WO2016203061A1

WO2016203061A1 - Reduction in deallylation of naloxone during storage of a sustained-release formulation containing naloxone

Info

Publication number: WO2016203061A1
Application number: PCT/EP2016/070719
Authority: WO
Inventors: Jiri Kubecek; Klaus Neuer; Andrea Andres
Original assignee: Acino Pharma Ag
Priority date: 2015-09-03
Filing date: 2016-09-02
Publication date: 2016-12-22
Also published as: DK201600098Y3; DE202016005375U1; AU2016101552A4; DK201600098U1

Abstract

The present invention relates to: a packaged drug comprising a pharmaceutical sustained-release formulation of naloxone or of a pharmaceutically acceptable salt thereof and a packaging; a method for producing a drug with high storage stability, the method comprising the packaging of a sustained-release formulation of naloxone or of a pharmaceutically acceptable salt thereof; the use of a packaging for stabilising the storage of a drug comprising a pharmaceutical sustained-release formulation of naloxone or of a pharmaceutically acceptable salt thereof; and also the use of a packaging for reducing the deallylation of naloxone or of the pharmaceutically acceptable salt thereof during the storage of a pharmaceutical sustained-release formulation of naloxone or of a pharmaceutically acceptable salt thereof.

Description

REDUCTION OF NALOXONE DEALLYLATION DURING THE STORAGE OF NALOXY-BASED RETARD FORMULATION

The present invention relates to a packaged pharmaceutical composition comprising a pharmaceutical sustained release formulation of naloxone or a pharmaceutically acceptable salt thereof and a package; a method for producing a storage stable drug, comprising packaging a sustained release formulation of naloxone or a pharmaceutically acceptable salt thereof; the use of a package for storage stabilization of a pharmaceutical composition comprising a pharmaceutical sustained-release formulation of naloxone or a pharmaceutically acceptable salt thereof; and the use of a package for reducing the deallylation of naloxone or the pharmaceutically acceptable acid thereof during storage of a sustained-release pharmaceutical formulation of naloxone or a pharmaceutically acceptable salt thereof.

Retarded formulations play a central role in the development of improved therapies, allowing the controlled and controlled release of the drug over a prolonged period of time (typically 2 to 24 hours). This reduces the frequency of taking the drug for the patient and increases the patient's compliance (compliance). By sustained-release formulations, the therapy may e.g. continue overnight without interrupting the patient's sleep. Another advantage of sustained-release formulations, especially in opioid analgesic therapy, is that they allow very uniform drug concentrations in the blood, resulting in reduced side effects and reducing the risk of addiction.

In the prior art, various measures are known that allow the formulation of a sustained release medicament form. These measures have in common that the active ingredients are processed with excipients to form bodies, such as tablets or dragees. The auxiliaries form a release or dissolution barrier for the active ingredient. Depending on the nature of the release barriers, different retardation methods can be distinguished. For example, there are osmotic systems, systems in which the retardation is effected by an enclosure, or systems in which the active ingredients are embedded, for example, in waxes, polymethacrylate, gelling agents or silicas. This is the so-called matrix form. The adjuvants used in the preparation of sustained-release formulations can lead to problems with drug stability during prolonged storage times. This problem may, for example, affect certain alkaloid-based drugs, including in particular some opioid agonists or opioid antagonists that are used in pain therapy. Opioid agonists are characterized in particular by an analgesic effect, while opioid antagonists are able to reduce or block the action or side effect (s) of the opioid agonists. In particular, the problem relates to delayed-release formulations of naloxone, an opioid antagonist customary in opioid analgesic therapy. Due to its antagonizing effect, naloxone is used in particular to prevent a parenteral, euphoric effect of the opioid and thus parenteral abuse of the opioid in combination preparations with opioids (see also US Pat. Nos. 3,773,955 and 3,966,940). In addition, naloxone can also be used to reduce side effects of opioids such as constipation (see also NP Sykes, "Oral naloxone in opioid-associated constipation ^" , The Lancet 1991, 337, p 1475 and AT Skarin, Cancer Pain Management; II ", Oncoiogy 2000, 5, pp. 1-12) The currently available tablets containing oxycodone hydrochloride and naloxone hydrochloride are available under the trademark Targin ©.

DE 102 15 131 A1 and DE 102 15 067 A1 relate to storage-stable, pharmaceutical oxycodone / naloxone formulations in a diffusion matrix. Herein, the problem of storage stability of the formulation is usually solved by using suitable amounts of ethytcellulose as the matrix-forming material, which result in formulations which can be stored on their own or per se! are.

Naloxone-containing pharmaceutical sustained-release formulations which do not comprise ethylcellulose, however, typically do not have any storage stability as per the formulations in DE 102 15 131 A1 and DE 102 15 067 A1.

For pharmaceutical sustained-release formulations of naloxone, which do not have per se storage stability such as the formulations in DE 102 15 131 A1 and DE 102 15 067 A1, there is thus a need to develop strategies to be able to store them under standard conditions, without the Change the release profile of the active ingredient from the sustained-release formulation or the active ingredient content as a result of the storage. In the context of the present invention, it has been found that when using a matrix-forming polymer or copolymer (for example a polymethacrylate, such as, for example, poly (ethylacrylate-co-methylmethacrylate-co-trimethylammonium-ethyl methacrylate chloride) in the preparation of a naloxone-containing pharmaceutical Sustained-release formulation, the naloxone is degraded during the subsequent storage of the sustained-release formulation per se under standard conditions, in particular extensively to noroxymorphone, which results from dealhalation naloxone.Naloxone degradation during storage could then surprisingly by a lower water content in the sustained-release formulation, achieved by a suitable packaging of the sustained release formulation Without being bound by theory, it is believed that the naloxone is deallylated to noroxymorphone, and that this degradation reaction requires the presence of water.

The problem of naloxone degradation in sustained-release formulations during storage is therefore achieved according to the invention by providing a packaged drug comprising a) a sustained-release pharmaceutical formulation, wherein the sustained-release pharmaceutical formulation comprises naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable delayed release naloxone or excipient the pharmaceutically acceptable salt thereof, and

b) a package, wherein the packaging is a blister pack comprising a mold film and a cover film, wherein mold film and cover independently have a water vapor permeability of <3.0 g / (m ² * d).

Alternatively, the problem is solved according to the invention by the provision of a packaged drug comprising a) a sustained-release pharmaceutical formulation, the sustained-release pharmaceutical formulation comprising naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable sustained-release excipient of the naloxone or pharmaceutically acceptable salt thereof; and

b) a packaging, wherein the packaging is a container with closure, wherein the container with closure comprises a desiccant. The problem is further solved according to the invention by a process for the preparation of a storage-stable drug, the process comprising packaging a sustained release pharmaceutical formulation, the naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for sustained release of the naloxone or the pharmaceutically acceptable salt thereof , in a blister pack comprising a mold film and a cover film, wherein mold film and cover independently have a water vapor permeability of <10.0 g / (m ² -d).

Alternatively, the problem is also solved according to the invention by a process for preparing a storage-stable drug, the process comprising packaging a sustained-release pharmaceutical formulation, the naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for sustained release of the naloxone or pharmaceutically acceptable salt thereof comprises, in a container with closure, wherein the container with closure comprises a drying agent.

The problem is also solved by the use of a package for storage stabilization of a pharmaceutical composition comprising a sustained-release pharmaceutical formulation comprising naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable sustained-release excipient of the naloxone or pharmaceutically acceptable salt thereof the packaging is a blister pack comprising a mold film and a cover film, wherein mold film and cover film independently have a water vapor permeability of 10.0 g / (m ² * d).

Alternatively, the problem is also solved according to the invention by the use of a package for storage stabilization of a pharmaceutical composition comprising a sustained-release pharmaceutical formulation comprising naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for delayed release of the naloxone or pharmaceutically acceptable salt thereof the packaging is a container with closure, the container with closure comprising a desiccant. Furthermore, the problem is solved according to the invention by the use of a

A package for reducing the deallylation of naloxone or a pharmaceutically acceptable salt thereof in a sustained-release pharmaceutical formulation comprising naloxone or the pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for sustained release of the naloxone or pharmaceutically acceptable salt thereof during storage thereof the packaging is a container with closure, the container with closure comprising a desiccant.

Further, the problem is also solved according to the invention by the use of a package for reducing the deallylation of naloxone or a pharmaceutically acceptable salt thereof in a sustained-release pharmaceutical formulation, the naloxone or the pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable sustained-release adjuvant of the naloxone or the like pharmaceutically acceptable salt thereof, during storage, wherein the packaging is a blister pack comprising a mold sheet and a cover sheet, the mold sheet and cover sheet independently having a water vapor permeability of <10.0 g / (m ^{2 *} d).

definitions

The term "pharmaceutical" as used in the present invention refers to a medicament suitable for administration In the context of the present invention, the medicament is a pharmaceutical sustained-release formulation. ,

The term "pharmaceutical" as used in the context of the present invention means that a therapeutic effect is produced which can be used in the treatment or prevention of a disease or resulting pain of a patient.

The term "active substance", as used in the context of the present invention, refers to the substance which causes a therapeutic effect which can be used in the treatment or prevention of a disease or the resulting pain Patients can be used. In the context of the present invention, the active ingredient, unless stated otherwise, is naloxone or a pharmaceutically acceptable salt thereof.

The term "formulation", as used in the context of the present invention, is understood to mean a dosage form of a pharmaceutically active substance, in particular of naloxone or a pharmaceutically acceptable salt thereof, with the aim of optimally coordinating application, distribution and To enable the unfolding of the active substance. The term "formulation unit", as used in the context of the present invention, denotes a single unit of the dosage form, for example a tablet.

By the term "sustained-release formulation" as used in the context of the present invention is meant a formulation which enables the pharmaceutically active agent, in the present case naloxone or a pharmaceutically acceptable salt thereof, to be administered after administration of the formulation over a formulation to release for immediate release longer period of time. A release of the active ingredient is preferred over a period of 2 to 24 hours, particularly preferably from 2 to 20 hours and more preferably from 2 to 16 hours or 2 to 12 hours. It is preferable to comply with the requirements of the legislator. In the context of the present invention, by "sustained-release formulation" is meant a solid dosage form for oral administration, i. a shaped body such as a tablet.

Release of the active ingredient over a longer period of time than in a formulation for immediate release of the active ingredient is also referred to herein as "sustained release" of the active ingredient allows the blood concentration, such as the bioplasma concentration, of the drug to be maintained within the therapeutically effective range, ie above the therapeutically effective minimum level but below toxic levels, using a period of twice daily or once daily administration of the sustained release formulation Preferably, twice daily administration of the sustained release formulation is used. The amount of active ingredient released from the sustained-release pharmaceutical formulation per

Time unit is also referred to as "release profile" or "release behavior". For this purpose, a period of from 2 to 24 hours, more preferably from 2 to 20 hours, and particularly preferably from 2 to 16 hours or 2 to 12 hours is preferably used. The measurement of the release profile is carried out as described below.

The term "storage stability" as used in the context of the present invention refers to the packaged drug, unless stated otherwise.To be "shelf-stable" within the meaning of the present invention, the drug must satisfy the following conditions i) and ii) cumulatively fulfill. i) Firstly, the active ingredient component of the sustained-release pharmaceutical formulation, in the present case naloxone or a pharmaceutically acceptable salt thereof, after storage of the drug, for at least two years immediately after its preparation under standard conditions (ie at room temperature (25 ° C) and 60% relative humidity) ) show a release profile as measured when measured immediately after preparation of the sustained-release formulation, ie without packaging the sustained-release formulation and without storage under standard conditions.

