WO2004091546A2 - Combinaison d'un stimulateur du systeme nerveux central et d'antagonistes d'opiates - Google Patents

Combinaison d'un stimulateur du systeme nerveux central et d'antagonistes d'opiates Download PDF

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Publication number
WO2004091546A2
WO2004091546A2 PCT/US2004/009161 US2004009161W WO2004091546A2 WO 2004091546 A2 WO2004091546 A2 WO 2004091546A2 US 2004009161 W US2004009161 W US 2004009161W WO 2004091546 A2 WO2004091546 A2 WO 2004091546A2
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WIPO (PCT)
Prior art keywords
cns stimulant
opioid antagonist
composition according
pharmaceutically acceptable
sustained release
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PCT/US2004/009161
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English (en)
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WO2004091546A3 (fr
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Robert Kaiko
Iwona Beczkowska
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Euro-Celtique S.A.
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Publication of WO2004091546A2 publication Critical patent/WO2004091546A2/fr
Publication of WO2004091546A3 publication Critical patent/WO2004091546A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

  • This application is directed to a combination of a CNS stimulant, e.g., methylphenidate. and an opioid antagonist and methods of administering the composition for the treatment of attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), narcolepsy, cocaine addiction, appetite suppression and depression.
  • a CNS stimulant e.g., methylphenidate.
  • an opioid antagonist e.g., acetylcholine, acetyline, nadyline, narcolepsy, cocaine addiction, appetite suppression and depression.
  • the combination provides an increased therapeutic effect and reduced abuse potential as compared to either of the drugs used alone.
  • Attention deficit disorder is a learning disorder that relates to developmentally inappropriate inattention- and impulsivity, which may be present with hyperactivity (ADHD) or without hyperactivity.
  • ADD is implicated in learning disorders and can influence the behavior of children at any cognitive level.
  • ADD is primarily a disorder experienced by children, but it may be present in adults as well.
  • ADD is estimated to affect 5 to 10% of school-aged children, precipitating half of the childhood referrals to diagnostic clinics, and it is seen 10 times more frequently in boys than girls.
  • the primary signs of ADD are a subject's display of inattention and impulsivity. ADHD is diagnosed when the signs of overactivity are obvious. Inappropriate inattention causes increased rates of activity and impersistence or reluctance to participate or respond. A subject suffering from ADD exhibits a consistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than is typically observed in individuals at a comparable level of development. To establish ADD, subjects must- suffer clear evidence of interference with developmentally appropriate social, academic, or occupational functioning. Although subjects with ADD (without hyperactivity) may not manifest high activity levels, most exhibit restlessness or jitteriness, short attention span, and poor impulse control. These are qualitatively different from those seen in conduct and anxiety disorders.
  • Inattention is described as a failure to finish tasks started, easy distractibility, seeming lack of attention, and difficulty concentrating on tasks requiring sustained attention.
  • Impulsivity is described as acting before thinking, difficulty taking turns, problems organizing work, and constant shifting from one activity to another. Impulsive responses are especially likely when involved with uncertainty and the need to attend carefully. Hyperactivity is featured as difficulty staying seated ' and sitting still, and running or climbing excessively.
  • Narcolepsy is characterized by insomnia, including attacks of sleep that may occur suddenly under conditions that are not normally conducive to sleep.
  • Treatments for narcolepsy include administration of tricyclic antidepressaiits or MAO inhibitors.
  • CNS stimulants e.g., methylphenidate
  • the use of stimulants is complicated by the risk of abuse and the likelihood of developing tolerance.
  • CNS stimulants produced weight loss, and they have since been used to treat obesity.
  • the stimulants promote weight loss by suppression of appetite, rather than by increasing energy expenditure.
  • Cocaine use is associated with it's effectiveness to block dopamine transport, which leads to increased dopaminergic stimulation at critical brain sites.
  • the dopaminergic stimulation causes a reinforcing effect and produces increased heart rate and blood pressure, as well as increased arousal, improved performance on tasks of vigilance and alertness, sense of self-confidence and euphoria.
  • Administration of certain CNS stimulants, e.g., methylphenidate produce subjective effects similar to cocaine by providing an increase in synaptic dopamine primarily by stimulation of presy ⁇ aptic release of dopamine rather than by blockade of reuptake, as is the case with cocaine.
  • Methylphenidate is approved for the treatment of attention deficit/hyperactivity disorders and narcolepsy and has a host of unlabeled uses, " e*g., as a treatment for cocaine addiction, and for the treatment of depression in elderly, cancer and post-stroke patients.
  • Methylphenidate is commercially available under the tradename Ritalin® (Ciba- Geigy) in 5mg, lOmg and 20mg immediate release tablets and 20mg sustained-release tablets; under the tradename ConcertaTM (Alza Pharmaceuticals) as 18mg, 36mg and 54mg tablets; and under, the Tradename Metadate CD ® 20mg (Celltech) as a sprinkle. dosage form.
  • Ritalin® Ciba- Geigy
  • ConcertaTM Alza Pharmaceuticals
  • Metadate CD ® 20mg Celltech
  • Symptoms of methylphenidate abuse are principally a result of CNS over-stimulation and excessive sympathomimetic effects, and can be characterized by the following: appetite suppression, wakefulness, increased focus/attentiveness, euphoria, vomiting, agitation, tremors, convulsions (possibly followed by a coma), confusion, hallucination, delirium, sweating, flushing, hyperpyrexia, headache, tachycardia, palpitations, cardiac arrhythmias, hypertension and dry mucous membranes.
  • Opioid antagonists typically block or reverse the effect of opioid agonists. Accordingly, opioid " antagonists can be used to block euphoric effects that might otherwise be obtained upon administration of opioid agonists to addicts; to determine whether individuals are physically dependent on opioid agonists; and to reverse the effects of opoid agonists on individuals who have overdosed on such drugs. Opioid antagonists have also been used to precipitate abstinence syndrome in subjects physically dependent on opioid agonists.
