HK1210042B

HK1210042B - Pharmaceutical compositions comprising hydromorphone and naloxone

Info

Publication number: HK1210042B
Application number: HK15110909.2A
Authority: HK
Inventors: 里卡多．阿尔贝托．瓦尔加斯林孔
Original assignee: 普渡制药公司
Priority date: 2012-11-09
Filing date: 2013-11-06
Publication date: 2018-06-08

Description

Pharmaceutical composition comprising hydromorphone and naloxone

Cross Reference to Related Applications

The instant application claims benefit of provisional patent application s.n.61/796,390 filed 11/9/2012, according to 35 u.s.c. § 119(e), the contents of which are incorporated herein by reference.

Background

Technical Field

In one of its aspects, the present invention relates to an extended release pharmaceutical dosage form (prolongated release pharmaceutical dosage form) comprising hydromorphone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof. In another of its aspects, the present invention relates to the use of such an extended release pharmaceutical dosage form for the treatment of a human.

Background

Extended release pharmaceutical dosage forms are important tools in the tool library of medical practitioners for the treatment of disease. One of the general benefits attributed to extended release pharmaceutical dosage forms, as compared to immediate release pharmaceutical dosage forms, includes increased patient compliance due to reduced frequency of administration.

There are a variety of techniques available to obtain an extended release dosage form. The extended release properties may be expressed by so-called extended release matrix systems, extended release coatings, osmotic dosage forms, multi-layered dosage forms, and the like.

When developing extended release formulations, it is often necessary to select the respective formulation technique with respect to the physicochemical and physiological properties of the pharmaceutical active agent in question. For the formulation specialist this means a lot of work. This is especially true when the dosage form contains a pharmaceutically active agent such as an opioid agonist (which in theory could be abused, i.e. not used for pharmaceutical purposes).

Accordingly, there is a continuing interest in pharmaceutical dosage forms comprising opioid analgesics as pharmaceutically active agents that provide extended release properties and take into account the potential for opioid abuse.

International publication No. WO 2011/141488[ Danagher et al (Danagher) ] teaches pharmaceutical compositions comprising hydromorphone and naloxone. While the formulations disclosed in Danagher represent a significant advance in the art, there is still room for improvement. In particular, there is room for improvement in one or both of the stability and dissolution properties of some particular embodiments of the pharmaceutical compositions exemplified in Danagher.

Disclosure of Invention

It is an object of the present invention to provide a new extended release pharmaceutical dosage form.

Accordingly, in one of its aspects, the present invention provides an extended release pharmaceutical dosage form comprising a plurality of coated beads, each of said coated beads comprising:

(a) particles;

(b) a first layer coated on the particle, the first layer comprising: (i) hydromorphone or a pharmaceutically acceptable salt thereof, (ii) naloxone or a pharmaceutically acceptable salt thereof, (iii) an antioxidant compound and (iii) a chelating compound; and

(c) a second layer coated on the first layer, the second layer comprising an extended release agent.

In another of its aspects, the present invention provides a coated bead comprising:

(a) particles;

In another of its aspects, the present invention provides an extended release pharmaceutical dosage form comprising a plurality of coated beads disposed in a hydroxypropyl methylcellulose capsule, each of said coated beads comprising:

(a) particles;

(b) a first layer coated on the particle, the first layer comprising: (i) hydromorphone hydrochloride, (ii) naloxone hydrochloride, (iii) an antioxidant compound, and (iii) a chelating compound, wherein (i) and (ii) are present in a weight ratio of about 2: 1;

(c) a second layer coated on the first layer, the second layer comprising ethyl cellulose; and

(d) a third layer coated on the second layer, the third layer comprising a polyvinyl alcohol-polyethylene glycol graft copolymer.

In yet another of its aspects, the present invention relates to the use of an antioxidant (e.g. sodium metabisulphite) in combination with a chelating agent (e.g. ethylenediaminetetraacetic acid disodium salt dihydrate) for improving the stability and/or dissolution properties of an extended release dosage form comprising (i) hydromorphone or a pharmaceutically acceptable salt thereof and (ii) naloxone or a pharmaceutically acceptable salt thereof.

The present inventors have found that the use of an antioxidant (e.g. sodium metabisulfite) in combination with a chelating agent (e.g. ethylenediaminetetraacetic acid disodium salt dihydrate) can be used to improve the stability and/or dissolution profile (or dissolution profile) -these terms being used interchangeably throughout) of an extended release dosage form comprising (i) hydromorphone or a pharmaceutically acceptable salt thereof and (ii) naloxone or a pharmaceutically acceptable salt thereof. While the embodiments illustrated below focus on such extended release dosage forms in the form of coated beads, it is believed that improvements in stability and/or dissolution properties may also be seen in other dosage forms, such as those described in Danagher. Thus, it is believed that improvements in stability and/or dissolution properties may also be seen in other dosage forms (e.g., matrix dosage forms, etc.) comprising as active ingredients (i) hydromorphone or a pharmaceutically acceptable salt thereof and (ii) naloxone or a pharmaceutically acceptable salt form thereof. Non-limiting examples of improving the stability of a dosage form include improving the 24 month shelf life (shelflife) stability of the dosage form.

The antioxidant compound is not particularly limited.

Preferably, the antioxidant compound is selected from sodium metabisulphite, Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), Propyl Gallate (PG), Cysteine (CYS), alpha tocopherol, ascorbic acid, phosphoric acid, potassium metabisulphite, sodium ascorbate providing ascorbic acid, sodium bisulphite, sodium sulphite and any mixture of two or more of these.

Preferably, the antioxidant compound is present in the following amounts: from about 0.001% to 1.0%, more preferably from about 0.01% to about 0.1%, more preferably from about 0.01% to 0.005%.

In a more preferred embodiment, the antioxidant compound is selected from the group consisting of (in preferred amounts in parentheses) sodium metabisulfite (about 0.001% to about 1.0%), Butylated Hydroxytoluene (BHT) (about 0.01% to about 1.0%), Butylated Hydroxyanisole (BHA) (about 0.001% to about 1.0%), Propyl Gallate (PG) (about 0.001% to 0.1%), Cysteine (CYS), alpha tocopherol (about 0.001% to about 0.05%), ascorbic acid (about 0.01% to about 0.1%), phosphoric acid (about 0.001% to about 0.005%), potassium metabisulfite (about 0.001% to about 1.0%), sodium ascorbate (about 0.01% to about 0.1%) providing ascorbic acid, sodium bisulfite (about 0.001% to about 1.0%), sodium sulfite (about 0.001% to about 1.0%), and any mixture of two or more of these.

The most preferred antioxidant is sodium metabisulfite (preferably used in an amount of about 0.001% to about 1.0%).

The chelating agent is not particularly limited.

Preferably, the chelating agent is ethylenediaminetetraacetic acid and/or salts thereof (e.g., EDTA HCl), fumaric acid, and any mixtures of two or more of these.

When the chelating agent is ethylenediaminetetraacetic acid or an ethylenediaminetetraacetate salt (e.g., EDTA HCl), it is preferably used in an amount of about 0.005% to about 0.1%.

When the chelating agent is fumaric acid, it is preferably used in an amount of up to about 0.004%.

The amounts of antioxidant compound and chelating agent indicated above are referred to as%. This is intended to mean the weight% of the drug containing portion of the extended release dosage form. In the case of the coated bead embodiments of the extended release dosage form of the present invention, the active ingredient is typically applied to the drug layer and the amount of the antioxidant compound/chelator described above may be the weight% of the drug layer. In the case of matrix embodiments of the extended release dosage form of the present invention, the active ingredient is typically mixed with one or more matrix-forming materials to form a matrix composition, and the amount of antioxidant compound/chelator described above may be the weight% of the matrix composition.

Detailed Description

The present invention illustratively described below may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein.

The present invention will be described with respect to particular embodiments and with reference to certain drawings but the invention is not limited thereto but only by the claims. Unless otherwise indicated, the terms listed below are generally to be understood in their ordinary sense.

When the term "comprising" is used in the present description and claims, it does not exclude other elements. For the purposes of the present invention, the term "consisting of" is considered to be a preferred embodiment of the term "comprising. If a group is defined below as comprising at least some number of embodiments, this is also to be understood as disclosing a group preferably consisting of only these embodiments.

Unless otherwise specifically stated, nouns without quantitative modification indicate one or more.

In the context of the present invention, the term "about" or "approximately" denotes an interval of precision understood by a person skilled in the art to still ensure the technical effect of the feature in question. The term generally means ± 10%, preferably ± 5% from the indicated value.

The term "in vitro release" and grammatical variations thereof and similar expressions refer to the release rate of a pharmaceutically active agent (e.g., hydromorphone HCl) from a pharmaceutical composition when the in vitro release rate is tested by the paddle method according to the european pharmacopoeia as described in ph.eur.2.9.3, 6 th edition. The paddle speed is typically set at 75rpm or 100rpm in 500ml or 900ml Simulated Gastric Fluid (SGF) dissolution media pH 1.2. Aliquots of the dissolution medium were withdrawn at each time point and analyzed by HPLC using a C18 column, eluting with 30mM phosphate buffer in acetonitrile (70: 70; pH2.9) at a flow rate of 1.0 ml/min and detecting at 220 nm. It is particularly indicated if a different test method (e.g. SGF with 40% (v/v) ethanol) is used to determine the in vitro release rate in the context of the present invention.