The permissible variations with regard to the release behavior are characterized in that the amount of active substance released per unit time is not more than ± 10%, preferably not more than ± 5%, based on the active ingredient content indicated in the instruction leaflet, of the immediately after the preparation of the For the measurement of the release profile, a period of 24 hours is preferred (see also Emea specification ICH Topic Q 6 A of May 2000). The release profile of the active ingredient is measured immediately after preparation of the sustained-release formulation, without packaging the sustained release formulation and without storage under standard conditions, and the times at which 20%, 50% and 80% of the active ingredient are released, based on the Ingredient Content (see also European Pharmacopeia, 5.17.1., Recommendations on Dissolution Testing). The measurement of the release profile is repeated after two years of storage of the drug under standard conditions. The deviations in those times when 20%, 50% and 80% of the active substance were released in the measurement directly after preparation of the sustained-release formulation must not exceed ± 10%, preferably not more than ± 5%. based on the drug content stated in the instruction leaflet. A release of, for example, 50% at a time X, for example after 10 hours, in the measurement of the release profile immediately after preparation of the sustained release formulation therefore means that in the measurement of the release profile after two years of storage of the drug release of 40 to 60% to this Time X, preferably a release of 45 to 55%, is tolerable, based on the active ingredient content indicated on the packaging.

The release profile of the active substance from the sustained-release formulation immediately after the preparation of the formulation and after two years of storage of the drug is determined during the averaging of 6 measurements. Methods for determining drug release are defined in the USP (American Pharmacopoeia) and in the European Pharmacopoeia. Preferably, the release of drugs from a sustained-release formulation is determined using a basket apparatus. The stirring speed is 100 rpm. The temperature of the test medium is 37 ° C. The test medium used is a phosphate buffer with a pH of 6.8. The volume of the test medium is 900 ml. Ii) In addition to requirement i), the active ingredient content of the sustained-release pharmaceutical formulation, in this case the naloxone or naloxone salt content of the sustained release formulation, after storage of the drug, for at least two years immediately after its production, under standard conditions (ie at room temperature (25 ° C) and 60% relative humidity) do not differ more than 5% from the initial active ingredient content immediately after preparation of the sustained-release formulation.

The active ingredient content of the sustained release pharmaceutical formulation is determined immediately after preparation of the formulation and after two years of storage of the drug under standard conditions in the course of each 6 measurements by averaging. For this purpose, the active ingredient, in this case naloxone or a pharmaceutically acceptable salt thereof, is extracted from the intact or crushed formulation with a suitable organic solvent, and the extract is analyzed quantitatively by means of liquid chromatography, for example HPLC with UV detection. A "storage-stable drug", as described in the context of the present invention, is therefore preferably a pharmaceutical sustained-release formulation for the storage stability in terms of the above definitions i) and ii) by using a package or by storing the sustained-release formulation in one

Packaging is achieved. Storage-stable pharmaceuticals according to the present invention show after removal of the packaging and immediate determination of the release profile according to i) and the active ingredient content according to ii) measured values which are within the limits defined in i) and ii).

In the context of the present invention, "sustained-release" pharmaceutical sustained-release formulations are understood as meaning sustained-release formulations which, on the basis of their composition, satisfy the above requirements i) and ii) cumulatively, such as, for example, those described in DE 102 15 131 A1 and DE 102 15 067 A1 per se storage-stable pharmaceutical sustained-release formulations satisfy the requirements i) and ii), even if they are not stored in a package as described in the present invention under standard conditions by the storage described in the context of the present invention pharmaceutical sustained-release formulation in a package no per se storage stability is achieved.

By "storage stabilization" of a drug according to the present invention, it is meant that the drug becomes more stable to storage by proper packaging and is determined for this purpose both for the unpacked and packaged drug immediately after the drug is made and after a certain storage period eg after two years, (i) the release profile of the active ingredient component of the sustained-release pharmaceutical formulation and (ii) the active ingredient content of the sustained-release pharmaceutical formulation Preferably, storage is under standard conditions {25 ° C, 60% relative humidity), for example for two years storage also at (a) 21 ° C, 45% relative humidity, (b) 30 ° C, 35% relative humidity, (c) 30 ° C, 65% relative humidity, (d) 30 ° C, 75% or (e) 40 ° C, 75% relative humidity, respectively, for example, for two years The release profile and the active substance content are always determined as described above for the term "storage stability". Storage stabilization of a drug by suitable packaging is given when (i) the release profile and / or (ii) the active ingredient content of the pharmaceutical Change the sustained release formulation by the storage of the packaged drug less than the unpackaged drug.

By "reducing" the dealiylation of naloxone or the pharmaceutically acceptable salt thereof in a sustained release formulation of the invention during storage by use of a package, it is meant that in the packaged sustained release formulation during its storage, eg, over two years, the dealiylation of naloxone or the pharmaceutically acceptable The storage is preferably carried out under standard conditions (25 ° C., 60% relative humidity), for example for two years, Alternatively, storage may also be carried out, for example, (a) 21 ° C., 45% relative atmospheric humidity; (b) 30 ° C, 35% relative humidity, (c) 30 ° C, 65% relative humidity, (d) 30 ° C, 75% relative humidity, or (e) 40 ° C, 75% relative humidity each for example for two years., For this purpose, the content of the naloxone (salt) - containing unpacked as well as packaged sustained-release formulation of noroxymorphone (salt), i. the degradation product of dealiylation, after storage.

To determine the content of the naloxone (salt) -containing pharmaceutical sustained release formulation of noroxymorphone (salt) in one aliquot, ie the amount of this degradation product _"a mixture of 20 zermörserten formulations contained in a suitable part of portion extracted with a suitable organic solvent, and Extract quantitatively analyzed by liquid chromatography, for example HPLC with UV detection.

The term "water vapor permeability", as used in the context of the present invention, denotes the basic permeability of a packaging for water vapor. The lower the water vapor permeability of a package, the less moisture is transferred from the environment to the interior of the package. The determination of the water vapor permeability is carried out according to DIN 53122-1 / DIN 53122-A or DIN 53122-2 / DIN53 22-2-A. For this purpose, a sample is used which preferably has a measuring surface of 100 cm ² and a defined thickness, for example 5 to 500 μm. A test container filled with desiccant is closed by the sample and exposed to a defined test environment. The amount of water permeating the sample is determined by weighing (method according to DIN 53122-1 / DIN 53122-A). Alternatively, the sample is placed in a permeation cell such that it blocks the barrier between two forms separate chambers. A tempered measuring chamber is rinsed with a carrier gas of defined air humidity. The permeating water through the sample is transported in the second chamber by means of a purge gas to the detector, where the concentration is determined, from which the water vapor permeability is calculated (method according to DIN 53122-2 / DIN53122-2-A). The determination of the water vapor permeability takes place depending on the expected permeability of the material.

The term "desiccant", as used in the context of the present invention, refers to chemical compounds that remove water. The water can be chemically bound, for example, by using water-pulling compounds is calcium chloride, or the drying can be carried out by adsorption, for example by using silica, molecular sieves or bentonite.

The term "ethyl cellulose-free" or "free of ethyl cellulose" as used in the context of the present invention means that the pharmaceutical sustained-release formulation of the present invention comprises substantially no ethyl cellulose. By this is meant that the sustained-release pharmaceutical formulation comprises less than 1% by weight of ethylcellulose.

The term "percent by weight" or "% by weight", as used in the context of the present invention, denotes the proportion by weight of a constituent of the sustained-release pharmaceutical formulation, based on the total weight of the formulation, unless otherwise stated or obvious under the given circumstances ,

The term "bioequivalent" or "bioequivalence" as used in the context of the present invention means that any differences in the area-of-the-curve (AUC) curve, Cmax (maximum plasma concentration) and (time of maximum Plasma concentration) of two drug-like drugs are sufficiently likely to be within the bioequivalence range. The drug-same medicines are test product (generic) and reference product (original product). Specifically, test product and reference product are considered to be bioequivalent if within a 95% confidence interval AUC, Cmax and tmax of the test product correspond to 80 to 125% of the reference product. Description of the pictures

Fig. 1 shows the release profile of oxycodone hydrochloride (OxyHCI) from a retard formulation according to the invention containing 40mg / 20mg oxycodone hydrochloride / naloxone hydrochloride (test product) compared to the release profile of

Oxycodone hydrochloride (OxyHCl) from the corresponding reference product Targin® containing 40 mg / 20 mg oxycodone hydrochloride / Naloxonhydrochlohd, each at pH 6.8 (Basket apparatus, stirring speed of 100 rpm).

FIG. 2 shows the release profile of naloxone hydrochloride (NalHCl) from a slow release formulation according to the invention containing 5 mg / 2.5 mg oxycodone hydrochloride / naloxone hydrochloride (test product) in comparison to the release profile of naloxone hydrochloride (NalHCl) from the corresponding reference product Targin® containing 5 mg / 2.5 mg oxycodone hydrochloride / Naloxone hydrochloride, each at pH 8.8 (Basket apparatus, stirring speed of 100 rpm).

Summary of the invention

The present invention relates to a

[1] packaged drug, comprising

a) a sustained-release pharmaceutical formulation, wherein the sustained-release pharmaceutical formulation comprises naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for sustained release of the naloxone or pharmaceutically acceptable salt thereof, and

b) a package, wherein the packaging is a blister pack comprising a mold film and a cover film, the mold film and cover film having independently of each other a water vapor permeability of <3.0 g / (m ² * d); one

[2] A packaged pharmaceutical product according to item [1], wherein the molding film is made of a material comprising at least one polymer or aluminum, and / or the covering film is made of a material comprising aluminum; one [3] packaged drug according to item [2], wherein the at least one polymer is selected from the group consisting of PVC, PVdC, PE, PET, PP and COC; one

[4] The packaged drug according to any of [1], [2] and [3], wherein the blister pack is a blister pack, a peel-off pack or a peel-through blister pack; one

[5] packaged drug, comprising

b) a package, wherein the package is a container with closure, the container with closure comprising a drying agent; one

[6] packaged drug according to item [5], wherein the container and the cap independently have a water vapor permeability of <10.0 g / (m ² * d); one

[7] The packaged drug according to any of [5] and [6], wherein the container and the closure independently consist of a material selected from the group consisting of LDPE, HOPE, PVC, PVdC, PP, polycarbonate, COC and PET is selected; one

[8] The packaged drug according to any of [5], [6] and [7], wherein the desiccant is selected from the group consisting of sodium sulfate, silica, molecular sieves (zeolites), alumina, calcium chloride, calcium oxide, potassium carbonate, copper sulfate, magnesium sulfate, Magnesium oxide, bentonite or a mixture thereof; one

[9] The packaged drug according to any of [5], [6], [7] and [8], wherein the desiccant is in the closure of the container; one

[10] The packaged drug of any one of the preceding items, wherein the sustained-release pharmaceutical formulation is free of ethylcellulose; one [1 1] A packaged pharmaceutical preparation according to any preceding item, wherein the sustained-release pharmaceutical formulation comprises polymethacrylate, preferably cationic polymethacrylate; one

[12] packaged drugs! according to any one of the preceding items, wherein the sustained-release pharmaceutical formulation is matrix-based and / or surrounded by a hydrophobic, film-forming sheath; one

[13] The packaged drug of any of the preceding items, wherein the sustained-release pharmaceutical formulation is matrix-based and comprises at least one matrix-forming material as a pharmaceutically acceptable excipient, wherein the at least one matrix-forming material is a polymethacrylate, preferably a cationic Polymethacrylate, and wherein preferably further at least one fatty alcohol, for example stearyl alcohol, is included; one

[14] packaged drugs! according to item [13], wherein the pharmaceutical sustained-release formulation comprises at least one polymethacrylate and at least one fatty alcohol in a weight ratio of 1: 3 to 1: 4 (polymethacrylate to fatty alcohol); one

[15] packaged pharmaceutical product according to any of [13] and [14], wherein in the pharmaceutical sustained-release formulation the weight fraction of the sum of polymethacrylate and fatty alcohol is from 25 to 40% by weight, preferably from 30 to 35% by weight, in each case on the total weight of the sustained-release formulation; one

[16] The packaged drug of any preceding item, wherein the sustained-release pharmaceutical formulation comprises at least one opioid agonist; one

[17] packaged drug according to item [16], wherein the opioid agonist is oxycodone or a pharmaceutically acceptable salt thereof, oxycodone preferably being present as base or as hydrochloride, in particular as hydrochloride; one

[18] packaged drug according to item [17] for the treatment of moderate to severe pain; one [19] A packaged pharmaceutical preparation according to any preceding item, wherein the sustained-release pharmaceutical formulation further comprises fillers, carrier materials, binders,

Granulating agents, lubricants, lubricants, dyes, plasticizers, preservatives, release agents and / or flavoring agents; one

[20] A packaged pharmaceutical preparation according to any preceding item, wherein the sustained-release pharmaceutical formulation is present as a (multi-layer) tablet, dragee, capsule, granule or powder, and

[21] A packaged pharmaceutical preparation according to any one of the preceding points, wherein the pharmaceutical sustained-release formulation without the packaging is not storage-stable.