  • Opioid antagonists e.g., naltrexone and naloxone
  • SSRIs serotonin- reuptake inhibitors
  • Opioid antagonists and certain CNS stimulants have common reward pathways and physiological mechanisms of euphoria. Further, it is believed that opioid antagonists increase dopamine levels in brain areas that do not respond to therapy by certain CNS stimulants such as methylphenidate. Accordingly, it would be advantageous to provide compositions and methods for treating attention deficit disorders (ADD, ADHD), narcolepsy, drug addiction, obesity and/or depression that preferably have reduced abuse potential and side effects.
  • ADD attention deficit disorders
  • narcolepsy drug addiction
  • obesity and/or depression preferably have reduced abuse potential and side effects.
  • It is an object of the present invention to provide a pharmaceutical composition comprising at least one CNS stimulant and at least one opioid antagonist.
  • drug addiction e.g., alcohol, opioid and/or cocaine addiction
  • narcolepsy e.g., narcolepsy, depression and/or obesity
  • It is an object of certain embodiments of the present invention to provide a method for reducing side effects ' and/or abuse potential associated with CNS stimulant therapy comprising co-administering at least one opioid antagonist with at least one CNS stimulant to a patient in need thereof, whereby a decreased amount of the CNS stimulant is required to achieve a therapeutic effect, as compared to when the CNS stimulant is used alone, thereby resulting in a reduction of side effects and/or abuse potential associated with the CNS stimulant therapy.
  • the present invention is related in part to administration of a pharmaceutical composition comprising a CNS stimulant and an opioid antagonist in a single dosage form or the co-administration of a CNS stimulant and an opioid antagonist as separate compositions.
  • the CNS stimulant and opioid antagonist can independently be administered by any appropriate route, e.g., orally, via implant, parenterally, sublingually, rectally, topically, or via inhalation.
  • co-administration means: (i) the administration of a single dosage form containing both the CNS stimulant and the opioid antagonist; or (ii) the administration of the CNS stimulant and the opioid antagonist as separate compositions, either simultaneously or sequentially, by the same route of administration or by a different route of administration to allow the benefit of the combination to be realized.
  • parenterally encompasses, e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, intradermal, intrasternal injection, intraspinal or infusion techniques.
  • topically encompasses administration by any transdermal technique known in the art, including, e.g., the use of creams, ointments, emulsions, gels, lotions, solutions, suspensions, aerosols, and transdermal delivery devices such as transdermal patchs, transdermal plasters, transdermal discs, and iontophoretic transdermal devices.
  • inhalation encompasses administration by any technique known in the art for pulmonary or nasal delivery, e.g., aerosols, dry powders, nebulized solutions or infusion.
  • sustained release is defined for purposes of the present invention asthe release of the drug from the formulation at a rate which will provide a longer duration of action than a single dose of the normal (i.e., immediate release) formulation.
  • a typical immediate release oral formulation may release the drug, e.g., over a 1 hour interval, as compared to a sustained release oral formulation which may release the drug, e.g., over a 4 to 24 hour interval.
  • a sustained release transdermal system can release the drug contained therein, e.g., over a 1 day to 30 day interval.
  • a sustained release formulation according to the present invention may also have an immediate release portion of drug contained therein to provide a prompt therapeutic effect.
  • central nervous system stimulant (hereinafter “CNS” stimulant) shall include the base form of the CNS stimulant, pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers and esters thereof, and mixtures of any of the foregoing.
  • opioid antagonist shall include the base form of the antagonist, pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers and esters thereof, and mixtures of any of the foregoing.
  • the CNS " stimulant is selected from the group consisting of methylphenidate, amphetamine, dextroamphetamine, methamphetamine, phentermine, benzphentamin ⁇ i phendimetrazine, diethylpropion, mazindol, fenfluramine, sibutramine, phenylpropanolamine, ephedrine, phenylephrine, mephentermine, norepinephrine, epinepl-rine, caffeine, doxapram, modafinil, pharmaceutically acceptable salts thereof and mixtures thereof.
  • the CNS stimulant is methylphenidate or a pharmaceutically acceptable salt thereof, e.g., methylphenidate hydrochloride.
  • the CNS stimulant and opioid antagonist are administered as a combination pharmaceutical composition, wherein both agents are contained in a single dosage form, e.g., an immediate release or sustained release tablet or capsule.
  • the CNS stimulant and opioid antagonist are co-administered as separate dosage forms.
  • the co-administration can be simultaneous, or sequential.
  • sequential administration the CNS stimulant can be administered and the opioid antagonist can be administered immediately thereafter, or within a specific time period, e.g., several minutes or hours thereafter.
  • the number of doses of each agent given per . day may be different, e.g.
  • the CNS stimulant is methylphenidate or a pharmaceutically acceptable salt thereof
  • the amount administered per dose is dependent on factors such as, e.g., the route of administration, the formulation containing the drug, and the frequency of administration. . '
  • the total oral daily dose of methylphenidate can be from about lmg to about 60mg, from about 5 mg to about 30 mg, or from about lOmg to about 20mg.
  • the actual amount of drug in each dose can be ascertained by one skilled in the art, taking into account the above . factors.
  • Opioid antagonists useful in the present invention include, but are not limited to naloxone, naltrexone, nalmefene, cyclazocine, nalo hine, levallorphan, pharmaceutically acceptable salts thereof and mixtures thereof.
  • Other drugs which exhibit opioid antagonistic effects are also useful in the present invention, e.g., mixed opioid agonist/aritagonist agents, such as pentazocine, nalbuphine, buprenorphine, pharmaceutically acceptable salts thereof - and mixtures thereof.
  • Naloxone, naltrexone, nalmefene and salts thereof are particularly preferred.
  • naltrexone, nalmefene and salts thereof are particularly preferred.
