HK1102769A - Opioids for the treatment of the restless leg syndrome - Google Patents

Description

Opioids for the treatment of Restless Leg Syndrome (RLS)

Technical Field

The present invention relates to the treatment of Restless Leg Syndrome (RLS). In particular, the invention relates to the use of opioids for the manufacture of a formulation for the treatment of RLS. The formulations of the present invention may be used to treat RLS-related insomnia and sleep disorders.

Background

Restless Leg Syndrome (RLS) is a neurological disorder characterized by unpleasant sensations in the legs and uncontrollable desire to move at rest to reduce these sensations. The RLS sensation is often described by people as burning, peristalsis, traction, or crawling like worms in the legs. Commonly referred to as paresthesia (abnormal sensation) or dysesthesia (unpleasant abnormal sensation) with sensation severity varying from uncomfortable to irritating to painful.

The most prominent or unusual feature of the symptoms is the activation of the syndrome when lying down and attempting to rest. As a result, most RLS patients have difficulty falling asleep and maintaining sleep. If left untreated, the symptoms can cause fatigue and daytime fatigue. Many RLS patients teach their work, interpersonal relationships, and activities of daily living are severely affected by this fatigue. They often fail to focus, have impaired memory, or perform daily tasks.

RLS occurs in both men and women, but the incidence is somewhat higher in women. Although the syndrome may occur at any age, even early in the young, most patients are severely ill in the middle or late years. Furthermore, as age increases, the disorder is more severe. The symptoms occur more frequently and for longer periods in elderly patients.

More than 80% of RLS patients also develop the more common known symptoms of Periodic Leg Movement (PLMD). PLMD is characterized by involuntary leg cramps or twitches that typically occur every 10-60 seconds during sleep, sometimes overnight. The syndrome causes repeated wakefulness from sleep and severe sleep interruptions. Unlike RLS, PLMD-induced activities are involuntary-the patient cannot control these activities. While most patients with RLS also develop PLMD, patients with PLMD do not typically develop RLS. Unlike RLS, the reason for PLMD is unknown. "treatment of RLS" within the meaning of the present invention also refers to "treatment of RLS and/or PLMD".

As mentioned above, RLS patients feel uncomfortable in their legs, especially when sitting or lying down, with a desire for irresistible activity. These sensations typically occur in the interior of the leg, between the knee and ankle; rarely occurs at the feet, thighs, arms and hands. Although sensation occurs only on one side of the body, most commonly bilateral attacks.

As moving the legs (or other affected parts of the body) reduces restlessness, RLS patients often maintain leg motion to reduce or prevent this sensation. They pace on the floor, often moving their legs while sitting and turning over on the bed.

Most patients find the daytime symptoms to be less pronounced and the night or nighttime symptoms to be more pronounced. Many patients lose symptoms in the early morning, during which time they can fall asleep again. Other triggering conditions are periods of inactivity such as long distance travel, sitting in a movie theater, long distance flight, holding in a mold, or during relaxation training.

The severity and duration of symptoms of RLS varies from person to person. Mild RLS episodes are intermittent, with only mild interruptions to sleep and less cause anxiety. In moderate to severe cases, symptoms occur only 1 or 2 times per week but sleep is severely delayed and some daytime activity is interrupted. In severe RLS cases, symptoms appear more than 2 times per week and result in excessive sleep disruption and impaired daytime activity.

Symptoms can begin at any stage of life, but the more common the disease is with age. Sometimes people experience spontaneous improvement over a period of weeks or months. Although rare, spontaneous improvement over the course of years can also occur. These improvements, if they occur, are usually in the early stages of the disease. However, in general, symptoms become more severe over time.

Generally, dopaminergic drugs, primarily used for the treatment of parkinson's disease, have been shown to alleviate RLS symptoms and PLMD and are considered as the initial treatment option. Benzodiazepines  (such as clonazepam and diazepam) may be prescribed for patients with mild or moderate symptoms. These drugs help patients to sleep more calmly but do not fully alleviate RLS symptoms and can cause daytime sleep.

Anticonvulsants such as carbamazepine and gabapentin are also used in some patients because they reduce sensory disturbances (crawling and peristaltic sensations). Possible side effects are dizziness, fatigue and sleep.

The use of opioids is suggested for the treatment of RLS. However, there remains a need for formulations comprising opioids that have improved patient compliance and facilitate constant administration. Long-term compliance is highly desirable.

Disclosure of Invention

It is an object of the present invention to provide an opioid oral dosage form having a long-term duration of action of preferably at least 12h, more preferably at least 24h, for the treatment of moderate to severe RLS symptoms, preferably severe RLS symptoms.

It is a further object of the present invention to provide an opioid formulation as previously described which causes fewer side effects such as respiratory depression and obstipation, and has abuse-preventing characteristics.

The invention also comprises methods of treating patients with RLS symptoms using one of the formulations of the invention and the use of these formulations in the manufacture of pharmaceutical formulations for the treatment of RLS patients.

Detailed Description

In the context of the present invention, the terms "opioid composition" or "opioid" or "active substance" are used interchangeably and are considered to include opioid agonists, opioid antagonists, mixed opioid antagonists/agonists and mixtures thereof. The formulation according to the invention comprises at least one opioid.

In the context of the present invention, the terms "slow release formulation or dosage form" or "controlled release formulation or dosage form", "extended release formulation or dosage form" or "sustained release formulation or dosage form" or "formulation or dosage form with extended duration of action" are used interchangeably and are to be understood as a formulation or dosage form which exhibits an extended release profile for the added active substance and provides a sufficient therapeutic effect for at least 12 hours in the steady state.

The present invention is based on the fact that opioid agonists are used to treat RLS/PLMD symptoms such as unpleasant sensation in the legs and uncontrollable desire to move while attending a certain event, difficulty in lying down and trying to relax and the associated difficulty in falling and/or maintaining sleep. In particular, the use of opioid sustained release oral dosage forms leads to better patient compliance and sustained administration to the patient, while being less limited by day and night dosing. The minimum amount of drug required for treatment can be administered, thereby reducing the risk of side effects and addiction. In particular, the combination of opioid agonist and antagonist is beneficial in reducing side effects and also reducing the risk of abuse.

Active ingredient

Opioid agonists according to the present invention include all compounds belonging to the NO2A class of opioid analgesics according to the ATC classification of the WHO and showing a therapeutic effect for the use according to the present invention. The formulation according to the invention comprises at least one opioid. The opioid agonist is preferably selected from morphine, oxycodone, hydromorphone, propoxyphene, nicotinoylmorphine, dihydrocodeine, heroin, opium alkaloid, codeine, ethylmorphine, phenylpiperidine and derivatives thereof, methadone, dextropropoxyphene, buprenorphine, pentazocine, tilidine, tramadol and dihydrocodeinone. Further examples of analgesics which may be used according to the invention are meperidine, oxymorphone, alfadine, meperidine, dextro-moramide, hydromorphone, levorphanol, phenazocine, etoheprazine, propiram, phenazopyrrole, finasteride, thienylcrotamine, folacin, codeine, dihydrocodeinone, fentanyl, 3-trans-dimethylamino-4-phenyl-4-trans-ethoxycarbonyl- Λ ' -cycloethylene, 3-dimethylamino-0- (4-methoxyphenyl-carbamoyl) -phenylethylketoxime, (-) beta-2 ' -hydroxy-2, 9-dimethyl-5-phenyl-6, 7-benzomorphan (benzomorphane), (-)2 ' -hydroxy-2- (3-methyl-2-butenyl) - 9-methyl-5-phenyl-6, 7-benzomorphane, cyanophenylpamide, (-) alpha-5, 9-diethyl-2' -hydroxy-2-methyl-6, 7-benzomorphane, ethyl 1- (2-dimethylaminoethyl) -4, 5, 6, 7-tetrahydro-3-methyl-4-oxo-6-phenyl-indole-2-carboxylate, 1-benzoylmethyl-2, 3-dimethyl-3- (m-hydroxy-phenyl) -piperidine, N-allyl-7 alpha (1-R-hydroxy-1-methylbutyl) -6, 14-endo-ethylidenetetrahydronorpapaverine, norpapaverine, norargemonine, and its use, (-) 2' -hydroxy-2-methyl-6, 7-benzomorphan, noracylmethoxamine, cumylpipedate, alpha-d 1-methoxamine, alpha-1-methoxamine, beta-d 1-acetylmethoxamine, alpha-1-acetylmethoxamine and beta-1-acetylmethoxamine. These lists are not to be construed as exclusive.

Particularly preferred opioid agonists with analgesic effect are oxycodone, dihydrocodeinone, hydromorphone, morphine, methadone, oxymorphone, fentanyl and sufentanil. More preferred embodiments comprise oxycodone or morphine.

Antagonists according to the present invention include compounds that are against opioid agonists (as defined previously). These compounds can also be found in the ATC classification of the WHO. According to the present invention, compounds are preferred which, when used according to the present invention, reduce the side effects, habitual effects and addictive potential caused by opioid agonists. Antagonists may include naltrexone, naloxone, nalmefene, nalprofen, nalbuphine, naloxonexazine, methylnaltrexone, ketyclazone, norbinaltorphimine, naldroindole, 6-beta-naloxonol (naloxonol), and 6-beta-naltrexone, among others.

Particularly preferred antagonists include naltrexone, nalmefene and naloxone. More preferred embodiments include naloxone.

A particularly preferred embodiment of the invention comprises a combination of oxycodone and naloxone in a sustained release oral dosage form. Preferably the oxycodone is present in excess of the unit dose of naloxone.

In the case of oxycodone and naloxone, the preferred weight ratio of agonist and antagonist is at most 25: 1, preferably at most 20: 1, with weight ratios in the range of 15: 1 and 10: 1 being particularly preferred, and 5: 1, 4: 1, 3: 1, 2: 1 and 1: 1 being more preferred.

The absolute amounts of agonist and antagonist used will depend on the choice of active compound. Preferably, the agonist and antagonist are released from the pharmaceutical formulation only in an independent and invariant manner.

If oxycodone and naloxone are used in a combined preparation, the oxycodone is preferably used in an amount of 10 to 150mg, particularly preferably 10 to 80mg (typical amount), and naloxone is preferably used in an amount of 1 to 50mg per unit dose.