The invention further relates to a

[22] A method of making a storage stable drug, the method comprising packaging a pharmaceutical sustained release formulation as defined in item [21] into a blister pack comprising a forming sheet and a cover sheet, wherein the forming sheet and cover sheet independently have a water vapor permeability of <10.0 g / (m ² * d); and a

[23] A method of making a storage stable drug, the method comprising packaging a pharmaceutical sustained release formulation as defined in item [21] into a container with closure, wherein the container with closure comprises a desiccant.

Accordingly, in a further aspect, the present invention relates to a process for the preparation of a storage-stable drug comprising a sustained release pharmaceutical formulation containing naloxone or a pharmaceutically acceptable salt thereof by means of packaging. The packaging serves to protect the sustained release formulation from moisture. Due to the protection against moisture, it is thus possible to produce a storage-stable drug despite the omission of ethylcellulose. The invention further relates to

[24] Use of a storage stabilization package of a pharmaceutical composition, the pharmaceutical composition comprising a sustained-release pharmaceutical formulation as defined in any of [1] to [21], and the package is a blister package comprising a forming sheet and a cover sheet , wherein mold film and cover independently have a water vapor permeability of <10.0 g / (m ² -d); and the

[25] Use of a package for storage stabilization of a pharmaceutical composition, the pharmaceutical composition comprising a pharmaceutical sustained-release formulation as defined in any of [1] to [21], and the packaging is a container with closure, the container having closure a desiccant.

Accordingly, in a further aspect, the present invention relates to the use of a storage stabilization package of a pharmaceutical composition comprising a sustained-release pharmaceutical formulation containing naloxone or a pharmaceutically acceptable salt thereof. The packaging serves to protect the sustained release formulation from moisture and thus stabilize it against storage.

The invention further relates to

[26] Use of a package for reducing the deallylation of naloxone or the pharmaceutically acceptable salt thereof in a pharmaceutical sustained-release formulation as defined in any one of items [1] to [21] during storage, the package being a container with closure wherein the container with closure comprises a desiccant; the

[27] Use of a package for reducing the deallylation of naloxone or the pharmaceutically acceptable salt thereof in a pharmaceutical sustained-release formulation as defined in any of [1] to [21] during storage, the package being a blister package a molding film and a cover film is, wherein mold film and cover independently have a water vapor permeability of <10.0 g / (m ^{2 *} d); the [28] Use according to any one of [26] and [27], wherein the pharmaceutical sustained release formulation comprises polymethacrylate, preferably cationic polymethacrylate, more preferably cationic copolymer of ethyl acrylate, methyl methacrylate and methacrylic acid ester with quaternary ammonium group, in particular poly (ethylacry! At-co-methylmethacrylate) co-trimethylammonium ethyl methacrylate salt), such as poly (ethyl acrylate-co-methylmethacrylate-co-trimethyl ammonium ethylmethacrylate chloride); and the

[29] Use according to item [28], wherein the weight ratio of ethyl acrylate, methyl methacrylate and methacrylic acid ester with quaternary ammonium group is 1: 2: 0.2 or 1: 2: 0.1.

In a further aspect, the present invention therefore relates to the use of a package for reducing the deallylation of naloxone or the pharmaceutically acceptable salt thereof in a sustained release pharmaceutical formulation containing naloxone or a pharmaceutically acceptable salt thereof during storage.

The invention will be described in detail below.

Detailed description

Packaged medicine

In the context of the present invention, it has been found that the storage of a sustained-release pharmaceutical formulation as described in the present invention in a package as described in the context of the present invention, the storage of a pharmaceutical sustained-release formulation of naloxone or a pharmaceutically acceptable salt thereof, eg for at least two years under standard conditions, without altering the release profile of the active ingredient and / or the active ingredient content of the sustained-release pharmaceutical formulation. Pharmaceutical sustained-release formulation and packaging, as described in the context of the present invention, together form the packaged medicament according to the invention which is storage-stable within the meaning of the definitions i) and ii) above. Preferably, the sustained-release pharmaceutical formulations of the present invention are non-per se storage-stable sustained-release formulations, ie sustained release formulations which do not per se satisfy the above definitions i) and ii) for storage stability in at least one point per se, ie on the basis of their composition. Due to the action of water, water vapor or moisture in general, these sustained release formulations without packaging are not storage stable, so that when storing the sustained release formulation without packaging under standard conditions, the active ingredient content in the formulation is reduced by chemical degradation of the active ingredient and / or the release profile of the active ingredient from the Retard formulation changed.

By storing the pharmaceutical sustained-release formulation described in the context of the present invention in a package, as described in the present invention, the storage of the formulation is allowed under standard conditions, without the release behavior of the active ingredient and / or the active ingredient content of the formulation in the above Definitions i) and ii) exceeds specified limits. Storage of the sustained-release pharmaceutical formulation in a package as described in the context of the present invention thus makes it possible to provide a storage-stable pharmaceutical according to the invention. Without the packaging, the pharmaceutical sustained-release formulation described in the context of the present invention is preferably not storage-stable.

The sustained-release pharmaceutical formulation of the present invention comprises naloxone or a pharmaceutically acceptable salt thereof as a pharmaceutically active agent. The naloxone can be used in the form of the free base or as a pharmaceutically acceptable salt, for example as the hydrochloride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, phosphate, malate, maleate, hydrobromide, hydroiodide, fumarate and succinate In the present invention, the hydrochloride of naloxone is preferred. Naioxone hydrochloride is usually used in the form of naloxone hydrochloride dihydrate. However, amounts with respect to Naioxonhydrochlorid in the present invention always refer to the anhydrous form, the same applies to any other active ingredients.

Naloxone or the pharmaceutically acceptable salt thereof is preferably used in an amount of from 1 to 50% by weight, based on the total weight of the formulation, in the pharmaceutical sustained-release formulation of the present invention. Particularly preferred is an amount of 1 to 20 weight percent, and more preferably an amount of 2 to 10 weight percent, each based on the total weight of the sustained release formulation included.

The pharmaceutical sustained-release formulation of the present invention preferably contains

1 mg to 100 mg, more preferably 1 mg to 25 mg, naloxone or a pharmaceutically acceptable salt thereof, for example naloxone hydrochloride. Particularly preferred single doses are 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and 20 mg.

The sustained-release pharmaceutical formulation as described in the present invention comprises for sustained release of the naloxone or the pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable excipient which affects the release profile of the naloxone or pharmaceutically acceptable salt thereof. The at least one pharmaceutically acceptable excipient is thus a material which permits or permits sustained release of the active substance in an aqueous medium.

The sustained-release excipients in question are conventional adjuvants commonly used in the field of sustained-release medicaments, for example hydrophilic and hydrophobic polymers such as gums, cellulose ethers, acrylic resins, polymethacrylates, polyvinyl acetate and protein derivatives; substituted and unsubstituted fatty acids, fatty alcohols, glycerol esters of fatty acids, mineral oils, vegetable oils, waxes; and polyalkylene glycols.

In the context of the present invention, preference is given to those auxiliaries which do not lead to a per se storage-stable pharmaceutical sustained-release formulation, as described in DE 102 15 131 A1 and DE 102 15 067. Particularly preferred as pharmaceutically acceptable excipients for sustained release are Poiymethacrylate, polyvinyl acetate and water-swellable materials such as Hydroxyalkylceilulosederivate, for example HPMC. Pharmaceutical sustained-release formulations in the sense of the present invention which comprise polymethacrylates or water-swellable materials as pharmaceutically acceptable auxiliaries are not per se storage-stable, ie they are not storage-stable on account of their composition, and can can not be stored without packaging under standard conditions without changing the release profile of the active substance and / or the active substance content of the formulation.

Preferably, the sustained-release pharmaceutical formulation of the present invention is free of ethylcellulose. In another preferred embodiment, the sustained-release pharmaceutical formulation of the present invention contains less than 0.1% by weight of ethylcellulose, e.g. 0% by weight of ethylcellulose.

In particular, as pharmaceutically acceptable excipients preferred in the context of the present invention are polymethacrylates. The polymethacrylates may be neutral or cationic polymethacrylates. Also preferred is polyvinyl acetate.

The neutral poly-methacrylates are preferably neutral copolymers of ethyl acrylate and methyl methacrylate (poly (ethyl acrylate-co-methyl methacrylate)), the weight ratio of ethyl acrylate and yethyl methacrylate preferably being 2: 1. The molecular weight of the neutral polymethacrylates is preferably between 500,000 g / mol and 1,000,000 g / mol, in particular between 600,000 g / mol and 750,000 g / mol.

Particular preference is given to using neutral polymethacrylates as aqueous dispersions Eudragit® NE 30D, Eudragit® NE 40D and Eudragit® NM 30D, which are commercially available from Evonik Industries.

The cationic polymethacrylates are preferably cationic copolymers of ethyl acrylate, methyl methacrylate and methacrylic acid esters having a quaternary ammonium group, for example poly (ethyl acrylate-co-methyl methacrylate-co-trimethyl ammonium ethyl methacrylate salts), in particular poly (ethyl acrylate-co-methyl methacrylate -co-trimethylammoniumethyl methacrylate chloride), wherein the weight ratio of ethyl acrylate, methyl methacrylate and methacrylic acid ester with quaternary ammonium group is preferably 1: 2: 0.2 or 1: 2: 0.1. The molecular weight of the cationic polymethacrylates is preferably between 20,000 g / mol and 50,000 g / mol, in particular between 25,000 g / mol and 40,000 g / mol. Particular preference is given to using cationic polymethacrylates as aqueous dispersions Eudragit® RS 30D and Eudragit® RL 30D, which are commercially available from Evonik Industries.

The sustained-release formulation as described in the present invention may contain from 1 to 80% by weight, based on the total weight of the formulation, of the at least one pharmaceutically acceptable sustained release excipient. Preference is given to 10 to 50 weight percent and particularly preferred are 20 to 40 weight percent of the at least one pharmaceutically acceptable excipient, each based on the total weight of the sustained release formulation.

Preferably, the pharmaceutical sustained-release formulation of the present invention does not contain a gelatin capsule.