  • the total oral daily dose of opioid antagonist administered can be from about 0.005mg to about 150mg, or from about Img to about 50mg.
  • the actual amount of antagonist in each dose can be ascertained by one skilled in the art, taking into account, e.g., the route of administration, the formulation containing the drug, and the frequency of administration.
  • the total oral daily dose can be from about 0.005mg to about 24mg, from about O.lmg to about lOmg or from about 0.4mg to about 2mg.
  • the total oral daily dose can be from about 0.005mg to about 150mg, from about O.lmg to about 75mg or from about lOmg to about 50mg.
  • the pharmaceutical composition(s) can be a dosage form independently selected from the group consisting of oral, sublingual, topical, implantable, inhalable and parenteral dosage forms.
  • the agents can be combined with excipients, e.g., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral administration, known in the art.
  • Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatins, carbohydrates such as lactose, amylose or starch; magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, etc.
  • compositions can be sterilized, and if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like.
  • compositions intended for oral use may be prepared according to any method known in the art- Such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients include, for example, an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
  • the tablets may be uncoated or they may be coated by known techniques for elegance or to delay release of the active ingredients.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with excipient.
  • Aqueous suspensions preferably contain the agent(s) in a mixture that has one or more excipients suitable as suspending agents, for example, pharmaceutically acceptable synthetic gums such as hydroxypropylmethylcellulose or natural gums.
  • Oily suspensions may be formulated by suspending the agent(s) in a vegetable oil or mineral oil.
  • the oily suspensions may contain a thickening -agent such as beeswax or cetyl alcohol.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the method of treatment and pharmaceutical compositions ' df the present invention may further include an additional active agent in addition to the CNS stimulant and opioid antagonist.
  • the additional agent can provide increased therapeutic benefit by treating a disease state not being treated by the combination of CNS stimulant and opioid antagonist, or alternatively can augment the intended therapy of the combination.
  • the oral pharmaceutical compositions of the present invention can be in the form of tablets, dragees, liquids, drops, gelcaps, troches, lozenges, aqueous or oily suspensions, multiparticulate formulations including dispersable powders, granules, pellets, matrix spheroids, coated inert beads, emulsions, hard or soft capsules, syrups, elixirs, microparticles (e.g., microcapsules, microspheres and the like), buccal tablets, etc.
  • the dosage forms of the present invention may preferably include any desired pha ⁇ aceutically acceptable excipients known to those skilled in the art.
  • the CNS stimulant and the opioid antagonist can each independently be released in (i) immediate release form, (ii) sustained release form, or (iii) both immediate and sustained release form.
  • Sustained release may be accomplished in accordance with formulations/methods of manufacture known to those skilled in the art of pharmaceutical formulation, e.g., via the incorporation of a sustained release carrier into a matrix containing the CNS stimulant and opioid antagonist; or via a sustained release coating of a matrix containing the CNS stimulant and opioid antagonist; or a combination thereof.
  • the CNS stimulant/opioid antagonist combination can be formulated as a controlled or sustained release oral formulation in any suitable tablet, coated tablet or multiparticulate formulation known to those skilled in the art.
  • the sustained release dosage form may optionally include a sustained release material which is (i) incorporated into a matrix along with the CNS stimulant and/or opioid antagonist, or (ii) coated on a substrate containing the agent(s).
  • the composition may include at least one sustained release excipient which provides a sustained release of the CNS stimulant, the opioid antagonist or both the CNS stimulant and the opioid antagonist.
  • the sustained release material preferably provides a sustained release from about 12 to about 24 hours for oral preparations or from about 3 to 7 days for transdermal formulations.
  • the sustained release dosage form may comprise particles containing the active ingredients, wherein the particles have a diameter from about 0.1 mm to about 2.5 mm, preferably from about 0.5 mm to about 2 mm.
  • the particles may be film coated with a material that permits release of the CNS stimulant and/or antagonist combination at a sustained rate in an aqueous medium.
  • the film coat may be chosen to achieve, in combination with the other stated properties, a desired in-vitro release rate.
  • the sustained release coating formulations of the present invention should be capable of producing a strong, continuous film that is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic, inert, and tack-free.
  • the particles can comprise immediate release matrices containing the CNS stimulant and/or the opioid antagonist.
  • the dosage forms of the present invention may optionally be coated with one or more materials suitable for the regulation of release or for the protection of the formulation.
  • coatings are provided to permit either pH-dependent or pH-indepe ⁇ dent release, e.g., when exposed to gastrointestinal fluid.
  • a pH-dependent coating serves to release the CNS stimulant and/or opioid antagonist in desired areas of the gastrointestinal (GI) tract, e.g., the stomach or small intestine.
  • GI gastrointestinal
  • the coating is designed to achieve optimal release regardless of pH-changes in the environmental fluid.
  • compositions which release a portion of the dose in one desired area of the GI tract, e.g., the stomach, and release the remainder of the dose in anotlier area of the GI tract, e.g., the small intestine.
  • Formulations according to the invention that utilize pH-dependent coatings to obtain formulations may also impart a repeat-action effect whereby unprotected drug is coated over the enteric coating and is released in the stomach, while the remainder, being protected by the enteric coating, is released further down the gastrointestinal tract.
  • Coatings that are pH- dependent which may be used in accordance with the present invention include shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, methacrylic acid ester copolymers, zein, and the like.
  • a substrate e.g., tablet core or matrix particle
  • a hydrophobic material selected from (i) an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof.
  • the coating may be applied in the form of an organic or aqueous solution • or dispersion.
  • the coating may be applied to obtain a weight gain from about 2 to about 25% of the substrate in order to obtain a desired sustained release profile. Coatings derived from aqueous dispersions are described in detail, e.g., in U.S. Pat. Nos. 5,273,760 and 5,286,493.