The amount of leachant and the rotational speed of the paddle apparatus may depend on the amount of active agent tested. For example, a pharmaceutical composition comprising up to 16mg hydromorphone HCl can be tested in 500ml of dissolution liquid at 75rpm, whereas higher dose strengths can be tested in 900ml of dissolution liquid at 100 rpm.

The term "simulated gastric fluid, pH 1.2" means 0.1N HCl, pH 1.2.

In the context of the present invention, the term "immediate release" or "conventional release" refers to a pharmaceutical composition that shows the release of an active substance that is not deliberately modified by a particular formulation design and/or manufacturing process. For oral dosage forms, this means that the dissolution profile of the active substance is essentially dependent on the intrinsic properties of the active substance. Generally, the term "immediate release" or "conventional release" refers to a pharmaceutical composition that releases > 75% (by weight) of a pharmaceutically active agent in vitro at 45 minutes.

In the context of the present invention, the terms "extended release" and "controlled release" are used interchangeably and refer to a pharmaceutical composition that shows a slower release of the active agent than a conventional release pharmaceutical composition administered by the same route. Prolonged or controlled release is achieved by specific formulation design and/or manufacturing methods. Generally, the terms "extended release" and "controlled release" refer to pharmaceutical compositions that release ≦ 75% (by weight) of the pharmaceutically active agent in vitro at 45 minutes.

The extended release properties can be obtained in different ways, for example by coating (which is subsequently designated as extended release coating).

To obtain "extended or controlled release" properties, materials known to prolong release from dosage forms comprising, for example, an extended release coating are typically used. Typical examples of such "extended or controlled release materials" are hydrophobic polymers (e.g. ethyl cellulose), hydrophilic polymers (e.g. hydroxypropyl cellulose), and the like. The nature of the "extended or controlled release material" may depend on whether the release properties are achieved by an "extended release coating". The term "extended release coating material" denotes a material used to obtain an extended release coating.

The term "extended release coating formulation" or "controlled release coating formulation" refers to a pharmaceutical composition comprising at least one extended release material or controlled release material and at least one of hydromorphone and naloxone or a pharmaceutically acceptable salt or derivative thereof. The terms "extended release material" and "controlled release material" are used interchangeably. In the "extended release coating formulation" or "controlled release coating formulation", an "extended release material" or a "controlled release material" is placed on a pharmaceutically active agent to form a diffusion barrier (diffusion barrier). Typically, unlike in matrix formulations, the active agent is not intimately mixed with the extended-release material and the extended-release coating does not form a three-dimensional structure in which the active agent is distributed. As the term refers, the extended release material forms a layer over the active agent. The pharmaceutically active agent is released from the extended release coating formulation over an extended period of time (e.g., 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, or 24 hours).

It is understood that a material is considered to be useful as an extended or controlled release material if the dissolution profile of the pharmaceutically active agent is slowed as compared to an immediate or conventional release formulation. An extended or controlled release material is considered to be an extended or controlled release coating material if it can be used to make an extended or controlled release coating.

Pharmaceutically acceptable excipients used to tailor an already extended or controlled release to a particular profile are not necessarily considered extended or controlled release materials.

When referring to placing an extended release coating on a pharmaceutically active agent, this is not necessarily to be construed as meaning that such a coating must be layered directly on such a pharmaceutically active agent. Of course, if the pharmaceutically active agent is layered on a carrier (e.g., nu-pareil beads), the coating may be placed directly thereon.

Pharmaceutical compositions having a controlled or extended release coating can be obtained by combining a pharmaceutically active agent with a carrier (e.g., non-pareil beads) and placing an extended release coating over the combination. Such coatings may be made from polymers such as cellulose ethers (preferably ethyl cellulose), acrylic resins, other polymers, and mixtures thereof. Such controlled or extended release coatings may comprise additional excipients such as pore-formers (pore-formers), binders, and the like.

The invention disclosed herein with respect to all aspects and embodiments is intended to encompass the use of any pharmaceutically acceptable salt or derivative of hydromorphone and naloxone. Any embodiment of the invention that relates to hydromorphone and naloxone also refers to salts thereof and preferably hydrochloride salts thereof, unless otherwise indicated.

Pharmaceutically acceptable salts include, but are not limited to: inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; amino acid salts such as arginine salts, asparagine salts, glutamate salts and the like; and metal salts such as sodium salt, potassium salt, cesium salt, etc.; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N' -dibenzylethylenediamine salt and the like.

Pharmaceutically acceptable derivatives of hydromorphone and naloxone include esters as well as modified forms thereof, such as glycosylated, pegylated, or hydroxyethylated (glycosylated) forms of hydromorphone and naloxone.

Unless specifically indicated, reference to a pharmaceutically active agent (e.g., using the term "hydromorphone") shall refer only to the free base, and if reference is made hereinafter to a pharmaceutically active agent (e.g., hydromorphone), this also typically includes reference to a pharmaceutically acceptable salt or derivative of the free base of the pharmaceutically active agent.

The hydrochloride salts of both hydromorphone and naloxone are preferably used.

In a preferred embodiment, the pharmaceutical dosage form comprises hydromorphone or a pharmaceutically acceptable salt or derivative thereof or naloxone or a pharmaceutically acceptable salt or derivative thereof as the only pharmaceutically active agent.

The pharmaceutical composition may comprise from about 1mg to about 64mg, for example about 1mg, about 2mg, about 3mg, about 4mg, about 8mg, about 12mg, about 16mg, about 24mg, about 32mg, about 40mg, about 48mg, or about 64mg of hydromorphone hydrochloride or any other pharmaceutically acceptable salt or derivative (including but not limited to hydrates and solvates) or an equivalent molar amount of the free base. When referring to the amount of hydromorphone hydrochloride, this refers to anhydrous hydromorphone hydrochloride. If a hydrated form of hydromorphone hydrochloride is used, it will be used in an amount equivalent to the aforementioned anhydrous hydromorphone hydrochloride.

The pharmaceutical composition may comprise from about 0.5mg to about 256mg, such as about 0.5mg, about 0.75mg, about 1mg, about 1.5mg, about 2mg, about 4mg, about 8mg, about 12mg, about 16mg, about 24mg, about 32mg, about 48mg, about 64mg, about 96mg, about 128mg or about 256mg naloxone hydrochloride or any other pharmaceutically acceptable salt, derivative or form including but not limited to hydrates, solvates or equivalent molar amounts of the free base. When referring to the amount of naloxone hydrochloride, this refers to anhydrous naloxone hydrochloride. If a hydrated form of naloxone hydrochloride is used, it will be used in an amount equivalent to the aforementioned anhydrous naloxone hydrochloride.

In some embodiments, the present invention relates to an extended release drug coated bead composition comprising at least hydromorphone or a pharmaceutically acceptable salt or derivative thereof or naloxone or a pharmaceutically acceptable salt or derivative thereof and at least one extended release material preferably in combination with these pharmaceutically active agents; wherein the amount of hydromorphone or a pharmaceutically acceptable salt or derivative thereof and/or naloxone or a pharmaceutically acceptable salt or derivative thereof to be released in vitro in 500ml or 900ml simulated gastric fluid (ph1.2) at 100rpm at 37 ℃ using the paddle method of the european pharmacopoeia is:

at 1 hour: 25% to 55% by weight of a pharmaceutically active agent,

at 2 hours: 45% to 75% by weight of a pharmaceutically active agent,

at 3 hours: 55 to 85% by weight of a pharmaceutically active agent,

at 4 hours: 60 to 90% by weight of a pharmaceutically active agent,

at 6 hours: 70 to 100% by weight of a pharmaceutically active agent,

at 8 hours: greater than 85% by weight of a pharmaceutically active agent,

at 10 hours: greater than 90% by weight of a pharmaceutically active agent.

The pharmaceutically active agent may preferably be hydromorphone HCl and naloxone HCl. The extended release pharmaceutical compositions may contain these active agents in the amounts specified above and in a weight ratio of from about 2: 1 to about 1: 2, for example about 2: 1, about 1: 1 or about 1: 2.

In some embodiments, the present invention relates to an extended release drug coated bead composition comprising at least hydromorphone or a pharmaceutically acceptable salt or derivative thereof or naloxone or a pharmaceutically acceptable salt or derivative thereof and at least one extended release material; wherein the amount of hydromorphone and/or a pharmaceutically acceptable salt or derivative thereof or naloxone or a pharmaceutically acceptable salt or derivative thereof to be released in vitro in 500ml or 900ml simulated gastric fluid (pH1.2) at 100rpm at 37 ℃ using the Paddle method of the European pharmacopoeia is:

at 1 hour: 30 to 50% by weight of a pharmaceutically active agent,

at 2 hours: 50 to 70% by weight of a pharmaceutically active agent,

at 3 hours: 60 to 80% by weight of a pharmaceutically active agent,

at 4 hours: 65 to 85% by weight of a pharmaceutically active agent,

at 6 hours: 75 to 95% by weight of a pharmaceutically active agent,

at 8 hours: greater than 90% by weight of a pharmaceutically active agent,

at 10 hours: greater than 95% by weight of a pharmaceutically active agent.

