US20080260819A1 - Sustained release compositions of drugs - Google Patents

Sustained release compositions of drugs Download PDF

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US20080260819A1
US20080260819A1 US12112937 US11293708A US2008260819A1 US 20080260819 A1 US20080260819 A1 US 20080260819A1 US 12112937 US12112937 US 12112937 US 11293708 A US11293708 A US 11293708A US 2008260819 A1 US2008260819 A1 US 2008260819A1
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drug
composition
microparticles
acid
group consisting
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Alison B. Fleming
Roman V. Rariy
Jane Hirsh
Alexander M. Klibanov
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Collegium Pharmaceutical Inc
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Collegium Pharmaceutical Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/485Morphinan derivatives, e.g. morphine, codeine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/20Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12Carboxylic acids; Salts or anhydrides thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic compounds, e.g. phospholipids, fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682Processes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682Processes
    • A61K9/1694Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4858Organic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5052Proteins, e.g. albumin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5084Mixtures 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

Abstract

A sustained release pharmaceutical composition has been developed. The composition resists dose dumping when broken, crushed or chewed, which enhances the safety of the dosage form should it be accidentally or intentionally physically compromised. In the preferred embodiment, a drug is modified to increase its lipophilicity. In preferred embodiments the modified drug is homogeneously dispersed within microparticles composed of a material that is either slowly soluble or not soluble in water. In some embodiments the drug containing microparticles coated with one or more coating layers. The sustained release composition retards the release of drug, even if the physical integrity of the formulation is compromised (for example, by chewing or crushing) and the resulting material is placed in 0.1N HCl. However, when administered as directed, the drug is slowly released from the composition as the composition is broken down or dissolved gradually within the GI tract by a combination of diffusion, surfactant action of bile acids, mechanical erosion, and in some embodiments, enzymatic degradation.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application is a Continuation-in-Part of U.S. Ser. No. 10/614,866 filed on Jul. 7, 2003 entitled “Abuse-Deterrent Pharmaceutical Compositions of Opiods and Other Drugs”, which claims priority to U.S. Ser. No. 60/393,876 filed Jul. 5, 2002 entitled “Abuse-Resistant Formulations of Oxycontin and Other Drugs” by Alexander M. Klibanov, Stephen L. Buchwald, Timothy M. Swager, and Whe-Yong Lo; U.S. Ser. No. 60/436,523 filed Dec. 23, 2002 by Alison B. Fleming, Roman V. Rariy, Alexander M. Klibanov, Whe-Yong Lo, and Jane Hirsh; U.S. Ser. No. 60/443,226 filed Jan. 28, 2003 by Jane Hirsh, Alison B. Fleming, Alexander M. Klibanov, and Whe-Yong Lo; U.S. Ser. No. 60/463,514 filed Apr. 15, 2003 by Jane C. Hirsh, Alison B. Fleming, Roman V. Rariy, Stephen L. Buchwald, and Timothy M. Swager; and U.S. Ser. No. 60/463,518 filed Apr. 15, 2003 by Jane C. Hirsh, Alison B. Fleming and Roman V. Rariy. The disclosures in the applications listed above are herein incorporated by reference.
  • BACKGROUND OF THE INVENTION
  • The present invention is generally in the field of pharmaceutical compositions, and specifically relates to compositions that are designed to provide a sustained release of drug over time after oral administration.
  • Sustained release pharmaceutical formulations, which release drug over an extended period of time, are widely used in the pharmaceutical industry. Such formulations provide several potential advantages to the patient including: (1) the convenience of reduced dosing frequency, (2) optimization of therapy by providing a smoother, more constant, plasma level of drug, and (3) a potential reduction in side effects.
  • Several formulations that achieve sustained release of drug when administered orally have been described in the literature. In general, oral sustained release dosage forms can be classified as diffusion-controlled, erosion-controlled or osmotic pressure-controlled. For diffusion based systems, control of drug release is usually achieved by dispersing the drug in an inert insoluble matrix or by coating a drug containing core with an insoluble polymeric film. Erosion controlled formulations can be achieved by dispersing the drug in a slowly soluble carrier material or by coating the drug with a slowly soluble material. Osmotic systems are monolithic in nature and consist of a core containing an osmotically active drug or a drug in combination with an osmotically active salt, surrounded by a semi-permeable membrane containing a small orifice.
  • Although many types of sustained release dosage forms have been described, currently available sustained release dosage forms have some inherent disadvantages. Monolithic dosage forms, such as tablets or capsules, can be difficult for some patients to swallow. Since sustained release formulations can be subject to dose dumping when they are crushed, these products come with specific instructions not to break, chew or crush them. While there are some available multiparticulate formulations (such as particles-in-capsule and sachet) that can be administered as particles, for example after sprinkling in applesauce, such formulations are still potentially dangerous if the particles are accidentally chewed, broken or their physical integrity is compromised, thus resulting in the destruction of the sustained release feature.
  • It is therefore an object of the present invention to provide a sustained-release, multiparticulate pharmaceutical composition that resists dose dumping when accidentally broken, crushed or chewed.
  • SUMMARY OF THE INVENTION
  • Sustained release pharmaceutical compositions and the methods of making and using the composition have been developed. The compositions can be used to improve the convenience and safety of administration when a sustained release dosage form is desired. In the preferred embodiment, the drug is chemically modified to increase its lipophilicity. In other embodiments, the formulation contains lipophilic or water-insoluble materials or is made using a process which increases the lipophilicity and/or water-insolubility of the composition. In some embodiments, the individual drug-containing microparticles or drug particles are coated with one or more independent coating layers.
  • The compositions retard the release of drug, even if the physical integrity of the dosage form is compromised (for example, by breaking or chewing).
  • The pharmaceutical compositions, when administered orally, result in a desired drug release profile. Such a release profile provides a therapeutic effect for an extended period of time, typically from 6 to 24 hours. Additional compositions are provided which achieve a small immediate dose that precedes the sustained release of drug. The compositions disclosed herein may optionally include a combination of active pharmaceutical agents.
  • DETAILED DESCRIPTION OF THE INVENTION
  • Disclosed herein are sustained-release pharmaceutical compositions and the method of making and using the compositions.
  • I. Compositions
  • As used herein, “composition” or “compositions” refers to the drug dosage unit for administration to a patient. This may also be used in reference to the final dosage form (tablet or capsule) or to components of the final dosage form (microparticles or coated microparticles).
  • Currently available sustained release formulations are subject to dose dumping when chewed or crushed because mechanical destruction of the dosage form exposes the encapsulated drug and allows for immediate dissolution of the drug into aqueous media. Two properties of the dosage form that contribute to this outcome are (1) the ease with which drug is exposed when the compositions are broken or chewed and (2) the high water solubility of the drug salt form.
  • In the composition disclosed herein, one or both of these properties are altered in order to achieve a composition which resists dose dumping when chewed or broken. Specifically, in the preferred embodiment, the drug is modified to increase its lipophilicity and, in additional preferred embodiments, is then homogeneously dispersed within a material that is either slowly soluble or not soluble in water and subsequently formulated into microparticles. The drug may be present in the form of discrete particles or may be partially or fully dispersed in the carrier material on a molecular level.
  • The sustained release composition preferably includes a drug modified to increase its lipophilicity. In other preferred embodiments, the drug is homogenously dispersed within microparticles composed of a material that is either slowly soluble in water or water insoluble. The compositions slow the release of drug if the dosage form is broken or chewed and the resulting material is swallowed since most of the drug will remain associated with or entrapped within portions of the core material of the microparticles. In some embodiments the drug containing microparticles or individual drug particles are coated with one or more coating layers.
  • A. Drugs to be Formulated
  • There are many drugs that it is desirable to deliver using the compositions described herein.
  • Exemplary drug agents useful for forming the composition described herein include, but are not limited to, analeptic agents; analgesic agents; anesthetic agents; antiasthmatic agents; antiarthritic agents; anticancer agents; anticholinergic agents; anticonvulsant agents; antidepressant agents; antidiabetic agents; antidiarrheal agents; antiemetic agents; antihelminthic agents; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents; antiinflammatory agents; antimigraine agents; antineoplastic agents; antiparkinsonism drugs; antipruritic agents; antipsychotic agents; antipyretic agents; antispasmodic agents; antitubercular agents; antiulcer agents; antiviral agents; anxiolytic agents; appetite suppressants; attention deficit disorder and attention deficit hyperactivity disorder drugs; cardiovascular agents including calcium channel blockers, antianginal agents, central nervous system (“CNS”) agents, beta-blockers and antiarrhythmic agents; central nervous system stimulants; diuretics; genetic materials; hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive agents; muscle relaxants; narcotic antagonists; nicotine; nutritional agents; parasympatholytics; peptide drugs; psychostimulants; sedatives; steroids; smoking cessation agents; sympathomimetics; tranquilizers; vasodilators; beta-agonist; and tocolytic agents.
  • Drugs that are most preferable include those that are currently formulated as sustained or controlled release compositions, where drug release is intended to occur over a prolonged period of time through the gastrointestinal tract, and immediate or burst release is undesirable. Specific examples of agents currently formulated in sustained or controlled release formulations include, but are not limited to, acetaminophen, acetazolamide, albuterol, alfuzosin, alprazolam, amoxicillin, amphetamine, aspirin, brompheniramine, bupropion, carbamazepine, carbidopa, carbinoxamine, cetirizine, chlorpheniramine, ciprofoxacin, clarithromycin, clavulanate, clorazepate, colestipol, desloratidine, dexbrompheniramine, dexmethylphenidate, dextroamphetamine, dextromethorphan, diclofenac, diethylpropion, diltiazem, dipyridamole, disopyramide, divalproex sodium, doxazosin, doxycycline, enalapril, etodolac, felodipine, fexofenadine, fluoxetine, fluvastatin, glipizide, guaifenesin, hyoscyamine, indomethacin, isosorbide dinitrate, isosorbide mononitrate, isradipine, ketoprofen, levodopa, loratidine, lovastatin, mesalamine, metformin, methscopolamine, methylphenidate, metoprolol, metronidazole, minocycline, morphine, naproxen, niacin, nicardipene, nifedipine, nsoldipine, nitroglycerin, orphenadrine, oxybutynin, oxycodone, oxymorphone, papaverine, paroxetine, pentoxifyline, phendimetrazine, phenylephrine, phenyloin, procainamide, propranolol, pseudophedrine, pyridostigime, quinidine, ranolazine, tamsulosin, theophylline, tolterodine, tramadol, trandolapril, venlafaxine, verapamil, and zolpidem.