  • sustained release formulations and coatings that may be used in accordance with the present invention include Assignee's U.S. Pat. Nos. 5,324,351; 5,356,46-7; and 5,472,712, hereby incorporated by reference in their entirety.
  • Cellulosic materials and polymers including alkylcelluloses, provide hydrophobic materials suited for coating the substrates according to the invention.
  • One preferred alkylcellulosic polymer is ethylcellulose, although the artisan will appreciate that other cellulose and/or alkylcellulose polymers may be readily employed, singly or in any combination, as all or part of a hydrophobic coating according to the invention.
  • Aquacoat ® FMC • Corp., Philadelphia, Pa., U.S.A.
  • Aquacoat ® is prepared by dissolving the ethylcellulose in a water-immiscible organic solvent and then emulsifying the same in water in the presence of a surfactant and a stabilizer. After homogenization to generate submicron droplets, the organic solvent is evaporated under vacuum to form a pseudolatex.
  • the plasticizer is not incorporated in the pseudolatex during the manufacturing phase. Thus, prior to using the same as a coating, it is necessary to intimately mix the Aquacoat ® with a suitable plasticizer prior to use.
  • aqueous dispersion of ethylcellulose is commercially available as Surelease ® (Colorcon, Inc., West Point, Pa., U.S.A.). This product is prepared by incorporating plasticizer into the dispersion during the manufacturing process. A hot melt of a 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 that can be applied directly onto substrates.
  • Surelease ® Colorcon, Inc., West Point, Pa., U.S.A.
  • the hydrophobic material comprising the controlled release coating is a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl ⁇ methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
  • acrylic acid and methacrylic acid copolymers including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(meth
  • the acrylic polymer is comprised of one or more ammonio • methacrylate copolymers.
  • Ammonio methacrylate copolymers are well known in the art, and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
  • methacrylic acid ester-type polymers are useful for preparing pH-dependent coatings which may be used in accordance with the present invention.
  • methacrylic acid copolymer or polymeric methacrylates commercially available as different grades of Eudragit ® from Rohm Tech, Inc.
  • the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the Tradenames Eudragit ® RL30D and Eudragit ® RS30D, respectively.
  • Eudragit ® RL30D and Eudragit ® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1 :20 in Eudragit ® RL30D and 1:40 in Eudragit ® RS30D.
  • the mean molecular weight is about 150,000.
  • RL high permeability
  • RS low permeability
  • the Eudragit ® RL/RS dispersions of the present invention may be mixed together in any desired ratio in order to obtain a sustained release formulation having a desirable dissolution profile. Desirable sustained release formulations may be obtained, for instance, from a retardant coating derived from 100% Eudragit ® RL or 50% Eudragit ® RL and 50% Eudragit ® RS or 10% Eudragit ® RL and Eudragit ® 90% RS. Of course, one skilled in the art will recognize that other acrylic polymers may also be used.
  • the inclusion of an effective amount of a plasticizer in the aqueous dispersion of hydrophobic material may further improve the physical properties of the sustained release coating.
  • a plasticizer into an ethylcellulose containing sustained release coating before using the same as a coating material.
  • the amount of plasticizer included in a coating solution is based on the concentration of the film-fo ⁇ rier, e.g., from about 1 to about 50 percent by weight of the film-former. Concentration of the plasticizer, however, may be properly determined after routine experimentation with the particular coating solution and method of application.
  • plasticizers for ethylcellulose include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin.
  • Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethylcellulose utilized in the present invention.
  • plasticizers for the acrylic polymers of the present invention include, but are not limited to citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and 1 ,2-propylene glycol.
  • Other plasticizers that have proved to be suitable for enhancing the elasticity of the films formed from acrylic films such as Eudragit ® RL/RS lacquer solutions include polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin.
  • Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of acrylic polymers utilized in the present invention.
  • Controlled release bead formulations prepared according to the present invention slowly release the therapeutically active agent, e.g., when ingested and exposed to gastrointestinal fluids.
  • the controlled release profile of the formulations of the invention can be altered, for example, by varying the amount of coating with the hydrophobic material, altering the manner in which the plasticizer is added to the hydrophobic material, by varying the amount of plasticizer relative to hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc.
  • the dissolution profile of the ultimate product may also be modified, for example, by increasing or decreasing the thickness of the retardant coating.
  • Substrates coated with a therapeutically active agent of the present invention can be prepared, e.g., by dissolving the therapeutically active agent(s) in water and then spraying the solution onto a substrate, for example, nu pariel 18/20 beads, using a Wuster insert.
  • additional ingredients can be added prior to coating. The additional ingredients can be used to assist the binding of the agent(s) to the spheroids or beads, and/or to provide color.
  • a product which includes hydroxypropylmethylcellulose, with or without colorant may be added to the solution and the solution mixed (e.g., for about 1 hour) prior to application of the same onto the spheroids or beads.
  • the resultant coated substrate, in this example spheroids or beads may then be optionally overcoated with a barrier agent, to separate the agent(s) from the hydrophobic controlled release coating.
  • a suitable barrier agent is one which comprises hydroxypropylmethylcellulose.
  • any film-former known in the art may be used. It is prefe ⁇ ed that the barrier agent does not affect the dissolution rate of the final product.
  • the substrates may then be overcoated with an aqueous dispersion of the hydrophobic material.
  • the aqueous dispersion of hydrophobic material preferably further includes an effective amount of plasticizer, e.g. triethyl citrate.
  • plasticizer e.g. triethyl citrate.
  • Pre-formulated aqueous dispersions of ethylcellulose, such as Aquacoat ® or Surelease ® may be used " . Tf Surelease is used, it is not necessary to separately add a plasticizer.
  • pre-formulated aqueous dispersions of acrylic polymers such as Eudragit can be used.
