and opioid -induced constipation suitable. However, this monolithic formulation has the disadvantage that the release kinetics for both active ingredients so the individual treatment success is difficult to optimize non-variable and.

In addition to infusion solutions for the treatment of opioid poisoning only naloxone combination preparations are available in the market in which naloxone and opiate present in a fixed ratio to each other. but for the treatment of opioid-induced constipation, it would be desirable to have a naloxone monopreparation, since this may be administered firstly independent of the nature of the opiate and the other in a variable quantity, whereby the desired Naloxonmenge precisely applied, and so an optimum treatment success can be achieved. Although in the patent literature naloxone mono preparations are described in WO 98/25613 A2. These preparations set the naloxone selectively depending on the ambient pH of the gastro-intestinal tract free, so a locally uniform supply throughout the gastrointestinal tract thus an optimal treatment outcome is not possible with naloxone and away.

OBJECT OF THE INVENTION

Object of the present invention is to provide an oral solid pharmaceutical composition comprising as active ingredient naloxone or a pharmaceutically acceptable salt thereof, wherein the composition is the active substance naloxone retarded release and so suitable for at least twelve-hour administration for the treatment of opioid-indexed constipation.

This object is achieved by a solid oral pharmaceutical composition comprising as active ingredient naloxone or a pharmaceutically acceptable salt thereof, wherein the composition comprises the active substance naloxone release retarded and an in vitro release rate of the drug naloxone, measured using the Paddle Method described in accordance with Eur. ph. at 75 U / min 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 of

comprising 30% to 100% in 16 h from 50% to 100% in 24 h and more than 80% in 36 h.

It has been found that the composition of the invention with said release profile is suitable for at least twelve-hour administration for the treatment of opioid-indexed constipation, and accordingly has a relatively high patient compliance.

The release rate in wiro using the paddle stirrer apparatus (apparatus 2) and the Paddle Method described, according Eur.Ph. (European Pharmacopoeia, 7th edition, 3rd supplement, 2.9.3 "drug release from solid dosage forms", pp 5519-5526) determined at 75 U / min in 500 ml of 0.1 N hydrochloric acid at 37 ° C. The amount of released active ingredient is preferably determined by means of UV detection at 220 nm.

Through the matrix the drug is releasing retarded, and the in vitro release rate of the drug naloxone, measured using the Paddle Method described in accordance with Eur. Ph. At 75 U / min in 500 ml of 0.1 N hydrochloric acid at 37 ° C, of 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 is over 80% in 36 h.

The opioid-induced constipation, which can be treated using the inventive composition may be sent for all of the opioid analgesics or opioid analgesics analogs, their salts and mixtures thereof. Examples of appropriate analgesics may be mentioned are: alfentanil, allylprodine, Alpha, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, Besomorphin, dextromoramide, dezocin, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, Nalbuphen, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, Propheptazin, promedol, properidine, propoxyphene, sufentanil, tilidine, and tramadol, wherein hydrocodone, morphine, hydromorphone, oxycodone, Bupren Orphin, codeine, fentanyl, levorphanol, meperidine, methadone, Methadone and Dextromethadon are inventively particularly preferred.

According to a preferred embodiment of the composition according to the invention it is provided that the composition has a h in vitro release rate of the drug from 0% to 50% in 2, from 5% to 95% in 4 h, from 20% to 90% in 10 h , having greater than 70% in 18 hours and more than 80% in 24 h.

According to another preferred embodiment of the composition according to the invention it is provided that the composition has a h in vitro release rate of the drug from 0% to 38% in 2, from 5% to 55% in 4 h, and from 20% to 75% in 10 comprising h.

According to another preferred embodiment of the composition according to the invention it is provided that the composition has a h in vitro release rate of the drug from 0% to 50% in 1 h of 10% to 95% in 4, from 35% to 100% in 8 h, of 55% to 100% in 12 h from 70% to 100% in 16 hours and more than 90% in 24 h has.

According to a further preferred embodiment of the composition according to the invention it is provided that the composition has a h in vitro release rate of the drug from 0% to 30% in 1 h from 0% to 40% in 2 of 3% to 55% in 4 h, h of 10% to 65% in 8 of 20% to 75% in 12 h from 30% to 88% in 16 h from 50% to 100% in 24 h and more than 80% in 36 h having.

According to another preferred embodiment of the composition according to the invention it is provided that the composition has a h in vitro release rate of active from 10% to 30% in 1, 17% to 37% in 2 h, from 27% to 47% in 4 h, from 40% to 60% in 8 hours, from 50% to 70% in 12 h from 60% to 80% in 16 h from 80% to 100% in 24 h has.

According to a particularly preferred embodiment of the composition according to the invention it is provided that the composition releases the active substance naloxone independent of the ambient pH of the gastro-intestinal tract. This ensures that the entire gastrointestinal tract can be supplied independent of the respective local pH environment smoothly and continuously with naloxone or a salt, thereby providing a further optimization of the treatment effect can be achieved. The pH-independent release of the inventive composition can be obtained by selecting known in the art of pharmaceutical excipients, where local in the gastrointestinal tract pH values ​​of about 1.2 (stomach) prevail to about 6.8 colon.

Under an independent of the ambient pH of the gastro-intestinal tract release of the active ingredient of the composition of the invention is thereby inventively preferred understood that the similarity factor f2 a first in vitro release at pH 1.2 to 6.8 and a second in vitro release greater than at any other pH 1.2 to 6.8 / equal 50th

The similarity factor f2 according SHAH VP, Tsong Y., P. Sathe, & LIU JP (1998), "In vitro dissolution profile comparison-statistics and analysis of the similarity factor, f2," Pharmaceutical Research, 15, 889-896 determined , Namely, the similarity factor f2 (engl, similarity factor) is calculated according to the following formula:

/ 2 = 50 - tep lc ([!