The pharmaceutically active agent may preferably be hydromorphone HCl and naloxone HCl. The extended release pharmaceutical compositions may contain these active agents in the amounts specified above and in a weight ratio of from about 2: 1 to about 1: 2 (e.g., a weight ratio of about 2: 1, about 1: 1, or about 1: 2).

at 1 hour: 10 to 30% by weight of a pharmaceutically active agent,

at 2 hours: 34% to 54% by weight of a pharmaceutically active agent,

at 3 hours: 53 to 73% by weight of a pharmaceutically active agent,

at 4 hours: 65 to 85% by weight of a pharmaceutically active agent,

at 6 hours: 75 to 95% by weight of a pharmaceutically active agent,

at 8 hours: 80 to 100% by weight of a pharmaceutically active agent,

at 10 hours: greater than 90% by weight of a pharmaceutically active agent.

at 1 hour: 5 to 45% by weight of a pharmaceutically active agent,

at 2 hours: 15 to 55% by weight of a pharmaceutically active agent,

at 3 hours: 30 to 70% by weight of a pharmaceutically active agent,

at 4 hours: 35% to 75% by weight of a pharmaceutically active agent,

at 6 hours: 40 to 80% by weight of a pharmaceutically active agent,

at 8 hours: 50 to 90% by weight of a pharmaceutically active agent,

at 10 hours: 60 to 100% by weight of a pharmaceutically active agent,

at 12 hours: 65% to 100% by weight of a pharmaceutically active agent.

Preferably, the amount of pharmaceutically active agent released in vitro in 500ml or 900ml simulated gastric fluid (ph1.2) at 100rpm at 37 ℃ using the paddle method of the european pharmacopoeia is:

at 1 hour: 8 to 42% by weight of a pharmaceutically active agent,

at 2 hours: 18 to 52% by weight of a pharmaceutically active agent,

at 3 hours: 33% to 67% by weight of a pharmaceutically active agent,

at 4 hours: 38% to 72% by weight of a pharmaceutically active agent,

at 6 hours: 43 to 77% by weight of a pharmaceutically active agent,

at 8 hours: 53 to 87% by weight of a pharmaceutically active agent,

at 10 hours: 63% to 97% by weight of a pharmaceutically active agent,

at 12 hours: 73% to 100% by weight of a pharmaceutically active agent.

More preferably, the amount of pharmaceutically active agent released in vitro in 500ml or 900ml simulated gastric fluid (ph1.2) at 100rpm at 37 ℃ using the paddle method of the european pharmacopoeia is:

at 1 hour: 15 to 37% by weight of a pharmaceutically active agent,

at 2 hours: 25% to 47% by weight of a pharmaceutically active agent,

at 3 hours: 38% to 62% by weight of a pharmaceutically active agent,

at 4 hours: 42 to 66% by weight of a pharmaceutically active agent,

at 6 hours: 50% to 74% by weight of a pharmaceutically active agent,

at 8 hours: 60 to 84% by weight of a pharmaceutically active agent,

at 10 hours: 68 to 92% by weight of a pharmaceutically active agent,

at 12 hours: 78% to 100% by weight of a pharmaceutically active agent.

Even more preferably, the amount of pharmaceutically active agent released in vitro in 500ml or 900ml simulated gastric fluid (ph1.2) at 100rpm at 37 ℃ using the paddle method of the european pharmacopoeia is:

at 1 hour: 19% to 33% by weight of a pharmaceutically active agent,

at 2 hours: 29 to 43% by weight of a pharmaceutically active agent,

at 3 hours: 43 to 47% by weight of a pharmaceutically active agent,

at 4 hours: 47% to 61% by weight of a pharmaceutically active agent,

at 6 hours: 55 to 69% by weight of a pharmaceutically active agent,

at 8 hours: 65 to 79% by weight of a pharmaceutically active agent,

at 10 hours: 73 to 87% by weight of a pharmaceutically active agent,

at 12 hours: 83% to 100% by weight of a pharmaceutically active agent.

at 1 hour: 1 to 15% by weight of a pharmaceutically active agent,

at 2 hours: 6 to 26% by weight of a pharmaceutically active agent,

at 3 hours: 15 to 35% by weight of a pharmaceutically active agent,

at 4 hours: 25% to 45% by weight of a pharmaceutically active agent,

at 6 hours: 40 to 60% by weight of a pharmaceutically active agent,

at 8 hours: 55 to 75% by weight of a pharmaceutically active agent,

at 10 hours: 60 to 80% by weight of a pharmaceutically active agent,

at 12 hours: 70% to 100% by weight of a pharmaceutically active agent.

In the context of the present invention, storage under fortified conditions means that the pharmaceutical composition is subjected to elevated temperature and/or Relative Humidity (RH) for a long time. For example, typical fortification conditions refer to storage at 25 ℃ and 60% RH for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, or 18 months. Other fortifying conditions refer to storage at 30 ℃ and 65% RH for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or 12 months. Other fortifying conditions refer to storage at 40 ℃ and 75% RH for at least 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months.

Such enhanced storage conditions are used to determine whether a pharmaceutical composition has a shelf life sufficient for long-term storage without adversely affecting its safety and efficacy under ordinary conditions in a patient's home. Such adverse effects may include in vitro release rates that change over time, such that the therapeutic efficacy of the composition is affected by the release of varying amounts of the active agent after administration. Similarly, adverse effects may also result from degradation of the pharmaceutically active agent, which may reduce the total amount of functional pharmaceutically active agent or result in the formation of toxic by-products.

If a change in the in vitro release profile or in the amount of active agent relative to the pharmaceutical composition is observed after storage under intensive conditions, this may indicate that stability problems exist. If no such change is observed, this in turn means that the pharmaceutical composition is storage stable.

The enhanced storage conditions described above can be used to assess whether a pharmaceutical dosage form has a shelf life of at least about 12 months, at least about 18 months, at least about 24 months, or at least about 36 months. A shelf life of typically 18 months or more may be desirable as this is typically better compatible with, for example, excipients, active agents, etc. supplied for manufacturing purposes. If the pharmaceutical composition is storage stable, i.e. has substantially the same release rate, after storage at 25 ℃ and 60% RH for at least 1 month, 2 months, 3 months, 4 months, 5 months or more, this typically indicates a shelf life of at least about 12 months. If the pharmaceutical composition is storage stable, i.e. has substantially the same release rate, after storage at 30 ℃ and 65% RH for at least 1 month, 2 months, 3 months, 4 months, 5 months or more, this typically indicates a shelf life of at least about 18 months. If the pharmaceutical composition is storage stable, i.e. has substantially the same release rate, after storage at 40 ℃ and 75% RH for at least 1 month, 2 months, 3 months, 4 months, 5 months or more, this typically indicates a shelf life of at least about 24 months, e.g. 36 months.

The term "substantially the same release rate" refers to the situation wherein the in vitro release rate of a pharmaceutical composition to be subjected to the potentiating conditions is compared to a reference composition. The reference composition is the same pharmaceutical composition, but it is not subjected to the fortification conditions. The in vitro release rates are considered to be substantially identical if the in vitro release profile of the composition subjected to the potentiating conditions deviates by no more than about 20%, preferably no more than about 15%, more preferably no more than 10% and even more preferably no more than about 5% from the in vitro release profile of the reference composition.

The term "hydromorphone and/or naloxone-related substance" and the like refers to a substance formed by a chemical reaction (e.g., degradation) of hydromorphone or naloxone, pharmaceutically acceptable salts and derivatives thereof. These substances can be distinguished as known hydromorphone-related substances (where the species of the substance and its source are known), known naloxone-related substances (where the species of the substance and its source are known), and unknown substances. For unknown substances, their species are unknown. However, it is speculated to be derived from hydromorphone and/or naloxone, pharmaceutically acceptable salts and derivatives thereof. It is to be understood that the term "hydromorphone and naloxone-related substances" includes the sum of known hydromorphone-related substances, known naloxone-related substances and unknown substances and is therefore equivalent to the term "total hydromorphone and naloxone-related substances".

Terms such as "less than about 4% of substances related to hydromorphone and naloxone or to pharmaceutically acceptable salts or derivatives thereof" or "less than about 3% of substances related to hydromorphone and naloxone or to pharmaceutically acceptable salts or derivatives thereof" etc. indicate that the amount of total substances mentioned in the preceding paragraph is less than e.g. 4% or 3% by weight based on the total amount of active ingredient (i.e. hydromorphone or naloxone) present in lower amounts or pharmaceutically acceptable salts or derivatives thereof present in lower amounts in the pharmaceutical composition. Thus, if the pharmaceutical composition comprises hydromorphone HCl and naloxone HCl in a ratio of 1: 2 by weight, the amount of total material is calculated from the sum of known hydromorphone HCl related material, known naloxone HCl related material and unknown material, when the amount of hydromorphone HCl is taken as reference. If the pharmaceutical composition comprises hydromorphone HCl and naloxone HCl in a ratio of 2: 1 by weight, the amount of total substance is calculated from the sum of known hydromorphone HCl related substances, known naloxone HCl related substances and unknown substances, when the amount of naloxone HCl is used as reference.

The "known hydromorphone-related substances" include hydromorphone n-oxide, noroxymorphone (noroxymorphone), and pseudohydromorphone (pseudohydromorphone).

"known naloxone-related substances" include noroxymorphone (noroxymorphon), 10 a-hydroxynaloxone (10 a-hydroxynaloxonon), 7, 8-didehydroanaloxone (7, 8-didehydroaloxon), pseudonaloxone (pseudonaloxonon), 3-o-allylnaloxone (3-o-allylnaloxonon).

Terms such as "less than 4% of known substances related to hydromorphone or to a pharmaceutically acceptable salt or derivative thereof" or "less than 3% of known substances related to hydromorphone or to a pharmaceutically acceptable salt or derivative thereof" etc. indicate that the amount of known hydromorphone-related substances is less than, for example, 4% or 3% by weight of known hydromorphone-related substances based on the total amount of hydromorphone or pharmaceutically acceptable salts or derivatives thereof in the composition.