  • the coating solutions of the present invention may contain, in addition to the film- former, plasticizer, and solvent system, a colorant to provide elegance and product distinction. Color may be added to the solution of the therapeutically active agent instead of, or in addition to the dispersion of hydrophobic material. Any suitable method of providing color to the formulations of the present invention may be used. . Suitable ingredients for providing color to the formulation when an aqueous dispersion of an acrylic polymer is used. include titanium- dioxide and color pigments, such as iron oxide pigments. The incorporation of pigments, may, however, increase the retardant effect of the coating.
  • Plasticized hydrophobic material m y be applied onto the substrate comprising the therapeutically active agent by spraying using any suitable spray equipment known in the art.
  • a Wurster fiuidized-bed system is used in which an air jet, injected from underneath, fluidizes the core material and effects drying while the acrylic polymer . coating is sprayed on.
  • a further overcoat of a film- former such as Opadry R , is optionally applied to the beads. This overcoat is provided, if at all, in order to substantially reduce agglomeration of the beads.
  • the release of the therapeutically active agent(s) from the controlled release formulation of the present invention can be further influenced, i.e., adjusted to a desired rate, by the addition of one or more release-modifying agents, or by providing one or more passageways through the coating.
  • Release-modifying agents may be, e.g., pore-formers.
  • Pore formers include organic or inorganic materials that can be dissolved, extracted or leached from a coating in an environment of use.
  • the pore-formers may comprise one or more hydrophilic materials such as hydroxypropylmethylcellulose.
  • the release-modifying agent is selected from hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of the foregoing.
  • the sustained release coatings of the present invention may also include an exit means comprising at least one passageway, orifice, or the like.
  • the passageway may be formed by such methods as those disclosed in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,063,064; and 4,088,864 (all of which are hereby incorporated by reference).
  • the passageway can. have any shape such as round, triangular, square, elliptical, irregular, .etc.
  • the controlled release formulation is achieved via a matrix having a controlled release coating as set forth above.
  • the present invention may also utilize a controlled release matrix that affords in-vitro dissolution rates of the CNS stimulant and/or opioid antagonist within the preferred ranges and that releases the CNS stimulant and/or opioid antagonist in a pH-dependent or pH-independent manner.
  • the materials suitable for inclusion in a controlled release matrix will depend on the method used to form the matrix.
  • a matrix in addition to the CNS stimulant and/or opioid antagonist may include (i) hydrophilic and/or hydrophobic materials, such as gums, cellulose ethers, acrylic resins and protein derived materials (ii) digestible, long chain (C 8 -Cso, especially C 12 -C o), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes, and stearyl alcohol; and iii) polyalkylene glycols.
  • the matrix material can melt or soften to the extent necessary to be extruded.
  • acrylic polymers such as Eudragit ® RSPO, and cellulose ethers such as hydroxyalkylcelluloses and carboxyalkylcelluloses are preferred.
  • the oral dosage form may contain between about 1% and about 80% (by weight) of at least one hydrophilic or hydrophobic material.
  • the hydrophobic material is a hydrocarbon
  • the hydrocarbon preferably has a melting point of between about 25° and about 90°C.
  • fatty (aliphatic) alcohols are preferred.
  • the oral dosage fonn may contain up to about 60% (by weight) of at least one digestible, long chain hydrocarbon.
  • the oral dosage fonn contains up to about 60% (by weight) of at least one polyalkylene glycol.
  • the hydrophobic material may be selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, or mixtures thereof.
  • the hydrophobic material is a pharmaceutically acceptable acrylic polymer, including but not limited to any of acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl - methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
  • acrylic acid and methacrylic acid copolymers
  • hydrophobic materials are water-insoluble with more or less pronounced hydrophilic and/or hydrophobic trends.
  • the hydrophobic materials useful in the invention have a melting point from about 30° to about 200°C, preferably from about 45° to about 90°C.
  • the hydrophobic material may comprise natural or synthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or preferably cetostearyl alcohol), fatty acids, including but not limited to fatty acid-esters, fatty acid glycerides (mono-, di-, and tri- glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic aid, stearyl alcohol, hydrophobic and hydrophilic materials having hydrocarbon backbones, and mixtures thereof.
  • Suitable waxes include, for example, beeswax, glycowax, castor wax or camauba wax.
  • a wax-like substance is defined as any material which is normally solid at room temperature and has a melting point of from about 30° to about 100°C.
  • Suitable hydrophobic materials which may be used in accordance with the present invention include digestible, long chain (C 8 -C 50 , especially C 1 2 -C 40 ), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids; mineral and vegetable oils and natural and synthetic waxes. Hydrocarbons having a melting point of between about 25° and about 90°C are preferred. Of the long chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred in certain embodiments.
  • the oral dosage fo ⁇ n may contain up to about 60% (by weight) of at least one digestible, long chain hydrocarbon. A combination of two or more hydrophobic materials may be included in the matrix formulations.
  • an additional hydrophobic material may be selected from natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures of the same. Examples include beeswax, carnauba wax, stearic acid or stearyl alcohol.
  • One particular suitable matrix comprises a water soluble hydroxyalkyl cellulose, a C ⁇ 2 -C 36 (preferably C ⁇ -C 22 ) aliphatic alcohol and, optionally, a polyalkylene glycol.
  • the hydroxyalkyl cellulose is preferably a hydroxy (Ci to C 6 ) alkyl cellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose or hydroxy ethylcellulose.
  • the amount of the hydroxyalkyl cellulose in the present oral dosage form will be determined, inter alia, by the precise rate of opioid release required.
  • the aliphatic alcohol may be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol.
  • the aliphatic alcohol is cetyl alcohol or cetostearyl alcohol.
  • the amount of the aliphatic alcohol in the present oral dosage form will be determined, as above, by the precise rate of CNS stimulant and/or opioid antagonist release required. It will also depend on whether a polyalkylene glycol is present in ' or absent from the oral dosage form. In the absence of a polyalkylene glycol, the oral dosage form may contain between about 20% and about 50% (by wt) of the aliphatic alcohol. When a polyalkylene glycol is present in the oral dosage form, the Combined weight of the aliphatic alcohol and the polyalkylene glycol may be between about 20% and about 50% (by wt) of the total dosage.