In this equation, Rt and Tt represent the amount released of the drug at the time t at the first pH and the second pH is. N is the number of time points. The f2-factor is determined under the following conditions: a) the minimum number of points in time for release is 3 (the time instant 0 is excluded), b) the time points for the first and second pH-value should be the same; c) for the amount released at each time point is indicated an average of 12 measurements for each pH value, d) not more than an average measured above a release of 85% must be taken into account in the calculation, e) the relative standard deviation, or variation coefficient of the release at a pH-value should be less for the first time than 20% and for the second and each subsequent time is less than 10%.

For f2-factor calculation, the in vitro release profiles using the paddle stirrer apparatus (apparatus 2) and the Paddle Method described are in accordance Eur.Ph. (European Pharmacopoeia, 7th edition, 3rd supplement, 2.9.3 "drug release from solid dosage forms", pages 5519- 5526) at 75 U / min in 500 ml buffer (according to European Pharmacopoeia, 7th edition, Supplement 7, 4.1.3 "buffer solutions", pages 7671-7679) determined at 37 ° C. The amount of released active ingredient is determined by means of UV detection at 220 nm. According to another preferred embodiment of the composition according to the invention, it is provided that the composition comprises a matrix which releases the active ingredient retarded.

The active ingredient can be released slowly cost especially when it is in a sustained release matrix.

The inventive composition may comprise a matrix containing the naloxone or the pharmaceutically acceptable salt thereof releases retarded. This can preferably be a so-called framework matrix that can be swellable or non-swellable, or a so-called erosive matrix according to the invention in the matrix. The matrix may also have properties of the two, both scaffold matrix and eroding matrix have.

In a scaffolding matrix, the active ingredient is incorporated in a matrix structure. During transport of the loaded scaffold matrix through the gastrointestinal tract, the active ingredient is gradually dissolved by the digestive juices from the matrix backbone. After this is done, the matrix scaffold is secreted into more or less unchanged or swollen form. In an eroding matrix, however, the matrix is ​​degraded or eroded, whereby drug particles reach the surface and dissolve. The release rate of the degree of matrix degradation or their erosion is dependent.

For the purposes of the formation of a substantially stable matrix backbone with a suitable drug release it is provided according to a further preferred embodiment of the composition according to the invention that the matrix comprises one or more water-insoluble matrix. In an alternative embodiment it is provided that the matrix comprises one or more water-soluble matrix.

According to a further preferred embodiment of the composition according to the invention, it is provided that the matrix is ​​water-insoluble.

According to another preferred embodiment of the composition according to the invention, it is provided that the matrix comprises, as matrix forming agent one or more compounds selected from the group consisting of cellulose esters, cellulose ethers, Polyetylenoxid polyvinylpyrrolidone / polyvinyl acetate mixtures, methacrylate-acrylate copolymers, waxes, fats such as for example glycerol esters and fatty alcohols. The classes of substances mentioned are particularly suitable as matrix for the inventive composition, according to the invention particularly preferred polyvinyl acetate in admixture with a polyvinylpyrrolidone and / or a glycerol-di-behenic acid ester are used as matrix. It is preferred that the solid oral pharmaceutical composition includes a matrix of glycerol-di-behenic acid ester as one of the matrix forming.

In this case the preferred mass ratio of naloxone to or comprises the matrix pictures (n) values ​​between 1: 1 and 1:10.

With respect to the Naloxonmatrix the composition comprises in a preferred embodiment, glycerol-di-behenic acid ester as matrix in an amount of 10-50% by weight. More preferably, the composition of glycerol-di-behenic acid ester contained in an amount of 10-50% by weight, preferably in an amount of 15-45% by weight, more preferably from 20-35%, and most preferably from 25-30% by weight.

Preference has glycerol-di-behenic acid ester in an amount of 29.4% by weight with respect to the Naloxonmatrix.

According to another preferred embodiment of the composition according to the invention it is provided that the composition is free of film-coated, naloxone-containing particles, wherein the film coating causes the sustained release of the naloxone.

According to a further preferred embodiment of the composition according to the invention, it is provided that the composition is tableted directly, since it is particularly inexpensive.

According to another preferred embodiment of the composition according to the invention it is provided that the composition is in the form of a tablet, capsule, granule, micro tablet, extruded particles or compressed into a tablet granulate is present.

According to another preferred embodiment of the composition according to the invention, it is provided that the composition as a one-daily- (once-a-day formulation) or Zweimal- daily formulation is formed (twice-a-day formulation).

In the inventive composition, is contained as active substance naloxone or a pharmaceutically acceptable salt thereof, wherein naloxone hydrochloride is particularly preferred due to its solubility, and its stability. One or more weiterere agents may be present in the composition. The naloxone or the pharmaceutically acceptable salt thereof is preferably contained in the inventive composition in an amount of 0.1 to 500 mg, more preferably in an amount of 1 mg to 50 mg and more 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 inventive composition for the treatment of opioid-induced constipation.