Terms such as "less than 4% of known naloxone-or a pharmaceutically acceptable salt or derivative thereof" or "less than 3% of known naloxone-or a pharmaceutically acceptable salt or derivative thereof" mean that the amount of known naloxone-related substances is less than e.g. 4% or 3.0% by weight of known naloxone-related substances, based on the total amount of naloxone or a pharmaceutically acceptable salt or derivative thereof in the composition.

To assess stability, the pharmaceutical composition may be subjected to the above-described fortification conditions and the amount of total hydromorphone and/or naloxone-related substances determined. The amount of total hydromorphone and/or naloxone-related substances is then determined for the same pharmaceutical composition that has not been subjected to the fortifying conditions. The composition is considered a reference composition. The detection of "total hydromorphone and/or naloxone-related substances" is usually performed by HPLC analysis using e.g. a CAT column. The amount of material (including the amount of unknown material) is then determined by calculating the area under each peak in the chromatogram. The identity of the substance can be determined by performing the same analysis using a pure known reference substance. In another aspect, the present invention aims to provide a pharmaceutical composition having less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.2% or even less than 0.1% of total substances related to hydromorphone or a pharmaceutically acceptable salt or derivative thereof and/or related to naloxone or a pharmaceutically acceptable salt or derivative thereof after storage under fortified conditions.

In another aspect, the present invention is directed to pharmaceutical compositions having less than 1% (e.g., less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than 0.1%, or even less than 0.05%) of a substance known to be associated with hydromorphone or a pharmaceutically acceptable salt or derivative thereof and less than 1% (e.g., less than 0.5%) of a substance known to be associated with naloxone or a pharmaceutically acceptable salt or derivative thereof after storage under fortified conditions.

The enhanced storage conditions may be the same as described above. Thus, typical fortification conditions may refer to storage at 25 ℃ and 60% RH, at 30 ℃ and 65% RH, or at 40 ℃ and 75% RH for more than at least 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months.

A pharmaceutical composition is therefore considered stable if it has no more than about 4% (e.g., no more than about 3%, preferably no more than about 2%, more preferably no more than about 1%, and even more preferably no more than about 0.5%) of hydromorphone and/or naloxone-related substance after subjecting it to a fortifying condition.

The extended release composition according to the present invention may be formulated into different dosage forms. For example, the extended release composition may take the form of a tablet or mini-tablet. The tablet may be a monolithic tablet comprising, for example, a continuous extended release matrix. However, tablets or mini-tablets may also be made from multiparticulates (which are compressed into tablets). Such multiparticulates may, for example, comprise an extended release matrix optionally having an immediate release phase or an active agent loaded bead having an extended release coating thereon and optionally having an immediate release phase. The dosage form may also take the form of such multiparticulates (e.g., granules or minitablets that may be filled into capsules).

The in vitro release rate of the extended release pharmaceutical composition is selected such that an in vivo therapeutic effect is achieved preferably over at least 12 hours and in some examples even up to 24 hours. Such compositions may be described as "twice a day" or "once a day" formulations, as the formulations may be administered according to such a regimen.

The extended release material may be any material known to impart controlled release properties to an active agent.

Such materials may be hydrophilic and/or hydrophobic materials, such as gums, cellulose ethers, acrylic polymers, materials from proteins, and the like.

The extension material may also include fatty acids, fatty alcohols, glycerol esters of fatty acids, polyethylene glycols, minerals and oils, and waxes. The fatty acids and fatty alcohols preferably have C₁₀To C₃₀Chain, preferably with C₁₂To C₂₄Chain and more preferably having C₁₄To C₂₀Chain or C₁₆To C₂₀Those of the chain. Materials such as stearyl alcohol, cetearyl alcohol, cetyl alcohol, myristyl alcohol, and polyalkylene glycol (polyalkylene glycol) may be preferred. The wax may be selected from natural and synthetic waxes, such as beeswax, carnauba wax. The oil may be a vegetable oil and includes, for example, castor oil.

The extended release matrix materials that are contemplated in the context of the present invention may also be selected from cellulose ethers.

The term "cellulose ether" includes polymers derived from cellulose with at least alkyl and/or hydroxyalkyl groups, which may be hydrophilic or hydrophobic.

For example, the extended release matrix material may be a hydrophilic hydroxyalkyl cellulose, such as hydroxyl (C)₁-C₆) Alkylcelluloses, such as hydroxypropylcellulose, hypromellose and especially preferably hydroxyethylcellulose.

Examples of hydrophobic cellulose ethers include, for example, ethyl cellulose. It may be preferred to use ethyl cellulose. Hydrophobic cellulose ethers such as ethyl cellulose may be particularly suitable for imparting alcohol resistance to pharmaceutical compositions.

Particularly suitable materials for the extended release matrix formulation according to the present invention may be selected from the group of acrylics. Such acrylic resins may be made of (meth) acrylic (co) polymers.

Various types of (meth) acrylic (co) polymers are available, which can be characterized according to the nature of their residues, such as neutral (meth) acrylic (co) polymers, (meth) acrylic (co) polymers with anionic residues or (meth) acrylate copolymers with cationic residues.

The neutral (meth) acrylic (co) polymer includes a polymer having 95 to 100% by weight of a polymerized monomer having a neutral residue. The monomer having a neutral residue may be C of acrylic acid or methacrylic acid₁To C₄Alkyl esters, such as methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate. For example, the neutral (meth) acrylic (co) polymer may comprise 20 to 40% by weight of ethyl acrylate and 60 to 80% by weight of methyl methacrylate. For example, such polymers may be respectively under the trade namesNE, obtained as a copolymer of 30% by weight of ethyl acrylate and 70% by weight of methyl methacrylate. The polymer is typically provided in the form of a 30% or 40% aqueous dispersion(s) (ii)NE 30D，NE 40D orNM 30D)。

The (meth) acrylic (co) polymer having functional anionic residues may be a C having 25 to 95% by weight of fully polymerized acrylic or methacrylic acid₁To C₄(meth) acrylic (co) polymers of alkyl esters and from 5 to 75% by weight of methyl acrylate monomers having an anionic group in the alkyl residue. C of acrylic acid or methacrylic acid₁To C₄Alkyl esters are also methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate. The (meth) acrylic monomer having an anionic group in the alkyl residue may be, for example, acrylic acid, and preferably methacrylic acid. Such a methacrylic copolymer having an anionic functional group may comprise, for example, 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of methyl methacrylate or 60 to 40% by weight of ethyl acrylate. These types of polymers can be used as eachL100/L12.5 orL 100-55/L30D-55.

For example,l100 is a copolymer of 50% by weight of methyl methacrylate and 50% by weight of methacrylic acid. It also served as a 12.5% solution (L12.5).L100-55 is a copolymer of 50% by weight ethyl acrylate and 50% by weight methacrylic acid. It also acts as a 30% dispersion (L30D-55).

The (meth) acrylic (co) polymer having an anionic functional group may further comprise 20 to 40% by weight of methacrylic acid and 80 to 60% by weight of methyl methacrylate. These types of polymers are generally available under the trade nameS is obtained. It also served as a 12.5% solution (S12.5). Another type of methacrylic copolymer having anionic functional groups can be sold under the trade nameFS, which typically comprises 10 to 30% by weight of methyl methacrylate, 50 to 70% by weight of methyl acrylate and 5 to 15% by weight of methacrylic acid. Therefore, the temperature of the molten metal is controlled,FS may be 25% by weight of methyl methacrylate, 65% by weight% methyl acrylate and 10% by weight of methacrylic acid. It is usually provided as a 30% dispersion (FS 30D)。

The (meth) acrylic (co) polymer having a cationic functional group may be a methacrylic copolymer having a tertiary amino group. Such copolymers may comprise from 30 to 80% by weight of C of fully polymerized acrylic or methacrylic acid₁-C₄An alkyl ester and 70 to 20% by weight of a methyl acrylate monomer having a tertiary amino group in the remainder of the alkyl group.

Suitable monomers having tertiary amino functionality are disclosed, for example, in U.S. patent 4,705,695 (see column 3, line 64 to column 4, line 13). These include, for example, dimethylaminoethyl acrylate, 2-dimethylaminopropyl acrylate, dimethylaminopropyl methacrylate, dimethylaminobenzyl acrylate, dimethylaminobenzyl methacrylate, (3-dimethylamino-2, 2-dimethyl) propyl acrylate, dimethylamino-2, 2-dimethylpropyl methacrylate, (3-diethylamino-2, 2-dimethyl) propyl acrylate and diethylamino-2, 2-dimethylpropyl methacrylate. Particularly suitable is dimethylaminoethyl methacrylate. The amount of the monomer having a tertiary amino group in the copolymer may be 20% to 70%, 40% to 60%, etc. C of acrylic acid or methacrylic acid₁To C₄The amount of alkyl ester may be within 70% to 30% by weight. C of acrylic acid or methacrylic acid₁To C₄Alcohol esters include methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, and butyl acrylate. A conventional (meth) acrylic (co) polymer having a tertiary amino group may comprise 20 to 30% by weight of methyl methacrylate, 20 to 30% by weight of butyl methacrylate, and 60 to 40% by weight of dimethylaminoethyl methacrylate. E.g. commercially availableE100 comprises 25% by weight of methyl methacrylate, 25% by weight of butyl methacrylate and 50% by weight of dimethylaminoethyl methacrylate. Another conventional commercially available polymerThe E PO comprises a copolymer of methyl methacrylate, butyl methacrylate and dimethylaminoethyl methacrylate in a ratio of 25: 50.