  • The terms “drug”, “active agent”, and “pharmacologically active agent” are used interchangeably herein to refer to a chemical compound that induces a desired pharmacological and/or physiological effect. The terms also encompass pharmaceutically acceptable derivatives of those active agents specifically mentioned herein, including, but not limited to, salts, solvates, hydrates, complexes with one or more molecules, prodrugs, active metabolites, analogs, and the like. When the terms “active agent”, “pharmacologically active agent” and “drug” are used, or when a particular drug, such as oxycodone, is identified, it is to be understood as including the active agent per se as well as pharmaceutically acceptable salts, solvates, hydrates, complexes with one or more molecules, prodrugs, active metabolites, and analogs.
  • Certain compounds described herein may exist in particular geometric or stereoisomeric forms. The composition disclosed herein contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, d-isomers, 1-isomers, the racemic mixtures thereof, compounds of different spacial conformations, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • The pharmaceutically acceptable salts of the compounds can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Optionally, the salt can also be formed as part of the manufacturing process for the composition. For fatty acid salts such as oleate, myristate, palmitate or stearate, this can be accomplished by melting the fatty acid, optionally along with other waxes, and adding the free base of the drug directly into this melt. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000, p. 704, the disclosure of which is hereby incorporated by reference.
  • Optionally, the composition described herein can include a combination of active pharmaceutical agents.
  • B. Drug Solubility Modification
  • In preferred embodiments, the solubility characteristics of a drug are altered prior to incorporation into the formulation. Modification of the drug to produce a more lipophilic derivative serves to reduce the water solubility of the drug and thus reduces the aqueous extractability. Furthermore, if the drug is made more lipophilic, it can be solubilized in the molten carrier material, rather than physically dispersed in a particulate form. When drug is solubilized in the carrier material it is difficult to extract drug from the resulting intimately dispersed composition.
  • The terms “lipophilic derivative” and “lipophililic drug derivative”, as used herein, refer to derivatives of the drug that are less soluble in water than the most soluble salt of the drug. The most soluble salt is selected from either drug alkaline metal salts (for acidic drugs) or salts of the drug with inorganic acids (for basic drugs). The examples of the latter include, but are not limited to, hydrohalates, sulfates, and nitrates.
  • Some of the methods that can be used to alter the drug's lipophilicity are outlined below. It is understood that two or more approaches can be combined to achieve a desired solubility profile.
  • Methods for Increasing Lipophilicity
  • In one embodiment drug is made more lipophilic by eliminating or reducing the overall charge of the drug molecule. For example, for a basic drug, a water soluble salt (such as hydrochloride, sulfate, or maleate) can be converted to a free base using techniques known in the art. Correspondingly, in the case of an acidic drug, a water soluble salt (such sodium, potassium, or the like) can be converted to a free acid.
  • In another embodiment, the drug's lipophilicity is increased by forming a salt between a drug molecule and a charged compound. In this case the lipophilicity, or water solubility, of the resulting salt can be manipulated by varying the counter-ion. In general, lipophilic acids or amines with chain lengths between C5-C30 are lipophilic counter-ion candidates. Some specific examples include, but are not limited to, linoleic acid, octanoic acid, lauric acid, stearic acid, palmitic acid, lauryl sulfate, oleic acid, octyl amine, lauryl amine, stearyl amine, palmityl amine, linoleyl amine, and oleyl amine. Other salts which may increase lipophilicity and, hence, lipid solubility relative to the parent drug compound include, but are not limited to, pectinate, tannate, phytate, salicylate, saccharinate, acesulfamate, gallate, and terephthalate salts. The counter-ion used for salt formation may also be polymeric in nature. For example, anionic copolymers based on methacrylic acid and methyl methacrylate sold under the trade name Eudragit (e.g., Eudragit L 100 and Eudragit S 100), acrylic acid polymers, and crosslinked acrylic acid polymers may be used to form a salt with drug molecules. Naturally occurring polymers and their derivatives, for example, carboxymethylcellulose, may also be used to form a salt with the drug molecules. In the case of polymeric counter-ions, the number of drug molecules reacted with the polymer to form a salt may or may not be equimolar with respect to the number of salt-forming sites on the polymer chain.
  • The formation of a salt composed of a pharmaceutically active agent and a fatty acid or amine can be accomplished by a melt process, with or without the use of a solvent. One or more fatty acids or amines are heated above their melting point and the pharmaceutically active agent, in free base or acid form, is added to the molten fatty acid or amine, respectively, either directly or after dissolution of the active agent in an appropriate solvent. The fatty acid or fatty amine may be present in an equimolar amount or may be present in excess with respect to the free base or free acid of the active agent.
  • In another embodiment, a drug is covalently modified to increase its lipophilicity. For example, a lipophilic compound can be covalently attached to a drug molecule via an ester or amide linkage. Such drug derivatives are cleaved in vivo, thus releasing the parent compound.
  • C. Drug Containing Microparticles
  • In preferred embodiments, drugs are formulated with a carrier material to form microparticles. As used herein, the term “microparticle” refers to a composition including a drug dispersed within a carrier material and “coated microparticle” refers to a composition including a drug containing microparticle or a drug particle coated with one or more coating layers of material. Microparticles and coated microparticles have a size range of 10 to 3000 microns in diameter.
  • Within microparticles, drug is preferably homogeneously dispersed in the form of fine particles within the carrier material. More preferably, drug is partially solubilized in molten carrier material or partially dissolved with the carrier material in a mutual solvent during the formulation of the microparticles. Most preferably, drug is completely solubilized in the molten carrier material or completely dissolved with the carrier material in a co-solvent during the formulation of the microparticles. This is accomplished through the selection of materials and the manner in which they are processed.
  • Carrier materials appropriate for the fabrication of drug containing microparticles are either slowly soluble in water or insoluble in water, but capable of degrading within the GI tract by means including enzymatic degradation, surfactant action of bile acids and mechanical erosion. As used herein, the term “slowly soluble in water” refers to materials that are not dissolved in water within a period of 30 minutes. Preferred examples include fats, fatty substances, waxes, wax-like substances and mixtures thereof. Suitable fats and fatty substances include fatty alcohols (such as lauryl, myristyl stearyl, cetyl or cetostearyl alcohol), fatty acids and derivatives, including but not limited to fatty acid esters, fatty acid glycerides (mono-, di- and tri-glycerides), and hydrogenated fats. Specific examples include, but are not limited to hydrogenated vegetable oil, hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated oils available under the trade name Sterotex®, stearic acid, cocoa butter, glyceryl behenate (available under the trade name COMPRITOL 888®), glyceryl dipalmitostearate (available under the trade name PRECIROL®), and stearyl alcohol. Mixtures of mono-, di- and tri-glycerides and mono- and di-fatty acid esters of polyethylene glycol, available under the trade name GELUCIRE®) are also suitable fatty materials. Suitable waxes and wax-like materials include natural or synthetic waxes, hydrocarbons, and normal waxes. Specific examples of waxes include beeswax, glycowax, castor wax, carnauba wax, paraffins and candelilla wax. As used herein, a wax-like material is defined as any material which is normally solid at room temperature and has a melting point of from about 30 to 300° C.
  • In some cases, it may be desirable to alter the rate of water penetration into the hydrophobic drug containing microparticles. To this end, rate-controlling (wicking) agents may be formulated along with the fats or waxes listed above. Examples of rate-controlling materials include certain starch derivatives (e.g., waxy maltodextrin and drum dried corn starch), cellulose derivatives (e.g., hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, and carboxymethylcellulose), alginic acid, lactose and talc. Additionally, a pharmaceutically acceptable surfactant (for example, lecithin) may be added to facilitate the degradation of such microparticles.
  • Proteins which are water insoluble, such as zein, are preferred carrier materials for the formation of drug containing microparticles. Additionally, proteins, polysaccharides and combinations thereof which are water soluble can be formulated with drug into microparticles and subsequently cross-linked to form an insoluble network.
  • Certain polymers may also be used as carrier materials in the formulation of drug containing microparticles. Suitable polymers include ethylcellulose and other natural or synthetic cellulose derivatives. Polymers which are slowly soluble and form a gel in an aqueous environment, such as hydroxypropyl methylcellulose or polyethylene oxide may also be suitable as carrier materials for drug containing microparticles.
  • Encapsulation or incorporation of drug into carrier materials to produce drug containing microparticles can be achieved through known pharmaceutical formulation techniques. To create a composition that protects drug from exposure upon mechanical disruption (e.g., breaking or chewing), the drug is intimately dispersed within the carrier material. In the case of formulation in fats, waxes or wax-like materials, the carrier material is heated above its melting temperature and the drug is added to form a mixture including drug particles suspended in the carrier material, drug dissolved in the carrier material, or a mixture thereof. Microparticles can be subsequently formulated through several methods including, but not limited to, the processes of congealing, extrusion, spray chilling or aqueous dispersion. In a preferred process, wax is heated above its melting temperature, drug is added, and the molten wax-drug mixture is congealed to form solid, spherical particles via a spraying or spinning disk process. Alternatively, the molten wax-drug mixture can be extruded and spheronized to form pellets or beads. Detailed descriptions of these processes can be found in “Remington—The science and practice of pharmacy”, 20th Edition, Jennaro et. Al., (Phila, Lippencott, Williams, and Wilkens, 2000. Detailed descriptions of the spinning disk process can be found in U.S. Pat. Nos. 3,015,128 and 7,261,529.
  • For some carrier materials it may be desirable to use a solvent evaporation technique to produce drug containing microparticles. In this case drug and carrier material are co-dissolved in a mutual solvent and microparticles can subsequently be produced by several techniques including, but not limited to, forming an emulsion in water or other appropriate media, spray drying, using a spinning disk process or by evaporating off the solvent from the bulk solution and milling the resulting material.
  • In addition to modification of the drug itself, processing conditions can be used to influence the dispersion of the drug within water-insoluble or slowly water-soluble material. For example, in the case where the water in-soluble or slowly soluble material is melted and drug is fully or partially dissolved under stirring conditions, the temperature, agitation rate and time of processing will influence the degree of dissolution achieved. More specifically, a more homogenous dispersion may be achieved with a higher temperature, faster stirring rate and longer processing time. Ultrasound can also be applied to the molten mixture to increase the degree of dispersion and/or the rate of dissolution of the drug.