With regard to a composition which is particularly suitable for twice daily administration, the present invention further relates to a solid oral pharmaceutical composition comprising as active substance naloxone or a pharmaceutically acceptable salt thereof, wherein the composition the active ingredient releases retarded and in vitro release rate of the active ingredient, as measured using the Paddle method described in accordance with Eur. Ph. at 75 U / min in 500 ml of 0.1 N hydrochloric acid at 37 ° C, from 5% to 50% in 1 h, from 10% to 75% h, 2 h, 20% to 95% in 4, from 40% to 100% in 8 hours, more than 50% in 12 h, more than 70% in 18 hours and more than 80% in 24 h having.

With regard to a composition which is particularly suitable for twice daily administration, the present invention further relates to a solid oral pharmaceutical composition comprising as active substance naloxone or a pharmaceutically acceptable salt thereof, wherein the composition the active ingredient releases retarded and in vitro release rate of the active ingredient, as measured using the Paddle method described in accordance with Eur. Ph. at 75 U / min 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 hours, and from 90% to 100% in 12 hours has.

With regard to a composition particularly for the administration is once a day suitable to the present invention further relates to a solid oral pharmaceutical composition comprising as active substance naloxone or a pharmaceutically acceptable salt thereof, wherein the composition the active ingredient releases retarded and in vitro release rate of the active ingredient, as measured using the Paddle method described in accordance with Eur. Ph. at 75 U / min in 500 ml of 0.1 N hydrochloric acid at 37 ° C, from 0% to 50% in 1 h, from 0% to 75% in 2 h, from 10% to 95% in 4 h, from 35% to 100% in 8 h, by 55% to 100% in 12 h from 70% to 100% in 16 hours and more than 90% in having 24 h. With regard to a composition particularly for the administration is once a day suitable to the present invention further relates to a solid oral pharmaceutical composition comprising as active substance naloxone or a pharmaceutically acceptable salt thereof, wherein the

Retarded composition releases the active ingredient and in-vitro release rate of the

Active ingredient, as measured using the Paddle Method described in accordance with Eur. Ph. At 75 U / min in

H 500 ml 0.1 N hydrochloric acid at 37 ° C, from 0% to 30% in 1 h, from 0% to 40% in 2 of 3% to 55% in

4 h, h of 10% to 65% in 8 of 20% to 75% in 12 h from 30% to 88% in 16 h from 50% to 100% in 24 h and more than 80% in 36 comprising h.

With regard to a composition particularly for the administration is once a day suitable to the present invention further relates to a solid oral pharmaceutical composition comprising as active substance naloxone or a pharmaceutically acceptable salt thereof, wherein the composition the active ingredient releases retarded and in vitro release rate of the active ingredient, as measured using the Paddle method described in accordance with Eur. Ph. at 75 U / min 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 hours, from 50% to 70% in 12 h from 60% to 80% in 16 h from 80% to 100% having in 24 h.

In keeping with good patient compliance, it is provided according to a further preferred embodiment of the composition according to the invention that the composition, preferably a tablet or a capsule, in wiro release rate of the active ingredient, as measured using the Paddle Method described in accordance with Eur. Ph. 75 h U / min in 500 ml of 0.1 N hydrochloric acid at 37 ° C, from 0% to 75% in 2 of 3% to 95% in 4 h, from 20% to 100% in 10 h from 30% to has 100% in 16 h from 50% to 100% in 24 h and more than 80% in 36 h.

According to a further preferred embodiment of the composition according to the invention it is suitable in terms of providing a composition H for at least 12 for the treatment of opioid-induced constipation, provided that the composition has an in vitro release rate of the drug from 0% to 50 % in 2 h, from 5% to 95% in 4 h, from 20% to 90% in 10 h, more than 70% in 18 hours and more than 80% in 24 h has.

According to the invention, the release rate is regulated by adjusting the mass ratio of naloxone to matrix. In a preferred embodiment, the mass ratio of naloxone to matrix images 1: 1, preferably 1: 2, more preferably 1: 3, more preferably 1: 4, more preferably 1: 5, more preferably 1: 6, more preferably 1: 7, 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 expressed by the retardation is small. Compared to a non-retarded composition of the maximum plasma concentration (C max) over the effective course of about 20x lower and compared to an intravenously given composition LooX lower.

The inhibition of receptors but is overall better over the course of action. Therefore, the low bioavailability in the system provides not only the obstipationsverhindernden effects of naloxone for a reduced likelihood and / or severity of side effects.

Since the inhibitory concentrations (IC 50) of naloxone for opioid receptors (μ, δ and κ) are known, there is a new size IC 50 / C ma) <enabling an assessment of the risks of the tablet. If the IC 50 is used for the μ-receptor results for a tablet according to the invention with 48 mg naloxone, an IC 50 / C max value of 54. In general, the higher the IC 5 o / C value is, the less are the risks of the inventive tablet. Below all details relating to the IC 50 for the μ-receptor.

In a preferred embodiment, the composition has an IC 50 / C max value of at least 30. In a more preferred embodiment, the composition has an IC 50 / C max - value of at least 35. In a more preferred embodiment, the composition has an IC 50 / C max value of at least 40. In the most preferred embodiment, the composition has an IC 50 / C max value of at least 50th

Also is characteristic of the present composition a particularly high value for the ratio t max of the active substance naloxone, for t max of its metabolite naloxone-3-glucuronide. T max is a classic indicator in the pharmacokinetics and describes the time to maximum plasma concentration of a substance.

Thus, the active ingredient is the higher the value of the ratio T max (naloxone) to T max (naloxone-3-glucuronide), the more slowly released from the composition and metabolized. Thus, the effect of the antagonist lasts longer. Surprisingly, the inventors ha ben found that as well as the side effects of the

are antagonists lower. For example, the reduction of opioid effect is less and also the

Withdrawal symptoms.