  • the ratio of, e.g., the hydroxyalkyl cellulose or acrylic resin to the aliphatic a cohol/polyalkylene glycol is a factor in the release rate of the CNS stimulant and/or the opioid antagonist from the formulation.
  • a ratio of hydroxyalkyl cellulose to the aliphatic alcohol/polyalkylene glycol of between 1:2 and 1 :4 is prefe ⁇ ed, with a ratio of between 1 :3 and 1 :4 being particularly preferred.
  • the polyalkylene glycol may be, for example, polypropylene glycol or more preferably, polyethylene glycol.
  • the average molecular weight of the polyalkylene glycol is preferably between about 1,000 and about 15,000, especially more preferably between about 1,500 and about 12,000.
  • Another suitable controlled release matrix would comprise an alkylcellulose (especially ethyl cellulose), a C 12 to C 36 aliphatic alcohol and, optionally, a polyalkylene glycol.
  • the matrix includes a pharmaceutically acceptable combination of at least two hydrophobic materials. .
  • a controlled release matrix may also contain suitable quantities of other materials, e.g. diluents, lubricants, binders, granulating aids, colorants, flavorants or glidants that are conventional in the pharmaceutical art.
  • a matrix may be prepared, for- example, by (a) forming granules comprising at least one water soluble hydroxyalkyl cellulose and the CNS stimulant and/or opioid antagonist; (b) mixing the granules of step (a) with a C ⁇ 2 -C 36 aliphatic alcohol; and (c) optionally, compressing and shaping the granules of step (b).
  • the granules are formed by wet granulating the hydroxyalkyl cellulose/agent(s) with water.
  • the amount of water added during the wet granulation step is preferably between 1.5 and 5 times, especially between 1.75 and 3.5 times, the dry weight of the agent(s).
  • a spheronizing agent together with the active ingredient, can be spheronized to form spheroids.
  • Microcrystalline cellulose is a prefe ⁇ ed spheronizing agent.
  • a suitable microcrystalline cellulose is, for example, the material sold as Avicel PH 101 (Trade Mark, FMC Corporation).
  • the spheroids may 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 hydroxypropylcellulose, are prefe ⁇ ed.
  • the spheroids may contain a water-insoluble polymer, such as an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose.
  • the sustained release coating may include a hydrophobic material such as a wax, a fatty alcohol, shellac, zein or mixtures thereof.
  • Sustained release matrices can also be prepared via melt-granulation or melt-extrusion techniques.
  • melt-granulation techniques involve melting a normally solid hydrophobic material, e.g. a wax, and incorporating a powdered drug therein.
  • a normally solid hydrophobic material e.g. a wax
  • an additional hydrophobic substance e.g. ethylcellulose or a water-insoluble acrylic polymer, into the molten wax hydrophobic material.
  • the additional hydrophobic material may comprise (i) a water-insoluble wax-like thermoplastic substances optionally mixed with (ii) a wax-like thermoplastic substances being less hydrophobic than the substance of (i).
  • a water-insoluble wax-like thermoplastic substances optionally mixed with (ii) a wax-like thermoplastic substances being less hydrophobic than the substance of (i).
  • the individual wax-like substances in the formulation should be substantially non-degradable and insoluble in gastrointestinal fluids during the initial release phases.
  • Useful water-insoluble wax-like substances may be those with a water-solubility that is lower than about 1 :5,000 (w/w).
  • a sustained release matrix or matrix multiparticulate formulation may also contain suitable quantities of other materials, e.g., diluents, lubricants, binders, granulating aids, colorants, flavorants or glidants that are conventional in the pharmaceutical art.
  • suitable quantities of these additional materials will be sufficient to provide the desired effect to the desired fo ⁇ nulation.
  • the preparation of a suitable melt-extruded matrix according to the present invention may, for example, include the steps of blending the CNS stimulant and/or the opioid antagonist together with a hydrophobic material to obtain a homogeneous mixture.
  • the homogeneous mixture is then heated to a temperature sufficient to at least soften the ' mixture sufficiently to extrude the same.
  • the resulting homogeneous mixture may then be extruded to form strands.
  • the extrudate is preferably cooled and cut into multiparticulates by any means known in the art.
  • the strands can be cooled and cut- into multiparticulates.
  • The. multiparticulates can then be separated into unit doses.
  • the extrudate may have a diameter of from about 0.1 to about 5 mm and provide sustained release of the therapeutically active agent for a time period of from about 8 to about 24 hours.
  • An optional process for preparing melt extrusions includes directly metering into an extruder a hydrophobic material, the agent(s), and an optional binder; heating the homogenous mixture; extruding the homogenous mixture to thereby form strands; cooling the . strands containing the homogeneous mixture; cutting the strands into particles having a size from about 0.1 mm to about 12 mm; and combining a plurality of the particles into a unit dosage form.
  • the diameter of the extruder aperture or exit port can also be adjusted to vary the thickness of the extruded .strands.
  • the exit port of the extruder need not be round; it can be oblong, rectangular, etc.
  • the exiting strands can be reduced to particles using a hot wire cutter, guillotine, etc.
  • the melt extruded multiparticulate system can be, for example, in the form of granules, spheroids or pellets depending upon the extruder exit port.
  • MEMs melt-extruded multiparticulate(s)
  • melt-extruded multiparticulates may have a range of from about 0.1 to about 12 mm in length and a diameter of from about 0.1 to .about 5 mm.
  • melt-extruded multiparticulates can be any geometrical shape within this size range.
  • the extrudate may simply be cut into desired lengths and separated into individual unit doses of the therapeutically active agent(s) without the need of a spheroniz tion step.
  • oral dosage forms are prepared to include an effective amount of melt-extruded multiparticulates within a capsule.