  • In some embodiments, drug in a particulate form is homogeneously dispersed in a water-insoluble or slowly water soluble material. To minimize the size of the drug particles within the composition, the drug powder itself may be milled to generate fine particles prior to formulation. The process of jet milling, known in the pharmaceutical art, can be used for this purpose. In some embodiments drug in a particulate form is homogeneously dispersed in a wax or wax like substance by heating the wax or wax like substance above its melting point and adding the drug particles while stirring the mixture. In this case a pharmaceutically acceptable surfactant may be added to the mixture to facilitate the dispersion of the drug particles.
  • For formulations including a pharmaceutically active agent in the free base form and one or more fatty acids, a homogeneous molten mixture, in which the drug particles are completely dissolved, can be achieved in the following manner. The one or more fatty acid(s) are heated above their melting point but below the melting point of the active agent. The active agent in free base form is mixed with the molten fatty acid until a clear, homogeneous mixture is formed. The active agent may be added in the solid form or may first be dissolved in an appropriate solvent. Optionally, one or more fats, fatty substances, waxes, and/or wax-like substances are co-melted into the mixture, either before the addition of the active agent or following the addition of the active agent. It is believed that a clear solution is formed due to the formation of a salt between the free base of the active agent and the one or more fatty acids present in the formulation. An analogous composition may be formed using the free acid of the active agent, one or more fatty amines, and, optionally, one or more fats, fatty substances, waxes, and/or wax-like substances.
  • D. Coated Drug Containing Microparticles
  • In some embodiments, drug containing microparticles or drug particles are encapsulated. Drug containing microparticles can be encapsulated in water insoluble materials, slowly water soluble materials, or materials with pH dependent solubilities.
  • In general, any coating procedure which provides a contiguous coating on each microparticle without significant agglomeration of particles may be used. Coating procedures known in the pharmaceutical art including, but not limited to, fluid bed coating processes and microencapsulation may be used to obtain appropriate coatings. Detailed descriptions of these processes can be found in “Remington—The science and practice of pharmacy”, 20th Edition, Jennaro et. Al., (Phila, Lippencott, Williams, and Wilkens, 2000.
  • The water-insoluble coating materials may be any of a large number of natural or synthetic film-formers used singly, in admixture with each other, and in admixture with plasticizers, pigments and other substances to alter the characteristics of the coating. A water-insoluble but water-permeable diffusion barrier may consist of ethyl cellulose, methyl cellulose and mixtures thereof. The water-permeable diffusion barrier may also include ammonio methacrylate copolymers sold under the trade name EUDRAGIT® (Rohm Pharma), such as EUDRAGIT RS, EUDRAGIT RL, EUDRAGIT NE and mixtures thereof. Other synthetic polymers, for example, polyvinyl acetate (available under the trade name KOLLICOAT®), can also be used to form water-insoluble but permeable coatings.
  • The coating may also include a water-insoluble but enzymatically degradable material. In some instances the substrates of digestive enzymes are naturally water-insoluble and can be utilized in the formulation without further processing. Solid esters of fatty acids, which are hydrolyzed by lipases, can be spray coated onto microparticles or drug particles. Mixtures of waxes (beeswax, carnauba wax, etc.) with glyceryl monostearate, stearic acid, palmitic acid, glyceryl monopalmitate and cetyl alcohol will also form films that are dissolved slowly or broken down in the GI tract. Zein is an example of a naturally water-insoluble protein. It can be coated onto drug containing microparticles or drug particles by spray coating or by wet granulation techniques. In addition to naturally water-insoluble materials, some substrates of digestive enzymes can be treated with cross-linking procedures, resulting in the formation of non-soluble networks. Many methods of cross-linking proteins, initiated by both chemical and physical means, have been reported. One of the most common methods to obtain cross-linking is the use of chemical cross-linking agents. Examples of chemical cross-linking agents include aldehydes (gluteraldehyde and formaldehyde), epoxy compounds, carbodiimides, and genipin. In addition to these cross-linking agents, oxidized and native sugars have been used to cross-link gelatin (Cortesi, R., et al., Biomaterials 19 (1998) 1641-1649). Cross-linking can also be accomplished using enzymatic means; for example, transglutaminase has been approved as a GRAS substance for cross-linking seafood products. Finally, cross-linking can be initiated by physical means such as thermal treatment, UV irradiation and gamma irradiation.
  • To produce a coating layer of cross-linked protein surrounding drug containing microparticles or drug particles, a water soluble protein can be spray coated onto the microparticles and subsequently cross-linked by the one of the methods described above. Alternatively, drug containing microparticles can be microencapsulated within protein by coacervation-phase separation (for example, by the addition of salts) and subsequently cross-linked. Some suitable proteins for this purpose include gelatin, albumin, casein, and gluten.
  • Polysaccharides can also be cross-linked to form a water-insoluble network. For many polysaccharides, this can be accomplished by reaction with calcium salts or multivalent cations which cross-link the main polymer chains. Pectin, alginate, dextran, amylose and guar gum are subject to cross-linking in the presence of multivalent cations. Complexes between oppositely charged polysaccharides can also be formed; pectin and chitosan, for example, can be complexed via electrostatic interactions. Insoluble coatings can be formed on particles in this fashion. It should be noted that in many cases polysaccharides are broken down specifically by enzymes produced by bacteria within the colon.
  • In some cases a water-insoluble but enzymatically degradable coating including both a protein and a polysaccharide can be produced if the components are oppositely charged polyelectrolytes. Under the proper temperature, pH, and concentrations, the two polymers can interact through their opposite electrical charges and form a water-insoluble complex. If a core particle is present at the time the complex phase separates, it will be coated. For example, gelatin and gum arabic can be coated onto a core particle utilizing this process. Optionally, the complex can be made irreversibly insoluble by subsequent cross-linking induced by chemical or physical means.
  • Coating materials may also include a pH sensitive polymer which is insoluble in the acid environment of the stomach, and soluble in the more basic environment of the GI tract. Such a coating is thus an enteric coating, creating a dosage form designed to prevent drug release in the stomach. Preventing drug release in the stomach has the advantage of reducing side effects associated with irritation of the gastric mucosa, and of minimizing exposure of drug to very low pH. Avoiding release within the stomach can be achieved using enteric coatings known in the art. The enteric coated formulation remains intact or substantially intact in the stomach, however, once the formulation reaches the small intestines, the enteric coating dissolves and exposes either drug-containing carrier particles or drug-containing carrier particles coated with extended release coating.
  • The enteric coated particles can be prepared as described in “Pharmaceutical dosage form tablets”, eds. Liberman et. al. (New York, Marcel Dekker, Inc., 1989), “Remington—The science and practice of pharmacy”, 20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000, and “Pharmaceutical dosage forms and drug delivery systems”, 6th Edition, Ansel et. al., (Media, Pa. Williams and Wilkins, 1995). Examples of suitable coating materials include, but are not limited to, cellulose polymers, such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and certain methacrylic resins that are commercially available under the trade name EUDRAGIT® (Rohm Pharma). Additionally the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, and surfactants.
  • In some cases it may be desirable to coat the particles with a coating which is soluble in aqueous solutions but insoluble in hydroalcoholic solutions. In this case the coating material may or may not have pH sensitive solubility in aqueous solutions.
  • In some cases it may be desirable to combine coating materials to produce a tailored release of drug. For example, combinations of insoluble polymers and pH dependent polymers can produce a pH dependent sustained release profile. Combinations of insoluble polymers (e.g., ethylcellulose), water-soluble polymers (e.g., HPMC or PEG) and pH dependent swellable polymers (e.g., carboxyvinylpolymer) have also been reported to produce pH dependent sustained release profiles (See, for example, Journal of Controlled Release, 2006, 111:309-315)
  • E. Dosage Forms
  • There are a number of drug compositions that meet the criteria outlined above. In one embodiment a drug is homogeneously dispersed, in a fine particulate form, within a water-insoluble or slowly water soluble material and the mixture is formulated into microparticles. In another embodiment a drug is partially dissolved within a water-insoluble or slowly water soluble material during the manufacturing process, for example, by mixing at a temperature above the melting point of the carrier material, and the mixture is formulated into microparticles. In yet another embodiment a drug is fully dissolved within a water-insoluble or slowly water soluble material during the manufacturing process, for example, by mixing at a temperature above the melting point of the carrier material, and the mixture is formulated into microparticles. In still a further embodiment, the drug containing microparticles, where the drug is homogeneously dispersed in a particulate form, or has been partially or fully dissolved within the carrier material during the manufacturing process, are coated with one or more coatings to form coated microparticles.
  • The microparticles, coated microparticles, or a mixture thereof are formed into a solid dosage form suitable for oral administration. For example, microparticles or coated microparticles can be incorporated into hard capsules, dispersed within a soft gelatin capsule, or combined with appropriate excipients and tableted by compression.
  • Dosage forms can include one or more drugs. If the drugs are compatible, several different drugs can be incorporated into the same microparticle composition or coated microparticle composition. The drugs can be incorporated into separate microparticle compositions where a first drug is formulated into microparticle compositions or coated microparticle compositions described herein and one or more additional drugs are incorporated into microparticle compostions or coated microparticle compositions described herein, sustained release compositions known in the art or immediate release compositions known in the art. The compositions including the different drugs are formulated into a single solid dosage form suitable for oral administration, for example, they can be incorporated into a gelatin capsule, or combined with appropriate excipients and compressed into a tablet form.
  • An immediate release dose can be incorporated into the formulation in several ways. Immediate release microparticles can be made utilizing standard methodologies and formulated along with sustained release microparticle and/or coated microparticle compositions in a suitable oral dosage form. Alternatively, a coating containing drug which is available for immediate release can be placed on a tablet including sustained release microparticle and/or coated microparticle compositions plus appropriate excipients. Additionally, an immediate dose of drug can be granulated or blended with rapidly dissolving excipients and subsequently compressed (1) as one layer of bi-layer tablets in which the sustained release microparticle and/or coated microparticle compositions are compressed as the other layer, or (2) as the outer layer of compression-coated tablets in which the sustained release microparticle and/or coated microparticle compositions are compressed as the inner core, or (3) into tablets in which sustained release microparticle and/or coated microparticle compositions are embedded.