It is preferred that the composition (glucuronoid naloxone-3) a value for t max (naloxone) / t max of at least 5 comprises.

In another embodiment, the composition additionally comprises at least one stabilizer which protects the active ingredient. In a preferred embodiment this is at least one stabilizer selected from the list comprising sulfur dioxide, sodium sulphite, sodium bisulphite, ascorbic acid and its derivatives and tocopherol, as well as dessenwasser- and fat-soluble derivatives, such as. B. tocopherol acetate, sulphites, bisulphites and hydrogen sulphites of alkali earth metal and other metals, PHB esters, 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 its salts, citraconic acid, cysteine, L-cystine, Conidendrine, Diäthylcarbonate, Methylendioxyphenole, cephalins, ß, ß '-dithiopropionic acid, biphenyl and other phenyl derivatives.

In another embodiment, the composition additionally comprises at least one stabilizer that protects the matrix. In a preferred embodiment this is at least one stabilizer selected from the list comprising butylated hydroxytoluene, sulfur dioxide, sodium sulphite, sodium bisulphite, ascorbic acid and its derivatives and tocopherol, as well as its water- and fat-soluble derivatives, such as. B. tocopherol acetate, sulphites, bisulphites and hydrogen sulphites of alkali earth metal and other metals, PHB esters, 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 its salts, citraconic acid, cysteine, L-cystine, Conidendrine, Diäthylcarbonate, Methylendioxyphenole, cephalins, ß, ß '-dithiopropionic acid, biphenyl and other phenyl derivatives.

In a further embodiment, the composition comprises at least one additive, wherein the additive is an emetic, or a hot substance drug is. In a preferred embodiment, the composition comprises an additive, said fabric is a Sharf drug selected from the group comprising Allii sativi eyeball, Asari rhizoma. Herba, Calami Rhizoma, capsici fructus (capsicum} 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, and Rhizoma Zingiberis Rhizoma Zedoariae, particularly preferably from the group consisting of Capsici fructus (capsicum), Capsici fructus acer (cayenne pepper) and

Piperis nigri fructus (pepper).

In a preferred embodiment, the composition comprises at least one additive, this is an emetic. In a preferred embodiment, the emetic is based on one or more constituents of ipecacuanha (ipecac). In a preferred embodiment, the emetic is based on the ingredient emetine, in an alternative embodiment, the emetic is apomorphine.

In a further embodiment, the composition comprises a dye. In a preferred embodiment of this dye is selected from the group consisting of red iron oxide, black iron oxide and indigo carmine.

In another embodiment, the composition additionally comprises at least one non-steroidal anti-inflammatory drug or antihistamine.

In an alternative embodiment, the composition further comprises at least one water-soluble lubricant. In a preferred embodiment, the composition comprises at least one water-soluble lubricant is selected from the group comprising adipic acid, fumaric acid, sodium benzoate and macrogols.

Object of the present invention is to provide a tablet, which as active substances comprising an opioid agonist or a pharmaceutically acceptable salt thereof and an opioid antagonist or a pharmaceutically acceptable salt thereof, and which is suitable for the parallel treatment of pain and opioid-induced constipation wherein an individual success of treatment can be readily optimized by means of the tablet.

This object is inventively achieved by a multilayer tablet comprising at least

- a first active layer containing as active ingredient an opioid agonist or a pharmaceutically acceptable salt thereof; and

- a second active layer comprising as active ingredient an opioid antagonist, or a

contains pharmaceutically acceptable salt thereof, wherein at least the second active layer releases the active ingredient retarded. In a preferred

Embodiment set the first and second active ingredient layer slow-release the drug. The

Multilayer tablet may also include other active ingredients.

The multilayer tablet of the invention is suitable for the parallel treatment of pain and opioid-induced constipation, wherein a variable release kinetics for each active ingredients therefore an individual treatment success can be easily optimized and implemented easily.

The multilayer tablet of the invention further has the advantage that in each layer a different etardierungssystem, for example, can be used with an extended release coated pellets or a sustained release matrix. This can be realized individually tailored to a specific patient particularly easy a specific release kinetics for each active substance and a variable proportion of the active ingredients.

The multilayer tablet of the invention has the additional advantage that means the same much more precise dosages of the two drugs are possible. This is common in small doses to bear.

The tablet according to the invention is furthermore of advantage when the two active ingredients are incompatible with each other.

According to a particularly preferred embodiment of the multilayer tablet according to the invention, it is provided that the multilayer tablet is a bilayer tablet. The multilayer tablet of this invention can process and simple and thus be realized at low cost in the form of a two-layer tablet.

According to a further preferred embodiment of the multilayer tablet according to the invention it is envisaged that the second drug layer comprises a matrix that retards the release of the opioid antagonist or the pharmaceutically acceptable salt thereof. A retarding action matrix can process and simple and therefore cost. This can preferably be a so-called framework matrix that can be swellable or non-swellable, or a so-called erosive matrix according to the invention in the matrix. The matrix may also have properties of the two, both scaffold matrix and eroding matrix have. In a scaffolding matrix, the active ingredient is incorporated in a matrix structure. during the

Transport of laden scaffold matrix through the gastrointestinal tract, the active ingredient is gradually dissolved by the digestive juices from the matrix backbone. After this is done, the matrix scaffold is secreted into more or less unchanged or swollen form. In an eroding matrix, however, the matrix is ​​degraded or eroded, whereby drug particles reach the surface and dissolve. Here is the

Release rate depending on the extent of matrix degradation or their erosion.