  • a plurality of the melt-extruded multiparticulates may be placed in a gelatin capsule in an amount sufficient to provide an effective sustained release dose when ingested and contacted by gastric fluid.
  • a suitable amount of the multiparticulate extrudate is compressed into an oral tablet using conventional tableting equipment using standard techniques. Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are also described in Remington's Pharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980), incorporated by reference herein. [0094] In certain embodiments, the extrudate can be shaped into tablets as set forth in U.S. Pat. No. 4,957,681 (Klimesch, et. al.), described in additional detail above and hereby incorporated by reference.
  • the sustained release melt-extruded multiparticulate systems or tablets can be coated, or the gelatin capsule can be further coated, with a sustained release coating such as the sustained release coatings described above.
  • a sustained release coating such as the sustained release coatings described above.
  • Such coatings may include a sufficient amount of hydrophobic material to obtain a weight gain level from about 2 to about 30 percent, although the coating may be greater depending upon the physical properties of the particular CNS stimulant and/or opioid antagonist compounds utilized and the desired release rate, among other factors.
  • the sustained release formulations of the present invention may slowly release the therapeutically active age ⁇ t(s), e.g., when ingested and exposed to gastrointestinal fluids.
  • the sustained release profile of the melt-extruded formulations of the invention can be altered, for example, by varying the amount of retardant, e.g., hydrophobic material, by varying the -amount of plasticizer relative to hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc.
  • the melt extruded material is prepared without the inclusion of the therapeutically active agent(s), which is/are added thereafter to the extrudate.
  • Such fo ⁇ nulations typically will have the therapeutically active agent(s) blended together with the extruded matrix material, and then the mixture would be tableted in order to provide a slow release formulation.
  • Such formulations may be advantageous, for example, when the therapeutically active agent(s) included in the formulation is/are sensitive to temperatures needed for softening the hydrophobic material and/or the retardant material.
  • suitable forms of injection include, but are not limited to intravenous, intramuscular, subcutaneous, intraspinal, intraperitoneal, or intradermal administration.
  • the parenteral dose of the CNS stimulant and/or opioid antagonist can be combined with a pharmaceutically acceptable vehicle for injection or implantation.
  • a pharmaceutically acceptable vehicle for injection or implantation.
  • the CNS stimulant and/or opioid antagonist can be dissolved in oils, propylene glycol or other solvents commonly used to prepare injectable solutions.
  • Suitable pharmaceutically, acceptable vehicles include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and any combinations or mixtures thereof.
  • aqueous vehicles examples include sodium chloride for injection, bacteriostatic sodium chloride for injection, Ringers solution, isotonic dextrose for injection, sterile water for injection, bacteriostatic sterile water for injection, dextrose lactated Ringers solution and any combinations or mixtures thereof.
  • Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, peanut oil and any combinations or mixtures thereof.
  • Antimicrobial agents in bacteriostatic or fungistatic concentrations include phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, ethyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride benzethonium chloride and mixtures thereof.
  • Isotonic agents include sodium chloride, dextrose and any combinations or mixtures thereof.
  • Buffers include acetate, phosphate, citrate and any combinations or mixtures thereof.
  • Antioxidants include ascorbic acid, sodium bisulfate and any combinations or mixtures thereof.
  • Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and any combinations or mixtures thereof.
  • Emulsifying agents include Polysorbate 80 (Tween 80).
  • Sequestering or chelating agents of -metal ions include ethylenediaminetetraacetic acid.
  • Additional pharmaceutically acceptable vehicles also include ethyl alcohol, polyethylene glycol, glycerin or propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment (e.g., to make the formulation isotonic) and any combinations or mixtures thereof.
  • the CNS stimulant and/or opioid antagonist can be administered as injectable microparticles (microcapsules and microspheres).
  • the microparticles administered by the methods of the present invention are in a size and distribution range suitable for implantation or injection.
  • the diameter and shape of the microparticles can be manipulated to modify the release characteristics. For example, larger diameter microparticles will typically provide slower rates of release and reduced tissue penetration and smaller diameters of microparticles will produce the opposite effects, relative to microparticles of different mean diameter, but of the same composition.
  • otlier particle shapes such as cylindrical shapes, can also modify release rates by virtue of the increased ratio of surface area to mass inherent to such alternative geometrical shapes, relative to a spherical shape.
  • the diameter. of microparticles may range in size from about 5 microns to about 200 microns in diameter. In a more preferred embodiment, the microparticles range in diameter from about 20 to about 120 microns.
  • naltrexone hydrochloride is added to the formulation during the granulation process.
  • the process is set forth below:
  • Milling Discharge the granulation and pass through a mill with approximately 1 mm openings (18 mesh screen).
  • Waxing Melt the stearyl alcohol at about 70 degrees C and add to the milled granulation using a high shear mixer. Allow to cool at room temperature on trays or a fluid bed.
  • Milling Pass the cooled granulation through a mill with approximately 18 mesh screen.
  • Lubrication Lubricate the granulation with talc and magnesium stearate using a mixer.
  • Film Coating Disperse the Opadry into water and apply an aqueous film coat to the tablets using a rotary pan.
  • Methylphenidate salt /naltrexone salt sustained release osmotic tablets are produced with the formula set forth in Table 2 below:
  • the methylphenidate hydrochloride, the naltrexone hydrochloride dihydrate, polyethylene oxide) possessing a 200,000 average molecular weight, and polyvinylpyrrolidone having a 40,000 average molecular weight are added to a mixer and mixed for 10 minutes. Then, denatured anhydrous alcohol is added to the blended materials with continuous mixing for 10 minutes. Then, the wet granulation is passed through a 20 mesh screen, allowed to dry at room temperature for 20 hou ⁇ s, and then passed through a 16 mesh screen. Next, the granulation is transfei ⁇ ed to the mixer, mixed and lubricated with magnesium stearate.