In other preferred embodiments of the present invention, the formulation may contain 5 to 50mg oxycodone, 10 to 40mg oxycodone, 10 to 30mg oxycodone, or about 20mg oxycodone. The preferred embodiment of the invention can also comprise a preparation of 1-40 mg naloxone, 1-30 mg naloxone, 1-20 mg naloxone or 1-10 mg naloxone per unit dose.

Preferably, the ratio of oxycodone and naloxone is chosen such that a suitable release profile of the two active substances is ensured and that the agonist can exhibit its therapeutic effect, while the amount of antagonist is chosen such that the habituation-inducing or addictive effects and side effects of the agonist are reduced or eliminated without (substantially) affecting the therapeutic effect of the agonist. According to the present invention, the development of habituation and addiction as well as obstipation and respiratory depression are considered side effects of therapeutically effective opioid agonists.

In the context of the present invention, all kinds of pharmaceutically acceptable salts and derivatives (including prodrugs) of the active ingredients may be used instead of, or together with, the active non-modified ingredients in amounts corresponding to the amounts of the non-modified active ingredients as described herein.

Oxycodone and naloxone may be present in the form of their hydrochloride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, phosphate, malate, maleate, hydrobromide, hydroiodide, fumarate or succinate salts.

Pharmaceutical dosage form

Preferably, the opioid is provided in an oral dosage form. The oral dosage form may be designed as a controlled release formulation or it may be an oral dosage form that combines immediate release and controlled release. Thus, the dosage form may, for example, comprise a controlled release portion that is over-wrapped with an immediate release formulation. The active ingredients may be the same or different in these different parts.

In certain embodiments, the oral dosage forms of the present invention comprise an opioid in combination with an excipient, i.e., a pharmaceutically acceptable organic or inorganic carrier material known in the art to be suitable for oral administration. Suitable pharmaceutically acceptable carriers include, but are not limited to, aqueous salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oils, digestible long-chain substituted or unsubstituted hydrocarbons such as fatty acid mono-and diglycerides, pentaerythritol fatty acid esters, hydrophilic or hydrophobic polymers such as cellulose and cellulose derivatives, such as alkylcelluloses or hydroxyalkylcelluloses, acrylic resins, such as those known under the trade name Eudragit^®Polymers of (a), polyvinylpyrrolidone, and the like. The pharmaceutical compositions can be sterilized and may be mixed as desired with auxiliary agents, for example, lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants, flavors and/or aromatic substances.

The oral pharmaceutical compositions of the present invention may be in the form of tablets, coated tablets, liquid preparations, drops, caplets, round lozenges, lozenge, aqueous or oily suspensions, multiparticulate (multiparticulate) preparations comprising dispersible powders, granules, pellets, matrix beads, beads or coated inert beads, emulsions, hard or soft capsules or syrups or elixirs, microparticles (e.g., microcapsules, microspheres, etc.), buccal tablets, and the like.

Oral compositions may be prepared according to methods known in the art, and such compositions may contain one or more agents selected from inert, non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose; granulating and disintegrating agents such as corn starch; binders such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for aesthetics or to delay release of the active ingredient. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

Aqueous suspensions preferably contain the opioid in admixture with one or more excipients suitable as suspending agents, for example, pharmaceutically acceptable synthetic gums such as hydroxypropylmethyl cellulose or natural gums. Oil suspensions may be prepared by suspending the above-mentioned combination of drugs in vegetable or mineral oil. The oil suspension may contain a thickening agent such as beeswax or cetyl alcohol. Syrups, elixirs and the like may be employed wherein a sweetening excipient is employed.

The pharmaceutical oral compositions of the present invention comprise an effective amount of opioid (at least one) in a sustained release formulation. For example, sustained release carriers may be included in the formulation to provide release of the opioid antagonist for greater than 12-24 hours. An effective amount of an opioid as used herein means an amount sufficient to provide the desired therapeutic effect for the desired period of time. The therapeutic effect may also be that of an antagonist.

For example, a sustained release oral dosage form effective at 24 hours at steady state comprises about 1 to about 640mg oxycodone or a pharmaceutically acceptable salt thereof (e.g., oxycodone hydrochloride). Preferably, the sustained release oral dosage form comprises from about 5 to about 500mg oxycodone, or a pharmaceutically acceptable salt thereof, more preferably from about 10 to about 320mg oxycodone, or a pharmaceutically acceptable salt thereof, and even more preferably from about 10 to about 160mg oxycodone, or a pharmaceutically acceptable salt thereof.

For example, a sustained release oral dosage form effective at 12 hours at steady state comprises about 1 to about 160mg oxycodone, or a pharmaceutically acceptable salt thereof (e.g., oxycodone hydrochloride).

Other opioids may be present in amounts equivalent to the amounts of oxycodone described above, depending on the desired therapeutic effect.

In certain preferred embodiments, the oral dosage form comprises a sustained release material co-contained within a matrix with at least one opioid for providing sustained release of the agent. The sustained-release substance may be hydrophobic or hydrophilic as required. The oral dosage forms of the present invention may be prepared as granules, pellets, matrix multiparticulates, and the like, comprising at least one opioid in a sustained release matrix that may be compressed into tablets or encapsulated. The oral dosage form of the present invention may optionally include other pharmaceutically acceptable ingredients (e.g., diluents, binders, colorants, lubricants, etc.).

In certain other embodiments, the oral dosage form of the present invention may be an osmotic dosage form having a push or displacement composition as a layer of a bilayer core for pushing at least one opioid out of the dosage form and a semipermeable wall composition surrounding the core, wherein the wall has at least one exit means or passageway for delivering at least the opioid from the dosage form. Alternatively, the core of the osmotic dosage form may comprise a single-layer core comprising the controlled release polymer and the at least one opioid.

Preferably, the dosage form of the invention provides an effect for at least about 12 hours after administration.

Sustained release matrix formulations

In a preferred embodiment of the invention, the formulation may be a matrix of at least one opioid interdispersed in a sustained release carrier for sustained release of the at least one opioid.

A non-limiting list of suitable sustained release materials that may be included in the sustained release matrix according to the present invention includes hydrophilic and/or hydrophobic materials such as gums, cellulose ethers, acrylic resins, protein derived materials, waxes, shellac, and oils such as hydrogenated castor oil and hydrogenated vegetable oil. However, any pharmaceutically acceptable hydrophobic or hydrophilic sustained release substance capable of providing sustained release of at least one opioid may be used according to the present invention. Preferred sustained release polymers include alkylcelluloses such as ethylcellulose, acrylic and methacrylic acid polymers and copolymers; and cellulose ethers, especially hydroalkylcelluloses (especially hydroxypropylmethylcellulose) and carboxyalkylcelluloses. Preferred acrylic and methacrylic polymers and copolymers include methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylate, ethyl acrylate, trimethylaminoethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly (acrylic acid), poly (methacrylic acid), alkylamine methacrylate copolymers, poly (meth) methacrylate, poly (methacrylic acid) (anhydride), polymethacrylate, polyacrylamide, poly (methacrylic anhydride), and glycidyl methacrylate copolymers. Certain preferred embodiments employ any mixture of the aforementioned sustained release materials in the matrix of the present invention.

The matrix may also comprise a binder. In these embodiments, the binder preferably helps to slow release of the opioid from the sustained release matrix.

If additional hydrophobic binder materials are included, they are preferably selected from natural and synthetic waxes, fatty acids, fatty alcohols and mixtures thereof. Examples include beeswax, carnauba wax, stearic acid, and stearyl alcohol. This list is not exclusive. In certain preferred embodiments, a combination of two or more hydrophobic binder materials is included in the matrix formulation.

Preferred hydrophobic binder materials which may be used according to the invention comprise digestible, long chain (C)₈～C₅₀In particular C₁₂～C₄₀) Substituted or unsubstituted hydrocarbons such as fatty acids, fatty alcohols, glycerol esters of fatty acids, mineral and vegetable oils, natural and synthetic waxes and polyalkylene glycols. Hydrocarbons having a melting point of 25 to 90 ℃ are preferable. Of the long chain hydrocarbon binder materials, aliphatic (aliphatic) alcohols are preferred in certain embodiments. The oral dosage form may contain up to 80% by weight of at least one digestible long chain hydrocarbon.

In certain embodiments, the hydrophobic binder material may comprise natural or synthetic waxes, fatty alcohols (such as dodecanol, tetradecanol, octadecanol, hexadecanol or preferably hexadecanol/octadecanol), fatty acids, including but not limited to fatty acid esters, glycerol fatty acid esters (mono-, di-and triglycerides), hydrogenated fats, hydrocarbons, normal waxes (normal wax), stearic acid, octadecanol and hydrophobic and hydrophilic materials having a hydrocarbon backbone. Suitable waxes include, for example, beeswax, glycowax, castor wax (caster wax), and carnauba wax. For the purposes of this invention, a waxy material is defined as any material that is normally solid at room temperature and has a melting point in the range of about 30 ℃ to about 100 ℃.

In certain preferred embodiments, the dosage form comprises a sustained release matrix comprising at least one opioid and at least one water-soluble hydroxyalkyl cellulose, at least one C₁₂～C₃₆In particular C₁₄～C₂₂An aliphatic alcohol and optionally at least one polyalkylene glycol. The hydroxyalkyl cellulose is preferably hydroxy C₁～C₆Alkylcelluloses, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and, in particular, hydroxyethylcellulose. The amount of the at least one hydroxyalkyl cellulose in the oral dosage form of the present invention may be determined, inter alia, by the precise rate of opioid release desired.