Another type of (meth) acrylic (co) polymer having a cationic functional group is a (meth) acrylic (co) polymer having a quaternary amino group. This type of (meth) acrylic (co) polymer typically comprises 50 to 70% fully polymerized methyl methacrylate, 20 to 40% by weight ethyl acrylate and 12 to 2% by weight 2-trimethylammoniumethyl methacrylate chloride. For example, such polymers may be referred to by the trade nameRS orRL is obtained.

For example,the RS comprises 65% by weight of fully polymerized units of methyl methacrylate, 30% by weight of ethyl acrylate and 5% by weight of 2-trimethylammoniumethyl methacrylate chloride.The RL contains 60% by weight of fully polymerized units of methyl methacrylate, 30% by weight of ethyl acrylate and 10% by weight of 2-trimethylammoniumethyl methacrylate chloride.

The amount of the extended release material in the extended release formulation may be about 5% to 90% by weight, about 10% to 70% by weight, about 20% to 60% by weight, about 20% to 55% by weight, about 25% to 50% by weight, about 25% to 45% by weight, preferably about 30% to 40% by weight, based on the weight of the pharmaceutical composition. The amount of extended release material incorporated into the composition may be one way to modulate the extended release properties. For example, if the amount of extended release material is increased, the release may be further extended. The foregoing amounts refer to the total amount of extended release material in the pharmaceutical composition. Thus, these amounts may refer to a mixture of various extended release materials such as neutral (meth) acrylic (co) polymers, hydrophobic cellulose ethers, and/or fatty alcohols.

If the cellulose ether is between the extended release materials, it is typically present in the following amounts: about 5% to about 50% by weight, about 5% to about 45% by weight, about 5% to about 40% by weight, about 5% to about 35% by weight, about 5% to about 30% by weight, about 5% to about 25% by weight, about 5% to about 20% by weight, for example about 5% by weight, about 7% by weight, about 10% by weight, about 15% by weight, about 18% by weight, about 20% by weight, based on the weight of the pharmaceutical composition.

If the fatty alcohol is between the extended release materials, it is typically present in the following amounts: about 5% to about 50% by weight, about 5% to about 45% by weight, about 5% to about 40% by weight, about 5% to about 35% by weight, about 10% to about 30% by weight, about 10% to about 25% by weight, such as about 10% by weight, about 15% by weight, about 20% by weight, or about 25% by weight, based on the weight of the pharmaceutical composition.

If the (meth) acrylic (co) polymer is between extended release materials, it is typically present in the following amounts: about 5% to about 50% by weight, about 5% to about 45% by weight, about 5% to about 40% by weight, about 5% to about 35% by weight, about 10% to about 30% by weight, about 10% to about 25% by weight, such as about 10% by weight, about 15% by weight, about 20% by weight, or about 25% by weight, based on the weight of the pharmaceutical composition.

The pharmaceutical composition according to the present invention may further comprise pharmaceutically acceptable excipients such as fillers, lubricants, binders, release rate modifiers, anti-adherents and the like.

Fillers, which may also be referred to as diluents, may include, for example, lactose (preferably anhydrous lactose), glucose or sucrose, starch, hydrolysates thereof, microcrystalline cellulose, cellatose, sugar alcohols (e.g., sorbitol or mannitol), poly-soluble calcium salts (e.g., calcium hydrogen phosphate, dicalcium phosphate or tricalcium phosphate), and combinations of two or more of the foregoing fillers.

It has been observed that the combination of hydromorphone and naloxone may be sensitive to moisture, especially when using cellulose ethers as extended release materials. In view of this, it may be preferable to use a filler that does not introduce moisture (e.g., in the form of water). In some preferred embodiments anhydrous fillers such as anhydrous lactose may therefore be used.

Lubricants can include highly dispersed silicon dioxide, talc, corn starch, magnesium oxide, and magnesium or calcium stearate, fats (e.g., hydrated castor oil), sodium stearyl fumarate, and combinations of two or more of the foregoing lubricants.

It may be preferred to use a combination of magnesium stearate and talc as a lubricant. It has been found that the flowability of granules for compression can be improved, for example, if appropriate amounts of these lubricants are selected.

Thus, it may be preferred to use the following amounts of lubricant: about 0.5% to about 4% by weight, about 0.7% to about 3% by weight, about 1% to about 2% by weight, based on the weight of the pharmaceutical composition, for example about 1.0% by weight, about 1.1% by weight, about 1.2% by weight, about 1.3% by weight, about 1.4% by weight, about 1.5% by weight, about 1.6% by weight, about 1.7% by weight, about 1.8% by weight, about 1.9% by weight, or about 2.0% by weight. Amounts of about 0.75% to about 1.25% by weight based on the weight of the pharmaceutical composition may be preferred, particularly when magnesium stearate and talc are used. The foregoing amounts refer to the amount of all lubricants (i.e., including mixtures) in the composition.

The binder may include hydroxypropyl cellulose (HPC), hypromellose, polyvinylpyrrolidone, carbopol, and combinations thereof.

It may be preferred to use HPC as a binder, as it may advantageously affect the hardness of the tablet.

Thus, it may be preferred to use the following amounts of binder: about 1% to about 10% by weight, about 2% to about 9% by weight, about 3% to about 7% by weight, about 3% to about 6% by weight, about 4% to about 5% by weight, e.g., about 4.0% by weight, about 4.1% by weight, about 4.2% by weight, about 4.3% by weight, about 4.4% by weight, about 4.5% by weight, about 4.6% by weight, about 4.7% by weight, about 4.8% by weight, about 4.9% by weight, or about 5.0% by weight, based on the weight of the pharmaceutical composition. An amount of about 4.4% to about 5.0% by weight based on the weight of the pharmaceutical composition may be preferred, especially when HPC is used as the binder. The foregoing amounts refer to the amount of all binders (i.e., including mixtures) in the composition.

It may be preferred not to use povidone as a binder.

The release rate modifier is a pharmaceutically acceptable excipient that can be used to modify the release that would otherwise be obtained using an extended release material, e.g., to accelerate the release or slow it further. Such release modifiers may be hydrophilic substances such as polyethylene glycol, hypromellose, hydroxyethylcellulose and the like or hydrophobic substances such as oils, waxes and the like. Other release modifiers may include some of the aforementioned (meth) acrylic (co) polymers, for exampleOf the RLPO typeA polymer or a gum (e.g. xanthan gum).

May preferably be such asA polymer of the RLPO type, a low molecular weight hydroxypropylmethylcellulose such as Hypromellose (Hypromellose) K100M, or a release rate modifier for xanthan gum.

Such release rate modifying agents may be present in the following amounts: about 1% to about 20% by weight, about 2% to about 19% by weight, about 3% to about 18% by weight, about 4% to about 17% by weight, about 5% to about 15% by weight, for example about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, or about 15% by weight, based on the weight of the pharmaceutical composition. The foregoing amounts refer to the amount of all release rate modifying agents (i.e., including mixtures) in the composition.

It is understood that the functions of the pharmaceutically acceptable excipients may overlap. For example, if an appropriate amount is selected, a sphering agent (e.g., microcrystalline cellulose) may also be used as a filler. Furthermore, HPMC may act not only as a release rate modifier but also as a binder if used, for example, in extended release formulations with a coating.

The extended release coating may be made of materials conventional in the art.

Thus, it may be selected, for example, from the group consisting of the following extended release materials: (i) an alkyl cellulose; (ii) an acrylic polymer; (iii) (iii) polyvinyl alcohol or (iv) mixtures thereof. Hydrophobic representatives of the aforementioned groups may be preferred. The coating may be applied in the form of an organic solution or an aqueous solution or dispersion.

In some embodiments, the controlled release coating is from an aqueous dispersion of a hydrophobic controlled release material. The coated composition may then be cured.

In some preferred embodiments, the controlled release coating includes a plasticizer, such as those described below.

In certain embodiments, the coating may be applied in an amount sufficient to obtain a weight gain level of about 2% to about 20% (e.g., about 2% to about 15% and preferably about 5% to about 10%, e.g., 6%, 7%, 8%, or 9%) to obtain a sufficiently extended release from the formulation.

Cellulosic materials and polymers including alkylcelluloses are extended release materials well suited for coating substrates (e.g., beads, granules, tablets, etc.) according to the present invention. By way of example only, one preferred alkyl cellulose polymer is ethyl cellulose.

One commercially available aqueous dispersion of ethyl cellulose isFor exampleECD30(FMC corp., philiadelphia, Pennsylvania, u.s.a.). Aquacoat is prepared by dissolving ethylcellulose in a water-immiscible organic solvent, and then emulsifying it in water in the presence of surfactants and stabilizers. After homogenization to produce submicron droplets, the organic solvent is evaporated under vacuum to form a pseudo-latex (pseudo latex).

Another aqueous dispersion of ethylcellulose as(Colorcon, Inc., WestPoint, Pennsylvania, U.S. A.). The product is prepared by incorporating a plasticizer into the dispersion during the manufacturing process. The hot melts of polymer, plasticizer (dibutyl sebacate or medium chain triglycerides) and stabilizer (oleic acid) are prepared as a homogeneous mixture and then diluted with an alkaline solution to obtain an aqueous dispersion, which can be applied directlyTo the substrate.