  • Optional excipients present in the oral dosage form including abuse deterrent microparticles or coated microparticles include, but are not limited to diluents, binders, lubricants, disintigrants, colorants, plasticizers and the like. Diluents, also termed “fillers,” are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets. Examples of diluents include cellulose, dry starch, microcrystalline cellulose, dicalcium phosphate, calcium sulfate, sodium chloride confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, sucrose, mannitol, powdered cellulose, sorbitol, and lactose. Binders are used to impart cohesive qualities powdered materials and can include materials such as starch, gelatin, sugars, natural and synthetic gums, polyethylene glycol, ethylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, waxes and polyvinyl pyrrolidone. Lubricants are used to facilitate tablet manufacture; examples of lubricants include talc, magnesium stearate, calcium stearate, hydrogenated vegetable oils stearic acid, sodium stearyl fumarate, sodium benzoate, sodium acetate, leucine, sodium oleate, sodium lauryl sulfate, magnesium lauryl sulfate and polyethylene glycol. Disintegrants can be added to pharmaceutical formulations in order to facilitate “breakup” or disintegration after administration. Materials used for this purpose include starches, clays, celluloses, aligns, gums, and cross-linked polymers. A plasticizer may be included in coating materials to alter their mechanical properties. Examples of plasticizers include benzyl benzoate, chlorobutanol, dibutyl sebacate, diethyl phthalate, glycerin, mineral oil, polyethylene glycol, sorbitol, triacetin, triethyl citrate, glycerol, etc. In addition to the additives above, coloring and flavoring agents may also be incorporated into the composition.
  • II. Methods of Administration
  • It is assumed that upon oral ingestion of the intact composition, drug is released as the formulation is gradually broken down or dissolved within the GI tract by a combination of diffusion, surfactant action of bile acids, mechanical erosion, and, in some embodiments, enzymatic degradation. This is a result of the unique ability of the human digestive system to efficiently break down or solubilize a variety of materials. The process within the GI tract that results in the digestion of food and the absorption of nutrients is well known. Following mastication within the mouth, food passes into the stomach where it is mixed with digestive juices. This fluid contains the proteolytic enzyme pepsin which, following activation by the low pH within the stomach, begins the process of cleaving ingested proteins into smaller peptide fragments. Food then enters the small intestine in the form of macromolecular aggregates, where it is digested into molecules near or in a form capable of being absorbed. This digestion is accomplished through the action of various enzymes which are produced in the pancreas and flow into the upper portion of the large intestine, the duodenum. The enzymes synthesized in the pancreas include proteases, amylases and lipases; these enzymes are capable of breaking down proteins, starches and fats, respectively. The digestion of fats is further facilitated by the secretion of bile into the duodenum since bile salts, which contain both hydrophobic and hydrophilic portions, are capable of emulsifying lipids into minute droplets in order to increase the surface area available for digestion by lipases. The material which remains following passage through the small intestine enters the large intestine. Bacteria capable of breaking down carbohydrates not digested in the small intestine (such as cellulose) are present in large numbers this region of the digestive tract. Finally, in addition to microbial fermentation, the large intestine functions to absorb water and electrolytes and to form and store feces until they are excreted.
  • In some embodiments, an immediate release of drug is achieved within the stomach in order to provide rapid therapeutic onset.
  • The pharmaceutical drug composition is administered orally. The appropriate dosage formulations can be obtained by calculation of the pharmacokinetics of the formulation, then adjusting using routine techniques to yield the appropriate drug levels based on the approved dosage forms. Any suitable amount of drug containing microparticles or coated microparticles can be included in the final formulation. The selection of a suitable amount of drug containing microparticles depends on the dosage desired and is readily determined by those skilled in the art.
  • In addition to oral administration, some embodiments may also be administered by other routes, including, but not limited to, rectal and nasal administration. Some embodiments may also be suitable for formulation as oral liquids.
  • The present composition and method of making and using the composition will be further understood by reference to the following non-limiting examples.
  • EXAMPLE 1 Preparation of Lipophilic Oxycodone Derivative Oxycodone Free Base
  • The free base of oxycodone can be prepared from its hydrochloride salt by the following method: Oxycodone hydrochloride is dissolved in water and sodium carbonate was added in the amount required to neutralize hydrochloric acid. Methylene chloride is added in order to extract the formed oxycodone free base. The obtained organic layer is dried over sodium sulfate and methylene chloride is evaporated using rotary evaporator. The obtained oxycodone free base is purified by crystallization.
  • EXAMPLE 2 Preparation of Drug Containing Microparticles
  • TABLE 1
    Compositions
    Composition Composition Composition Composition
    of of of of
    Formulation Formulation Formulation Formulation
    Ingredient A B C D
    Oxycodone  5 g  5 g 10 g  5 g
    Base
    Myristic Acid 50 g 30 g
    Stearic Acid 34 g 34 g
    Yellow 10 g 10 g 10 g
    Beeswax
    Carnauba wax  5 g 10 g 20 g 10 g
  • Procedure:
  • 1. Fatty acid (myristic or stearic acid) was melted in an erlenmeyer flask in a silicone oil bath at 100° C. Note the composition was subjected to stirring and was kept under an argon blanket for this and all subsequent steps.
    2. Oxycodone base was introduced into the molten fatty acid and the melt was stirred until all oxycodone base dissolved and a clear liquid was formed.
    3. Yellow beeswax was added and melted under constant stirring.
    4. Carnauba wax was added and melted under constant stirring.
    5. The resulting homogeneous molten solution was poured onto aluminum foil and allowed to solidify at room temperature.
    6. The bulk wax obtained was combined with dry ice and subjected to size reduction in a mortar and pestle.
    7. The dry ice was allowed to dissipate and the particles were sieved to obtain various size ranges. Particles 20-40 mesh in size (400-841 micron) were subjected to testing.
  • EXAMPLE 3 Release of Drug from Crushed Microparticles
  • In vitro testing was conducted in order to assess the influence of crushing of the microparticles produced in Example 2 on the release in simulated stomach conditions. A currently marketed sustained release formulation of oxycodone, OxyContin®, was also subjected to crushing and dissolution for comparison purposes.
  • Microparticles (Formulations A, B, C or D, all 20-40 mesh in starting particle size) or tablets were crushed using a glass mortar & pestle. The resulting crushed material was placed in a dissolution vessel equipped with paddles (USP Apparatus II). 900 mL of 0.1N HCl pre-warmed to 37° C. was added to the vessels and stirring was conducted for 15 minutes. After 15 minutes the amount of oxycodone released was determined. See Table 2.
  • TABLE 2
    Oxycontin Formulations
    % Released in 15
    minutes in 0.1N HCl
    Sample (n = 3)
    Oxycontin ® 95.6 +/− 2.7
    (40 mg Tablet)
    Formulation A 31.6 +/− 2.6
    (microparticles containing 40 mg oxycodone HCl
    equivalent)
    Formulation B 19.7 +/− 1.4
    (microparticles containing 40 mg oxycodone HCl
    equivalent)
    Formulation C 14.8 +/− 1.1
    (microparticles containing 20 mg oxycodone HCl
    equivalent)
    Formulation D 18.2 +/− 1.6
    (microparticles containing 20 mg oxycodone HCl
    equivalent)
  • As illustrated in the table above, the microparticle compositions of Example 2 release only a fraction of the total drug load in simulated stomach conditions when crushed. In contrast, a currently marketed sustained release composition, OxyContin®, releases approximately 96% of the drug load when crushed and exposed to identical conditions.
  • EXAMPLE 4 Preparation of Coated Drug Containing Microparticles
  • The drug-containing particles from Example 2 are spray coated with cellulose acetate phalate.
  • EXAMPLE 5 Preparation of Capsules for Oral Administration
  • The drug containing microparticles from Example 2 and/or the coated microparticles from Example 3 are blended with a lubricant and incorporated into standard gelatin capsules.
  • Modifications and variations of the present invention will be obvious to those skilled in the art.

Claims (21)

  1. 1. An orally administrable sustained release pharmaceutical composition comprising a therapeutically effective amount of microparticles consisting of
    (a) a lipophilic drug or lipophilic derivative of a drug other than a drug prone to abuse and
    (b) one or more carrier materials selected from the group consisting of fats, fatty substances, waxes, wax-like substances and mixtures thereof
    wherein the drug is dispersed within the one or more carrier materials, and the release of a portion of incorporated drug is retarded when the physical integrity of the composition is compromised and the compromised composition is exposed to 0.1N HCl.
  2. 2. An orally administrable sustained release pharmaceutical composition comprising a therapeutically effective amount of microparticles consisting of a lipophilic derivative of a drug other than a drug prone to abuse dispersed within one or more carrier materials which are either slowly soluble in water or insoluble in water, wherein the release of a portion of incorporated drug is retarded when the physical integrity of the composition is compromised and the compromised composition is exposed to 0.1N HCl.
  3. 3. The composition of claim 1 or 2, wherein the portion of the drug released immediately when the physical integrity of the composition is compromised is less than 80% of the total amount of drug incorporated into formulation.
  4. 4. The composition of claim 1 or 2, wherein the lipophilic derivative of a drug is a free base or a free acid of the drug.
  5. 5. The composition of claim 1 or 2, wherein the lipophilic derivative of a drug is a salt comprising the ionized drug and a counter-ion.
  6. 6. The composition of claim 1 or 2, wherein the lipophilic derivative of a drug is an ester or amide formed between the drug and a fatty acid.
  7. 7. The composition of claim 5 wherein the counter-ion is selected from the group consisting of stearic acid, palmitic acid, myristic acid, and mixtures thereof.
  8. 8. The composition of claim 5 wherein the counter-ion is selected from the group consisting of methacrylic acid-methyl methacrylate copolymers, acrylic acid polymers, crosslinked acrylic acid polymers and carboxymethylcellulose.
  9. 9. The composition of claim 2 wherein the microparticles consist of drug dispersed in a material selected from the group consisting of fats, fatty substances, waxes, wax-like substances and mixtures thereof.
  10. 10. The composition of claim 1 or 2 comprising one or more carrier materials selected from the group consisting of stearic acid, palmitic acid, and mixtures thereof.