According to a further preferred embodiment of the multilayer tablet according to the invention it is provided that the matrix contains one or more water-insoluble matrix. In an alternative embodiment it is provided that the matrix contains one or more water-soluble matrix.

According to a further preferred embodiment of the multilayer tablet according to the invention, it is provided that the matrix comprises, as matrix forming one or more components 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. The said components are particularly suitable as matrix for the inventive tablet, according to the invention particularly preferred polyvinyl acetate in admixture with a polyvinylpyrrolidone and / or a glycerol-di- come behenic acid ester as matrix are used.

According to the invention, the release rate is regulated by adjusting the mass ratio of naloxone to matrix. In a preferred embodiment, the mass ratio of naloxone to matrix images 1: 1, preferably 1: 2, more preferably 1: 3, more preferably 1: 4, more preferably 1: 5, more preferably 1: 6, more preferably 1: 7, more preferably 1: 8, more preferably 1: 9, and most preferably 1:10.

With respect to the Naloxonmatrix the multilayer tablet includes in a preferred embodiment, glycerol-di-behenic acid ester as matrix in an amount of 10-50% by weight. More preferably, the multilayer tablet of glycerol-di-behenic acid ester contained in an amount of 15-45% by weight, more preferably from 20-35%, and most preferably from 25-30% by weight.

Preference has glycerol-di-behenic acid ester in an amount of 29.4% by weight with respect to the Naloxonmatrix. According to a further preferred embodiment of the multilayer tablet according to the invention it is envisaged that the second active layer to the active substance, ie, the opioid antagonist or the pharmaceutically acceptable salt thereof, releases irrespective of the ambient pH of the gastro-intestinal tract. This ensures that the entire gastrointestinal tract is supplied independently of the respective local pH environment evenly with the opioid antagonist or a salt thereof is ensured, whereby a further optimization of the treatment effect can be obtained. The pH-independent release of the composition according to the invention can be achieved by selection of suitable components, local in the gastrointestinal tract pH values ​​of about 1.2 (stomach) prevail to about 7.0 colon.

According to a further preferred embodiment of the multilayer tablet according to the invention it is provided that the opioid antagonist is selected from the group consisting of naloxone, N-methylnaloxone and N-methylnaltrexone, and pharmaceutically acceptable salts thereof, wherein naloxone hydrochloride according to the invention particularly preferred.

According to a further preferred embodiment of the multilayer tablet according to the invention it is provided that the opioid agonist or the pharmaceutically acceptable salt thereof is contained in the first drug layer in the form of pellets containing the opioid agonist and a release of the opioid agonists retarding layer is applied.

According to a further preferred embodiment, 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 50th

It is preferred that the multi-layer tablet (glucuronoid naloxone-3) a value for t max (naloxone) / t max comprises of at least the 5th

According to a further preferred embodiment of the multilayer tablet according to the invention it is provided that opioid agonist is selected from the group consisting of: alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, Besomorphin, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,

Dioxaphetyl, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,

Etonitazen, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone,

Ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,

Methadone, metopon, morphine, myrophine, narceine, Nico morphine, norlevorphanol, normethadone,

Nalorphine, Nalbuphen, normorphine, norpipanone, opium, oxycodone, oxymorphone, Papaveretum,

Pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, Piritramid,

Propheptazin, promedol, properidine, propoxyphene, sufentanil, tilidine, and tramadol and pharmaceutically acceptable salts, hydrocodone, morphine, hydromorphone, oxycodone,

Buprenorphine, codeine, fentanyl, levorphanol, meperidine, methadone, and Levomethadon

Dextromethadon and their pharmaceutically acceptable salts according to the invention are particularly preferred.

According to a further preferred embodiment of the multilayer tablet according to the invention, it is provided that at least the second active layer is tableted directly, since this is particularly inexpensive to produce.

In another embodiment, the multilayer tablet additionally comprises at least one stabilizer that protects the active substance naloxone. In a preferred embodiment this is at least one stabilizer selected from the list comprising sulfur dioxide, sodium sulphite, sodium bisulphite, ascorbic acid and its derivatives and tocopherol, as well as dessenwasser- and fat-soluble derivatives, such as. B. tocopherol acetate, sulphites, bisulphites and hydrogen sulphites of alkali earth metal and other metals, PHB esters, 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 its salts, citraconic acid, cysteine, L-Cy ~ tin, Conidendrine, Diäthylcarbonate, Methylendioxyphenole, cephalins, ß, ß '-dithiopropionic acid, biphenyl and other phenyl derivatives.

In another embodiment, the multilayer tablet additionally comprises at least one stabilizer that protects the matrix. In a preferred embodiment this is at least one stabilizer selected from the list comprising butylated hydroxytoluene, sulfur dioxide, sodium sulphite, sodium bisulphite, ascorbic acid and its derivatives and tocopherol, as well as its water- and fat-soluble derivatives, such as. B. tocopherol acetate, sulphites, bisulphites and hydrogen sulphites of alkali earth metal and other metals, PHB esters, 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 , lecithin, mono- and polyhydroxylated

Benzene derivatives, ethylenediaminetetraacetic acid and its salts, citraconic acid, cysteine, L-cystine,

Conidendrine, Diäthylcarbonate, Methylendioxyphenole, cephalins, ß, ß '-dithiopropionic acid,

Biphenyl and other phenyl derivatives.