In addition to the type and weight fraction of drug release delaying, i. releasing agents in the sustained-release formulation, the release profile of the active substance contained therein or of the active substances contained therein can be controlled, in particular, by the use of water-soluble release-non-retarding inert materials. Without being bound by theory, it is believed that due to the presence of such materials in the sustained release formulation, after placement of the sustained release formulation in an aqueous phase, such as e.g. Gastric juice form pores, which lead to an acceleration of the release of the active ingredient or the active ingredients. Preferably, this material is lactose or lactose monohydrate.

The packaging for storing the pharmaceutical sustained-release formulation described in the context of the present invention is, on the one hand, a blister pack comprising a shaped film and a cover film, wherein the molded film and cover film independently have a water vapor permeability of <3.0 g / (m ² J) ,

The molding film is a packaging component which accommodates the drug, in this case the pharmaceutical sustained-release formulation, in chambers.

The material of the molding film preferably comprises at least one polymer (polymer-based molding film). The polymer is preferably a polymer film. As polymer materials or Polymeric film materials are in particular PVC (polyvinyl chloride), PVdC (polyvinyl chloride), PE (polyethylene), PET (polyethylene terephthalate), PP (polypropylene) and COC (cycloolefin copolymers) in question. Such polymer-based mold films can be obtained by thermoforming.

The molding film may consist of several layers of polymer films. Particularly preferred are polymer films comprising layers of PVdC and PVC. Such polymer films are commercially available under the designation "Duplex ™." Also particularly preferred are polymer films comprising layers of PVC, PE and PVdC. Such polymer films are commercially available under the name "Triplex ™".

The thickness of the polymer-based molding film is preferably between 5 and 500 μιτι, more preferably between 10 and 400 pm, more preferably between 20 and 300 pm.

As an alternative to the polymer-based molding film as described above, the material of the molding film may also include aluminum (aluminum-based molding film), and an aluminum molding film may be obtained by cold-forming aluminum. The aluminum is preferably aluminum foil. The thickness of the aluminum-based shaped film is preferably between 5 and 500 μm, particularly preferably between 10 and 400 μm, particularly preferably between 20 and 300 μm.

The water vapor permeability of the molded film is preferably: 2.5 g / (m ² -d),

<2.0 g / (m ² -d), <1.5 g / (m ² * d), more preferably <1.0 g / (m ² -d), <0.9 g / (m ² J),

<0.8 g / (m -d), <0.7 g / (m ² "d), <0.8 g / (m ² -d), <0.5 g / (m ² -d), <0.4 g / ( m ² -d), <0.3 g / (m ² -d),

<0.2 g / (m ² -d), and more preferably <0.1 g / (m ² -d), said water vapor permeabilities being applicable to both polymer-based and aluminum-based molded films, and in the case of the polymer-based shaped films, the number of layers and the thickness of the material and, in the case of the aluminum-based shaped film, the thickness of the material.

The cover material is a support material which is connected to the molding film by means of a sealing agent, for example a heat-sealable lacquer, and closes the chambers of the molding film. The cover material is preferably made of a material that includes aluminum. The thickness of the cover material is preferably between 5 and 300 μm, particularly preferably between 10 and 200 μm, in particular preferably between 20 and 100 μm.

The water vapor permeability of the cover material is preferably 2.5 2.5 g / (m ² * d),

<2.0 g / (m ² -d), <1.5 g / (m ² -d), particularly preferably <1.0 g / (m ² -d), <0.9 g / (m ² -d),

<0.8 g / (m ² -d), <0.7 g / (m ² -d), <0.6 g / (m ² -d), <0.5 g / (m ² -d), <0.4 g / (m ² .d), <0.3 g / (m ² -d),

<0.2 g / (m ² -d), and particularly preferably s 0.1 g / (m ² -d), and is influenced by the thickness of the material and the material components.

The water vapor permeabilities of the molding film and the covering material are therefore independently of one another preferably <2.5 g / (m ² -d), 2.0 g / (m ² * d), <1.5 g / (m ² -d), particularly preferably <1.0 g / (m ² -d), <0.9 g / (m ² -d), <0.8 g / (m ^? -d), <0.7 g / (m ² -d),

<0.6 g / (m ² "d), <0.5 g / (m ² -d), <0.4 g / (m ² -d), <0.3 g / (m ² -d), <0.2 g / {m ^2- d), and particularly preferably s 0.1 g / (m ² * d).

The blister pack described within the scope of the present invention is preferably a blister pack, a peel-off pack or a peel-through blister pack.

The blister pack comprises a molding film having at least one chamber in which a formulation unit of the pharmaceutical sustained-release formulation described in the context of the present invention, for example a tablet, is stored. The chamber is closed by the cover material. The formulation unit may be forced through the cover material by the application of pressure to the chamber and thus exposed for administration.

For example, the mold film of a blister pack may comprise one or more polymer films, for example, PVdC and PVC. The cover material of the blister pack consists for example of aluminum foil. Alternatively, the mold film of the blister pack may be made of aluminum and the aluminum foil cover material ("AI / Al blister pack").

The peel-off package comprises a forming film having at least one chamber in which a formulation unit of those described in the context of the present invention pharmaceutical sustained-release formulation, for example a tablet stores. The chamber is closed by the cover material, which is removable in this case. By stripping the cover material, the formulation unit is exposed for administration.

For example, the mold film of the peel-off package is either aluminum or at least one polymeric film, such as a Duplex ™ or Triplex ™ film. The mold film of the peel-off pack preferably consists of aluminum. The cover material of the peel-off pack is, for example, a polyester-aluminum laminate which can be removed by peeling. The peel-off film may additionally include an outer layer of paper which is attached to the PET film by means of an adhesive, such as polyurethane-based.

The peel-through blister pack comprises a shaped film having at least one chamber in which a formulation unit of the pharmaceutical sustained-release formulation described in the context of the present invention, for example a tablet, is stored. The chamber is closed by the cover material. The cover material comprises at least two layers of different materials, wherein one of the at least two layers can be removed by peeling, and the formulation unit can be exposed by the remaining layers by squeezing for administration.

In addition to protecting the sustained release formulation from moisture, the peel-off blister pack has the advantage of hampering access to the sustained release formulation, thus providing protection against unauthorized access by, for example, children.

The mold film of the peel-off blister pack may be made of, for example, aluminum or at least one polymer film, for example a Duplex ™ or Triplex ™ film. The mold film of the peel-off blister pack is preferably made of aluminum. The cover material of the peel-off pack preferably comprises several layers. The outer layer may be a paper layer which is attached by means of an adhesive, for example a polyurethane-based adhesive, on a film layer, for example made of PET. The film layer is applied by means of an adhesive, for example based on polyurethane, on an aluminum layer, for example of aluminum foil, which represents the innermost layer and is connected to the molding film by means of a sealing agent. The formulation unit, for example in the form of a Tablet, can be pushed through the aluminum layer after the peelable layers have been removed. In the context of the present invention, the preferred blister packaging is an aluminum-aluminum blister pack, since this offers particularly high protection against moisture.

Also particularly preferred as a blister pack is a peel-through blister pack in which the mold sheet is made of aluminum and the cover material is a multilayer system, the outer sheet being a paper layer attached to a PET film layer by means of a polyurethane-based adhesive. The PET film layer is attached by means of an adhesive, for example based on polyurethane, on an aluminum layer, for example aluminum foil, which represents the innermost layer. The formulation unit, for example in the form of a tablet, may be forced through the aluminum layer after the peelable layers have been removed. Such a peel-through blister allows a particularly low water vapor permeability and additionally protects the sustained-release formulation against unauthorized access, for example by children.

The blister packs described within the scope of the present invention preferably comprise 5 to 20 chambers, in each of which a formulation unit, for example in the form of a (multi-layer) tablet, a dragee, a capsule, a granule or a powder stores. For example, the blister pack 6, 7, 8, 10, 12, 14, 16, 18 or 20 chambers, in particular 10 or 14 chambers, especially 10 chambers.

As an alternative to the blister pack, the package for storing the pharmaceutical sustained-release formulation described in the context of the present invention is a container with closure, wherein the container with closure comprises a desiccant.

The desiccant is selected from the group consisting of sodium sulfate, silica, molecular sieves (zeolites), alumina, calcium chloride, calcium oxide, potassium carbonate,

Copper sulfate, magnesium sulfate, magnesium oxide, bentonite or a mixture thereof. Particularly preferred as a drying agent is silica. The desiccant causes the container to be opened and closed several times without destabilizing the retard formulation therein, for example in the form of a tablet, by absorbing water, water vapor or moisture in general.

The desiccant is preferably in the closure of the container. For this purpose, the closure preferably comprises a device for receiving the drying agent.

The closure of the container preferably contains 100 mg to 5 g of the desiccant, more preferably 500 mg to 3 g, even more preferably 1 g to 2.5 g and especially 2 g of the desiccant.

The container and the closure, as described in the context of the present invention, independently of each other, preferably have a water vapor permeability of: s 10.0 g / (m ² -d). Particularly preferred is a water vapor permeability of

<7.0 g / (m ² ^* d), <5.0 g / (m ² * d), <3.0 g / (m ² -d), <2.0 g / (m ² -d), <1.5 g / (m ² - d), <1.0 g / (m ² -d), <0.9 g / (m ² -d), <0.8 g / (m ² -d), <0.7 g / (m ² -d), <0.6 g / (m ² -d), <0.5 g / (m ² * d), <0.4 g / (m ² -d),

<0.3 g / (m ^{2 "} d), s 0.2 g / (m ² * d), and particularly preferred is a water vapor permeability of <0.1 g / {m -d), each independently for container and closure. The water vapor permeability of the container and the closure is influenced by the material of the container and the closure.

The container is preferably made of a material comprising low density polyethylene (LOPE), high density polyethylene (HOPE), polyvinylchloride (PVDC), polyvinyldichloride (PVdC), polypropylene (PP), Polycarbonate, PET (polyethylene terephthalate) or a mixture thereof. Particularly preferred is a container made of HOPE.

The container is, for example, a can or a bottle. This preferably contains 10 to 100 formulation units, for example in the form of a tablet. Preferably, it includes 10, 14, 20, 28, 30, 50, 56, 60, 98 or 100 formulation units. Preference is given to a bottle which can be used in particular for the storage of (multi-layer) tablets, dragees or capsules of the slow-release formulation described in the context of the present invention. The closure of the container is used to open and close the container several times. It can be designed as a rotatable or hinged closure. It is preferably a (ab) rotatable closure.

The closure is also made of a material comprising LDPE, HOPE, PVC, PVDC, PP, polycarbonate, PET or a mixture thereof. Especially preferred is a HOPE closure.

The container and closure are therefore independently of each other made of a material comprising LDPE, HOPE, PVC, PVDC, PP, polycarbonate, PET or a mixture thereof.

The pharmaceutical sustained-release formulation as described in the context of the present invention is preferably matrix-based and / or surrounded by a hydrophobic, film-forming sheath.

Particularly preferred is a matrix-based sustained-release formulation comprising at least one matrix-forming material as a pharmaceutically acceptable excipient which effects sustained release of the naloxone or the pharmaceutically acceptable naloxone salt.