  11. 11. The composition of claim 1 or 2 comprising one or more carrier materials selected from the group consisting of beeswax, carnauba wax, hydrogenated oil, and mixtures thereof.
  12. 12. The composition of claim 1 or 2 wherein the carrier materials are selected from the group consisting of myristic acid, palmitic acid, stearic acid, carnauba wax, beeswax and mixtures thereof.
  13. 13. The composition of claim 2 wherein the microparticles consist of a drug dispersed in a carrier material selected from the group consisting of naturally water insoluble proteins, naturally water insoluble polysaccharides, naturally water insoluble lipids and phospholipids, cross-linked water soluble proteins, cross-linked water soluble polysaccharides and combinations thereof.
  14. 14. The composition of claim 1 or 2 wherein the individual microparticles are coated with one or more independent layers.
  15. 15. The composition of claim 14 wherein the coated layer(s) comprise a material selected from the group consisting of naturally water insoluble proteins, naturally water insoluble polysaccharides, naturally water insoluble lipids and phospholipids, cross-linked proteins, cross-linked polysaccharides, mixtures of waxes and fatty substances, and combinations thereof.
  16. 16. The composition of claim 15 wherein the coated layer(s) comprise a material selected from the group of pH dependent coatings, water insoluble diffusion barrier coatings, water soluble coatings and combinations thereof.
  17. 17. The composition of claim 1 or 2 wherein the lipophilic derivative is dissolved in the carrier material in a molten state to result in a uniform dispersion within the carrier material.
  18. 18. The composition of claim 1 or 2 wherein the lipophilic derivative is dissolved in a co-solvent along with a carrier material to result in a uniform dispersion within the carrier material.
  19. 19. The composition of claim 1 or 2, wherein the individual microparticles are further formulated into a tablet or capsule for oral administration.
  20. 20. The composition of claim 19, wherein the individual microparticles contain one or more drugs.
  21. 21. The composition of claim 19, wherein the tablet or capsule further comprises one or more drugs formulated as an immediate release dose, a sustained release dose, a delayed release dose, or a combination thereof.
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US12965572 US8840928B2 (en) 2002-07-05 2010-12-10 Tamper-resistant pharmaceutical compositions of opioids and other drugs
US14054513 US9248195B2 (en) 2002-07-05 2013-10-15 Abuse-deterrent pharmaceutical compositions of opioids and other drugs
US14320086 US9682075B2 (en) 2002-07-05 2014-06-30 Tamper-resistant pharmaceutical compositions of opioids and other drugs
US14321125 US20150005332A1 (en) 2002-07-05 2014-07-01 Tamper-resistant pharmaceutical compositions of opioids and other drugs
US14946275 US9592200B2 (en) 2002-07-05 2015-11-19 Abuse-deterrent pharmaceutical compositions of opioids and other drugs
US15457153 US20170182032A1 (en) 2002-07-05 2017-03-13 Abuse-deterrent pharmaceutical compositions of opioids and other drugs
US15606112 US10004729B2 (en) 2002-07-05 2017-05-26 Tamper-resistant pharmaceutical compositions of opioids and other drugs
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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050281748A1 (en) * 2004-06-12 2005-12-22 Collegium Pharmaceutical, Inc. Abuse-deterrent drug formulations
US20080199530A1 (en) * 2002-07-05 2008-08-21 Collegium Pharmaceuticals Inc. Abuse-deterrent pharmaceutical compositions of opioids and other drugs
US20090297617A1 (en) * 2002-07-05 2009-12-03 Collegium Pharmaceuticals Inc. Abuse-deterrent pharmaceutical compositions of opioids and other drugs
US20100310666A1 (en) * 2009-06-05 2010-12-09 Kraft Foods Global Brands Llc Delivery of Functional Compounds
US20100307542A1 (en) * 2009-06-05 2010-12-09 Kraft Foods Global Brands Llc Method of Reducing Surface Oil on Encapsulated Material
US20100310726A1 (en) * 2009-06-05 2010-12-09 Kraft Foods Global Brands Llc Novel Preparation of an Enteric Release System
US20110076325A1 (en) * 2007-08-13 2011-03-31 Abuse Deterrent Pharmaceutical, Llc Abuse resistant drugs, method of use and method of making
US20110142943A1 (en) * 2002-07-05 2011-06-16 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opiods and other drugs
US20110159103A1 (en) * 2009-06-05 2011-06-30 Kraft Foods Global Brands Llc Novel Preparation of an Enteric Release System
US20110223247A1 (en) * 2008-11-07 2011-09-15 Samyang Corporation Pharmaceutical compositions for release control of methylphenidate
WO2012097144A1 (en) * 2011-01-12 2012-07-19 Thetis Pharmaceuticals Llc Lipid-lowering antidiabetic agent
WO2013049749A3 (en) * 2011-09-29 2013-07-11 Plx Pharma Inc. pH DEPENDENT CARRIERS FOR TARGETED RELEASE OF PHARMACEUTICALS ALONG THE GASTROINTESTINAL TRACT, COMPOSITIONS THEREFROM, AND MAKING AND USING SAME
US8765811B2 (en) 2012-07-10 2014-07-01 Thetis Pharmaceuticals Llc Tri-salt form of metformin
US8859005B2 (en) 2012-12-03 2014-10-14 Intercontinental Great Brands Llc Enteric delivery of functional ingredients suitable for hot comestible applications
US8940729B1 (en) * 2007-05-22 2015-01-27 Pisgah Laboratories, Inc. Abuse deterrent and anti-dose dumping pharmaceutical salts useful for the treatment of attention deficit/hyperactivity disorder
US9242008B2 (en) 2014-06-18 2016-01-26 Thetis Pharmaceuticals Llc Mineral amino-acid complexes of fatty acids
US9382187B2 (en) 2012-07-10 2016-07-05 Thetis Pharmaceuticals Llc Tri-salt form of metformin
US9505709B2 (en) 2014-05-05 2016-11-29 Thetis Pharmaceuticals Llc Compositions and methods relating to ionic salts of peptides
US9737530B1 (en) 2016-06-23 2017-08-22 Collegium Pharmaceutical, Inc. Process of making stable abuse-deterrent oral formulations
US9861629B1 (en) 2015-10-07 2018-01-09 Banner Life Sciences Llc Opioid abuse deterrent dosage forms
US9999626B2 (en) 2014-06-18 2018-06-19 Thetis Pharmaceuticals Llc Mineral amino-acid complexes of active agents

Families Citing this family (90)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK1041987T3 (en) 1997-12-22 2006-08-21 Euro Celtique Sa An oral pharmaceutical dosage form comprising a combination of an opioid agonist and naltrexone
US6375957B1 (en) 1997-12-22 2002-04-23 Euro-Celtique, S.A. Opioid agonist/opioid antagonist/acetaminophen combinations
US20060014697A1 (en) * 2001-08-22 2006-01-19 Travis Mickle Pharmaceutical compositions for prevention of overdose or abuse
US8394813B2 (en) 2000-11-14 2013-03-12 Shire Llc Active agent delivery systems and methods for protecting and administering active agents
RU2230556C2 (en) 1999-10-29 2004-06-20 Эро-Селтик, С.А. Hydrocodon preparative sustained-release formulations
US8133881B2 (en) 2003-01-13 2012-03-13 Shire Llc Carbohydrate conjugates to prevent abuse of controlled substances
JP2004512354A (en) 2000-10-30 2004-04-22 ユーロ−セルティーク,エス.エイ. Hydrocodone controlled-release formulation
CA2446550C (en) 2001-05-11 2012-03-06 Endo Pharmaceuticals, Inc. Abuse-resistant controlled-release opioid dosage form
US8101209B2 (en) 2001-10-09 2012-01-24 Flamel Technologies Microparticulate oral galenical form for the delayed and controlled release of pharmaceutical active principles
KR100717591B1 (en) 2002-04-05 2007-05-15 유로-셀띠끄 소시에떼 아노님 Matrix for sustained, invariant and independent release of active compounds
CA2480826C (en) 2002-04-09 2012-02-07 Flamel Technologies Oral pharmaceutical formulation in the form of microcapsule aqueous suspension allowing modified release of active ingredient(s)
US7776314B2 (en) 2002-06-17 2010-08-17 Grunenthal Gmbh Abuse-proofed dosage system
US20070048228A1 (en) * 2003-08-06 2007-03-01 Elisabeth Arkenau-Maric Abuse-proofed dosage form
DE10336400A1 (en) 2003-08-06 2005-03-24 Grünenthal GmbH Abuse-proofed dosage form
DK1842533T3 (en) * 2003-08-06 2013-05-27 Gruenenthal Gmbh Dosage protected against abuse
US8075872B2 (en) 2003-08-06 2011-12-13 Gruenenthal Gmbh Abuse-proofed dosage form
US7169752B2 (en) * 2003-09-30 2007-01-30 New River Pharmaceuticals Inc. Compounds and compositions for prevention of overdose of oxycodone
DE10361596A1 (en) * 2003-12-24 2005-09-29 Grünenthal GmbH A process for preparing a secured against misuse dosage form
EP3228308A1 (en) 2005-01-28 2017-10-11 Euro-Celtique S.A. Alcohol resistant dosage forms