In other embodiments of the present invention, the extended release coating material is a pharmaceutically acceptable acrylic polymer, including but not limited to: acrylic and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, poly (acrylic acid), poly (methacrylic acid), alkyl amide methacrylate copolymers, poly (methyl methacrylate), polymethacrylates, poly (methyl methacrylate) copolymers, polyacrylamides, aminoalkyl methacrylate copolymers, poly (methacrylic anhydride), and glycidyl methacrylate copolymers.

In certain preferred embodiments, the acrylic polymer comprises one or more ammonium methacrylate copolymers. Ammonium methacrylate copolymers are well known in the art and are described as fully polymerized copolymers of acrylates and methacrylates having a small amount of quaternary ammonium groups. Typical examples includeRS30D (which is a low permeability ammonium methacrylate polymer) andRL30D (which is a highly permeable ammonium methacrylate polymer). Eudragit RL and Eudragit RS are water swellable and the amount of water absorbed by these polymers is pH dependent, however, dosage forms coated with Eudragit RL and RS are pH independent.

The acrylic coating may comprise the trade name from Rohm PharmaRL30D anda mixture of two commercially available acrylic paints from RS 30D. According to the inventionThe RL/RS dispersion can be mixed in any desired ratio to ultimately obtain an extended release formulation with a desired dissolution profile.

Other polymers that may be used as extended release coating materials, if applied in sufficient amounts, are, for example, hydrophilic polymers (e.g., hypromellose).

The coatings described above may also be applied in combination. Furthermore, the release properties of the dosage form can be influenced by increasing the amount of coating material and thus the thickness of the coating.

In some embodiments of the invention wherein the coating comprises an aqueous dispersion of a hydrophobic controlled release material, the inclusion of an effective amount of plasticizer in the aqueous dispersion of hydrophobic material may also improve the physical properties of the extended release coating. For example, because ethylcellulose has a relatively high glass transition temperature and is not capable of forming a flexible film under normal coating conditions, it may be preferred to incorporate a plasticizer into the ethylcellulose coating containing the extended release coating prior to its use as a coating material. Typically, the amount of plasticizer included in the coating solution is based on the concentration of the film former, for example, most often about 1% to about 50% by weight of the film former.

Examples of suitable plasticizers for ethylcellulose include water-insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, although other water-insoluble plasticizers (e.g., acetylated monoglycerides, phthalate esters, castor oil, etc.) may also be used. Triethyl citrate is a particularly preferred plasticizer for the aqueous dispersion of ethylcellulose of the present invention.

Examples of suitable plasticizers for the acrylic acid-based polymers of the present invention include, but are not limited to, citric acid esters (e.g., triethyl citrate NF XVI, tributyl citrate), dibutyl phthalate, and possibly 1, 2-propylene glycol. Have proven suitable for reinforcing films made of acrylic acid (for exampleRL/RS lacquer solutions) include polyethylene glycol, polypropylene glycol, diethyl phthalate, castor oil, and glyceryl triacetate.

The pharmaceutical compositions according to the invention described herein may be formulated to provide an average AUCt of from about 1162 to about 2241 and preferably from about 1328 to about 2075h pg/ml per mg of hydromorphone administered and an average Cmax of from about 122 to about 234 and preferably from about 139 to about 218pg/ml per mg of hydromorphone administered and an average tmax of from about 1 to about 4.5 hours, preferably from about 1.5 to about 4 hours and more preferably from about 1.5 to about 3 hours. These values are preferably single dose administration to healthy subjects. Preferably, administration is in the fasted state. The mean values of Cmax, AUCt and tmax are geometric mean values.

Pharmaceutical compositions according to the invention described herein (particularly embodiments of the coated beads) can be formulated to provide an average AUCt of from about 5.900ng ah/mL to about 8.400ng ah/mL and preferably from about 6.500ng hg/mL to about 8.400ng hg/mL per mg hydromorphone administered and an average Cmax of from about 0.390ng/mL to about 0.726ng/mL and preferably from about 0.590ng/mL to about 0.726ng/mL per mg hydromorphone administered and an average tmax of from about 1 hour to about 4.5 hours, preferably from about 1.5 hours to about 4 hours and more preferably from about 4.0 hours to about 6.5 hours. These values are preferably single dose administration to healthy subjects. Preferably, administration is in the fasted state. The mean values of Cmax, AUCt and tmax are geometric mean values.

"Cmax value" indicates the maximum plasma concentration of the active agent hydromorphone.

"tmax value" indicates the point in time at which the Cmax value is reached. In other words, tmax is the point in time at which the maximum plasma concentration is observed.

The "AUC (area under the curve)" value corresponds to the area of the concentration curve. The AUC value is proportional to the total amount of active agent absorbed into the blood circulation and is therefore a measure of bioavailability.

The "AUCt value" is the value of the area under the plasma concentration-time curve from the time of administration versus the final measurable concentration. The AUCt value is usually calculated using a linear trapezoidal method.

When measuring pharmacokinetic parameters such as mean t of healthy subjects (which may be healthy persons)_max、c_maxAnd AUCt, which is typically obtained by measuring the development of plasma values over time in a test population of about 16 to 24 healthy human subjects. Regulatory agencies such as the European drug administration for the Evaluation of medicinal products (EMEA) or the U.S. Food and Drug Administration (FDA) typically receive data obtained from, for example, 16 or 24 testers. However, initial trials involving fewer participants (e.g., 8-bit to 16-bit participants) may also be acceptable.

The term "healthy" subject in this context refers to a typical male or female, usually caucasian, with average values of height, weight and physiological parameters (e.g. blood pressure, etc.). Healthy human subjects for the purposes of the present invention are selected according to inclusion and exclusion criteria based on and recommended by the International Conference for harmony of Clinical Trials (ICH).

For the purposes of the present invention, healthy subjects can be identified according to conventional inclusion and exclusion criteria.

Thus, inclusion criteria include, for example, an age of ≧ 18 years and ≦ 45 years; 19kg/m²To 29kg/m²BMI in the range, as well as male body weight in the range of 60kg to 100kg and female body weight in the range of 55kg to 90kg, women must be non-nursing, non-pregnant, and provide a negative urine β -hCG pregnancy test within 24 hours prior to receiving the study medication, a generally good health status, as evidenced by the finding that there are no significant abnormalities in medical history, physical examinations, clinical laboratory tests, vital signs, ECG, and the like.

Exclusion criteria included, for example, exposure to any study drug (intravenous drug) or placebo within 3 months of the first dose of the test drug (study medication); any significant disease occurred within 30 days before the first administration of the test drug; identifying any clinically significant abnormalities in medical history, physical examination or laboratory analysis at screening prior to the study; any prescribed medication (except contraceptives and HRT for menopausal women) is used within 21 days before the first administration of the test medication, or over-the-counter medications are used within 7 days, including acid control agents, vitamins, herbal products and/or mineral supplements; concurrent medical conditions known to interfere with gastrointestinal drug absorption (e.g., delay of gastric emptying, malabsorption syndrome), distribution (e.g., obesity), metabolism, or excretion (e.g., hepatitis, glomerulonephritis); or a history of a concurrent medical condition that the researcher considers to compromise the ability of the subject to safely complete the study; a history of epileptic seizures for which a subject is in need of pharmacological treatment; the current smoking history of more than 5 cigarettes a day; a subject having evidence of a past history of abuse of an active agent or of abuse of a substance or alcohol according to DSM-IV criteria; reporting subjects who regularly ingest 2 or more alcoholic drinks per day or who have a blood alcohol level of greater than or equal to 0.5% at the time of screening; donate more than 500mL of blood or blood products or other large blood losses in 3 months prior to the first administration of the test drug; ethanol, opioids, barbiturates, amphetamines, cocaine metabolites, methadone, propoxyphene, phencyclidine, benzodiazepine, which are known to be sensitive to hydromorphone, naloxone, or related compounds in urine specimens collected at screening in pre-study screeningAny positive result in classes and cannabinoids.

Pharmaceutically acceptable excipients may include fillers, binders, lubricants, release rate modifiers, spheronizing agents, anti-adherent agents, and the like, as mentioned above. However, some of these excipients (e.g., lubricants) may be added at a later stage.

Such particles can be obtained by different techniques. For example, drum granulation or fluid bed granulation may be used.

The granules produced by wet granulation extrusion may be dried prior to mixing with the at least one pharmaceutically active agent.

Typically, drying is carried out at a humidity of about 0.5% to about 5.0% at a temperature of about 20 ℃ to about 90 ℃ for a time of about 10 minutes to about 3 hours. Drying and holding at a temperature of about 40 ℃ to about 90 ℃ for a time period of about 15 minutes to about 2 hours may be preferred at ambient humidity.

The particles may then optionally be screened to select particles of substantially uniform size. Selecting substantially uniformly sized particles prior to compressing them may improve the extended-release properties of the final extended-release pharmaceutical composition, since it is then assumed that the active agent and particles exhibit a more uniform distribution, which may prevent irregularities in the release profile. Particles at least about 70%, preferably at least about 80%, more preferably at least about 90% of which are about the same average size are generally considered to be substantially uniformly sized particles.

Preferably, the following average size particles are selected: from about 100 μm to about 2mm, more preferably from about 100 μm to about 1mm, and even more preferably from about 100 μm to about 600 μm. Selection may be made using a sieve having an appropriate mesh size.