In certain other preferred embodiments, the dosage form comprises a sustained release matrix comprising at least one opioid and at least one acrylic resin, at least one C₁₂～C₃₆In particular C₁₄～C₂₂An aliphatic alcohol and optionally at least one polyalkylene glycol. Acrylic resins include, but are 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 is comprised of one or more ammonium methacrylate copolymers. Methacrylic acid ammonium saltPolymers are well known in the art and are described as fully polymerized copolymers of acrylic and methacrylic acid esters having a low content of quaternary ammonium groups. Preferred acrylic resins are acrylic polymers or acrylic copolymers such as poly (meth) acrylate or methacrylic acid-ethyl acrylate copolymers or poly (meth) acrylate copolymerized with trimethylammonium (meth) acrylate hydrochloride, such as poly (meth) acrylate with 5% trimethylammonium methacrylate hydrochloride. The amount of the at least one acrylic resin in the oral dosage form of the present invention may be determined, inter alia, by the precise rate of opioid release desired. In order to obtain the desired dissolution profile, it is necessary to add two or more ammonium methacrylate copolymers having different physical properties, such as different molar ratios of quaternary ammonium groups and neutral (meth) acrylate. Certain methacrylate-based polymers are used to prepare the pH-dependent matrix that can be used in accordance with the present invention. For example, there is a family of copolymers synthesized from diethylaminoethyl methacrylic acid copolymers or polymerized methacrylates, available as Eudragit ® from R ö hm Tech, Inc. There are several different types of Eudragit ®. For example, Eudragit E is an example of a methacrylic acid copolymer that does not swell at about pH < 5.7 and dissolves at about pH > 6. Eudragit S does not swell at about pH < 6.5 and dissolves at about pH > 7. Eudragit RL and Eudragit RS are swellable in water and the amount of water absorbed by these polymers is pH dependent. However, the formulations containing Eudragit RL and Eudragit RS are pH independent. In certain preferred embodiments, the acrylic matrix comprises a mixture of two acrylic resins available from Rohm Pharma under the tradenames Eudragit ® RL30D and Eudragit ® RS30D, respectively. Eudragit ® RL30D and Eudragit ® RS30D are copolymers of acrylic acid and methacrylic acid esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth) acrylic acid ester in Eudragit ® RL30D being 1: 20 and in Eudragit ® RS30D being 1: 40. The average molecular weight is about 150,000. The designations RL (high permeability) and RS (low permeability) refer to the osmotic properties of these agents. The Eudragit ® RL/RS mixture is insoluble in water and digestive juices. However, from the same speciesThe coating formed is swellable and permeable in aqueous and digestive fluids. The Eudragit ® RL/RS dispersions of the invention can be mixed together in any desired ratio to ultimately provide a controlled release formulation with desired dissolution characteristics. Desirable controlled release formulations are obtainable, for example, from delay matrices available from Eudragit ® RL, Eudragit ® RL and Eudragit ® RS and Eudragit ® RL and Eudragit ® RS. Of course, one skilled in the art will recognize that other acrylic polymers may be used, such as Eudrahit ® L.

The aliphatic alcohol may be, for example, dodecanol, tetradecanol, hexadecanol/octadecanol or octadecanol. However, in a particularly preferred embodiment of the oral dosage form of the invention, the at least one aliphatic alcohol is cetyl alcohol or cetyl/stearyl alcohol. The amount of aliphatic alcohol in the oral dosage form of the present invention may, as described above, be determined by the precise rate of opioid release desired. It may also depend on the presence or absence of at least one polyalkylene glycol in the oral dosage form. In the absence of at least one polyalkylene glycol, the oral dosage form preferably comprises from about 20% to about 50% by weight of an aliphatic alcohol. When at least one polyalkylene glycol is present in the oral dosage form, the combined weight of the aliphatic alcohol and the polyalkylene glycol preferably comprises from about 20% to about 50% by weight of the total dosage form.

In a preferred embodiment, for example, the ratio of the at least one hydroxyalkyl cellulose or acrylic resin and the at least one aliphatic alcohol/polyalkylene glycol is largely dependent on the release rate of the opioid from the formulation. In certain embodiments, the ratio of hydroxyalkyl cellulose and aliphatic alcohol/polyalkylene glycol is preferably from 1: 1 to 1: 4, particularly preferably from 1: 2 to 1: 3.

In certain embodiments, the polyalkylene glycol may be, for example, polypropylene glycol or, preferably, polyethylene glycol. The average molecular weight of the at least one polyalkylene glycol is preferably from 1,000 to 15,000, particularly preferably from 1,500 to 12,000.

Another suitable sustained release matrix comprises an alkylcellulose (especially ethylcellulose)，C₁₂～C₃₆An aliphatic alcohol and optionally a polyalkylene glycol.

In addition to the ingredients mentioned above, the sustained-release matrix may also contain suitable amounts of other substances, such as diluents, lubricants, binders, granulation aids, colorants, flavors, and glidants, which are conventional in the pharmaceutical art.

To facilitate the preparation of the solid, sustained release oral dosage form according to the invention, the addition of the opioid to the matrix may be achieved, for example, by:

(a) particles are formed comprising at least one of the foregoing hydrophobic and/or hydrophilic substances (e.g., water-soluble hydroxyalkyl cellulose or acrylic resin) and an opioid.

(b) Mixing particles comprising at least one hydrophobic and/or hydrophilic substance and at least one C₁₂～C₃₆Aliphatic alcohols, (and in some cases other matrix components) and

(c) optionally, compressing and shaping the particles.

The granules may be formed by any procedure known to those skilled in the art of pharmaceutical formulation. For example, in one preferred method, the hydroxyalkyl cellulose/opioid and water may be wet granulated to form granules. In a particularly preferred embodiment of the process, the amount of water added during wet granulation is preferably 1.5 to 5 times, in particular 1.75 to 3.5 times the dry weight of the opioid.

The sustained release matrix may also be prepared by, for example, melt-granulation or melt-extrusion techniques. Generally, melt-granulation techniques involve melting a generally solid hydrophobic binder material such as a wax and adding a powdered drug thereto. In order to obtain a sustained release formulation, it is necessary to add a hydrophobic sustained release material such as ethylcellulose or a water-insoluble acrylic polymer to the melted waxy hydrophobic binder material. Examples of sustained release formulations prepared by melt-granulation techniques are found, for example, in U.S. patent No.4,861,598 (incorporated by reference).

The additional hydrophobic binder material may comprise one or more water-insoluble waxy thermoplastic materials and may be mixed with one or more waxy thermoplastic materials that are less hydrophobic than the one or more water-insoluble waxy materials in the formulation and should not substantially degrade and dissolve in gastrointestinal fluids during the initial release phase. Useful water-insoluble waxy binder materials can be those having a water solubility of less than about 1: 5,000 (w/w).

Extruded formulations employing starches such as disclosed in DE 19918325A 1 (incorporated by reference) may be advantageously used in the context of the present invention.

The preparation of a suitable melt-extruded matrix according to the invention may for example comprise the step of blending at least one opioid, a slow-release substance and preferably a binder substance to obtain a homogeneous mixture. The homogeneous mixture is then heated to a temperature sufficient to at least sufficiently soften the mixture for it to be extruded. The resulting homogeneous mixture is then extruded, for example, using a twin screw extruder, to form strands (strands). The extrudate is preferably cooled and cut into multiparticulates by any means known in the art. The matrix multiparticulates are then divided into unit dosage forms. The extrudate preferably has a diameter of about 0.1 to about 5mm, providing a sustained release of the at least one opioid for at least about 24 hours.

An optional method of preparing the melt-extruded formulation of the present invention comprises directly metering the hydrophobic sustained release material, the at least one opioid and the optional binder material into an extruder; heating the homogeneous mixture; extruding the homogeneous mixture, thereby forming strands; cooling the strands containing the homogeneous mixture; cutting the strands into matrix multiparticulates having a particle size of about 0.1mm to about 12 mm; and dividing the particles into unit doses. In this aspect of the invention, a relatively continuous production sequence is achieved.

Plasticizers, such as those described above, may be included in the melt-extruded matrix. The plasticizer preferably comprises from about 0.1 to about 30% by weight of the matrix. Other pharmaceutical excipients, for example, talc, mono-or polysaccharides, coloring agents, flavoring agents, lubricants and the like, may be added to the sustained-release base of the present invention as desired. The amount added depends on the desired properties to be achieved.

The diameter of the extruder orifice or outlet can be adjusted to vary the thickness of the extruded strand. Also, the outlet portion of the extruder need not be circular, it may be oval, rectangular, etc. The exiting strands may be reduced to pellets using hot shears, or the like.

The melt-extruded matrix multiparticulate system can be in the form of, for example, granules, pellets or pellets, depending on the extruder discharge orifice. For the purposes of the present invention, the terms "melt-extruded matrix multiparticulate" and "melt-extruded matrix multiparticulate system" and "melt-extruded matrix granulate" shall mean a plurality of units, preferably within a small particle size and/or shape range, comprising one or more active substances and one or more excipients, preferably comprising a hydrophobic sustained release substance as described herein. Preferably, the melt-extruded matrix multiparticulates range from about 0.1 to about 12mm in length and from about 0.1 to about 5mm in diameter. Furthermore, it is to be understood that the melt-extruded matrix multiparticulates can be of any geometry within this particle size range. In certain embodiments, the extrudate can be simply cut to the desired length and divided into unit doses of the therapeutically active agent without the need for a spheronization step.

In a preferred embodiment, the prepared oral dosage form comprises an effective amount of melt-extruded matrix multiparticulates within a capsule. For example, a plurality of melt-extruded matrix multiparticulates can be placed in a gelatin capsule in an amount sufficient to provide an effective sustained release dosage upon digestion and contact by gastrointestinal fluids.

In another embodiment, a suitable amount of the multiparticulate extrudate is compressed into oral tablets by conventional tableting equipment using conventional techniques. Techniques and compositions for preparing tablets (compression and molding), capsules (hard and soft gelatin) and pills are also described in Remington's Pharmaceutical Sciences (Arthur Oso, eds.), 1553-1593 (1980).

In yet another preferred embodiment, the extrudate can be formed into tablets, such as in the aforementioned U.S. patent No.4,957,681(Klimesch et al).

Optionally, the sustained release matrix multiparticulate system, tablet or capsule may be coated with a sustained release coating such as the sustained release coatings described herein. These coatings preferably contain a sufficient amount of hydrophobic and/or hydrophilic sustained release materials to achieve a level of weight gain of about 2 to about 25%, although the outer coating may be larger depending, for example, on the desired release rate.

The dosage form of the present invention may further comprise a combination of melt-extruded matrix multiparticulates comprising at least one opioid. Furthermore, the dosage form may also contain an amount of an immediate release therapeutically active opioid with immediate therapeutic effect. Immediate release opioids may be incorporated into gelatin capsules, for example, as individual multiparticulates, or coated on the surface of, for example, melt-extruded matrix multiparticulates.

The sustained release characteristics of the melt-extruded formulations of the present invention may be varied, for example, by varying the amount of the sustained release material, by varying the amount of plasticizer relative to other matrix components, by varying the amount of hydrophobic material, by introducing other ingredients or excipients, by varying the method of production, and the like.