DE602005026786D1 (en) * 2004-03-30 2011-04-21 Euro Celtique Sa A process for producing oxycodone hydrochloride with less than 25 ppm 14-hydroxycodeinone
DE102004020220A1 (en) * 2004-04-22 2005-11-10 Grünenthal GmbH A process for preparing a secured against misuse, solid dosage form
EP1604667A1 (en) * 2004-06-08 2005-12-14 Euro-Celtique S.A. Opioids for the treatment of the restless leg syndrome
EP1604666A1 (en) * 2004-06-08 2005-12-14 Euro-Celtique S.A. Opioids for the treatment of the Chronic Obstructive Pulmonary Disease (COPD)
JP5259183B2 (en) * 2004-07-01 2013-08-07 グリューネンタール・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング Protected oral dosage form against abuse
JP5700904B2 (en) * 2004-07-01 2015-04-15 グリューネンタール・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング (1r, 2r) -3- (3- Dimethylamino-1-ethyl-2-methyl-propyl) - abuse prevention oral dosage forms containing phenol
DE102004032049A1 (en) * 2004-07-01 2006-01-19 Grünenthal GmbH Abuse-proofed, oral dosage form
DE102004032051A1 (en) 2004-07-01 2006-01-19 Grünenthal GmbH A process for preparing a secured against misuse, solid dosage form
US7226619B1 (en) 2004-09-07 2007-06-05 Pharmorx Inc. Material for controlling diversion of medications
ES2531735T3 (en) * 2004-10-15 2015-03-18 Supernus Pharmaceuticals, Inc. pharmaceutical preparations with lower abuse potential
FR2878161B1 (en) * 2004-11-23 2008-10-31 Flamel Technologies Sa An oral pharmaceutical composition, solid and designed to prevent misuse
FR2878158B1 (en) * 2004-11-24 2009-01-16 Flamel Technologies Sa oral pharmaceutical form, solid microparticulate designed to prevent misuse
DE102005005446A1 (en) * 2005-02-04 2006-08-10 Grünenthal GmbH Unbreakable dosage forms with delayed release
DE102005005449A1 (en) * 2005-02-04 2006-08-10 Grünenthal GmbH A process for preparing a secured against misuse dosage form
FR2881652B1 (en) * 2005-02-08 2007-05-25 Flamel Technologies Sa microparticulate oral pharmaceutical form anti-mesuage
EP1695700A1 (en) * 2005-02-28 2006-08-30 Euro-Celtique S.A. Dosage form containing oxycodone and naloxone
FR2889810A1 (en) * 2005-05-24 2007-02-23 Flamel Technologies Sa An oral pharmaceutical composition, microparticulate, anti-measurement
WO2006133733A1 (en) * 2005-06-13 2006-12-21 Flamel Technologies Oral dosage form comprising an antimisuse system
RU2008104638A (en) * 2005-07-07 2009-08-20 Фарнэм Компаниз, Инк. (Us) The pharmaceutical compositions are well soluble in water medicaments that ensure their slow release
WO2007050975A3 (en) * 2005-10-26 2007-09-20 Banner Pharmacaps Inc Hydrophilic vehicle-based dual controlled release matrix system as capsule fill
CA2627351C (en) * 2005-10-26 2012-05-01 Banner Pharmacaps, Inc. Lipophilic vehicle-based dual controlled release matrix system
US8329744B2 (en) * 2005-11-02 2012-12-11 Relmada Therapeutics, Inc. Methods of preventing the serotonin syndrome and compositions for use thereof
WO2007056142A3 (en) * 2005-11-02 2007-11-08 Najib Babul Methods of preventing the serotonin syndrome and compositions for use therefor
FR2892937B1 (en) * 2005-11-10 2013-04-05 Flamel Tech Sa microparticulate oral pharmaceutical form anti-misuse
US8652529B2 (en) 2005-11-10 2014-02-18 Flamel Technologies Anti-misuse microparticulate oral pharmaceutical form
US20090317355A1 (en) * 2006-01-21 2009-12-24 Abbott Gmbh & Co. Kg, Abuse resistant melt extruded formulation having reduced alcohol interaction
US20100172989A1 (en) * 2006-01-21 2010-07-08 Abbott Laboratories Abuse resistant melt extruded formulation having reduced alcohol interaction
US20090082466A1 (en) * 2006-01-27 2009-03-26 Najib Babul Abuse Resistant and Extended Release Formulations and Method of Use Thereof
CA2649360A1 (en) * 2006-04-10 2007-10-25 Shire Llc Mono and di-substituted oxycodone compounds and compositions
US20100144645A1 (en) * 2006-04-14 2010-06-10 Shire Llc Compositions and methods for enhancing analgesic potency of covalently bound-compounds, attenuating its adverse side effects, and preventing their abuse
US20080020032A1 (en) * 2006-07-21 2008-01-24 Michael Crowley Hydrophobic abuse deterrent delivery system for hydromorphone
US7976872B2 (en) * 2006-07-24 2011-07-12 L. Perrigo Company Method for distributing a pharmaceutically active compound in an excipient
CN102688241B (en) 2006-08-25 2017-04-12 普渡制药公司 Anti containing an opioid analgesic oral dosage form is tampered
US20080069891A1 (en) 2006-09-15 2008-03-20 Cima Labs, Inc. Abuse resistant drug formulation
US8445018B2 (en) 2006-09-15 2013-05-21 Cima Labs Inc. Abuse resistant drug formulation
US8187636B2 (en) * 2006-09-25 2012-05-29 Atlantic Pharmaceuticals, Inc. Dosage forms for tamper prone therapeutic agents
DE102007011485A1 (en) * 2007-03-07 2008-09-11 Grünenthal GmbH Dosage form with impeded abuse
WO2008134071A1 (en) * 2007-04-26 2008-11-06 Theraquest Biosciences, Inc. Multimodal abuse resistant extended release formulations
CA2687192C (en) 2007-06-04 2015-11-24 Egalet A/S Controlled release pharmaceutical compositions for prolonged effect
US20090022798A1 (en) * 2007-07-20 2009-01-22 Abbott Gmbh & Co. Kg Formulations of nonopioid and confined opioid analgesics
WO2009092601A1 (en) * 2008-01-25 2009-07-30 Grünenthal GmbH Pharmaceutical dosage form
JP2011511782A (en) 2008-02-12 2011-04-14 アボット・ラボラトリーズAbbott Laboratories Extended release hydrocodone acetaminophen and its related methods and applications
EP2273983B1 (en) 2008-05-09 2016-07-20 Grünenthal GmbH Process for the preparation of an intermediate powder formulation and a final solid dosage form under usage of a spray congealing step
JP5406288B2 (en) * 2008-07-07 2014-02-05 ユーロ−セルティーク エス.エイ. The use of an opioid antagonist for the treatment of urinary retention
CA2736119C (en) * 2008-09-04 2016-08-23 Farnam Companies, Inc. Chewable sustained release formulations
WO2010066034A8 (en) * 2008-12-12 2010-08-19 Paladin Labs Inc. Narcotic drug formulations with decreased abuse potential
CA2751667C (en) 2009-02-06 2016-12-13 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
CA2754853C (en) 2009-03-10 2015-04-28 Euro-Celtique S.A. Immediate release pharmaceutical compositions comprising oxycodone and naloxone
WO2010149169A3 (en) 2009-06-24 2011-06-16 Egalet A/S Controlled release formulations
WO2011009602A1 (en) * 2009-07-22 2011-01-27 Grünenthal GmbH Hot-melt extruded controlled release dosage form
ES2560210T3 (en) 2009-07-22 2016-02-17 Grünenthal GmbH Dosage form resistant to manipulation for opiádes sensitive to oxidation
EP2506836B1 (en) * 2009-12-02 2018-02-14 Adare Pharmaceuticals S.R.L. Fexofenadine microcapsules and compositions containing them
US9125867B2 (en) * 2010-02-24 2015-09-08 Invincible Biotechnology Diversion- and/or abuse-resistant compositions and methods for making the same
JP2013526523A (en) 2010-05-11 2013-06-24 シマ ラブス インク. Alcohol resistant sustained release oral dosage form comprising metoprolol
RU2607499C2 (en) 2010-09-02 2017-01-10 Грюненталь Гмбх Destruction-resistant dosage form containing anionic polymer
EP2654734A2 (en) 2010-12-22 2013-10-30 Purdue Pharma LP Encased tamper resistant controlled release dosage forms
CA2822769C (en) 2010-12-23 2016-10-04 Purdue Pharma L.P. Tamper resistant solid oral dosage forms
EP2768481A4 (en) * 2011-10-21 2015-07-08 Subhash Desai Compositions for reduction of side effects
US20130225697A1 (en) 2012-02-28 2013-08-29 Grunenthal Gmbh Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
JP6208261B2 (en) 2013-02-05 2017-10-04 パーデュー、ファーマ、リミテッド、パートナーシップPurdue Pharma L.P. Tampering resistant pharmaceutical preparations
US20140271896A1 (en) 2013-03-15 2014-09-18 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
CA2913209A1 (en) 2013-05-29 2014-12-04 Grunenthal Gmbh Tamper resistant dosage form with bimodal release profile
US9770514B2 (en) 2013-09-03 2017-09-26 ExxPharma Therapeutics LLC Tamper-resistant pharmaceutical dosage forms
WO2015065547A1 (en) 2013-10-31 2015-05-07 Cima Labs Inc. Immediate release abuse-deterrent granulated dosage forms
US8846923B1 (en) 2013-12-18 2014-09-30 Cody Laboratories, Inc. Preparation of 14-hydroxycodeinone sulfate
US9062062B1 (en) 2013-12-18 2015-06-23 Cody Laboratories, Inc. Synthesis of oxycodone hydrochloride
US20150283087A1 (en) * 2014-04-07 2015-10-08 Banner Life Sciences Llc Abuse-deterrent controlled release formulations