Suitable matrix-forming materials are those commonly used in the field of matrix-based sustained-release formulations, ie hydrophilic and hydrophobic polymers, such as gum, alkylcellulose, hydroxyalkylcelluloses, cellulose ethers, acrylic resins, polymethacrylates, and protein derivatives; substituted and unsubstituted fatty acids, glycerol esters of fatty acids, mineral oil, vegetable oils, waxes; and polyalkylene glycols, for example polyvinylpyrrolidone; Hydroxyceliuloses such as hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, hydroxymethylcellulose, poly (vinyl) alcohols, polyvinylacetate, alginates, hydrogenated hydroxyalkylcellulose and hydroxypropylmethylcellulose ethers; Acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate copolymers, cyanoethyl methacrylates, aminoalkyl methacrylate copolymers,

Poly (acrylic acids), poly (methacrylic acids), polymethacrylates, poly (methyl methacrylate) copolymers, polyacrylamines or alginic acid; Ethylcellulose, propylcellulose; Fatty alcohols, such as lauryl, myristyl, stearyl, cetylstearyl, ceryl and / or Cetialkohole, in particular Stearyiaikohol.

Particular preference is given in the context of the present invention to those matrix-forming materials which do not lead to a per se storage-stable sustained-release formulation of naloxone or a pharmaceutically acceptable salt thereof, as described in DE 102 15 131 A1 and DE 102 15 067 A1.

Preferably, the sustained-release pharmaceutical formulation of the present invention is a matrix-based sustained-release formulation that is free of ethyl cellulose.

Particular preference is given to a matrix-based sustained-release formulation comprising as matrix-forming material at least one polymethacrylate and at least one fatty alcohol, wherein the polymethacrylate is preferably a cationic polymethacrylate and / or the fatty alcohol is preferably steary-alcohol. Inter alia, by suitably adjusting the proportions of the matrix-forming materials, the release of naloxone or the pharmaceutically acceptable salt thereof from the matrix can be controlled in a targeted manner. Polymethacrylate and the fatty alcohol are preferably included in a weight ratio of 1: 3 to 1: 4 (polymethacrylate to fatty alcohol). Particularly preferred is a weight ratio of polymethacrylate to fatty alcohol of 1: 3.3 to 1: 3.9. It has been found that, with such a weight ratio of polymethacrylate to fatty alcohol, formulations which are suitable for once or twice daily administration can be prepared particularly well.

The polymethacrylate, which is preferably a cationic polymethacrylate, is preferably contained in an amount of from 4.0 to 10.0% by weight, based on the total weight of the formulation. The fatty alcohol, which is preferably steary alcohol, is preferably contained in an amount of from 12.0 to 40.0% by weight, based on the total weight of the formulation.

It has been found that with a weight proportion of the sum of polymethacrylate and fatty alcohol of from 25 to 40% by weight, preferably from 30 to 35% by weight, based in each case on the total weight of the formulation, it is particularly possible to prepare formulations which are suitable for once or twice daily administration. Preferably, for this purpose are the polymethacrylate and the fatty alcohol! in a weight ratio of 1: 3 to 1: 4 (polymethacrylate to fatty alcohol), in particular from 1: 3.3 to 1: 3.9, before.

In a sustained-release formulation, the weight fraction of the naloxone or pharmaceutically acceptable salt thereof used, e.g. Naloxone hydrochloride, and / or the proportion by weight of any further active ingredient used in the sustained release formulation, such as e.g. Oxycodone or a pharmaceutically acceptable salt thereof, e.g. Oxycodone hydrochloride, reduced, so a comparable release profile of the drug or the active ingredients at different pH levels, especially at pH <7, in particular by using a suitable amount of a water-soluble release non-retarding inert material such. Lactose or lactose monohydrate can be achieved. Without wishing to be bound by theory, it is believed that the pore formation reduced by the lower active ingredient use with the addition of acidic medium to the sustained-release formulation which affects release is further enhanced by additional pore formation due to said inert material, e.g. Lactose or lactose monohydrate can be compensated. By a comparable release profile of the active substance (s) is meant in particular that the release profiles, measured as cumulative percentage release of active ingredient, at different proportions by weight of active ingredient by not more than 20 absolute% (percentage points), preferably by not more than 15 absolute. %, more preferably not more than 10 absolute%, and especially not more than 5 absolute%. The release profiles are determined by averaging 6 measurements. Methods for determining drug release are defined in the USP (American Pharmacopoeia) and in the European Pharmacopoeia. Preferably, the release is determined using a basket apparatus. The stirring speed is 100 rpm. The temperature of the test medium is 37 ° C. As the test medium, e.g. a phosphate buffer with a pH of 6.8 can be used. The volume of the test medium is 900 ml.

Preferably, the amount of inert material used as described above, such as lactose or lactose monohydrate, based on the anhydrous form, is at least 50% by weight of the drug reduction, more preferably 55 to 100%, even more preferably 60 to 90% .-%, in particular 65 to 80 wt .-% of the drug reduction. Becomes For example, in a sustained-release formulation, the amount of naloxone hydrochloride used is reduced from 20 mg to 5 mg, so 50% by weight of the active ingredient reduction corresponds to 7.5 mg.

Alternatively or additionally to the use of an inert material as described above, release curves comparable to active substance reduction can be used at different pH values, in particular at pH <7, for example by (a) suitable adaptation of the weight fraction of retarding excipient in the sustained-release formulation, and / or (b) , provided as a retarding excipient, a mixture is used, for example from Poymethacrylat and fatty alcohol, suitable adjustment of the weight ratio of the retarding excipients in the sustained release formulation can be achieved.

Further, in drug reduction in the sustained-release formulation, further filler may be incorporated to approximate the original weight of the sustained-release formulation, i. to achieve the weight before drug reduction.

In the present case, a non-per se iager-stable sustained-release formulation comprising naloxone or a pharmaceutically acceptable salt thereof, in particular with polymethacrylates and

Fatty alcohols formed as matrix-forming materials. Pharmaceutical sustained-release formulations according to the present invention which contain polymethacrylates and / or fatty alcohols as matrix-forming materials do not fulfill the above definitions for storage stability per se, i. due to their composition,

The matrix-based sustained-release formulation according to the present invention can be obtained by conventional methods for preparing matrix-based sustained-release formulations, for example by melting the naloxone or the pharmaceutically acceptable Naioxon salt by melting, spray staring, spray-drying, granulating, direct tableting and / or extruding into the matrix. forming material is embedded.

Preferred is a method comprising the following steps; Formulation of granules of naloxone or a pharmaceutically acceptable salt thereof, the matrix-forming material and other pharmaceutically acceptable excipients, for example by spray granulation, mixing the resulting granules with other pharmaceutically acceptable excipients as described below, and, optionally, drying and Pressing the granules. The granules are preferably formed by spray granulation with subsequent drying,

Alternatively, the preparation of the matrix-based sustained release formulation may be by extrusion, which is a cost effective and efficient alternative to granulation.

The pharmaceutical sustained-release formulation described in the context of the present invention can comprise, alternatively or in addition to the matrix form, a hydrophobic film-forming sheath which influences or delays the release of the naloxone or the pharmaceutically acceptable naloxone salt.

This aspect becomes particularly relevant when naloxone or the pharmaceutically acceptable salt thereof is provided in spheroids. Such spheroids typically have a diameter of 0.5 mm to 2.5 mm and preferably a diameter of 0.5 mm and 2 mm. The spheroids include a material capable of being formed into spheroids together with the naloxone or a pharmaceutically acceptable salt thereof. Preference is given to microcrystalline cellulose.

The spheroids comprise a hydrophobic film-forming sheath comprising a pharmaceutically acceptable excipient capable of retarding the release of the naloxone or the pharmaceutically acceptable naloxone salt. Suitable materials for this are generally water-insoluble materials, such as waxes, fatty alcohols, shellac, zein, water-insoluble cellulose, in particular ethylcellulose, or polymethacrylates, in particular Eudragit® polymethacrylates as described above, in question. The hydrophobic film-forming casing comprises at least one of the above-described water-insoluble materials and, in addition to influencing the release profile of the active ingredient, may also contain water-soluble materials, for example polyvinylpyrrolidone or hydroxypropylcellulose. Preferred within the scope of the present invention is a casing which comprises auxiliaries which do not lead to a storage-release formulation per se.

Preferably, the sustained-release formulation described in the context of the present invention is in the form of a matrix. In a preferred embodiment of the present invention, the sustained-release pharmaceutical formulation further comprises at least one opioid agonist and / or another opioid antagonist as pharmaceutically active ingredient,

In the context of the present invention, opioid agonists are all substances which belong to the class NO2A of the opioid analgesics according to the ATC classification of the WHO and which develop an analgesic effect after appropriate application. By opioid antagonists are meant substances which counteract the opioid agonists. Such substances can also be found in the WHO ATC classification.

The candidate opioid agonists are preferably morphine, oxycodone, hydromorphone, propoxyphene, nicomorphine, dihydrocodeine, diamorphine, papaveretum, codeine, ethylmorphine, phenylpiperidine and derivatives thereof, methadone, dextropropoxyphene, buprenorphine, pentazocine, tilidine, tramadol, Hydrocodone, dihydrocodeine, oxymorphone, fentanyl or sufentanyl or pharmaceutically acceptable salts thereof. Most preferably, the opioid agonist is oxycodone, hydrocodone, hydromorphone, morphine, codeine, dihydrocodeine, methadone, oxymorphone, fentanyl and sufentanyl or pharmaceutically acceptable salts thereof. Particularly preferred as the opioid agonist is oxycodone or a pharmaceutically acceptable salt thereof. Oxycodone is preferably present as base or as hydrochloride, in particular as hydrochloride.

The other candidate opioid antagonists are preferably naltrexone, nalmefene, Naiorphin, Nalbuphin, Naloxonazines, Methylnaltrexone, Ketylcyclazocin, Norbinaltorphimin, Naltrindol, 6-.beta.-naloxol, 6-.beta.-naltrexol or pharmaceutically acceptable salts thereof. Particularly preferred are naltrexone and nalmefene or pharmaceutically acceptable salts thereof as opioid antagonists.

Particularly preferred is an embodiment in which the sustained-release pharmaceutical formulation of the present invention further comprises at least one opioid agonist, wherein the opioid agonist is preferably oxycodone or a pharmaceutically acceptable salt thereof, in particular oxycodone hydrochloride. Such sustained-release formulations are preferably used to treat moderate to severe pain. Especially preferred is an embodiment in which the sustained-release pharmaceutical formulation (i) contains naloxone base and oxycodone base or (ii) contains naloxone hydrochloride and oxycodone hydrochloride. The weight ratio of oxycodone base to naloxone base or oxycodone hydrochloride to naloxone hydrochloride is preferably 2: 1 to 20: 1, in particular 2: 1. Retardformuiierungen with such a weight ratio have when used, ie oral application an analgesic effect, whereas their parenteral abuse leads to withdrawal symptoms (see also US 3,966,940 and US 3,773,955). Preferably, the sustained-release formulations (i) and (ii) are used for the treatment of moderate pain to severe pain and / or second-line therapy of patients with severe to very severe idiopathic Restless Legs Syndrome. Particularly preferred is a formulation comprising oxycodone hydrochloride and naloxone hydrochloride in a weight ratio of 2: 1.

Preferably, the sustained-release formulation contains 40 mg, 30 mg, 20 mg, 15 mg, 10 mg, 5 mg or 2.5 mg oxycodone and naloxone in an amount of 50% by weight of the respective amount of oxycodone. Also preferred is a sustained release formulation containing 40 mg, 30 mg, 20 mg, 15 mg, 10 mg, 5 mg or 2.5 mg oxycodone hydrochloride and naloxone hydrochloride in an amount of 50 wt .-% of the respective amount of oxycodone hydrochloride. The stated amounts of oxycodone hydrochloride and naloxone hydrochloride are also contained in the Targin® brand tablets.

Preferably, the sustained-release pharmaceutical formulation of (i) and / or (ii) is a matrix-based sustained-release formulation that is free of ethyl cellulose.