  • the displacement or push composition for pushing the methylphenidate HCL/naltrexone HCL composition from the dosage form is prepared as follows: first 3910 g of hydroxypropylmethylcellulose possessing a 11,200 average molecular weight is dissolved in 45,339 g of water. Then, 101 g of butylated hydroxytoluene is dissolved in 650 g of denatured anhydrous alcohol. Next, 2.5 kg of the hydroxypropylmethylcellulose aqueous solution is added with continuous mixing to the butylated hydroxytoluene alcohol solution. Then, binder solution preparation is completed by adding with continuous mixing the remaining hydroxypropylmethylcellulose aqueous solution to the butylated hydroxytoluene alcohol solution.
  • the binder solution is sprayed from 3 nozzles onto the powder.
  • the granulating is monitored during the process as follows: total solution spray rate of 800 g/min; inlet temperature 43 °C and air flow 4300 m 3 /hr.
  • 45,033 g of the resultant coated granulated particles are subjected to a drying process for 35 minutes.
  • the coated granules are sized using a Quadro Comil® mill with an 8 mesh screen. The granulation is transfe ⁇ ed to a Tote® Tumbler, mixed and lubricated with 281.7 g of magnesium s.tearate.
  • the drug composition comprising the methylphenidate hydrochloride/naltrexone hydrochloride and the push composition are compressed into bilayer tablets on a Kilian® Tablet press.
  • the drug composition is added to the die cavity and precompressed; then, 135 mg of the push composition is added and the layers are pressed under a pressure head of • 3 metric tons into a 11/32 inch (0.873 cm) diameter contacting layer a ⁇ angement.
  • the bilayered a ⁇ angements are coated with a semipe ⁇ neable wall.
  • Tire wall forming composition comprises 100% cellulose acetate having a 39.8% acetyl content.
  • the wall- forming composition is dissolved in acetone:water (95:5 wtiwt) cosolvent to make a 4% solid solution.
  • the wall-forming composition is sprayed onto and around the bilayers in a 24 inch (60 cm) Nector® Hi-Coater. Next, one 20 mil (0.508 mm) exit passageway is drilled through the semipermeable wall to connect the drug methylphenidate layer with the exterior of the dosage form.
  • the residual solvent is removed by drying for 72 hours at 45 °C and 45% humidity.
  • the osmotic dosage systems are dried for 4 hours at 45 °C to remove excess moisture.
  • Hydrocodone 5 mg/naltrexone 0.0625 g sustained release capsules are prepared with the formula set forth in Table 3 below:
  • the formulation above is prepared according to the following procedure: 1. Pass the stearyl alcohol flakes through an impact mill.
  • Methylphenidate 5 mg/naltrexone- 0.0625 mg sustained release capsules are prepared according to the following procedure:
  • Drug layering solution Dissolve hydrocodone HC1 and Opadry Clear in water.
  • Controlled release coating solution Homogenize triethyl citrate in water. Add the dispersion to Eudragit® RS 30 D and Eudragit® RL 30 D then add Cab-O-Sil® to mixture.
  • Coating Apply the control release coating solution followed by the seal coat solution onto Methylphenidate HCl IR beads using a fluidized bed bottom-spray technique.
  • Naltrexone sustained release beads 0.0625mg of Naltrexone per unit can be included in the above formulation. It can be dissolved together with the Methylphenidate HCl in the purified water before being sprayed onto the NuPareil beads.

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Abstract

Dans certains modes de réalisation, l'invention concerne une composition pharmaceutique comprenant un stimulateur du SNC et un antagoniste d'opiatés.
PCT/US2004/009161 2003-03-31 2004-03-25 Combinaison d'un stimulateur du systeme nerveux central et d'antagonistes d'opiates WO2004091546A2 (fr)

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WO2019236121A1 (fr) * 2018-06-06 2019-12-12 John Hsu Composition comprenant un agent thérapeutique et un stimulant respiratoire, et procédé d'utilisation associé
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102005033543A1 (de) * 2005-07-14 2007-01-18 Grünenthal GmbH Ein einen Duftstoff aufweisendes transdermales therapeutisches System
DE102006015734A1 (de) * 2006-04-04 2007-10-11 Hermann, Holger Lars, Dr. Kombinationspräparate aus Modafinil, Ritalin und Topiramat und deren Derivaten zur Behandlung von Kokainabhängigkeit und/oder Impulskontrollstörung
AU2007235860B2 (en) * 2006-04-11 2012-05-24 Nls-1 Pharma Ag Mazindol combination in the treatment of attention deficit/hyperactivity
WO2007116076A1 (fr) * 2006-04-11 2007-10-18 Assistance Publique - Hopitaux De Paris Association du mazindol dans le traitement du deficit de l'attention/hyperactivite
JP2009533388A (ja) * 2006-04-11 2009-09-17 アシスタンス ピュブリック−オピト ド パリ 注意欠陥／多動障害の治療におけるマジンドールの併用
FR2899476A1 (fr) * 2006-04-11 2007-10-12 Assist Publ Hopitaux De Paris Association du mazindol dans le traitement du deficit de l'attention/hyperactivite
US8293779B2 (en) 2006-04-11 2012-10-23 Assistance Publique-Hopitaux De Paris Mazindol combination in the treatment of attention deficit/hyperactivity
EP2564872A1 (fr) * 2006-04-11 2013-03-06 Assistance Publique, Hopitaux De Paris Association du mazindol dans le traitement du déficit de l'attention/hyperactivité
JP2013189467A (ja) * 2006-04-11 2013-09-26 Assistance Publique-Hopitaux De Paris 注意欠陥／多動障害の治療におけるマジンドールの併用
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WO2019236121A1 (fr) * 2018-06-06 2019-12-12 John Hsu Composition comprenant un agent thérapeutique et un stimulant respiratoire, et procédé d'utilisation associé
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