JP2017518980A (en) 2014-05-12 2017-07-13 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Containing tapentadol, modified prevent immediate release capsule formulation
CA2949422A1 (en) 2014-05-26 2015-12-03 Grunenthal Gmbh Multiparticles safeguarded against ethanolic dose-dumping
US9132096B1 (en) 2014-09-12 2015-09-15 Alkermes Pharma Ireland Limited Abuse resistant pharmaceutical compositions
JP2018517676A (en) 2015-04-24 2018-07-05 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Modified anti formulations resistant to immediate and solvent extraction

Citations (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2404319A (en) * 1941-06-28 1946-07-16 Wm S Merrell Co Butanolamine salts of theophylline
US3015128A (en) * 1960-08-18 1962-01-02 Southwest Res Inst Encapsulating apparatus
US3336200A (en) * 1963-05-28 1967-08-15 Warner Lambert Pharmaceutical Tablet structure
US3773955A (en) * 1970-08-03 1973-11-20 Bristol Myers Co Analgetic compositions
US3966940A (en) * 1973-11-09 1976-06-29 Bristol-Myers Company Analgetic compositions
US3980766A (en) * 1973-08-13 1976-09-14 West Laboratories, Inc. Orally administered drug composition for therapy in the treatment of narcotic drug addiction
US4070494A (en) * 1975-07-09 1978-01-24 Bayer Aktiengesellschaft Enteral pharmaceutical compositions
US4457933A (en) * 1980-01-24 1984-07-03 Bristol-Myers Company Prevention of analgesic abuse
US4569937A (en) * 1985-02-11 1986-02-11 E. I. Du Pont De Nemours And Company Analgesic mixture of oxycodone and ibuprofen
US4599326A (en) * 1984-01-06 1986-07-08 Orion-Yhtyma Oy Acetyl erythromycin stearate, and compositions containing it
US4675140A (en) * 1984-05-18 1987-06-23 Washington University Technology Associates Method for coating particles or liquid droplets
US4722941A (en) * 1978-06-07 1988-02-02 Kali-Chemie Pharma Gmbh Readily absorbable pharmaceutical compositions of per se poorly absorbable pharmacologically active agents and preparation thereof
US4861598A (en) * 1986-07-18 1989-08-29 Euroceltique, S.A. Controlled release bases for pharmaceuticals
US4869904A (en) * 1986-12-26 1989-09-26 Nisshin Flour Milling Co., Ltd. Sustained release drug preparation
EP0375063A1 (en) * 1988-12-20 1990-06-27 Yamanouchi Europe B.V. Granulates for multiparticulate controlled-release oral compositions
US5190947A (en) * 1990-08-23 1993-03-02 Ciba-Geigy Corporation Codeine salt of a substituted carboxylic acid, its use and pharmaceutical compositions thereof
US5356467A (en) * 1992-08-13 1994-10-18 Euroceltique S.A. Controlled release coatings derived from aqueous dispersions of zein
US5460826A (en) * 1994-06-27 1995-10-24 Alza Corporation Morphine therapy
US5508042A (en) * 1991-11-27 1996-04-16 Euro-Celtigue, S.A. Controlled release oxycodone compositions
US5756483A (en) * 1993-03-26 1998-05-26 Merkus; Franciscus W. H. M. Pharmaceutical compositions for intranasal administration of apomorphine
US5849240A (en) * 1993-11-23 1998-12-15 Euro-Celtique, S.A. Method of preparing sustained release pharmaceutical compositions
US5891471A (en) * 1993-11-23 1999-04-06 Euro-Celtique, S.A. Pharmaceutical multiparticulates
US5914129A (en) * 1996-07-23 1999-06-22 Mauskop; Alexander Analgesic composition for treatment of migraine headaches
US5952005A (en) * 1993-03-30 1999-09-14 Pharmacia & Upjohn Aktiebolag Controlled release preparation for administering morphine
US5958459A (en) * 1991-12-24 1999-09-28 Purdue Pharma L.P. Opioid formulations having extended controlled released
US5958452A (en) * 1994-11-04 1999-09-28 Euro-Celtique, S.A. Extruded orally administrable opioid formulations
US5968551A (en) * 1991-12-24 1999-10-19 Purdue Pharma L.P. Orally administrable opioid formulations having extended duration of effect
US6048736A (en) * 1998-04-29 2000-04-11 Kosak; Kenneth M. Cyclodextrin polymers for carrying and releasing drugs
US6068855A (en) * 1994-11-03 2000-05-30 Euro-Celtique S. A. Pharmaceutical composition containing a fusible carrier and method for producing the same
US6103261A (en) * 1993-07-01 2000-08-15 Purdue Pharma Lp Opioid formulations having extended controlled release
US6156764A (en) * 1996-02-28 2000-12-05 Lts Lohmann Therapie-Systeme Gmbh Morphine and diamorphine salts of anionic non-narcotic analgesics of the substituted carboxylic acid type
US6255502B1 (en) * 1996-07-11 2001-07-03 Farmarc Nederland B.V. Pharmaceutical composition containing acid addition salt of basic drug
US20010006650A1 (en) * 1997-09-19 2001-07-05 Beth A. Burnside Solid solution beadlet
US6277384B1 (en) * 1997-12-22 2001-08-21 Euro-Celtique S.A. Opioid agonist/antagonist combinations
US6290990B1 (en) * 1994-04-18 2001-09-18 Basf Aktiengesellschaft Slow-release matrix pellets and the production thereof
US6310072B1 (en) * 1995-10-19 2001-10-30 The University Of Queensland Production of analgesic synergy by co-administration of sub-analgesic doses of a MU opioid agonist and a kappa-2 opioid agonist
US6309668B1 (en) * 1994-02-01 2001-10-30 Aventis Pharma Limited Abuse resistant tablets
US6328979B1 (en) * 1997-12-26 2001-12-11 Yamanouchi Pharmaceuticals, Co. Ltd. Sustained release medicinal compositions
US20020032166A1 (en) * 1992-10-14 2002-03-14 University Technology Corporation Biocompatible cationic detergents and uses therefor
US6375957B1 (en) * 1997-12-22 2002-04-23 Euro-Celtique, S.A. Opioid agonist/opioid antagonist/acetaminophen combinations
US6379707B2 (en) * 1999-03-24 2002-04-30 Fmc Corporation Method of making granular pharmaceutical vehicle
US20030059397A1 (en) * 2001-09-17 2003-03-27 Lyn Hughes Dosage forms
US20030064099A1 (en) * 2001-08-06 2003-04-03 Benjamin Oshlack Pharmaceutical formulation containing bittering agent
US6696088B2 (en) * 2000-02-08 2004-02-24 Euro-Celtique, S.A. Tamper-resistant oral opioid agonist formulations
US20040052731A1 (en) * 2002-07-05 2004-03-18 Collegium Pharmaceuticals, Inc. Abuse-deterrent pharmaceutical compositions of opiods and other drugs
US20040062778A1 (en) * 2002-09-26 2004-04-01 Adi Shefer Surface dissolution and/or bulk erosion controlled release compositions and devices
US6723343B2 (en) * 1999-08-31 2004-04-20 Gruenenthal Gmbh Pharmaceutical tramadol salts
US20050013862A1 (en) * 2001-09-05 2005-01-20 Vectura Limited Functional powders for oral delivery
US20050181050A1 (en) * 2004-01-28 2005-08-18 Collegium Pharmaceutical, Inc. Dosage forms using drug-loaded ion exchange resins
US20050281748A1 (en) * 2004-06-12 2005-12-22 Collegium Pharmaceutical, Inc. Abuse-deterrent drug formulations
US7011846B2 (en) * 2001-12-21 2006-03-14 Shire Laboratories, Inc. Oral capsule formulation with increased physical stability
US20060104909A1 (en) * 2002-09-23 2006-05-18 Farid Vaghefi Abuse-resistant pharmaceutical compositions
US7261529B2 (en) * 2005-09-07 2007-08-28 Southwest Research Institute Apparatus for preparing biodegradable microparticle formulations containing pharmaceutically active agents
US7670612B2 (en) * 2002-04-10 2010-03-02 Innercap Technologies, Inc. Multi-phase, multi-compartment capsular delivery apparatus and methods for using same
US20110142943A1 (en) * 2002-07-05 2011-06-16 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opiods and other drugs
US8557291B2 (en) * 2002-07-05 2013-10-15 Collegium Pharmaceutical, Inc. Abuse-deterrent pharmaceutical compositions of opioids and other drugs

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2426812A1 (en) 1974-06-04 1976-01-02 Klinge Co Chem Pharm Fab A process for the preparation of granules
CA2100045A1 (en) 1992-07-08 1994-01-09 Janko Zmitek Inclusion complexes of clavulanic acid and of alkali salts thereof with hydrophilic and hydrophobic .beta. - cyclodextrin derivatives, a proce ss for the preparation thereof and the use thereof
EP2036558A3 (en) * 1993-10-07 2010-04-28 Euro-Celtique S.A. Orally administrable opioid formulations having extended duration of effect
WO1997049402A1 (en) 1996-06-27 1997-12-31 Janssen Pharmaceutica N.V. Sustained release sufentanil compositions
JP2001503406A (en) 1996-10-28 2001-03-13 ファーマーク、ニーダーランド、ベスローテン、フェンノートシャップ Pharmaceutical compositions
US6294192B1 (en) 1999-02-26 2001-09-25 Lipocine, Inc. Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents
CA2379987A1 (en) 1999-07-29 2001-02-08 Roxane Laboratories, Inc. Opioid sustained-released formulation
ES2253364T3 (en) * 2000-03-28 2006-06-01 Farmarc Nederland B.V. Inclusion complexes of alprazolam and their pharmaceutical compositions.