Particularly preferred are sustained-release formulations (i) and (ii) which comprise as the matrix-forming material at least one polymethacrylate and at least one fatty alcohol, the polymethacrylate preferably being a cationic polymethacrylate and / or the fatty alcohol preferably stearyl alcohol. By suitably adjusting the proportions of the matrix-forming materials, it is possible to selectively control the release of naloxone or naloxone hydrochloride and oxycodone or oxycodone hydrochloride from the matrix. Polymethacrylate and the fatty alcohol are preferably included in a weight ratio of 1: 3 to 1: 4 (polymethacrylate to fatty alcohol). Particularly preferred is a weight ratio of polymethacrylate to fatty alcohol of 1: 3.3 to 1: 3.9. It has been found that at such a weight ratio of polymethacrylate and fatty alcohols are particularly good in producing formulations that are suitable for once or twice daily administration.

The polymethacrylate, which is preferably a cationic polymethacrylate, is preferably contained in an amount of from 4.0 to 10.0% by weight, based on the total weight of the formulation. The fatty alcohol, which is preferably stearyl alcohol, is preferably present in an amount of 12.0 to 40.0% by weight, based on the total weight of the formulation.

It has also been found that the sustained-release formulations (i) and (ii) can be prepared particularly well as formulations which are suitable for once or twice daily administration if the proportion by weight of the sum of polymethacrylate and fatty alcohol is 25 to 40% by weight. , preferably 30 to 35 wt .-%, each based on the total weight of the formulation is. Moreover, if the polymethacrylate and the fatty alcohol in a weight ratio of 1: 3 to 1: 4 (polymethacrylate to fatty alcohol) before, in particular from 1: 3.3 to 1: 3.9, can be in this way sustained release formulations containing (i) oxycodone and naloxone in a weight ratio of 2: 1 or (ii) oxycodone hydrochloride and naloxone hydrochloride in a weight ratio of 2: 1 which are bioequivalent to Targin®. In these formulations, oxycodone or oxycodone hydrochloride is preferably in an amount of 2 to 20 wt .-%, in particular from 4 to 16 wt .-%, and naloxone or Naloxonhydrochiorid preferably in an amount of 1.0 to 10.0 wt .-%, in particular Preferred single doses of sustained - release formulation containing oxycodone hydrochloride / naloxone hydrochloride in a weight ratio 2: 1 comprise 40 mg oxycodone hydrochloride and 20 mg naloxone hydrochloride or 20 mg oxycodone hydrochloride and 10 mg naloxone hydrochloride or 10 mg oxycodone hydrochloride and 5 mg naloxone hydrochloride or 5 mg oxycodone hydrochloride and 2.5 mg naloxone hydrochloride.

If, in a sustained-release formulation comprising oxycodone and naloxone or oxycodone hydrochloride and naloxone hydrochloride, in each case in a weight ratio of 2: 1, and polymethacrylate and fatty alcohol as retarding auxiliaries, the proportion by weight of said active ingredients is reduced while maintaining the weight ratio of said active substances, then a comparable release profile of the active substances can be achieved at various pH values, in particular at pH <7, in particular by use an appropriate amount of a water-soluble non-sustained release inert material such as lactose or lactose monohydrate. By a comparable release profile of the active ingredients is meant in particular that the release profiles, measured as cumulative percentage release of active ingredient, at different proportions by weight of active ingredient by not more than 20 absolute%, preferably not more than 15 absolute%, more preferably not more than 10 absolute%, and in particular not differ by more than 5 absolute%. The release profiles are determined by averaging 6 measurements. Methods for determining drug release are defined in the USP (American Pharmacopoeia) and in the European Pharmacopoeia. Preferably, the release is determined using a basket apparatus. The stirring speed is 100 rpm. The temperature of the test medium is 37 ° C. As a test medium, for example, a phosphate buffer having a pH of 6.8 can be used. The volume of the test medium is 900 ml.

Preferably, the amount of inert material used is as described above, e.g. Lactose or lactose monohydrate, based on the anhydrous form, at least 50% by weight of the total active substance reduction, more preferably 55 to 100% by weight, more preferably 60 to 90% by weight, and especially 65 to 80% by weight the entire drug reduction. By "total drug reduction" is meant the sum of the reduction of the active ingredients oxycodone and naloxone or oxycodone hydrochloride and naloxone hydrochloride.

Alternatively or additionally to the use of an inert material as described above, release curves comparable to active substance reduction can be used at different pH values, in particular at pH <7, for example by (a) suitable adaptation of the weight fraction of retarding excipient in the sustained-release formulation (mixture of polymethacrylate and fatty alcohol) and / or (b) suitably adjusting the weight ratio of polymethacrylate to fatty alcohol in the sustained release formulation.

Further, with drug reduction in the sustained-release formulation, (further) filler may be incorporated to achieve approximately the original weight of the sustained release formulation, ie, the weight before drug reduction. Due to the fact that at different levels of oxycodone and naloxone or oxycodone hydrochloride and Naioxonhydrochiorid in the sustained release formulation by the use of water-soluble release non-retarding inert materials, such as lactose or lactose monohydrate, by adjusting the weight fraction of retarding excipient (polymethacrylate and fatty alcohol ) and / or can achieve comparable release curves by suitably adjusting the weight ratio of polymethacrylate to fatty alcohol, for all dosage strengths of Targin® sustained release formulations with a weight proportion of the sum of polymethacrylate and fatty alcohol of 25 to 40 wt .-% and a weight ratio of polymethacrylate to fatty alcohol from 1: 3 to 1: 4, which are bioequivalent to the corresponding dose level of Targin®.

The pharmaceutical sustained-release formulation of the present invention preferably further comprises pharmaceutically acceptable fillers, carrier materials, binders, granulating agents, lubricants, lubricants, dyes, plasticizers, preservatives, release agents and / or flavoring agents which are conventional in the field of drug formulation.

The sustained-release pharmaceutical formulation as described in the present invention may preferably contain from 20 to 98% by weight, based on the total weight of the formulation of these materials. Particularly preferred is a content of 25 to 95 weight percent and particularly preferred is a content of 30 to 90 weight percent of these other materials, each based on the total weight of the pharmaceutical sustained-release formulation.

As fillers, for example, sugars such as lactose, lactose monohydrate, glucose or sucrose, starches and their hydrolysates, (microcrystalline) cellulose, cellactose, sugar alcohols such as sorbitol or mannitol, sparingly soluble calcium salts such as calcium hydrogen phosphate, dicalcium or tricalcium phosphate can be used. Preference is given to using microcrystalline cellulose and / or lactose, if appropriate as monohydrate. The microcrystalline cellulose is preferably contained in an amount of from 20.0 to 40.0% by weight, based on the total weight of the formulation. Lactose or lactose monohydrate is preferably contained in an amount of 0 to 15.0 wt .-%, based on the total weight of the formulation. As described above, can in particular lactose or lactose monohydrate can be used to adjust the release profile of the sustained release formulation.

Binders, such as polyvinylpyrrolidone (povidone), are preferably used in an amount of from 1.0 to 9.0% by weight, based on the total weight of the formulation.

Lubricants are, for example, highly dispersed silicic acids (Aerosil ^®), talcum, corn starch, magnesium oxide, magnesium or calcium, in particular magnesium stearate is used as Gieitmittel. Lubricants are preferably used in an amount of from 0.1 to 1.5% by weight, based on the total weight of the formulation.

Lubricants, for example magnesium stearate, calcium stearate, fatty acids such as stearic acid, or fats, such as hydrogenated castor oil, polyethylene glycols or highly dispersed silicic acids (Aerosil ^®), preferably highly dispersed silicic acids (Aerosil ^®) is used as a lubricant. Lubricants are preferably used in an amount of from 0.1 to 1.5% by weight, based on the total weight of the formulation.

Plasticizers, such as triacetin, are preferably used in an amount of 0.5 to 2.0% by weight, based on the total weight of the formulation. Retard formulations may possibly have a certain brittleness after prolonged storage, which may influence the release behavior of the sustained release formulation. By using plasticizer in the stated amount, this problem can be solved.

Release agents, such as talc, are preferably used in an amount of from 1.5 to 4.0 percent by weight, based on the total weight of the formulation.

The pharmaceutical sustained-release formulation described in the context of the present invention is intended for oral administration. It can be present as a (multi-layered) tablet, dragee, capsule, granules or powder.

Preferably, it is present as a multi-layer tablet. This has a film-forming casing, which preferably comprises hypromellose as a coating agent, polyethylene glycol as a plasticizer and talc as a release agent, wherein Hypromel! Ose preferably in an amount of 1.0 to 4.5 wt .-%, Poiyethylengiykol preferably in an amount of 0.1 to 1.5 wt .-% and Taikum preferably in an amount of 0.1 to 1.5 wt .-%, in each case based on the Total weight of the multi-layer tablet.

Further, the cladding may contain dyes selected, for example, from the group consisting of titanium dioxide, red iron oxide 30 E 172, yellow iron oxide 10 E 172 and FD & C Blue or a mixture thereof.

The (multi-layer) tab preferably has a weight between 100 and 300 mg, preferably between 120 and 260 mg.

Process for the preparation of a storage-stable drug

In the context of the present invention, a process has also been found for preparing a storage-stable drug, the process comprising packaging a pharmaceutical sustained-release formulation as described in the present invention into a blister pack comprising a mold film and a cover film, wherein the mold film and cover film are independent of one another a water vapor permeability of

<10.0 g / (m ² -d).

The sustained-release pharmaceutical formulation described in this process according to the invention is the sustained-release pharmaceutical formulation as described in connection with the packaged drug, ie a sustained-release pharmaceutical formulation comprising naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable sustained-release excipient Naloxone or the pharmaceutically acceptable salt thereof, together with preferred embodiments as described above. In particular, the pharmaceutical sustained-release formulation without the packaging is preferably not storage-stable.

The water vapor permeability of the molded film described in the process according to the invention is preferably <7.0 g / (m ² * d), <5.0 g / (m ² -d), <3.0 g / (m ^{2 «} d),

<2.0 g / (m ² -d), <1.0 g / (m ² -d), <0.9 g / (m ² -d), <0.8 g / {m ² "d), <0.7 g / (m ^{2 "} d), <0.6 g / (m ^? -D), <0.5 g / (m ² -d), <0.4 g / (m ² -d), <0.3 g / (m ² -d), <0.2 g / (m -d), and particularly preferred is a water vapor permeability of <0.1 g / (m ² * d).

The water vapor permeability of the cover film described in the context of the method according to the invention is preferably s 7.0 g / (m ² -d), <5.0 g / (m ² d), <3.0 g / (m * d),

<2.0 g / (m ² * d), <1.0 g / (m ² -d), <0.9 g / (m ² .d), <0.8 g / (m ² -d), <0.7 g / (m ² -d), <0.6 g / (m ² .d),

<0.5 g / (m-d), <0.4 g / (m ² * d), <0.3 g / (m ² * d), <0.2 g / {m ² * d), and particularly preferred is a water vapor permeability of <0.1 g / (m ² -d).

The water vapor permeabilities of the shaped film and covering film described in the context of the process according to the invention are therefore preferably independently <7.0 g / (m ² -d), <5.0 g / (m ² -d), <3.0 g / (m ² -d), <2.0 g / (m ² -d), <1 .0 g / (m ² -d),

<0.9 g / (m ² * d), <0.8 g / (m ² -d), <0.7 g / (m ² -d), <0.6 g / (m ² -d), <0.5 g / (m ² * d), <0.4 g / (m ² -d),

<0.3 g / (m ² -d), <0.2 g / (m ² d), and particularly preferred is a water vapor permeability of <0.1 g / (m ² -d).