In other embodiments of the invention, the melt-extruded formulation is prepared without the introduction of at least one opioid which is subsequently added to the extrudate. These formulations typically mix the opioid and extruded matrix material together and then tablet the mixture to provide a slow release formulation. These formulations may be advantageous, for example, when the therapeutically active agent in the formulation is sensitive to the temperature required to soften the hydrophobic substance and/or the retarding substance.

A typical melt-extrusion production system suitable for use in the present invention includes a suitable extruder drive motor with variable speed and constant torque control, start-stop control and metering. In addition, the production system includes a temperature console throughout the length of the extruder that includes a temperature sensor, a cooling device, and a temperature indicator. Furthermore, the production system comprises an extruder such as a twin-screw extruder consisting of two counter-rotating intermeshing screws enclosed in a barrel having an orifice or die at the outlet. The raw material enters through a hopper and passes through a barrel by a screw, is forced through a die to become strands, which are then conveyed, such as by a continuously moving belt, to allow cooling and directed to a pelletizer or other suitable device such that the extruded rope becomes a matrix multiparticulate system. The pelletizer may consist of rollers, stationary knives, rotary cutters, etc. Suitable devices and systems are available from vendors such as brabender Instruments, inc. Other suitable devices will be apparent to those skilled in the art.

In preparing the melt-extruded matrix multiparticulates described above, the amount of air introduced into the extrudate is controllable and the release rate of the at least one opioid therefrom is variable.

Thus, the melt-extruded product is prepared in a manner that substantially excludes air during the extrusion stage of the process. This can be done, for example, by using a Leistritz extruder with a vacuum attachment. The extruded matrix multiparticulates prepared under vacuum using a Leistritz extruder according to the present invention provide melt-extruded products having different physical properties. In particular, the extrudate is substantially non-porous when magnified, for example, using a scanning electron microscope. These substantially nonporous formulations can provide for faster release of the therapeutically active agent relative to the same non-vacuum prepared formulations. Scanning electron micrographs of matrix multiparticulates prepared using an extruder under vacuum were very smooth compared to non-vacuum prepared multiparticulates. It was observed that the use of extrusion under vacuum provided a more pH dependent extruded matrix multiparticulate product in at least some formulations than similar formulations prepared without vacuum.

Alternatively, melt-extruded products were prepared using a Werner-Pfleiderer twin screw extruder.

In certain embodiments, a spheronizing agent (spheronizing agent) is added to the particles or matrix multiparticulates, which are then spheronized to produce sustained release pellets. The pellets are then optionally overcoated with a slow release coating, such as by the methods described above.

Spheronizing agents that may be used to prepare the matrix multiparticulate formulations of the present invention include any of the spheronizing agents known in the art.

Cellulose derivatives are preferred, microcrystalline cellulose being particularly preferred. Suitable microcrystalline cellulose is for example the material sold as Avicel PH101 (trade mark, FMC company). The spheronizing agent preferably comprises about 1 to about 99% by weight of the matrix multiparticulates.

In certain embodiments, the pellet may comprise a binder in addition to the active ingredient and the spheronizing agent. Suitable binders such as low viscosity, water soluble polymers are well known to those skilled in the pharmaceutical art. However, water-soluble hydroxy lower alkyl celluloses such as hydroxypropyl cellulose are preferred. In addition (or as an alternative) the pellet may comprise a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer such as methacrylic acid-ethyl acrylate copolymer or ethylcellulose.

In certain embodiments, the sustained release coating is used to sustain release of the beads, granules or matrix multiparticulates. In these embodiments, the extended release coating may comprise a water insoluble material such as (a) a wax, alone or in admixture with a fatty alcohol; or (b) shellac or zein. The coating is preferably obtained from an aqueous dispersion of a hydrophobic sustained-release substance.

In certain embodiments, it may be necessary to overcoat the sustained release pellets, granules or matrix multiparticulates containing at least one opioid and a sustained release carrier with a sufficient amount of an aqueous dispersion of, for example, an alkylcellulose or acrylic polymer to obtain a level of weight gain of about 2 to about 50%, such as about 2 to about 25%, to obtain a sustained release formulation. The outer coating may be less or more depending on, for example, the desired release rate, the incorporation of plasticizers in the aqueous dispersion, and the manner in which they are added. Cellulosic materials and polymers, including alkylcelluloses, are slow release materials and are well suited for coating slow release pellets, granules or matrix multiparticulates according to the invention. By way of example only, one preferred alkyl cellulose polymer is ethyl cellulose, but the skilled person will appreciate that other cellulose and/or alkyl cellulose polymers may be used alone or in any combination as all or part of the hydrophobic coating according to the invention.

One commercially available aqueous dispersion of ethyl cellulose is Aquacoat^®(FMCCorp，Philadelphia，Pennsylvania，U.S.A.)。Aquacoat^®Prepared by dissolving ethylcellulose in a water-immiscible organic solvent, followed by emulsification in water in the presence of a surfactant and a stabilizer. Upon homogenization submicron droplets are formed and the organic solvent is evaporated under vacuum to form a pseudolatex (pseudolatex). The plasticizer is not included in the pseudolatex during the production stage. Therefore, it is necessary to thoroughly mix Aquacoat ® with an appropriate plasticizer prior to use before using it as a coating.

Another commercially available aqueous dispersion of ethylcellulose is Surelease^®(Colorcon, Inc., Weset Point, Pennsylvania, U.S. A). The product is prepared by adding the plasticizer to the dispersion during the manufacturing process. A hot melt of polymer, plasticizer (dibutyl sebacate) and stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion which can be used directly for slow release pellets, granules or matrix multiparticulates.

In other preferred embodiments of the present invention, the sustained release material comprising the sustained release coating is a pharmaceutically acceptable acrylic polymer including, but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, poly (acrylic acid), poly (methacrylic acid), alkyl methacrylate amide copolymers, poly (methyl methacrylate), polymethacrylates, poly (methyl methacrylate) copolymers, polyacrylamides, aminoalkyl methacrylate copolymers, poly (methacrylic anhydride), and glycidyl methacrylate copolymers. Useful acrylic polymers are known under the trade name Eudragit ® and are available from Rohm Pharma. These acrylic resins can be adjusted to provide pH-dependent and pH-independent active release rates.

In addition to the above ingredients, the pellets, granules or matrix multiparticulates may contain suitable amounts of other materials such as diluents, lubricants, binders, granulating aids, coloring agents, flavoring agents and glidants which are conventional in the pharmaceutical art, in amounts up to about 50% by weight of the formulation as desired. The amount of these additional substances will be sufficient to provide the desired effect for the desired formulation.

Specific examples of orally acceptable carriers and excipients that can be used to formulate oral dosage forms areHandbook of Pharmaceutical ExcipientsDescribed in the American society for pharmacy (1986).

It has further been found that the addition of a small amount of talc to the slow release coating reduces the tendency of the aqueous dispersion to block during preparation and acts as a polishing agent.

If oxycodone is used for the preparation, a formulation is selected, the matrix comprising at least one acrylic resin and at least one C₁₂～C₃₆Aliphatic alcohols, as previously described. The formulation is preferably achieved by the granulation process described above, with the preferred amounts of ingredients described above.

If oxycodone and naloxone are used in the combined preparation, the formulation is selected to ensure that the active compound is released from the formulation in a sustained, independent and invariant manner. Preferably those formulations are storage stable.

The terms "release from the formulation in a sustained, independent and unaltered form" and "storage stable" as used herein are defined in PCT/EP 03/03541.

If oxycodone and naloxone are used in the combined preparation, the formulation is selected such that it comprises a release matrix characterized by a substantially non-aqueous or non-buffer swellable and non-aggressive diffusion matrix, as defined in PCT/EP 03/0354. PCT/EP03/0354 is incorporated by reference.

If oxycodone and naloxone are used for the combined preparation, the formulations particularly preferably comprise ethylcellulose or Surelease ® E-7-7050 as substance for the construction of the matrix (matrix-building), octadecanol as fatty alcohol, magnesium stearate as lubricant, lactose as filler and polyvinylpyrrolidone as granulation aid.

In principle, these formulations can be produced in all common application forms which are suitable for delayed formulation and ensure release of the active compound in the manner described above. Particularly suitable are tablets, multilayer tablets and capsules. Additional application forms such as granules or powders may be used, only those application forms may provide sufficient delay and release behavior as described above.

These pharmaceutical formulations may also comprise a film coating. However, it is ensured that the film coating does not adversely affect the release profile of the active compound from the matrix and the storage stability of the active compound within the matrix. These film coatings may be colored or contain an initial dose of the active compound, if desired. The initial dose of active compound will be released rapidly and thus therapeutically effective plasma levels will be reached quickly.

For a detailed description of the preparation of these oxycodone/naloxone combination formulations, reference is made to PCT/EP 03/0354.

Method for preparing matrix beads

The controlled release dosage form according to the present invention may also be prepared as a matrix bead formulation. The matrix beads comprise a spheronizing agent and at least one opioid.

The at least one opioid preferably comprises from about 0.01 to about 99% by weight of the matrix bead. Preferably, the at least one opioid comprises from about 0.1 to about 50% by weight of the matrix bead.

Spheronizing agents useful in preparing the matrix bead formulations of the present invention include any known spheronizing agent in the art. Cellulose derivatives are preferred, with microcrystalline cellulose being particularly preferred. Suitable microcrystalline cellulose is, for example, the material sold as Avicel PH101 (trade Mark, FMC Corporation). The spheronizing agent preferably comprises about 1 to about 99% by weight of the matrix beads.

In addition to the active ingredient and spheronizing agent, the pellets may also contain a binder. Suitable binders such as low viscosity, water soluble polymers are well known to those skilled in the pharmaceutical art. However, water-soluble hydroxy lower alkyl celluloses such as hydroxypropyl cellulose are preferred.

In addition to the at least one opioid and spheronizing agent, the matrix bead formulations of the present invention may contain a controlled release material such as described above. Preferred controlled release materials for incorporation into the matrix bead formulation include acrylic and methacrylic acid polymers or copolymers and ethyl cellulose. When present in the formulation, the amount of controlled release material added is from about 1 to about 80% by weight of the matrix bead. The controlled release material is preferably included in the matrix bead formulation in an amount effective to provide controlled release of the at least one opioid from the beads.

Pharmaceutical processing aids such as binders, diluents, and the like may be included in the matrix bead formulation. The amount of these agents included in the formulation will vary depending on the desired effect to be exhibited by the formulation.