In some embodiments, the particles may be milled prior to selection of the particle size. Milling can increase the yield of the selection step and improve the suitability of the granules for a subsequent pressing step. For the grinding, for example, a rotary hammer mill (rotary hammer mill) or a top/bottom driven cone mill (chemical mill) can be used.

For compression of the pharmaceutically active agent with the granules, typical tabletting equipment may be used, such as a Fette or Kilian tabletting machine.

When compressing the granules and active agent, pharmaceutically acceptable excipients may also be included as they are commonly used in the art. For example, lubricants, anti-adherents, binders, and the like may be added. For lubricants, magnesium stearate and/or talc used in the aforementioned amounts may be advantageous.

As mentioned above, the extended release pharmaceutical dosage form according to the invention may additionally be subjected to a heat treatment step as already described above.

The extended release coating may be produced by methods conventional in the art, such as fluidized bed spraying.

Various embodiments of the present application will be illustrated with reference to the following non-limiting examples, which should not be used to interpret the scope of the invention.

Examples

While the embodiments illustrated below focus on such extended release dosage forms in the form of coated beads, it is believed that improvements in stability and/or dissolution properties may also be found in other dosage forms, such as those described in Danagher. Thus, it is believed that improvements in stability and/or dissolution properties may also be found in other dosage forms (e.g., matrix dosage forms, etc.) comprising as active ingredients (i) hydromorphone or a pharmaceutically acceptable salt thereof and (ii) naloxone or a pharmaceutically acceptable salt form thereof. Thus, the present invention is intended to encompass these additional extended release dosage forms.

The controlled release bead formulations from formulation a and formulation B in example 18 of Danagher were further improved to meet the stability requirements for the relevant substances and dissolution release rates over the shelf life of the product. It has been found that inclusion of an oxidizing agent (e.g., sodium metabisulfite) in combination with a chelating agent (e.g., sodium EDTA) in formulations a and B of example 18 of Danager results in an improvement in total impurities at the recommended shelf life of 24 months-i.e., an improvement in formulation stability.

A number of variables were studied and excipients were identified and adjusted based on the study to obtain a finished product that was stable over the shelf life of the product. The general method of manufacture is described below, followed by a variety of studies and findings.

Controlled release multiparticulate bead formulations of hydromorphone and naloxone can be conveniently manufactured in the following 3 stages: (i) (ii) immediate release coating (drug layering), controlled release coating and (iii) outer coating. In the following examples, all 3 stages were carried out in a fluidized bed dryer with a Wurster column.

Example 1

This example involves the addition of one or both of an antioxidant (e.g., sodium metabisulfite) and a chelating agent (e.g., ethylenediaminetetraacetic acid disodium salt dihydrate). These are added at the drug layering stage to prevent any degradation of the active pharmaceutical ingredient. Pharmaceutical formulations were produced according to the details shown in table 1. It should be noted that formulation a and formulation B are the same as those in example 18 of Danagher-these formulations do not contain antioxidants and/or chelating agents.

TABLE 1 Effect of antioxidants and chelating Agents on Total impurities

From the stability data it can be concluded that the addition of sodium metabisulfite and disodium ethylenediaminetetraacetate dihydrate improved the stability of hydromorphone HCl and naloxone HCl in the finished product. Based on these results, it is believed that the use of an antioxidant (e.g., sodium metabisulfite) and a chelating agent (e.g., ethylenediaminetetraacetic acid disodium salt dihydrate) for the drug layer results in an improvement in formulation stability.

Example 2

This embodiment focuses on the core substrate. In particular, during the drug layering process, an aqueous solution is prepared by mixing hydromorphone HCl/naloxone HCl with a binder (e.g., hypromellose, polyethylene glycol film coating concentrate, or polyvinyl alcohol-polyethylene glycol graft copolymer), and sodium metabisulfite and disodium ethylenediaminetetraacetate dihydrate. The solution is sprayed onto a core substrate.

The core substrate type was varied to see the effect on the degradation stability profile of the finished product. Initial evaluation indicated that sugar spheres may be incompatible with hydromorphone HCl and naloxone HCl. Thus, four types of substrates were then selected to produce the formulation based on the details listed in table 2:

(1) microcrystalline cellulose spheres (MCC spheres,700)，

(2) microcrystalline cellulose spheres (MCC spheres,700) the shape of the ball, as described for the KPM ball,

(3) silica spheres, and

(4) mannitol-polyvinylpyrrolidone spheres (18/20 mesh).

TABLE 2 Effect of core substrate on Total impurities

Addition to Kollicoat Protect

The stability data indicates that the starting core substrate material has a significant effect on the amount of total impurities in the finished product. Based on the accelerated stability data, it is evident that mannitol-polyvinylpyrrolidone spheres and KPM spheres are more effective in providing more stable finished products in controlling the formation of degradation products. Furthermore, it has been determined that mannitol-polyvinylpyrrolidone spheres are more effective in controlling unknown degradation products, whereas KPM spheres are more effective in controlling known degradation products than MCC spheres. However, mannitol-polyvinylpyrrolidone and microcrystalline cellulose uncoated spheres more effectively control the formation of unknown degradation products in the finished product. Thus, mannitol-polyvinylpyrrolidone and microcrystalline cellulose uncoated spheres are considered to be superior overall for use in the extended release dosage form of the present invention.

Thus, during the drug layering process, an aqueous solution is prepared by mixing hydromorphone HCl, naloxone HCl, sodium metabisulfite, disodium edetate dihydrate, and hypromellose, polyethylene glycol film coating concentrate, or polyvinyl alcohol-polyethylene glycol graft copolymer in water. The clear solution was then sprayed onto microcrystalline cellulose spheres (MCC spheres) or mannitol-polyvinylpyrrolidone spheres to make Immediate Release (IR) beads.

Controlled Release (CR) beads (also referred to throughout the specification as extended release) are produced by coating IR beads with a dispersion of an aqueous ethylcellulose dispersion and a porogen (e.g., a polyethylene glycol film coating concentrate). The amount of the controlled release suspension is optimized by applying several different ratios (80: 20 to 97: 3) of aqueous ethylcellulose dispersion to polyethylene glycol film coating concentrate, depending on the equipment and manufacturing batch size. The percent weight gain (8% to 17%) was also varied to effectively control the release rate and achieve the same target dissolution profile as each of formulation a and formulation B in example 18B of Danagher.

Example 3

This example focuses on the use of an outer coating on controlled release beads to achieve the desired dissolution and total impurity levels and, if desired, the effect of the polymer used at the stage of the outer coating process on the stability and dissolution rate of the product. Details of the formulations produced in this example are listed in table 3.

TABLE 3 Effect of the outer coating on the dissolution Release Rate over time

Addition to Kollicoat Protect

TABLE 3-continuous. Effect of the outer coating on the dissolution Release Rate over time

This result of this example clearly demonstrates the advantageous effect of adding an outer coating to the controlled release beads. It can be concluded that the addition of polymer has an improved effect on the stability of the finished product. The addition of an outer coating increases the dissolution rate of the beads during the controlled release phase. When polyvinyl alcohol-polyethylene glycol graft copolymer was added at a weight gain of 2% to 3% of the controlled release bead, the increase was less than 5%. In all other cases, whether another polymer is added to the controlled release beads or no outer coating is added, the release rate is greater than 5% and continues to increase over time. In addition, other polymers commonly used as moisture control barrier polymers (e.g., Opadry clear, Opadry amb, Opadry 200, and Kollicoat Protect) do not provide significant moisture protection as does polyvinyl alcohol-polyethylene glycol graft copolymer. When the stability data shows 4.99% total impurities held at 60 ℃/95% RH for 96 hours, no dissolution test of batch HN1207 was performed.

Batch PT120027 and its overcoat batch PT120028 clearly show less than 5% change in dissolution release profile at different time points.

Batches PT120028 and HN1216KU, in which polyvinyl alcohol-polyethylene glycol graft copolymer was added at a weight gain of 2% to 3% during the manufacture of the outer coated beads, also showed less than 10% change in dissolution rate over time.

Based on the results in this example, the controlled release beads were more stable when coated with an aqueous solution of polyvinyl alcohol-polyethylene glycol graft copolymer at stage 3 of the manufacturing process.

The dissolution rate is an important quality attribute of the finished product, which can be controlled by the addition of a polyvinyl alcohol-polyethylene glycol graft copolymer as an over-coating system, as set forth in the results of this example. Note that both formulation a and formulation B in example 18 of Danagher do not contain this polymer in the outer coating layer.

The following plant process conditions were used in this example:

equipment: GPCG1 Wurster coating machine

Nozzle diameter: 1.0mm

Atomization pressure: 2 bar

Air flow rate: 6 to 7m/s

The coating temperatures and spray rates used at the various stages are provided in table 4.

TABLE 4 Process parameters during the manufacturing Process

Example 4

In this example, a number of pharmaceutical formulations were prepared based on the details listed in table 5.

The batch (bulk) beads were filled into hard shell capsules. This can be done using hydroxypropylmethylcellulose (also known as hypromellose) or hard gelatin capsules. The study focused on determining the effect of capsule shell type on product stability.

TABLE 5 Effect of capsule Shell type on Total impurities

Hard gelatin capsules and hypromellose were used to encapsulate the final batch of product (outer coated beads) and stability studies were performed simultaneously. The stability data shows a significant reduction in degradation product levels in hypromellose capsules. The results in this study demonstrate that the use of hypromellose capsules instead of hard gelatin capsules facilitates the production of finished products that meet the total impurity requirements over the shelf life of the product. Note that formulations a and B in Danagher example 18 were encapsulated in hard gelatin capsules instead of hypromellose capsules.