The water vapor permeabilities of the molded sheet and the cover sheet are influenced by the same factors as those associated with the packaged drug described above.

Furthermore, with regard to the blister packaging described in the context of the method according to the invention, comprising molding and cover film, the same preferred embodiments as described in connection with the packaged medicament apply.

In the context of the present invention, an alternative method for

The method comprises packaging a pharmaceutical sustained release formulation as described in the present invention into a container with closure, wherein the container with closure comprises a desiccant.

The pharmaceutical sustained-release formulation described in the context of the alternative method according to the invention is the pharmaceutical

Sustained release formulation as described in connection with the packaged medicament, ie a pharmaceutical sustained release formulation comprising naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for sustained release of the naloxone or pharmaceutically acceptable salt thereof, together with preferred embodiments as described above.

In particular, the pharmaceutical sustained-release formulation without the packaging is preferably not storage-stable.

The desiccant is the same desiccant as described in the context of the packaged drug, with silica being also preferred as the desiccant.

The container and the closure, as described in the context of the alternative method according to the invention, independently of one another preferably have a water vapor permeability of <10.0 g / (m ² -d). Particularly preferred is a water vapor permeability of <7.0 g / (m ² -d), <5.0 g / (m ² -d), <3.0 g / (m ² * d),

<2.0 g / (m ² -d), <1.0 g / (m -d), <0.9 g / (m -d), <0.8 g / (m ² -d), <0.7 g / (m ² - d), <0.6 g / (m ^? -d),

<0.5 g / (m ² "d), <0.4 g / (m ² -d), <0.3 g / (m ² -d), <0.2 g / (m ² -d), and particularly preferred is a water vapor permeability of <0.1 g / (m ² -d), each independently for container and closure.

The water vapor permeability of the container with closure described in the alternative method according to the invention is influenced by the same factors as in connection with the packaged medicament described above.

Furthermore, with regard to the container with closure described in the context of the alternative method, the same preferred embodiments as described in connection with the packaged medicament apply.

The methods according to the invention for the preparation of a storage-stable drug make it possible, in particular, not to store storage-stable pharmaceutical sustained-release formulations for at least two years under standard conditions without the release profile of the active ingredient and / or the active ingredient content of the sustained-release formulation exceeding those given in definitions i) and ii ) for storage stability. Thus, in particular the storage of pharmaceutical sustained-release formulations is possible, which do not have per se storage stability. Use of a package for storage stabilization of a drug

In the context of the present invention, it has furthermore been found that a package for the storage stabilization of a medicament which comprises a pharmaceutical sustained-release formulation as described in the context of the present invention can be used, the packaging being a blister pack comprising a shaped film and a cover film , wherein the molding film and covering film independently of one another have a water vapor permeability of <10.0 g / {m ² * d).

The sustained-release pharmaceutical formulation described in the context of this use according to the invention is the sustained release pharmaceutical formulation as described in connection with the packaged drug, ie a sustained-release pharmaceutical formulation comprising naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable sustained-release excipient Naloxone or the pharmaceutically acceptable salt thereof, together with preferred embodiments as described above. In particular, the pharmaceutical sustained-release formulation without the packaging is preferably not storage-stable.

The water vapor permeability of the molded film described in the context of the use according to the invention is preferably s 7.0 g / (m ² * d), <5.0 g / (m ² * d), s 3.0 g / (m ^{2 «} d),

<2.0 g / (m ² -d), <1.0 g / (m ² -d), <0.9 g / (m ² -d), <0.8 g / {m ² -d), <0.7 g / (m ² -d), <0.6 g / (m ² -d),

<0.5 g / (m ² -d), <0.4 g / (m ² -d), <0.3 g / (m ² * d), <0.2 g / (m -d), and particularly preferred is a water vapor permeability of <0.1 g / (m ² * d).

The water vapor permeability of the cover film described in the context of the use according to the invention is preferably <7.0 g / (m ² -d), <5.0 g / (m -d), <3.0 g / (m ² -d),

<2.0 g / (m ² * d), <1.0 g / (m -d), <0.9 g / (m ² -d), <0.8 g / (m ^{2 «} d), <0.7 g / ( m ² -d), <0.6 g / (m ² -d),

<0.5 g / (m ² -d), <0.4 g / (m ² * d), <0.3 g / (m ² -d), <0.2 g / (m ² * d), and particularly preferred is one Water vapor permeability of <0.1 g / (m ² * d).

The water vapor permeabilities of the molded film and cover film described in the context of the use according to the invention are therefore preferably independently <7.0 g / (m ² .d), <5.0 g / (m ² -d), <3.0 g / (m ² -d), <2.0 g / (m ^{2 "} d), <1.0 g / (m ² * d),

<0.9 g / (m ² -d), <0.8 g / (m ² -d), <0.7 g / (m ² -d), <0.6 g / (m -d), <0.5 g / (m ² -d), <0.4 g / {m -d), <0.3 g / (m ² * d), 0.2 g / (m ² * d), and particularly preferred is a water vapor permeability of <0.1 g / (m ² -d).

Furthermore, with regard to the blister packaging described in the context of the use according to the invention, comprising molding and cover film, the same preferred embodiments as described in connection with the packaged medicament apply.

In the context of the present invention, it has also been found that, for the storage stabilization of a pharmaceutical composition comprising a pharmaceutical sustained release formulation as described in the context of the present invention, an alternative packaging can be used, wherein the packaging is a container with closure, wherein the container Container with closure comprises a drying agent.

The sustained-release pharmaceutical formulation described in the context of using an alternative packaging is the sustained release pharmaceutical formulation as described in connection with the packaged pharmaceutical, that is, a sustained-release pharmaceutical formulation comprising naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient Release of the naloxone or the pharmaceutically acceptable salt thereof, together with preferred embodiments as described above. In particular, the pharmaceutical sustained-release formulation without the packaging is preferably not storage-stable.

The container and the closure, as described in the context of the alternative use according to the invention, independently of one another preferably have a water vapor permeability of <10.0 g / (m ² * d). Particularly preferred is a Water vapor permeability of <7.0 g / (m ² * d), s 5.0 g / (m ² -d), <3.0 g / (m ^{2 «} d),

<2.0 g / (m ² .d), <1.0 g / (m ² -d), <0.9 g / (m ² * d), <0.8 g / (m ² -d), <0.7 g / (m ² "d), <0.6 g / (m ² -d),

<0.5 g / (m ² -d), <0.4 g / (m ² * d), <0.3 g / (m ² -d), <0.2 g / (m -d), and particularly preferred is a water vapor permeability of <0.1 g / (m ² * d), each independently for container and closure.

The water vapor permeability of the container with closure described in the context of the alternative use according to the invention is influenced by the same factors as in connection with the packaged medicament described above.

Furthermore, with regard to the container with closure, the same preferred embodiments as described in connection with the packaged medicament apply.

The use according to the invention of the packaging for the storage stabilization of a medicament described herein makes it possible, in particular, to store storage-stable pharmaceutical sustained-release formulations for at least two years under standard conditions, without the release profile of the active ingredient and / or the active ingredient content of the sustained-release formulation exceeding those specified in the definitions i ) and ii) set limits. Thus, in particular the storage of pharmaceutical sustained-release formulations is possible, which do not have per se storage stability.

Use of packaging to reduce the deallylation of naloxone

It has also been found within the scope of the present invention that a package for reducing the deallylation of naloxone or a pharmaceutically acceptable salt thereof in a pharmaceutical sustained-release formulation as described in the context of the present invention during its storage, e.g. for two years under standard conditions, where the package is a blister pack comprising a mold sheet and a cover sheet, the mold sheet and cover sheet independently of each other having a water vapor permeability of

<10.0 g / (m ^{2 *} d).

The pharmaceutical sustained-release formulation described in the context of this use according to the invention is the pharmaceutical A sustained-release formulation as described in connection with the packaged pharmaceutical, that is to say a pharmaceutical sustained-release formulation comprising naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for the sustained release of the naloxone or the pharmaceutically acceptable salt thereof, together with preferred embodiments as described above. In particular, the pharmaceutical sustained-release formulation without the packaging is preferably not storage-stable.

The water vapor permeability of the molded film described in the context of the use according to the invention is preferably <7.0 g / (m ² * d), <5.0 g / (m ² * d), <3.0 g / (m ² * d),

<2.0 g / (m ² * d), <1.0 g / (m ² * d), <0.9 g / (m ² "d), <0.8 g / (m ^{2 *} d), <0.7 g / (m ^{2 *} d), <0.6 g / (m ^{2 *} d),

<0.5 g / (m ² * d), <0.4 g / (m ² * d), <0.3 g / (m ² * d), <0.2 g / (m ² * d), and particularly preferred is a water vapor permeability of <0.1 g / (m ^{2 *} d).

The water vapor permeability of the cover film described in the context of the use according to the invention is preferably <7.0 g / (m ^{2 *} d), <5.0 g / (m ² * d), <3.0 g / (m ² * d),

<2.0 g / (m ² * d), <1.0 g / (m ^{2 *} d), <0.9 g / (m ² * d), <0.8 g / (m ^{2 *} d), <0.7 g / {m ^{2 *} d), <0.6 g / (m ² * d),

<0.5 g / (m ^{2 *} d), <0.4 g / (m ² * d), <0.3 g / (m ^{2 *} d), <0.2 g / (m ² * d), and particularly preferred is a water vapor permeability of 0.1 g / (m ^{2 *} d).

The water vapor permeabilities of the molded film and cover film described in the context of the use according to the invention are therefore preferably independently <7.0 g / (m ² * d), <5.0 g / (m ^{2 *} d), <3.0 g / (m ² * d), <2.0 g / (m ² * d), <1.0 g / (m ² * d),

<0.9 g / (m ² * d), <0.8 g / (m ² * d), <0.7 g / (m ² * d), <0.6 g / (m ² * d), <0.5 g / (m ² * d), <0.4 g / (m ² * d),

<0.3 g / (m ^{2 *} d), <0.2 g / (m ^{2 *} d), and particularly preferred is a water vapor permeability of <0.1 g / (m ^{2 *} d).

Furthermore, with regard to the blister packaging described in the context of the use according to the invention, comprising molding and cover film, the same preferred embodiments as described in connection with the packaged medicament apply. In the context of the present invention, it has also been found that in order to reduce the deal! Yiierung of naloxone or the pharmaceutically acceptable salt thereof used in an as described in the present invention pharmaceutical sustained release formulation during their storage, for example, for two years under standard conditions, an alternative packaging can be, wherein the packaging is a container with closure, wherein the container with closure comprises a desiccant.

The container and the closure, as described in the context of the alternative use according to the invention, independently of one another preferably have a water vapor permeability of <10.0 g / (m ^{2 *} d). Particularly preferred is a water vapor permeability of <7.0 g / (m ² * d), <5.0 g / (m ^{2 *} d), <3.0 g / (m ² * d),

<2.0 g / (m ² * d), <1.0 g / (m ^{2 *} d), <0.9 g / (m ² * d), <0.8 g / (m ^{2 *} d), <0.7 g / (m ² * d), <0.6 g / (m ² * d),

<0.5 g / (m ² * d), <0.4 g / (m ^{2 *} d), <0.3 g / (m ² * d), <0.2 g / (m ² * d), and particularly preferred is a water vapor permeability of <0.1 g / (m ² * d), each independently for container and closure.

The water vapor permeability of the container with closure described in the context of the alternative use according to the invention is influenced by the same factors as in connection with the packaged medicament described above. Furthermore, with regard to the container with closure, the same preferred embodiments as described in connection with the packaged medicament apply.