The matrix beads may be overcoated with a controlled release coating comprising a controlled release material such as described above. A controlled release coating may be used to achieve a weight gain of about 5 to about 30%. The amount of controlled release coating used will vary depending on factors such as the composition of the matrix beads.

The matrix beads are typically prepared by granulating the spheronizing agent and the reagent together, for example, by wet granulation. The particles were then spheronized to produce matrix beads. The matrix beads are then optionally overcoated with a controlled release coating by the methods described above.

Another method of preparing matrix beads is, for example, by (a) forming particles comprising at least one water-soluble hydroxyalkyl cellulose and an opioid (b) mixing the hydroxyalkyl cellulose-containing particles and at least one C₁₂～C₃₆An aliphatic alcohol; and (c) optionally, compressing and shaping the granules. Preferably, the hydroxyalkyl cellulose/opioid and water are wet granulated to form granules.

In yet another alternative embodiment, the spheronizing agent and active ingredient may be spheronized to form a pellet. Microcrystalline cellulose is preferred. Suitable microcrystalline cellulose is, for example, the material sold as Avicel PH101 (trademark, FMCCorporation). In these embodiments, the pellet may comprise a binder in addition to the active ingredient and the spheronizing agent. Suitable binders such as low viscosity, water soluble polymers are well known to those skilled in the pharmaceutical art. However, water-soluble hydroxy lower alkyl celluloses such as hydroxypropyl cellulose are preferred. Additionally (or alternatively) the beads may comprise a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer such as methacrylic acid-ethyl acrylate copolymer or ethylcellulose. In these embodiments, the extended release coating typically comprises a water insoluble material such as (a) a wax, either alone or in admixture with a fatty alcohol; or (b) shellac or zein.

In a particularly preferred embodiment, the oral dosage form comprises an effective amount of controlled release pellets contained within a gelatin capsule.

In yet another embodiment of the present invention, the controlled release dosage form comprises a pellet containing an active ingredient, said pellet being coated with a controlled release coating comprising a controlled release material. The term pellet is known in the pharmaceutical art and means, for example, a pellet particle of 0.1mm to 2.5mm or 0.5mm to 2mm in diameter. This range is not limiting as the diameter may be greater or less than the diameters disclosed previously.

The pellet is preferably film coated with a controlled release material, allowing release of the opioid at a controlled rate in an aqueous medium. When combined with other described features, the membrane coating is selected such that a desired in vitro release rate is achieved. The controlled release coating formulations of the present invention preferably produce a strong, continuous film that is smooth and aesthetically pleasing, can support pigments and other coating additives, is non-toxic, inert, and non-tacky.

Sustained-release coated preparation

The oral dosage forms of the present invention may optionally be coated with one or more coatings suitable for modified release, for protection of the formulation. In one embodiment, a coating is provided to allow pH-dependent or pH-independent release, for example, when exposed to gastrointestinal fluids. Where a pH dependent coating is desired, the coating is designed to achieve optimal release to avoid dose emptying despite changes in the pH of the environmental fluid, e.g., the gastrointestinal tract. Other preferred embodiments include a pH dependent coating that releases the opioid antagonist in a desired region of the Gastrointestinal (GI) tract, such as the stomach and small intestine. The composition may also be formulated to release a portion of the dose in one desired region of the gastrointestinal tract, e.g., the stomach, and the remainder of the dose in other regions of the gastrointestinal tract, e.g., the small intestine.

The formulation according to the present invention using a pH-dependent coating may also provide an effect of repeated action, whereby the drug, which is not protected, is coated outside the enteric coating and released in the stomach, and the remaining part, which is protected by the enteric coating, is further released in the lower part of the gastrointestinal tract. The pH-dependent coating that may be used in accordance with the present invention comprises controlled release substances such as shellac, Cellulose Acetate Phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalate and methacrylate copolymers, zein and the like.

In another preferred embodiment, the present invention relates to a stable solid controlled release dosage form comprising an opioid, said dosage form being coated with a hydrophobic controlled release material selected from (i) an alkylcellulose, (ii) an acrylic polymer, or (iii) a mixture thereof. The coating can be applied in the form of an organic or aqueous solution or dispersion.

In certain preferred embodiments, the controlled release formulation coating is obtained from an aqueous dispersion of a hydrophobic controlled release material. The opioid-containing coated substrate (e.g., tablet core or inert pharmaceutical bead or pellet) is then solidified until an endpoint is reached at which the substrate provides stable dissolution. The end-point of cure can be determined by comparing the dissolution profile (curve) of the dosage form immediately after curing to the dissolution profile (curve) of the dosage form after exposure to accelerated storage conditions, e.g., at a temperature of 40 ℃ and a relative humidity of 75%, for at least 1 month. These formulations are described in detail in U.S. Pat. nos. 5,273,760 and 5,286,493. Examples of other controlled release formulations and coatings that may be used in accordance with the present invention include the U.S. patent nos. 5,324,351, 5,356,467, and 5,472,712 to Assignee.

In a preferred embodiment, the controlled release coating comprises a plasticizer such as described below.

In certain embodiments, it may be necessary to overcoat the opioid-containing substrate with a sufficient amount of an aqueous dispersion of, for example, an alkylcellulose or acrylic polymer to obtain a level of weight gain of from about 2% to about 50%, such as from about 2% to about 25%, to obtain a controlled release formulation. The outer coating may be less or more depending on, for example, the physical properties of the therapeutically active agent and the desired release rate, the incorporation of plasticizers in the aqueous dispersion, and the manner of addition thereof.

Alkyl cellulose polymers

Cellulosic materials and polymers, including alkyl celluloses, are controlled release materials well suited for coating substrates such as beads, tablets, and the like according to the present invention. By way of example only, one preferred alkyl cellulose polymer is ethyl cellulose, but the skilled artisan will recognize other celluloses and/or partially hydrophobic coatings according to the present invention.

One commercially available aqueous dispersion of ethyl cellulose is Aquacoat ® (FMCCorp, philiadelphia, Pennsylvania, usa). Aquacoat ® is prepared by dissolving ethylcellulose in a water-immiscible organic solvent, followed by emulsification in water in the presence of surfactants and stabilizers. Upon homogenization, submicron droplets are formed and the organic solvent is evaporated under vacuum to form a pseudolatex. The plasticizer is not included in the pseudolatex during the production stage. Therefore, it is necessary to thoroughly mix Aquacoat ® with an appropriate plasticizer prior to use before using it as a coating.

Another commercially available aqueous dispersion of ethyl cellulose is Surelease ® (Colorcon, inc., West Point, Pennsylvania, usa). The product is prepared by adding the plasticizer to the dispersion during the manufacturing process. A hot melt of polymer, plasticizer (dibutyl sebacate) and stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to give an aqueous dispersion which can be applied directly to a substrate.

Acrylic acid polymer

In other preferred embodiments of the present invention, the controlled release material comprising the controlled release coating 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 methacrylate amide 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 is comprised of one or more ammonium methacrylate copolymers. Ammonium methacrylate copolymers are well known in the art and are described as fully polymerized copolymers of acrylic and methacrylic acid esters having a low content of quaternary ammonium groups.

In order to obtain the desired dissolution profile, it is necessary to add two or more ammonium methacrylate copolymers having different physical properties, such as different molar ratios of quaternary ammonium groups and neutral (meth) acrylate.

Certain methacrylate-based polymers are used to prepare the pH-dependent matrix that can be used in accordance with the present invention. For example, there is a family of copolymers synthesized from diethylaminoethyl methacrylic acid copolymers or polymerized methacrylates, available as Eudragit ® from R ö hm Tech, Inc. There are several different types of Eudragit ®. For example, Eudragit E is an example of a methacrylic acid copolymer that does not swell at about pH < 5.7 and dissolves at about pH > 6. Eudragit S does not swell at about pH < 6.5 and dissolves at about pH > 7. Eudragit RL and Eudragit RS are swellable in water and the amount of water absorbed by these polymers is pH dependent. However, the dosage forms coated with Eudragit RL and Eudragit RS are pH independent.

In certain preferred embodiments, the acrylic coating comprises a mixture of two acrylic resin paints available from Rohm Pharma under the trade names Eudragit ® RL30D and Eudragit ® RS30D, respectively. Eudragit ® RL30D and Eudragit ® RS30D are copolymers of acrylic acid and methacrylic acid esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth) acrylic acid ester in Eudragit ® RL30D being 1: 20 and in Eudragit ® RS30D being 1: 40. The average molecular weight is about 150,000. The designations RL (high permeability) and RS (low permeability) refer to the osmotic properties of these agents. The Eudragit ® RL/RS mixture is insoluble in water and digestive juices. However, coatings formed from the same materials are swellable and permeable in aqueous and digestive fluids.

The Eudragit ® RL/RS dispersions of the invention can be mixed together in any desired ratio to ultimately provide a controlled release formulation with desired dissolution characteristics. The desired controlled release formulation can be obtained, for example, from a delayed coating obtained from 100% Eudragit ® RL, 50% Eudragit ® RL and 50% Eudragit ® RS and 10% Eudragit ® RL: eudragit ® RS. Of course, those skilled in the art will recognize that other acrylic polymers may be used, such as Eudragit ® L.

Plasticizer

In embodiments of the invention wherein the coating comprises an aqueous dispersion of a hydrophobic controlled release material, the incorporation of an effective amount of a plasticizer in the aqueous dispersion of the hydrophobic material will further improve the physical properties of the controlled release coating. For example, since ethylcellulose has a relatively high glass transition temperature and cannot form a flexible film under normal coating conditions, a plasticizer is preferably added to the controlled-release coating containing the ethylcellulose coating before using it as a coating material. Typically, the amount of plasticizer added to the coating solution is based on the concentration of the film-forming agent, e.g., most typically from about 1 to about 50% by weight of the film-forming agent. However, the concentration of plasticizer can only be determined correctly after careful testing with specific coating solutions and coating methods.

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 (such as acetylated monoglycerides, phthalate esters, castor oil, and the like) may also be used. Triethyl citrate is a particularly preferred plasticizer for the aqueous ethylcellulose dispersion of the present invention.