In another embodiment, the multilayer tablet comprises at least one additive, wherein the additive is an emetic, or a hot substance drug is. In a preferred embodiment, the composition comprises an additive, said fabric is a Sharf drug selected from the group comprising Allii sativi eyeball, Asari rhizoma. Herba, Calami Rhizoma, capsici fructus (capsicum} 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 Zingiberis Rhizoma and, particularly preferably from the group consisting of Capsici fructus (capsicum), Capsici fructus acer (cayenne pepper) and Piperis nigri fructus (pepper).

In a preferred embodiment, the multilayer tablet comprises at least one additive, this is an emetic. In a preferred embodiment, the emetic is based on one or more constituents of ipecacuanha (ipecac). In a preferred embodiment, the emetic is based on the ingredient emetine, in an alternative embodiment, the emetic is apomorphine.

In another embodiment, the multilayer tablet comprising a colorant. In a preferred embodiment of this dye is selected from the group consisting of red iron oxide, black iron oxide and indigo carmine.

In another embodiment, the composition additionally comprises at least one non-steroidal anti-inflammatory drug or antihistamine.

In an alternative embodiment, the composition further comprises at least one water-soluble lubricant. In a preferred embodiment, the composition comprises at least one water-soluble lubricant is selected from the group comprising adipic acid, fumaric acid, sodium benzoate and macrogols. According to a further preferred embodiment of the invention

A multilayer tablet, it is provided that is formed the tablet for once-daily administration

(Once-daily-formulation).

According to a further preferred embodiment of the multilayer tablet according to the invention it is provided that the tablet for twice-daily administration is formed (twice-Daily Formulation).

According to a further preferred embodiment of the multilayer tablet according to the invention it is provided that the multilayer tablet contains from 0.1 mg to 500 mg of opioid agonist or a pharmaceutically acceptable salt thereof and from 0.1 mg to 500 mg of opioid antagonist and includes a pharmaceutically acceptable salt thereof, according to the invention particularly preferably in a ratio (agonist: antagonist) from 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 of

- providing a first tablet composition comprising as active ingredient an opioid agonist or a pharmaceutically acceptable salt thereof, and optionally a etardierungsmittel;

- providing a second tablet composition comprising as active ingredient an opioid antagonist or a pharmaceutically acceptable salt thereof, and a

retarding agent;

- filling a first filling shoe a tablet compression tool with the first

Tabletting mass and a second feed shoe of the tablet press tool with the second tablet mass;

- compressing the first and second tablet mass to obtain a multilayer tablet.

The present invention further relates to a second process for the preparation of the multilayer tablet according to the invention comprising the steps of

- providing a first tablet composition comprising as active ingredient an opioid agonist or a pharmaceutically acceptable salt thereof, wherein the opioid agonist or pharmaceutically acceptable salt thereof is contained in the first tablet mass in the form of pellets containing the opioid agonist and a release of the opioid agonist release-slowing layer is applied; - providing a second tablet composition comprising as active ingredient an opioid antagonist or a pharmaceutically acceptable salt thereof and a etardierungsmittel;

- filling a first filling shoe a tablet compression tool with the first

Tabletting mass and a second feed shoe of the tablet press tool with the second tablet mass;

- compressing the first and second tablet mass to obtain a multilayer tablet.

In a preferred embodiment, the second tablet mass to a IC 50 / C max value of at least 30th In a more preferred embodiment, the second tablet mass an IC 5 o / C value of at least 35. In a further preferred embodiment, the second tablet mass know an IC 50 / C max value of at least on 40th In the most preferred embodiment, the second tablet mass an IC 50 / C ma) on <value of at least 50th

Furthermore, it is preferred that the second mass tableting comprising a matrix with at least one matrix forming agent as a retardant. Encompasses the preferred mass ratio of the antagonist in the second tablet mass, to the matrix or the images (n) values ​​between 1: 1 and 1:10.

With respect to the second Naloxonmatrix the tabletting mass includes in a preferred embodiment, glycerol-di-behenic acid ester as matrix in an amount of 10-50% by weight.

More preferably, the second tablet mass glycerol-di-behenic acid ester contained in an amount of 15-45% by weight, more preferably from 20-35%, and most preferably from 25-30% by weight.

Preference has glycerol-di-behenic acid ester in an amount of 29.4% by weight with respect to the Naloxonmatrix.

Furthermore, it is preferable that the multi-layer tablet prepared by one of the methods includes a value for t max (naloxone) / t max (naloxone-3-glucuronoid) 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 examples serve to illustrate the invention.

EXAMPLES

ORAL COMPOSITION

The following embodiments are used in conjunction with the drawings illustrate the invention. It shows:

Fig. 1: Release profiles of the tablets according to the embodiments 1 and 2.

Embodiment 1:

Tablets were prepared with the following composition:

The components of naloxone hydrochloride and glycerol-di-behenic acid ester were sieved and mixed together. the colloidal silica was first sieved in shape to the resulting mixture and then mixed with the magnesium stearate. The mixture thus obtained was compressed using a conventional tablet press to tablets. Embodiment 2:

Tablets were the following composition analogous to Embodiment 1 was prepared:

Kollidon ® SR consisting of 80 wt .-% polyvinyl acetate, 19 wt .-% povidone, 0.8 wt .-% sodium lauryl sulfate and 0.2 wt .-% colloidal silica.