The use according to the invention of the packages described herein for reducing the deallylation of naloxone or a pharmaceutically acceptable salt thereof in a sustained-release pharmaceutical formulation during its storage, e.g. for two years under standard conditions, it is not possible to store, in particular, non-storage-stable pharmaceutical sustained-release formulations for at least two years under standard conditions without the release profile of the active ingredient and / or the content of the sustained-release formulation exceeding those specified in definitions t) and ii) Change limits beyond. Thus, in particular the storage of pharmaceutical sustained-release formulations is possible, which do not have per se storage stability.

Preferably, a pharmaceutical sustained release formulation packaged in accordance with the present invention and as described herein contains less than 2% by weight after storage for two years under standard conditions due to the reduction in dealhalation of naloxone or a pharmaceutically acceptable salt thereof; preferably less than 1% by weight, more preferably less than 0.5% by weight, and in particular less than 0.2% by weight of noroxymorphone (salt), in each case based on the active ingredient content stated in the instruction leaflet.

Examples

example 1

Preparation of naloxone hydrochloride-containing tablets with EUDRAGIT® RS30D and Surelease® E-7-7050 (comparison) as matrix-forming materials:

The following quantities of the specified components were used for the preparation of the tablets; Nai-5-Eud Nal-5-Sure

{Comparison from DE 102 15 131 A1)

Naloxone HCl: 5.0 mg 5.0 mg

Lactose Flow Lac 100: 74.25 mg 74.25 mg

Povidone 30; 5.0 mg 5.0 mg

Eudragit ^® RS30D; 10 mg of solid

Surelease® E-7-7050: 10 mg solid

Triacetin: 2.0 mg

Stearyl alcohol: 25.0 mg 25.0 mg

Talc: 2.5 mg

Magnesium stearate: 1, 25 mg. 1, 25 mg

Eudragit ^® RS30D is available from Evonik Industries (gas No .: 33434-24-1). Surelease® E-7-7050 is available from Colorcon Ltd ..

For the production of naloxone tablets each haitigen naloxone HCI were 30 and Lactose Flow Lac 100 Povidone mixed in a tumbling mixer (Bohle) and then with Eudragit ^® RS30D or Surelease® E-7-7050 in a fluidized bed coater (GPCG3) spray granulated , The material was then passed through a Comill 1, 4 mm sieve. In addition, a granulation step was carried out with molten fatty alcohol in a forced mixer (Collette). The tablet cores thus prepared had a weight of 125 mg based on the dry substance.

Example 2

Storage stability of the naloxone hydrochloride-haitigen tablets from Example 1:

The naloxone hydrochloride-containing tablets of Example 1 were stored at 25 ° C and 60% relative humidity for 24 months. At various times the release behavior was investigated.

In the Eudragit ^® RS30D (Nal-5-Eud) formulated naloxone hydrochloride haitigen tablet was found that the release profile of the active ingredient Naloxone hydrochloride distinguishes already after 24 months from that immediately after preparation of the tablet such that the tablet could no longer be regarded as stable on storage.

When ^® with Surelease E-7-7050 (Nal-5-Sure) formulated naloxone hydrochloride-containing

Tablet (comparison), the release remained largely the same even after 24 months storage time, i. E. the storage stability criterion i) according to the invention with regard to the release was fulfilled.

When the Nal-5-Eud tablet was stored in an aluminum-aluminum blister package (aluminum-aluminum blister pack) or in an HDPE container with an HDPE cap and silica as the desiccant in the cap, it was found to be released even after 24 months Storage time remained largely the same.

Example 3

Preparation of Ethyl Cellulose-Free Reiard Formulations Containing Naloxone Hydrochloride (Nal-HCl) and Oxycodone Hydrochloride (Oxy-HCl):

The following procedure may be used for the preparation of tablets containing oxycodone hydrochloride / aloxone hydrochloride in the amounts of 40mg / 20mg, 20mg / 10mg, 10mg / 5mg and 5mg / 2.5mg. The amounts of the excipients are in the preferred ranges indicated in the general part.

Step 1: Preparation of the Intermediate 1

Oxycodone hydrochloride, naloxone hydrochloride, microcrystalline cellulose and lactose monohydrate (lactose monohydrate only provided in formulations containing oxycodone hydrochloride / naloxone hydrochloride in the amounts of 10 mg / Srog and 5 mg / 2.5 mg) are mixed in the dry state in a suitable mixing device.

Povidone is dissolved in water. Talc is added to the solution and suspended therein. Triacetin is suspended in the aqueous dispersion Eudragit® RS 30D. The triacetin / Eudragit® RS 30D suspension is added to the povidone / talc suspension. The resulting suspension is used to granulate the dry mix. The resulting granules are dried and then sieved. The sieved granules are mixed, resulting in Intermediate 1 results.

Step 2: Making the Intermediate 2

Intermediate 1 is placed in a high shear mixer and mixed briefly.

Stearylalkoho! is melted. The molten stearic alcohol is added to Intermediate 1. The resulting mixture is kneaded and mixed.

The resulting granules are screened and then mixed, resulting in intermediate 2 results.

Step 3: Compression to tablet cores

Intermediate 2 is mixed with highly dispersed silicic acid and magnesium stearate. The mixture thus obtained is compressed in tablet cores.

Step 4: Film-forming sheath

Polyethylene glycol and hypromellose are dissolved in one half of the water. Talc,

Titanium dioxide and optionally one or more dyes are suspended in the other half of the water. The suspension is added to the solution. The sheathing of the tablet cores is carried out by spraying with the resulting suspension.

The table below provides information on the quantitative composition of the sustained-release tablets produced.

Table: Key figures of the produced retard tabs. Example 4

Release profiles of the tablets prepared in Example 3 containing naloxone hydrochloride and oxycodone hydrochloride:

In Figures 1 and 2 are exemplary release profiles at pH 6.8 (Basket apparatus, stirring speed of 100 rpm) of oxycodone hydrochloride (OxyHCI) or naloxone hydrochloride (NaiHCI) from the sustained release formulations prepared according to the procedure in Example 3, containing 40mg / 20mgund 5mg / 2.5mg OxyHCi / NalHCI (test products) compared to the corresponding Targin® reference products containing 40mg / 20mg and 5mg / 2.5mg OxyHCl / NalHCl. shown.

As the figures show by way of example, the release curves of oxycodone hydrochloride and naloxone hydrochloride of the test products and reference products are very close together at pH 6.8. The same applies to the corresponding release profiles at pH 1 and pH 4.5.

Accordingly, bioequivacy could be detected between the test products and the reference products.

Claims

claims

1. Packaged pharmaceutical product comprising

a) a sustained-release pharmaceutical formulation, wherein the sustained-release pharmaceutical formulation comprises naloxone or a pharmaceutically acceptable salt thereof, oxycodone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable sustained release excipient of the naloxone or pharmaceutically acceptable salt thereof;

b) a package, wherein the packaging is a blister pack comprising a mold film and a cover film, wherein mold film and cover independently have a water vapor permeability of <3.0 g / {m ² d ').

2. The packaged pharmaceutical composition according to claim 1, wherein the molding film is made of a material comprising at least one polymer or aluminum, and / or the covering film is made of a material comprising aluminum, wherein the at least one polymer is preferably selected from the group consisting of PVC , PVdC,

PE, PET, PP and COC is selected.

3. Packaged medicine, comprising

a) a pharmaceutical sustained release formulation, wherein the pharmaceutical

A sustained release formulation comprising naloxone or a pharmaceutically acceptable salt thereof, oxycodone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable sustained release excipient of the naloxone or pharmaceutically acceptable salt thereof, and

b) a packaging, wherein the packaging is a container with closure, wherein the container with closure comprises a desiccant.

4. The packaged drug of claim 3, wherein the container and closure are independently of one another selected from the group consisting of LOPE, HOPE, PVC, PVdC, PP, polycarbonate, COC and PET. The packaged drug according to any one of claims 3 and 4, wherein the desiccant is selected from the group consisting of sodium sulfate, silica, molecular sieves (zeolites), alumina, calcium chloride, calcium oxide,

Potassium carbonate, copper sulfate, magnesium sulfate, magnesium oxide, bentonite or a mixture thereof, Packaged pharmaceutical product according to any one of the preceding claims, wherein the pharmaceutical sustained-release formulation is free of ethyl cellulose. The packaged pharmaceutical composition of any one of the preceding claims, wherein the sustained-release pharmaceutical formulation is matrix-based and / or surrounded by a hydrophobic film-forming shell, wherein the sustained-release pharmaceutical formulation is preferably matrix-based and comprises at least one matrix-forming material as a pharmaceutically acceptable excipient the at least one matrix-forming material is preferably a polymethacrylate, in particular a cationic polymethacrylate. The packaged drug according to claim 7, wherein the pharmaceutical sustained-release formulation comprises as the at least one matrix-forming material at least one polymethacrylate, in particular a cationic polymethacrylate, and at least one fatty alcohol, in particular stearyl alcohol,

wherein the polymethacrylate and the fatty alcohol are preferably in a weight ratio of 1: 3 to 1: 4 (polymethacrylate to fatty alcohol), and / or wherein in the pharmaceutical sustained release formulation, the weight ratio of the sum of polymethacrylate and fatty alcohol 25 to 40 wt .-%, preferably 30 to 35 wt .-%, in each case based on the total weight of the sustained release formulation. Packaged medicament according to any of the preceding claims, wherein the sustained-release formulation contains oxycodone hydrochloride and naloxone hydrochloride, preferably in a weight ratio of 2: 1 (oxycodone hydrochloride to naloxone hydrochloride).

10. Packaged pharmaceutical preparation according to one of the preceding claims, wherein the pharmaceutical sustained-release formulation is present as (ehrschicht-) Tabiette, dragee, capsule, granules or powder, preferably as a multilayer tablet.

1 1. Packaged medicament according to one of the preceding claims, wherein the pharmaceutical sustained-release formulation without the packaging is not storage-stable,

12. A method of producing a storage stable drug, the method comprising packaging a pharmaceutical sustained release formulation as defined in claim 11 into a blister pack comprising a forming sheet and a cover sheet, wherein the forming sheet and cover sheet independently have a water vapor permeability of <10.0 g / ( m ² * d).

13. A method for producing a storage stable drug, the method comprising packaging a pharmaceutical sustained release formulation as defined in claim 11 into a container with closure, wherein the container with closure comprises a desiccant.

Use of a package for storage stabilization of a pharmaceutical composition, wherein the pharmaceutical composition comprises a pharmaceutical sustained-release formulation as defined in any one of claims 1 to 11, and the package is a blister package comprising a molding film and a cover film, wherein molding film and Cover film independently have a water vapor permeability of <10.0 g / (m ² -d).

Use of a package for storage stabilization of a pharmaceutical composition, wherein the pharmaceutical composition comprises a pharmaceutical sustained-release formulation as defined in any of claims 1 to 11, and the packaging is a container with closure, the container with closure comprising a drying agent.

Use of a package for reducing the deallylation of naloxone or the pharmaceutically acceptable salt thereof in a pharmaceutical sustained-release formulation as defined in any one of claims 1 to 11 during its storage, the package being a container having a closure, the Container with closure comprises a drying agent. Use of a package for reducing the deallylation of naloxone or the pharmaceutically acceptable salt thereof in a sustained-release pharmaceutical formulation as defined in any one of claims 1 to 11 during storage thereof, wherein the package is a bi-pack package comprising a forming sheet and a cover sheet , wherein the molding film and covering film independently of one another have a water vapor permeability of <10.0 g / (m ² * d).