Examples of suitable plasticizers for the acrylic polymer of the present invention include, but are not limited to, citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate and possibly 1, 2-propylene glycol. Other plasticizers which have proven useful for increasing the elasticity of films formed from acrylic films such as Eudragit ® RL/RS paint solutions include polyethylene glycol, propylene glycol, diethyl phthalate, castor oil and triacetin. Triethyl citrate is a particularly preferred plasticizer for the aqueous ethylcellulose dispersion of the present invention.

It has further been found that the addition of a small amount of talc to the controlled release coating reduces the tendency of the aqueous dispersion to block during processing and acts as a polishing agent.

Preparation of coated bead preparation

When an aqueous dispersion of a hydrophobic substance is used to coat a substrate, e.g., inert pharmaceutical beads such as nu pariel18/20 beads, the resulting plurality of stable, solid controlled-release beads can then be placed in a gelatin capsule in an amount sufficient to provide an effective controlled-release dosage when digested and contacted by an environmental fluid, e.g., gastric fluid or dissolution media.

The stabilized release bead formulations of the present invention slowly release the opioid antagonist, for example, when digested and exposed to gastric fluid, followed by intestinal fluid. The controlled release characteristics of the formulations of the present invention may be varied, for example, by varying the amount of the outer coating containing the aqueous dispersion of the hydrophobic controlled release material, by varying the manner in which the plasticizer is added to the aqueous dispersion of the hydrophobic controlled release material, by varying the amount of plasticizer relative to the hydrophobic controlled release material, by introducing other ingredients or excipients, by varying the method of production, and the like. The dissolution profile of the final product may also be varied, for example by increasing or decreasing the thickness of the controlled release coating.

Substrates coated with a therapeutically active agent are prepared, for example, by dissolving the therapeutically active agent in water and then spraying the solution onto a substrate, such as nupariel 18/20 bead, using a Wuster insert. Optionally, additional ingredients are also added prior to coating the beads to aid in the binding of the opioid to the beads, and/or to color the solution, etc. E.g., with or without colorant (e.g., Opadry)^®Commercially available from Colorcon, Inc) may be added to the solution and the solution mixed (e.g., for about 1h) prior to applying it to the substrate. The resulting coated substrate may then optionally be overcoated with a barrier agent (barrier agent) to separate the therapeutically active agent and the hydrophobic controlled release coating.

Examples of suitable blocking agents are agents of hydroxypropyl methylcellulose. However, any film former known in the art may be used. Blocking agents that do not affect the dissolution rate of the final product are preferred.

The substrate may then be overcoated with an aqueous dispersion of a hydrophobic controlled release material. The aqueous dispersion of the hydrophobic controlled release material preferably further comprises an effective amount of a plasticizer, such as lemonTriethyl citrate. Aqueous dispersions of pre-formulated ethyl cellulose, such as Aquacoat, may be used^®Or Surelease^®. If Surelease is used^®It is not necessary to add a plasticizer separately. Alternatively, a pre-formulated aqueous dispersion of an acrylic polymer such as Eudragit may be used^®。

In addition to the film former, plasticizer, and solvent system (i.e., water), the coating solution of the present invention preferably contains a colorant to provide aesthetics and product differentiation. The color may be added to a solution of the therapeutically active agent or to an aqueous dispersion of the hydrophobic substance. For example, the colorant can be added to the plasticized Aquacoat by using an alcohol or propylene glycol based colorant dispersion, ground aluminum lake, and an opacifying agent such as titanium dioxide under shear by adding the colorant to a water-soluble polymer solution, then adding the colorant under low shear^®To add color to Aquacoat^®In (1). Alternatively, any suitable method may be used to provide color to the formulations of the present invention. When an aqueous dispersion of an acrylic polymer is used, suitable formulations for providing color to the formulation include titanium dioxide and pigments, such as iron oxide pigments. However, the incorporation of pigments increases the retarding effect of the coating.

The aqueous dispersion of plasticized hydrophobic controlled release material can be applied to a substrate comprising a therapeutically active agent by using any suitable spraying device known in the art. In a preferred process, a Wurster fluidized bed system is used, in which a bottom-injected air nozzle fluidizes the core material and effects drying as the acrylic polymer coating is sprayed. In view of the physical properties of the therapeutically active agent, the manner of introduction of the plasticizer, etc., it is preferred to use a sufficient amount of the aqueous dispersion of the hydrophobic substance to obtain a predetermined controlled release of the therapeutically active agent when the coated substrate is exposed to an aqueous solution, such as gastric fluid. After coating with the hydrophobic controlled release substance, a further coating of film forming agent, such as Opadry^®Optionally applied to the beads. The outer coating, if any, is provided to substantially reduce agglomeration of the beads.

The release of the therapeutically active agent in the controlled release formulation of the present invention may be further influenced, i.e. adjusted to a desired rate, by the addition of one or more release modifiers, or by providing one or more channels through the coating. The ratio of hydrophobic controlled release material to water soluble material is determined by, inter alia, the desired release rate and the dissolution properties of the selected material.

The release modifier used as a pore former may be organic or inorganic and includes materials that are soluble, extractable or leachable from the coating in the environment of use. The pore former may comprise one or more hydrophilic substances such as hydroxypropylmethyl cellulose.

The controlled release coating of the present invention may also contain dissolution-promoting agents (such as starches and gums).

The controlled release coating of the present invention may also comprise materials used in the environment of use to prepare microporous films, such as polycarbonates composed of polyesters of linear carbonic acid, in which carbonate groups reappear in the polymer chain.

The release modifier may also comprise a semipermeable polymer. In certain preferred embodiments, the release modifier is selected from the group consisting of hydroxypropylmethylcellulose, lactose, metal stearate, and mixtures of any of the foregoing.

The controlled release coating of the present invention may further comprise an expulsion means comprising at least one passageway, aperture, or the like. The channels can be formed by the methods disclosed in U.S. patent nos. 3,845,770, 3,916,889, 4,063,064, and 4,088,864. The channels may have any shape, such as circular, triangular, square, oval, irregular, and the like.

Another method of producing controlled release bead formulations suitable for administration over about 24 hours is by powder layering. U.S. patent No.5,411,745 teaches the preparation of 24h morphine formulations by powder lamination technology using a processing aid consisting essentially of indiscernible hydrated lactose. Powder laminated beads were prepared by spraying an aqueous binder solution onto inert beads to give a tacky surface, followed by spraying powder onto the tacky beads, which was a homogeneous mixture of morphine sulfate and lactose hydrate, which was not detectable. The beads are then dried and coated with a hydrophobic substance, such as those previously described, to achieve the desired drug release when the final formulation is exposed to ambient fluids. The appropriate amount of controlled release beads is then e.g. encapsulated to give a final dosage form providing an effective plasma concentration of morphine of about 24 h.

Sustained release osmotic dosage form

Sustained release dosage forms according to the invention may also be prepared as osmotic dosage formulations. The osmotic dosage form preferably includes a bilayer core comprising a drug layer and a delivery or push layer, wherein the bilayer core surrounds the semipermeable wall and optionally at least one passageway disposed therein.

"channels" for the purposes of the present invention include pores, mouths, holes, pores, porous elements through which the opioid can be pumped, diffused or removed through a fiber, capillary, porous covering, porous insert, microporous element or porous composition. The channels may also include compounds that erode or leach from the walls in the fluid environment of use to create at least one channel. Representative compounds for forming channels include polyglycolic or polylactic acid, gelatin fibers erodible in the wall; water-removable polyvinyl alcohol, leachable compounds such as fluid-removable pore-forming polysaccharides, acids, salts, or oxides. Channels may be formed by leaching compounds from the walls, such as sorbitol, sucrose, lactose, maltose or fructose, to form a pore channel of sustained release dimensions. The channels may be of any shape, such as circular, triangular, square and oval, to facilitate sustained, metered release of the at least one opioid from the dosage form. The dosage form may be prepared by forming one or more channels spaced apart on one or more surfaces of the dosage form. U.S. patent nos. 3,845,770, 3,916,899, 4,063,064, and 4,088,864 disclose channels and apparatus for forming channels. U.S. patent nos. 4,200,098 and 4,285,987 disclose channels comprising release pores formed by water leaching that are sized, shaped and adapted to provide a sustained release rate.

In certain embodiments, the bilayer core comprises a drug layer comprising at least one opioid and a displacement or push layer. In certain embodiments, the drug layer may further comprise at least one polymeric hydrogel. The average molecular weight of the polymeric hydrogel is about 500 to about 6,000,000. Examples of polymer hydrogels include, but are not limited to, maltodextrin polymers having the formula (C)₆H₁₂O₅)_n.H₂O, wherein n is 3 to 7500, and the maltodextrin polymer has a number average molecular weight of 500 to 1,250,000; polyalkylene oxides, which are represented by, for example, polyethylene oxide and polypropylene oxide, polyethylene oxide having a weight average molecular weight of 50,000 to 750,000, especially at least one of 100,000, 200,000, 300,000 or 400,000; alkali metal carboxyalkyl cellulose, wherein the alkali metal is sodium or potassium, the alkyl group is methyl, ethyl, propyl or butyl, and the weight average molecular weight is 10,000-500,000; and an ethylene-acrylic acid copolymer comprising methacrylic acid and ethacrylic acid (ethacylic acid) having a number average molecular weight of 10,000 to 500,000.

In certain embodiments of the invention, the delivery or push layer comprises an osmopolymer. Examples of osmopolymers include, but are not limited to, components selected from polyalkylene oxides and carboxyalkyl celluloses. The weight average molecular weight of the polyalkylene oxide is 1,000,000 to 10,000,000. The polyalkylene oxide may be selected from the group consisting of polymethylene oxide having an average molecular weight of 5,000,000, polyethylene oxide, polypropylene oxide, polyethylene oxide having an average molecular weight of 7,000,000, crosslinked polymethylene oxide having an average molecular weight of 1,000,000, polypropylene oxide having an average molecular weight of 1,200,000. Typical osmopolymers, carboxyalkyl celluloses, comprise a component selected from the group consisting of alkali metal carboxyalkyl celluloses, sodium carboxymethyl cellulose, potassium carboxymethyl cellulose, sodium carboxyethyl cellulose, lithium carboxymethyl cellulose, sodium carboxyethyl cellulose, carboxyalkyl hydroxyalkyl cellulose, carboxymethyl hydroxyethyl cellulose, carboxyethyl hydroxyethyl cellulose, and carboxymethyl hydroxypropyl cellulose. The osmopolymer used for the displacement layer has an osmotic pressure gradient across the semi-permeable wall. The osmopolymer absorbs fluid into the dosage form, thereby swelling and expanding into an osmotic hacrogel (also known as an osmotic gel), thereby pushing the opioid out of the osmotic dosage form.