Embodiment 3:

film-coated bilayer tablets of the following composition were prepared:

Placebo layer

Sugar pellets (diameter: 500-600 carrier μηι 10.00)

Hypromellose filler 10.00 10.00 microcrystalline cellulose filler of colloidal silica glidant 0.25

Magnesium stearate lubricant 0.25

Total weight of the placebo-layer 30,50

Total weight of the two-layer tablet core 56.00

Opadry film tablets 3.00

Total weight of 59.00 bilayer tablet

The components of the 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. Further, the components of the placebo layer were ie sugar pellets, hypromellose, microcrystalline cellulose, colloidal silica and magnesium stearate sieved and mixed together to form a second powdery mixture.

The first and second mixtures were pressed by means of a conventional two-layer tablet press to the 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.

release profiles

The in vitro release profiles of the tablets according to the embodiments 1 and 2 (apparatus 2) and the Blattrüh rer method were in accordance with using the paddle stirrer apparatus Eur.Ph. (European Pharmacopoeia, 7. Ausga be, 3rd supplement, 2.9.3 "drug release from solid dosage forms", pp 5519-5526) at 75 U / min in 500 ml of 0.1 N hydrochloric acid, determined at 37 ° C. The amount of of active ingredient released 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 Figure 1.

MULTI-LAYER TABLET

Embodiment 1:

film-coated bilayer tablets of the following composition were prepared:

The components of the oxycodone layer, ie the retarded oxycodone pellets, microcrystalline

Cellulose, colloidal silica and magnesium stearate were sieved and mixed together to form a first mixture.

Further, the components of the naloxone layer were 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 into bi-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 wt .-% polyvinyl acetate, 19 wt .-% povidone, 0.8 wt .-% sodium lauryl sulfate and 0.2 wt .-% colloidal silica.

Opadry II ® consists of polyvinyl alcohol, iron oxide or titanium dioxide, Macrogol and talc. Embodiment 2:

film-coated bilayer tablets of the following composition were prepared analogously to EXAMPLE 1

Embodiment 3:

film-coated bilayer tablets of the following composition were prepared analogously to EXAMPLE 1

List of Figures

Figure 1: release profile of naloxone from an inventive composition.