Test method

In the above examples, a number of test results were reported. The following methods were used to develop the test results.

Dissolution of various formulations was performed in 900ml simulated gastric fluid (without enzymes) at 37 ℃ at 100rpm using the basket method of USP. Samples were withdrawn at various time points and analyzed on HPLC using a UV detector. In vitro release data are expressed as a percentage of dissolution based on the labeled level of active agent tested.

The impurities of various formulations were determined using a gradient HPLC method. The sample was extracted with methanol and water and separated on a reverse phase column using a mobile phase consisting of potassium dihydrogen phosphate buffer and methanol. The active agent and impurities were detected with a UV detector. The results for known degradation products and individual unknown degradation products as well as total impurities are reported in%.

While the present invention has been described with reference to exemplary embodiments and examples, the description is not intended to be construed in a limiting sense. Thus, many modifications and other embodiments of the exemplary embodiments of this invention will be apparent to those skilled in the art in view of this description. It is, therefore, contemplated that the appended claims will cover any such modifications or embodiments.

All publications, patents, and patent applications cited herein are incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application were specifically and individually indicated to be incorporated by reference in its entirety.

Claims

1. An extended release pharmaceutical dosage form comprising a plurality of coated beads, each of said coated beads comprising:

(a) particles;

(b) a first layer coated on the particle, the first layer comprising: (i) hydromorphone or a pharmaceutically acceptable salt thereof, (ii) naloxone or a pharmaceutically acceptable salt thereof, (iii) an antioxidant compound, and (iii) a chelating compound; and

(c) a second layer coated on the first layer, the second layer comprising an extended release agent,

wherein the antioxidant compound comprises sodium metabisulfite,

wherein the chelating compound comprises ethylenediaminetetraacetic acid and/or an ethylenediaminetetraacetate salt,

wherein the antioxidant compound is present in an amount of 0.001% to 1.0% by weight of the first layer, and

wherein the chelating compound is present in an amount of 0.005% to 0.1% by weight of the first layer.

2. The extended release pharmaceutical dosage form according to claim 1, wherein (i) and (ii) are present in a weight ratio of from 2: 1 to 1: 2.

3. An extended release pharmaceutical dosage form according to claim 1 or 2, wherein (i) is a pharmaceutically acceptable salt of hydromorphone.

4. The extended release pharmaceutical dosage form according to claim 1 or 2, wherein (i) is hydromorphone hydrochloride.

5. The extended release pharmaceutical dosage form according to claim 1 or 2, wherein (ii) is a pharmaceutically acceptable salt of naloxone.

6. The extended release pharmaceutical dosage form according to claim 1 or 2, wherein (ii) is naloxone hydrochloride.

7. The extended release pharmaceutical dosage form according to claim 1 or 2, wherein the extended release agent is selected from the group consisting of: hydrophobic polymers, hydrophilic polymers, materials from proteins, gums, substituted or unsubstituted hydrocarbons, digestible carbohydrates, fatty acids, fatty alcohols, glycerides of fatty acids, natural oils, synthetic oils, natural waxes, synthetic waxes and any mixture of two or more of any of these.

8. The extended release pharmaceutical dosage form according to claim 1 or 2, wherein the extended release agent is selected from the group consisting of: cellulose ethers, acrylic acid-based polymers, acrylic acid-based copolymers, methacrylic acid-based polymers, methacrylic acid-based copolymers, fatty alcohols, and any mixtures of two or more of any of these.

9. The extended release pharmaceutical dosage form according to claim 1 or 2, wherein the extended release agent is selected from the group consisting of: neutral acrylic acid-based polymers, neutral acrylic acid-based copolymers, neutral methacrylic acid-based polymers, neutral methacrylic acid-based copolymers, hydrophobic cellulose ethers, fatty alcohols, and any mixtures of two or more of any of these.

10. The extended release pharmaceutical dosage form according to claim 1 or 2, wherein the extended release agent is ethylcellulose.

11. The extended release pharmaceutical dosage form according to claim 1 or 2, wherein the particles are selected from uncoated microcrystalline cellulose particles and mannitol-polyvinylpyrrolidone particles.

12. The extended release pharmaceutical dosage form according to claim 1 or 2, further comprising:

(d) a third layer coated on the second layer, the third layer comprising a moisture resistant agent.

13. The extended release pharmaceutical dosage form according to claim 12, wherein the moisture barrier comprises a polyvinyl alcohol-polyethylene glycol graft copolymer.

14. The extended release pharmaceutical dosage form according to claim 1 or 2, in the form of a capsule.

15. The extended release pharmaceutical dosage form of claim 14, wherein the capsule comprises a plurality of coated beads.

16. The extended release pharmaceutical dosage form according to claim 14, wherein the capsule is a hydroxypropyl methylcellulose capsule.

17. A coated bead comprising:

(a) particles;

wherein the antioxidant compound comprises sodium metabisulfite,

18. The coated bead defined in claim 17, wherein (i) and (ii) are present in a weight ratio of from 2: 1 to 1: 2.

19. The coated bead defined in claim 17 or claim 18, wherein (i) is a pharmaceutically acceptable salt of hydromorphone.

20. The coated bead defined in claim 17 or claim 18, wherein (i) is hydromorphone hydrochloride.

21. The coated bead defined in claim 17 or 18, wherein (ii) is a pharmaceutically acceptable salt of naloxone.

22. The coated bead defined in claim 17 or 18, wherein (ii) is naloxone hydrochloride.

23. The coated bead defined in claim 17 or 18, wherein the extended-release agent is selected from the group consisting of: hydrophobic polymers, hydrophilic polymers, materials from proteins, gums, substituted or unsubstituted hydrocarbons, digestible carbohydrates, fatty acids, fatty alcohols, glycerides of fatty acids, natural oils, synthetic oils, natural waxes, synthetic waxes and any mixture of two or more of any of these.

24. The coated bead defined in claim 17 or 18, wherein the extended-release agent is selected from the group consisting of: cellulose ethers, acrylic acid-based polymers, acrylic acid-based copolymers, methacrylic acid-based polymers, methacrylic acid-based copolymers, fatty alcohols, and any mixtures of two or more of any of these.

25. The coated bead defined in claim 17 or 18, wherein the extended-release agent is selected from the group consisting of: neutral acrylic acid-based polymers, neutral acrylic acid-based copolymers, neutral methacrylic acid-based polymers, neutral methacrylic acid-based copolymers, hydrophobic cellulose ethers, fatty alcohols, and any mixtures of two or more of any of these.

26. The coated bead defined in claim 17 or 18, wherein the extended release agent is ethylcellulose.

27. The coated bead defined in claim 17 or claim 18, wherein the granule is selected from the group consisting of an uncoated microcrystalline cellulose granule and a mannitol-polyvinylpyrrolidone granule.

28. The coated bead defined in claim 17 or 18, further comprising:

29. The coated bead defined in claim 28, wherein the moisture barrier agent comprises a polyvinyl alcohol-polyethylene glycol graft copolymer.

30. An extended release pharmaceutical dosage form comprising a plurality of coated beads disposed in a hydroxypropyl methylcellulose capsule, each of said coated beads comprising:

(a) particles;

(b) a first layer coated on the particle, the first layer comprising: (i) hydromorphone hydrochloride, (ii) naloxone hydrochloride, (iii) an antioxidant compound, and (iii) a chelating compound, wherein (i) and (ii) are present in a weight ratio of 2: 1;

(d) a third layer coated on the second layer, the third layer comprising a polyvinyl alcohol-polyethylene glycol graft copolymer,

wherein the antioxidant compound comprises sodium metabisulfite,

31. The extended release pharmaceutical dosage form according to claim 30, wherein the particles are uncoated microcrystalline cellulose particles.

32. The extended release pharmaceutical dosage form according to claim 30, wherein the particles are mannitol-polyvinylpyrrolidone particles.

33. Use of an antioxidant compound in combination with a chelating compound for improving the stability and/or dissolution properties of an extended release dosage form comprising (i) hydromorphone or a pharmaceutically acceptable salt thereof and (ii) naloxone or a pharmaceutically acceptable salt thereof, wherein the antioxidant compound comprises sodium metabisulfite and wherein the chelating compound comprises ethylenediaminetetraacetic acid and/or ethylenediaminetetraacetate salt, wherein the antioxidant compound is present in an amount of 0.001 to 1.0% by weight of the drug-containing part of the extended release dosage form and wherein the chelating compound is present in an amount of 0.005 to 0.1% by weight of the drug-containing part of the extended release dosage form.

34. The use of claim 33, wherein the dosage form is a matrix dosage form.

35. The use of claim 33, wherein the dosage form is a coated bead dosage form.

36. The use of claim 33, wherein the dosage form is a coated granular dosage form.

37. Use according to any one of claims 33 to 36, wherein (i) and (ii) are present in a weight ratio of from 2: 1 to 1: 2.

38. The use according to any one of claims 33 to 36, wherein (i) is a pharmaceutically acceptable salt of hydromorphone.

39. Use according to any one of claims 33 to 36, wherein (i) is hydromorphone hydrochloride.

40. The use according to any one of claims 33 to 36, wherein (ii) is a pharmaceutically acceptable salt of naloxone.

41. The use according to any one of claims 33 to 36, wherein (ii) is naloxone hydrochloride.