The push layer may also comprise one or more osmotically effective compounds also known as osmolytes (osmagents) and osmotically effective solutes. They absorb environmental fluids, e.g., from the gastrointestinal tract into the dosage form, facilitating the delivery kinetics of the displacement layer. Examples of osmotically active compounds include components selected from osmotic salts and osmotic carbohydrates. Examples of specific osmotic agents include, but are not limited to, sodium chloride, potassium chloride, magnesium sulfate, lithium phosphate, lithium chloride, sodium phosphate, potassium sulfate, potassium phosphate, glucose, fructose, and maltose.

The push layer may optionally include a hydroxypropyl alkylcellulose having a number average molecular weight of 9,000 to 450,000. The hydroxypropyl alkylcellulose is represented by a component selected from hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, hydroxypropyl isopropyl cellulose, hydroxypropyl butyl cellulose and hydroxypropyl amyl cellulose.

The push layer optionally may contain a non-toxic colorant or dye. Examples of colorants or dyes include, but are not limited to, food and drug administration colorants (FD & C), such as blue dye No. 1 of FD & C, red dye No.4 of FD & C, red iron oxide, yellow iron oxide, titanium dioxide, carbon black, and indigo.

The push layer may also optionally contain an antioxidant that inhibits oxidation of the component. Some examples of antioxidants include, but are not limited to, those selected from the group consisting of ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, mixtures of 2 and 3-tert-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodium erythorbate, dihydroguatic acid, potassium sorbate, sodium bisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate, vitamin E, 4-chloro-2, 6-di-tert-butylphenol, alpha-tocopherol, and gallic acid lactone.

In certain alternative embodiments, the dosage form comprises a homogeneous core comprising the opioid, a pharmaceutically acceptable polymer (e.g., polyethylene oxide), an optional disintegrant (e.g., polyvinylpyrrolidone), an optional absorption enhancer (e.g., fatty acids, surfactants, chelating agents, bile salts, etc.). The homogeneous core is surrounded by a semi-permeable wall having a channel (as described previously) for release of the opioid.

In certain embodiments, the semipermeable wall comprises a component selected from the group consisting of cellulose ester polymers, cellulose ether polymers, and cellulose ester-ether polymers. Representative wall polymers comprise those selected from the group consisting of cellulose acrylates, cellulose diacrylates, cellulose triacrylates, cellulose acetates, cellulose diacetate, cellulose triacetate, mono-, di-and tri-cellulose alkenyl esters, and mono-, di-and tri-cellulose alkynyl esters (alklylates). The number average molecular weight of the polycellulose used in the invention is 20,000-7,500,000.

Other semipermeable polymers useful for the purposes of the present invention include acetaldehyde dimethyl cellulose acetate, cellulose acetate ethyl carbamate, cellulose acetate methyl carbamate, cellulose diacetate, propyl carbamate, cellulose acetate diethylaminoacetate, semipermeable polyamides, semipermeable polyurethanes, semipermeable sulfonated polystyrenes, semipermeable cross-linked polymers formed by co-precipitation of polyanions and polycations as disclosed in U.S. Pat. Nos. 3,173,876, 3,276,586, 3,541,005, 3,541,006 and 3,546,876, semipermeable polymers as disclosed in U.S. Pat. No.3,133,132 to Loeb and Sourirajan, semipermeable cross-linked polystyrenes, sodium semipermeable cross-linked polystyrenesulfonates, semipermeable cross-linked polyvinylbenzyltrimethylammonium chloride, and a fluid permeability as expressed by an atmosphere of hydrostatic force or osmotic pressure difference across each semipermeable wall of 2.5X 10^-8～2.5×10^-2(cm²Hr.atm). Other Polymers useful in the present invention are those known in the art from U.S. patent nos. 3,845,770, 3,916,899, and 4,160,020 and the general polymer Handbook (Handbook of common Polymers, Soctt, j.r. and w.j.roff, 1971, CRC Press, Cleveland, Ohio).

In certain embodiments, it is preferred that the semi-permeable wall be non-toxic, inert and capable of maintaining its physical and chemical integrity during the dispensing period of the drug. In certain embodiments, the dosage form contains a binder. Examples of the binder include, but are not limited to, therapeutically acceptable vinyl polymers having a viscosity average molecular weight of 5,000 to 350,000 represented by components selected from the group consisting of poly-n-vinylamide, poly-n-vinylacetamide, polyvinylpyrrolidone, also referred to as poly-n-vinylpyrrolidone, poly-n-vinylcaprolactone, poly-n-vinyl-5-methyl-2-pyrrolidone, and poly-n-vinylpyrrolidone copolymers having components selected from the group consisting of vinyl acetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl butyrate, vinyl laurate and vinyl stearate. Other binders include, for example, acacia, starch, gelatin, and hydroxypropyl alkylcellulose having an average molecular weight of 9,200-250,000.

In certain embodiments, the dosage form comprises a lubricant, which may be used to prevent and adhere to the die wall or puch face during the manufacture of the dosage form. Examples of lubricants include, but are not limited to, magnesium stearate, sodium stearate, stearic acid, calcium stearate, magnesium oleate, oleic acid, potassium oleate, carprylic acid, sodium stearyl fumarate, and magnesium palmitate.

In certain embodiments, the invention encompasses a therapeutic composition comprising 1 to 640mg opioid, 25 to 500mg polyalkylene oxide having an average molecular weight of 150,000 to 500,000, 1 to 50mg polyvinylpyrrolidone having an average molecular weight of 40,000, and 0 to about 7.5mg lubricant.

In certain embodiments, the present invention also provides methods of administering at least one opioid via an oral dosage form, the oral dosage form comprises 1-640 mg opioid, a semi-permeable wall of channels permeable to water-biological fluids and impermeable to the opioid, wherein the semipermeable wall surrounds an interior space containing an opioid composition comprising 1 to 640mg of opioid, 25 to 500mg of polyalkylene oxide having an average molecular weight of 150,000 to 500,000, 1 to 50mg of polyvinylpyrrolidone having an average molecular weight of 40,000 and 0 to 7.5mg of lubricant, and a push composition comprising 15 to 2500mg of polyalkylene oxide having an average molecular weight of 3,000,000 to 7,500,000, 0 to 75mg of osmotic agent, 1 to 50mg of hydroxyalkyl cellulose, 0 to 10mg of ferric oxide, 0 to 10mg of lubricant and 0 to 10mg of antioxidant; the passage of the absorbed fluid through the semipermeable wall into the dosage form causes the opioid composition to partition and causes the composition to be urged to expand and urge the opioid through the passage, thereby delivering the opioid at a therapeutically effective dose and at a controlled rate over a sustained release period by the combined operation of the dosage form.

The dosage form of the present invention may optionally be coated with one or more coatings suitable for modified release or protective formulations. In one embodiment, a coating is provided to allow pH-dependent or pH-independent release, for example, when exposed to Gastrointestinal (GI) fluids. When a pH independent coating is desired, the coating is designed to achieve optimal release despite pH changes in environmental fluids, such as the GI tract. In other preferred embodiments, the pH-dependent coating releases the opioid in a desired region of the GI tract, e.g., the stomach or small intestine, thus providing an absorption profile capable of providing a therapeutic effect to the patient for at least about 12 hours and preferably about 24 hours or more. The composition may also be formulated to release a portion of the dose in one desired region of the gastrointestinal tract, e.g., the stomach, and the remainder of the dose in other regions of the gastrointestinal tract, e.g., the small intestine.

The formulation according to the present invention using a pH-dependent coating may also provide an effect of repeated action, whereby the drug, which is not protected, is coated outside the enteric coating and released in the stomach, and the remaining part, which is protected by the enteric coating, is further released in the lower part of the gastrointestinal tract. The pH-dependent coating that may be used in accordance with the present invention comprises controlled release substances such as shellac, Cellulose Acetate Phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalate and methacrylate copolymers, zein and the like.

In certain embodiments of the invention, an effective amount of an opioid in immediate release form is included in the formulation. The unit dose contains such an effective amount of an immediate release opioid. In these embodiments, an effective amount of an immediate release form of the opioid may be coated on the tablets of the present invention. For example, where the at least one opioid is time released from the formulation due to the extended release coating, the immediate release layer is overcoated over the extended release coating. In another aspect, the immediate release layer may be coated on the surface of the tablet, wherein the at least one opioid is contained within the sustained release matrix. Those skilled in the art will recognize that there are other alternatives to incorporating an immediate release opioid portion into the formulation. Such alternatives are considered to be encompassed by the appended claims.

The following examples illustrate some preferred formulations. And should not be construed as limiting the claims in any way.

Example 1 production of tablets containing different amounts of oxycodone/naloxone in a non-swelling diffusion matrix by spray granulation

The component amounts listed below were used to produce oxycodone/naloxone tablets.

Preparation (name)	Oxy/Nal-0	Oxy/Nal-5	Oxy/Nal-10
				Hydrochloric acidOxycodone hydrochloride naloxone FlowLac 100 lactose polyvinylpyrrolidone 30Surelease ® Octadecanol Talc magnesium stearate	20.0mg-59.25mg5.0mg10.0mg solid matter 25.0mg2.5mg1.25mg	20.0mg of 5.0mg of 54.25mg of 5.0mg of 10.0mg of solid matter 25.0mg of 2.5mg of 1.25mg	20.0mg10.0mg49.25mg5.0mg10.0mg solid substance 25.0mg2.5mg1.25mg

The used Surelease^®The polymer blend E-7-7050 contained the following components.

Surelease®

Ethyl cellulose 20cps

Dibutyl sebacate

Ammonium hydroxide

Oleic acid

Silicon dioxide

Water (W)

Oxycodone hydrochloride, naloxone hydrochloride, polyvinylpyrrolidone 30 and Flow Lac 100 lactose were mixed in a tumbler mixer (Bohle) and then with Surelease^®E-7-7050 tablets were produced by spray granulation in a fluidized bath granulation apparatus (GPCG 3). The material was sieved through a Comill 1.4mm sieve. An additional granulation step was performed with molten fatty alcohol in a high shear mixer (Collette). All tablet cores produced by this method had a weight of 123mg on a dry matter basis.