Claims

De WO 2016/091805 weiz AG CH Ilger AnwaltpCT / Ep2015 / 078827Schweiz Fasanenstraße 29Unser sign: B193-0007WO1 10719 Berlin CLAIMS
1. A solid oral pharmaceutical composition comprising as active ingredient naloxone or a pharmaceutically acceptable salt thereof, wherein the composition comprises a matrix with glycerol di-behenic acid ester as matrix, in a mass ratio of naloxone to matrix pictures (n) is between 1: 1 and 1: 10, wherein retarded by the matrix the drug is release, and when in i // 'froFreisetzungsrate of the drug naloxone, measured using the Paddle method described in accordance with Eur. Ph. at 75 U / min in 500 ml of 0.1 N hydrochloric acid 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 hours and more than 80% in 36 h by weight, and the composition has an IC 50 / C max - value of at least 40 has.
2. Composition according to claim 1, wherein the composition comprises glycerol-di-behenic acid ester, in
With respect to the Naloxonmatrix, in an amount of 10-50% by weight (w / w), preferably 15- 45% w / w, 20-40% w / w and 25-35% w / w, includes.
3. Composition according to claim 1, wherein the composition comprises glycerol-di-behenic acid ester contained in an amount of 29.4% in relation to the Naloxonmatrix.
4. A composition according to any one of the preceding claims, wherein the composition comprises a value for t max (naloxone) / t max (naloxone-3-glucuronoid) of at least. 5
5. A composition according to any one of the preceding claims, wherein the composition releases the active substance naloxone una epending from the ambient pH of the gastro-intestinal tract.
6. The composition according to any one of the preceding claims, characterized in that the composition has an in vitro release rate of the drug naloxone from 0% to 50% in 2 h, from 5% to 95% in 4 h, from 20% to 90% in 10 hours, more than 70% in 18 hours and more than 80% in 24 ufweist ha.
7. The composition according to any one of claims 1 to 5, characterized in that
The composition has an in vitro release rate of the active agent from 0% to 38% in 2 h, from 5% to 55% in 4 h, and from 20% to 75% in 10 h.
8. The composition according to any one of claims 1 to 5, characterized in that
Composition an hour in vitro release rate of the drug from 0% to 50% in 1 h, from 10% to 95% in 4, from 35% to 100% in 8 h, by 55% to 100% in 12 h, 70 having% to 100% in 16 hours and more than 90% in 24 h.
9. A composition according to any one of claims 1 to 5, characterized in that
Composition an hour in vitro release rate of the drug from 0% to 30% in 1 h, from 0% to 40% in 2 of 3% to 55% in 4 h, from 10% to 65% in 8 h, 20 % to 75% in 12 h from 30% to 88% in 16 h from 50% to 100% in 24 h and more than 80% in 36 hours has.
10. The composition according to any one of the preceding claims, characterized in that the composition is directly tabletted.
11. The composition according to any one of the preceding claims, characterized in that the composition is designed as a once-daily formulation.
12. The composition according to any one of the preceding claims 1 to 10, characterized in that the composition is formed as a twice-daily formulation.
13. A multilayer tablet comprising at least
- a first active layer containing as active ingredient an opioid agonist or a pharmaceutically acceptable salt thereof; and
- a second drug layer, which contains as active ingredient an opioid antagonist in a matrix with at least one matrix,
wherein the first and the second active substance layer retarded release the active ingredient and the second active layer has a IC50 / Cmax value of at least 40 and a mass ratio of antagonist to matrix pictures (n) is between 1: 1 and includes 1:10.
14. A multilayer tablet comprising at least:
- a first active layer containing as active ingredient an opioid agonist or a pharmaceutically acceptable salt thereof; and
- a second active layer wherein the first and the second active substance layer retarded release the active ingredient as an active ingredient an opioid antagonist and the second
A drug layer IC50 / Cmax value of at least 40, and in a tmax (antagonist) / tmax (antagonist metabolite) value of at least. 5
15. A multilayer tablet according to claim 13 or 14, wherein the composition comprises glycerol-di- behenic acid as matrix.
16. A multilayer tablet according to claim 15, wherein the composition comprises glycerol-di- behenic acid ester in an amount of 20-40% weight / weight with respect to the Naloxonmatrix.
17. A multilayer tablet according to claim 16, wherein the composition comprises glycerol-di-behenic acid ester in an amount of 29.4% in relation to the Naloxonmatrix.
18. A multilayer tablet according to any one of the preceding claims 13 to 17, characterized
in that the opioid agonist or pharmaceutically acceptable salt thereof is contained in the first drug layer in the form of pellets containing the opioid agonist and the release of the opioid agonist release-slowing layer is applied to one.
19. A multilayer tablet according to any one of the preceding claims 13 to 18, characterized
in that the opioid agonist is selected from the group consisting of
Hydrocodone, morphine, hydromorphone, oxymorphone, oxycodone, buprenorphine, codeine, fentanyl, levorphanol, meperidine, methadone, Methadone and Dextromethadon and their
pharmaceutically acceptable salts thereof.
20. A method for manufacturing a multilayer tablet according to one of claims 13 to 19,
comprising the steps of:
- providing a first tablet composition comprising as active ingredient an opioid agonist or a pharmaceutically acceptable salt thereof and a etardierungsmittel;
- providing a second tablet composition comprising as active ingredient an opioid antagonist or a pharmaceutically acceptable salt thereof and at least one retarding agent, characterized in that the second tablet mass an IC 50 / C max - having a value of at least 40 and a mass ratio of antagonist to slow-release agent (n) is between 1: 1 and 1:10. - filling a first filling shoe of a Ta blettenpresswerkzeuges with the first
Tabletting mass and a second feed shoe of the tablet press tool with the second tablet mass;
- compressing the first and second tablet mass to obtain a multilayer tablet.
21. A method for manufacturing a multilayer tablet according to one of claims 13 to 19,
comprising the steps of
- providing a first tablet composition comprising as active ingredient an opioid agonist or a pharmaceutically acceptable salt thereof, wherein the opioid agonist or pharmaceutically acceptable salt thereof is contained in the first tablet mass in the form of pellets containing the opioid agonist and a release of the opioid agonist release-slowing layer is applied,
- providing a second tablet composition comprising marked as active ingredient an opioid antagonist or a pharmaceutically acceptable salt thereof and a etardierungsmittel characterized in that the second tablet mass having an IC50 / Cmax value of at least 40, a mass ratio of antagonist to slow-release agent (s) is between 1 : 1 and 1:10.
- filling a first filling shoe of a Ta blettenpresswerkzeuges with the first tablet mass and a second feed shoe of the tablet press tool with the second tablet mass;
- compressing the first and second tablet mass to obtain a multilayer tablet.
22. A method for manufacturing a multilayer tablet according to one of claims 13 to 19,
comprising the steps of:
- providing a first tablet composition comprising as active ingredient an opioid agonist or a pharmaceutically acceptable salt thereof and a retarding agent;
- providing a second tablet composition comprising as active ingredient an opioid antagonist or a pharmaceutically acceptable salt thereof and a retarding agent, characterized in that the second tablet mass ma) has a IC 50 / C <value of at least 40 and a value of at least 5 for t max (antagonist) / t max (antagonist metabolite).
- filling a first filling shoe of a Ta blettenpresswerkzeuges with the first tablet mass and a second feed shoe of the tablet press tool with the second tablet mass;
- compressing the first and second tablet mass to obtain a multilayer tablet.
23. A process for the preparation of a multilayer tablet according to one of claims 13 to 19, comprising the steps of
- providing a first tablet composition comprising as active ingredient an opioid agonist or a pharmaceutically acceptable salt thereof, wherein the opioid agonist or pharmaceutically acceptable salt thereof is contained in the first tablet mass in the form of pellets containing the opioid agonist and a release of the opioid agonist release-slowing layer is applied,
- providing a second tablet composition comprising an opioid antagonist or a pharmaceutically acceptable salt thereof, and a slow-release agent characterized as an active ingredient, the second tablet mass having an IC50 / Cmax value of at least 40 and a value of at least 5 for tmax (antagonist) / t max (antagonist metabolite).
- filling a first filling shoe of a Ta blettenpresswerkzeuges with the first tablet mass and a second feed shoe of the tablet press tool with the second tablet mass;
- compressing the first and second tablet mass to obtain a multilayer tablet.
24. A solid oral pharmaceutical composition according to any one of claims 1 to 12 for
Use in the treatment of opioid-induced constipation.
25. A multilayer tablet according to one of claims 13 to 19 for use in the treatment of opioid-induced constipation.
EP20150817094 2014-12-08 2015-12-07 Naloxone monopreparation and multi-layer tablet Pending EP3229785A2 (en)

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JP6144274B2 (en) * 2011-12-09 2017-06-07 パーデュー、ファーマ、リミテッド、パートナーシップ Poly (epsilon - caprolactone) and pharmaceutical dosage forms containing polyethylene oxide
WO2015086528A1 (en) * 2013-12-11 2015-06-18 Develco Pharma Schweiz Ag Naloxone mono-product and multi-layer tablet

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