Example 2 production of tablets containing oxycodone and naloxone in a non-swelling diffusion matrix by extrusion

The component amounts listed below are used for the production of oxycodone/naloxone tablets according to the invention

Preparation (name)	Oxy/Nal-extract
		Hydroxycodeinone hydrochloride polyvinylpyrrolidone 30FlowLac 100 lactose Ethyl cellulose 45cps Octadecanol Talcum magnesium stearate	20mg10mg6mg49.25mg10mg24mg2.5mg1,25mg

The recited amounts of oxycodone hydrochloride, naloxone hydrochloride, ethylcellulose 45cps, polyvinylpyrrolidone 30, octadecanol and Flow Lac 100 lactose were mixed in a tumbler mixer (Bohle). The mixture was then extruded using a counter-rotating twin-screw extruder of the type Micro 18 GGL (Leistritz AG, N ü rnberg, Germany). The temperature of the heating section 1 is 25 ℃, the temperature of the heating section 2 is 50 ℃, the temperature of the heating section 3-5 is 60 ℃, the temperature of the heating section 6-8 is 55 ℃, the temperature of the heating section 9 is 60 ℃, and the temperature of the heating section 10 is 65 ℃. The screw speed was 150 revolutions per minute (rpm), the resulting melt temperature was 87 ℃, the feed rate was 1.5kg/h, and the nozzle diameter was 3 mm. The extrudates were sieved through a Frewitt 0.68X 1.00mm sieve. The milled extrudate was then blended with talc and magnesium stearate, which were added using a 1mm hand sieve, and compressed into tablets.

In contrast to oxycodone/naloxone tablets produced by spray granulation (cf. example 1) which also have a non-swelling diffusion matrix based on Surelease ®, the extruded formulations contain less components.

Example 3-release profile of oxycodone/naloxone tablets in example 1:

the release of active compound within 12h was determined by HPLC using the Basket Method according to USP (Basket Method) at pH 1.2. Tablets Ox/Nal-0, Ox/Nal-5 and Ox/Nal-10 were tested.

It can be seen from the table that the method is based on Surelease^®In the case of the non-swelling diffusion matrix of (a), the release rates for different amounts of oxycodone, independent of the amount of naloxone, remain equal (constant). Accordingly, a constant release profile of naloxone was observed at different amounts of oxycodone.

Time (min)	Ox/Nal-0	Ox/Nal-5-O	Ox/Nal-5-N	Ox/Nal-10-O	Ox/Nal-10-N
						015120420720	Oxy026.162.191.798.1	Oxy024.96394.599.6	Nal023.56191.996.6	Oxy022.857.589.495.7	Nal024.160.293.5100.6

The release values are referenced to oxycodone or naloxone (line 2) and are expressed as a percentage. The mean release of naloxone at e.g. 420min was 92.7%. The maximum deviation at 420min is 1%. Oxy represents oxycodone and Nal represents naloxone, indicating the active compound tested.

Example 4-release profile of oxycodone/naloxone tablets at different pH values in example 2:

the release of active compound from the tablets was determined at pH1.2 over 12h, or at pH1.2 over 1h and then at pH6.5 over 11 h. The release rate was determined by the basket method according to USP using HPLC.

The release rate at pH1.2 over 12h is as follows.

Time (min)	Oxy/Nal-extract-1, 2-OOxy	Oxy/Nal-extract-1, 2-NNal
			015120420720	024.162.992.996.9	024.063.593.998.1

The release rates at pH1.2 over 1h and pH6.5 over 11h are shown below.

Time (min)	Oxy/Nal-extract-6, 5-OOxy	Oxy/Nal-extract-6, 5-NNal
			060120240420	048.165.083.394.1	049.264.781.892.3

The release rates are referenced to oxycodone or naloxone (row 2) and are expressed as percentages. Oxy represents oxycodone and Nal represents naloxone, indicating the active compound tested.

PCT/EP03/03541 discloses further examples of suitable combinations of oxycodone as an agonist and naloxone as an antagonist.

Examples 5 and 6 controlled Release oxycodone formulations, 10 and 20mg tablets

Eudragit ® RS30D and triacetin were mixed while passing through a 60 mesh screen and mixed under low shear for about 5min or until a homogeneous dispersion was observed.

Next, the appropriate amounts of oxycodone hydrochloride, lactose and polyvinylpyrrolidone were placed in the tank of a fluid bed granulator/dryer (FBD) and the suspension was sprayed onto the powder in the fluid bed. After spraying, the granules were passed through a #12 sieve as needed to reduce caking. The dried granules were placed in a mixer.

At the same time, the required amount of octadecanol melts at about 70 ℃. Molten octadecanol is added to the granules while mixing takes place. The waxy particles are transferred to a fluid bed granulator/dryer or pan and cooled to room temperature or below. The cooled pellets were then passed through a #12 sieve. Thereafter, the waxy granules were placed in a mixer/blender, lubricated with the desired amounts of talc and magnesium stearate for about 3 minutes, and then the granules were compressed into 125mg tablets on a suitable tablet press.

The formulation of the tablet of example 5(10mg tablet) is shown in the following table:

components	Mg/sheet	% by weight
			Hydroxycodeketolactose hydrochloride (spray dried) polyvinylpyrrolidone Eudragit ® RS30D (solid) Triacetin ® Stetadecanol TalcMagnesium stearate	10.069.255.010.0*2.025.02.51.25	8.055.44.08.01.620.02.01.0
In total:	125.0	100.0

^*approximately 33.33mg of aqueous Eudragit ® RS30D dispersion corresponded to 10mg of dry Eudragit ® RS 30D.

The formulation of the tablet of example 6(20mg tablet) is shown in the following table:

components	Mg/sheet
		Hydroxycodeketolactose hydrochloride (spray dried) polyvinylpyrrolidone Eudragit ® RS30D (solid) Triacetin ® Stetadecanol TalcMagnesium stearate	20.059.255.010.0*2.025.02.51.25
In total:	125.0

the tablets of examples 7 to 5 were subjected to dissolution test by USP basket method at 37 ℃ and 100rpm in 700ml of simulated gastric fluid at pH1.2 and then 900ml at pH7.5 within 1 hour. The results are shown in the following table:

time (h)	Percent dissolution of oxycodone
		1248121824	38.047.562.079.891.194.998.7

The tablets of examples 8 to 6 were subjected to dissolution test by USP basket method at 3 ℃ and 100rpm in 700ml of simulated gastric fluid at pH1.2 and then 900ml at pH7.5 within 1 hour. The results are shown in the following table:

time (h)	Percent dissolution of oxycodone
		1248121824	31445771798689

Examples of other suitable oxycodones as agonists and corresponding in vivo data are disclosed in EP 0576643 (incorporated herein by reference).

Example 9-formulation of 24h 160mg oxycodone sustained release capsules prepared as follows:

components	Mg/cell
		Oxycodone hydrochloride stearyl stearateEudragit RSPO	1608020140
Total of	400

The above formulation was prepared according to the following procedure:

1. the octadecanol flakes were passed through an impact mill.

2. Oxycodone hydrochloride, stearic acid, stearyl alcohol and Eudragit RSPO were blended in a suitable input end (lener)/mixer.

3. The blend was continuously fed into a twin screw extruder at elevated temperature and the strands on the conveyor were collected.

4. The wire harness is cooled on a conveyor.

5. The strands were cut into 1mm pellets using a pelletizer.

6. The pellets for refining were screened and re-screened to an acceptable range of about 0.8 to 1.4mm size.

7. Encapsulating, and filling weight of each capsule is 400mg (encapsulating size 00 capsule).

Example 10-determination of the dissolution of the tablets in example 9. The pellets were then subjected to the following steps: fiber optic uv dissolution at 282nm was monitored in 900ml Simulated Gastric Fluid (SGF) and 900ml Simulated Intestinal Fluid (SIF) using USP apparatus 1 (rotating basket) at 100 rpm.

The dissolution parameters of the above formulation are shown in the following table:

time (h)	Percentage dissolution in SGF	Percent dissolution in SIF
			1248121824	32476686939595	20284260707780

Claims (13)

1. Use of an opioid controlled release oral dosage form comprising at least one opioid for the manufacture of a medicament for the treatment of patients with Restless Leg Syndrome (RLS).

2. Use of an opioid controlled release oral dosage form comprising at least one opioid for the manufacture of a medicament for the treatment of patients with Restless Leg Syndrome (RLS), which medicament provides effective treatment when administered every 12 hours at steady state.

3. Use of an opioid controlled release oral dosage form comprising at least one opioid for the manufacture of a medicament for the treatment of patients with Restless Leg Syndrome (RLS), which medicament provides effective treatment when administered every 24 hours at steady state.

4. Use according to any one of the preceding claims, wherein the oral dosage form comprises an opioid agonist selected from the group comprising: oxycodone, dihydrocodeinone, hydromorphone, morphine, methadone, oxymorphone, fentanyl, and sufentanil in free base or pharmaceutically acceptable salt form.

5. Use according to any one of the preceding claims, wherein the oral dosage form comprises a mixture of an opioid agonist and an opioid antagonist selected from the group comprising: naltrexone, nalmefene and naloxone in the form of the free base or a pharmaceutically acceptable salt.

6. Use according to any of the preceding claims, wherein the oral dosage form comprises oxycodone or a pharmaceutically acceptable salt thereof.

7. Use according to any of the preceding claims, wherein the oral dosage form comprises morphine or a pharmaceutically acceptable salt thereof.

8. Use according to any of the preceding claims, wherein the oral dosage form comprises a mixture of oxycodone and naloxone as free bases or as pharmaceutically acceptable salts thereof.

9. Use according to claim 8, wherein the oral dosage form is a storage-stable pharmaceutical formulation and the active compound is released from the formulation in a sustained, invariant and independent manner.

10. Use according to claim 8 or 9, wherein oxycodone is present in excess relative to the unit dose of naloxone.

11. Use according to claims 8-10, wherein naloxone is present in an amount ranging from 1 to 50 mg.

12. Use according to claims 8-11, wherein the oxycodone is used in an amount ranging from 10 to 150mg, preferably from 10 to 80 mg.

13. Use according to claims 8 to 12, wherein the weight ratio of oxycodone and naloxone is in the range of at most 25: 1, preferably at most 20: 1, 15: 1, particularly preferably 5: 1, 4: 1, 3: 1, 2: 1 or 1: 1.