DE60223254D1 (en) 2001-07-06 2007-12-13 Penwest Pharmaceuticals Co The sustained release formulations of oxymorphone
EP2316418A3 (en) 2003-02-24 2011-09-21 Pharmaceutical Productions Inc. Transmucosal drug delivery system
WO2008027283A3 (en) * 2006-08-25 2008-12-31 Daniel J Arriola Production of meta-block copolymers by polymer segment interchange

Patent Citations (76)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2404319A (en) * 1941-06-28 1946-07-16 Wm S Merrell Co Butanolamine salts of theophylline
US3015128A (en) * 1960-08-18 1962-01-02 Southwest Res Inst Encapsulating apparatus
US3336200A (en) * 1963-05-28 1967-08-15 Warner Lambert Pharmaceutical Tablet structure
US3773955A (en) * 1970-08-03 1973-11-20 Bristol Myers Co Analgetic compositions
US3980766A (en) * 1973-08-13 1976-09-14 West Laboratories, Inc. Orally administered drug composition for therapy in the treatment of narcotic drug addiction
US3966940A (en) * 1973-11-09 1976-06-29 Bristol-Myers Company Analgetic compositions
US4070494A (en) * 1975-07-09 1978-01-24 Bayer Aktiengesellschaft Enteral pharmaceutical compositions
US4722941A (en) * 1978-06-07 1988-02-02 Kali-Chemie Pharma Gmbh Readily absorbable pharmaceutical compositions of per se poorly absorbable pharmacologically active agents and preparation thereof
US4457933A (en) * 1980-01-24 1984-07-03 Bristol-Myers Company Prevention of analgesic abuse
US4599326A (en) * 1984-01-06 1986-07-08 Orion-Yhtyma Oy Acetyl erythromycin stearate, and compositions containing it
US4675140A (en) * 1984-05-18 1987-06-23 Washington University Technology Associates Method for coating particles or liquid droplets
US4569937A (en) * 1985-02-11 1986-02-11 E. I. Du Pont De Nemours And Company Analgesic mixture of oxycodone and ibuprofen
US4861598A (en) * 1986-07-18 1989-08-29 Euroceltique, S.A. Controlled release bases for pharmaceuticals
US4869904A (en) * 1986-12-26 1989-09-26 Nisshin Flour Milling Co., Ltd. Sustained release drug preparation
EP0375063A1 (en) * 1988-12-20 1990-06-27 Yamanouchi Europe B.V. Granulates for multiparticulate controlled-release oral compositions
US5190947A (en) * 1990-08-23 1993-03-02 Ciba-Geigy Corporation Codeine salt of a substituted carboxylic acid, its use and pharmaceutical compositions thereof
US5508042A (en) * 1991-11-27 1996-04-16 Euro-Celtigue, S.A. Controlled release oxycodone compositions
US6294195B1 (en) * 1991-12-24 2001-09-25 Purdue Pharma L.P. Orally administrable opioid formulations having extended duration of effect
US20020081333A1 (en) * 1991-12-24 2002-06-27 Benjamin Oshlack Orally administrable opioid formulations having extended duration of effect
US5968551A (en) * 1991-12-24 1999-10-19 Purdue Pharma L.P. Orally administrable opioid formulations having extended duration of effect
US5958459A (en) * 1991-12-24 1999-09-28 Purdue Pharma L.P. Opioid formulations having extended controlled released
US5356467A (en) * 1992-08-13 1994-10-18 Euroceltique S.A. Controlled release coatings derived from aqueous dispersions of zein
US20020032166A1 (en) * 1992-10-14 2002-03-14 University Technology Corporation Biocompatible cationic detergents and uses therefor
US5756483A (en) * 1993-03-26 1998-05-26 Merkus; Franciscus W. H. M. Pharmaceutical compositions for intranasal administration of apomorphine
US5952005A (en) * 1993-03-30 1999-09-14 Pharmacia & Upjohn Aktiebolag Controlled release preparation for administering morphine
US6103261A (en) * 1993-07-01 2000-08-15 Purdue Pharma Lp Opioid formulations having extended controlled release
US5891471A (en) * 1993-11-23 1999-04-06 Euro-Celtique, S.A. Pharmaceutical multiparticulates
US5965163A (en) * 1993-11-23 1999-10-12 Euro-Celtique, S.A. Substained release compositions and a method of preparing pharmaceutical compositions
US5849240A (en) * 1993-11-23 1998-12-15 Euro-Celtique, S.A. Method of preparing sustained release pharmaceutical compositions
US6162467A (en) * 1993-11-23 2000-12-19 Euro-Celtique, S.A. Sustained release compositions and a method of preparing pharmaceutical compositions
US6309668B1 (en) * 1994-02-01 2001-10-30 Aventis Pharma Limited Abuse resistant tablets
US6290990B1 (en) * 1994-04-18 2001-09-18 Basf Aktiengesellschaft Slow-release matrix pellets and the production thereof
US5460826A (en) * 1994-06-27 1995-10-24 Alza Corporation Morphine therapy
US6068855A (en) * 1994-11-03 2000-05-30 Euro-Celtique S. A. Pharmaceutical composition containing a fusible carrier and method for producing the same
US6335033B2 (en) * 1994-11-04 2002-01-01 Euro-Celtique, S.A. Melt-extrusion multiparticulates
US20010036476A1 (en) * 1994-11-04 2001-11-01 Euro-Celtique S.A. Melt-extruded orally administrable opioid formulations
US6261599B1 (en) * 1994-11-04 2001-07-17 Euro-Celtique, S.A. Melt-extruded orally administrable opioid formulations
US5958452A (en) * 1994-11-04 1999-09-28 Euro-Celtique, S.A. Extruded orally administrable opioid formulations
US6743442B2 (en) * 1994-11-04 2004-06-01 Euro-Celtique, S.A. Melt-extruded orally administrable opioid formulations
US6706281B2 (en) * 1994-11-04 2004-03-16 Euro-Celtique, S.A. Melt-extrusion multiparticulates
US5965161A (en) * 1994-11-04 1999-10-12 Euro-Celtique, S.A. Extruded multi-particulates
US6310072B1 (en) * 1995-10-19 2001-10-30 The University Of Queensland Production of analgesic synergy by co-administration of sub-analgesic doses of a MU opioid agonist and a kappa-2 opioid agonist
US6156764A (en) * 1996-02-28 2000-12-05 Lts Lohmann Therapie-Systeme Gmbh Morphine and diamorphine salts of anionic non-narcotic analgesics of the substituted carboxylic acid type
US6255502B1 (en) * 1996-07-11 2001-07-03 Farmarc Nederland B.V. Pharmaceutical composition containing acid addition salt of basic drug
US5914129A (en) * 1996-07-23 1999-06-22 Mauskop; Alexander Analgesic composition for treatment of migraine headaches
US20010006650A1 (en) * 1997-09-19 2001-07-05 Beth A. Burnside Solid solution beadlet
US6692767B2 (en) * 1997-09-19 2004-02-17 Shire Laboratories Inc. Solid solution beadlet
US6475494B2 (en) * 1997-12-22 2002-11-05 Euro-Celtique S.A. Opioid agonist/antagonist combinations
US6375957B1 (en) * 1997-12-22 2002-04-23 Euro-Celtique, S.A. Opioid agonist/opioid antagonist/acetaminophen combinations
US6277384B1 (en) * 1997-12-22 2001-08-21 Euro-Celtique S.A. Opioid agonist/antagonist combinations
US6919372B1 (en) * 1997-12-26 2005-07-19 Yamanouchi Pharmaceutical Co., Ltd. Sustained release pharmaceutical compositions
US6328979B1 (en) * 1997-12-26 2001-12-11 Yamanouchi Pharmaceuticals, Co. Ltd. Sustained release medicinal compositions
US6048736A (en) * 1998-04-29 2000-04-11 Kosak; Kenneth M. Cyclodextrin polymers for carrying and releasing drugs
US6379707B2 (en) * 1999-03-24 2002-04-30 Fmc Corporation Method of making granular pharmaceutical vehicle
US6723343B2 (en) * 1999-08-31 2004-04-20 Gruenenthal Gmbh Pharmaceutical tramadol salts
US6696088B2 (en) * 2000-02-08 2004-02-24 Euro-Celtique, S.A. Tamper-resistant oral opioid agonist formulations
US20030064099A1 (en) * 2001-08-06 2003-04-03 Benjamin Oshlack Pharmaceutical formulation containing bittering agent
US20050013862A1 (en) * 2001-09-05 2005-01-20 Vectura Limited Functional powders for oral delivery
US20030059397A1 (en) * 2001-09-17 2003-03-27 Lyn Hughes Dosage forms
US7011846B2 (en) * 2001-12-21 2006-03-14 Shire Laboratories, Inc. Oral capsule formulation with increased physical stability
US7670612B2 (en) * 2002-04-10 2010-03-02 Innercap Technologies, Inc. Multi-phase, multi-compartment capsular delivery apparatus and methods for using same
US20130045960A1 (en) * 2002-07-05 2013-02-21 Collegium Pharmaceuticals, Inc. Abuse-Deterrent Pharmaceutical Compositions of Opiods and Other Drugs
US8557291B2 (en) * 2002-07-05 2013-10-15 Collegium Pharmaceutical, Inc. Abuse-deterrent pharmaceutical compositions of opioids and other drugs
US20110142943A1 (en) * 2002-07-05 2011-06-16 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opiods and other drugs
US20040052731A1 (en) * 2002-07-05 2004-03-18 Collegium Pharmaceuticals, Inc. Abuse-deterrent pharmaceutical compositions of opiods and other drugs
US20080199530A1 (en) * 2002-07-05 2008-08-21 Collegium Pharmaceuticals Inc. Abuse-deterrent pharmaceutical compositions of opioids and other drugs
US7399488B2 (en) * 2002-07-05 2008-07-15 Collegium Pharmaceutical, Inc. Abuse-deterrent pharmaceutical compositions of opiods and other drugs
US20060104909A1 (en) * 2002-09-23 2006-05-18 Farid Vaghefi Abuse-resistant pharmaceutical compositions
US20040062778A1 (en) * 2002-09-26 2004-04-01 Adi Shefer Surface dissolution and/or bulk erosion controlled release compositions and devices
US20050181050A1 (en) * 2004-01-28 2005-08-18 Collegium Pharmaceutical, Inc. Dosage forms using drug-loaded ion exchange resins
US8449909B2 (en) * 2004-06-12 2013-05-28 Collegium Pharmaceutical, Inc. Abuse-deterrent drug formulations
US20100260834A1 (en) * 2004-06-12 2010-10-14 Collegium Pharmaceutical, Inc. Abuse-deterrent drug formulations
US20130310413A1 (en) * 2004-06-12 2013-11-21 Collegium Pharmaceutical, Inc. Abuse-deterrent drug formulations
US20050281748A1 (en) * 2004-06-12 2005-12-22 Collegium Pharmaceutical, Inc. Abuse-deterrent drug formulations
US7771707B2 (en) * 2004-06-12 2010-08-10 Collegium Pharmaceutical, Inc. Abuse-deterrent drug formulations
US7261529B2 (en) * 2005-09-07 2007-08-28 Southwest Research Institute Apparatus for preparing biodegradable microparticle formulations containing pharmaceutically active agents

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
"castor oil, hydrogenated", European Pharmacopoeia V.5 "castor oil, hydrogenated" (p. 1197-1198) (2005) *
Buist et al., Structural Chemistry, Acta Crystallographica, Section C, C70: 220-224 (2014) *
Bush et al. (Annals of Allergy, 41: 13-17 (1978) (Abstract only) *
Chemical Abstract Society (CAS), Properties for HPMC (CAS reg. no. 9004-65-3) accessed 6/29/2013 *
Choi et al. (International Journal of Pharmaceutics, 203: 193-202 (2000) *
Lan et al. (Journal of Applied Polymer Science, 92: 2163-2168 (2004) *
Ozturk et al., Journal of Controlled Release, 14: 203-213 (1990) *
Raffin et al. (International Journal of Pharmaceutics, 324: 10-18 (2006) *
Redden et al. (International Journal of Pharmaceutics, 165: 87-96 (1998) *
Yow et al., The American Journal of Medicine, p. 613 (1954) *

Cited By (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110142943A1 (en) * 2002-07-05 2011-06-16 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opiods and other drugs
US20080199530A1 (en) * 2002-07-05 2008-08-21 Collegium Pharmaceuticals Inc. Abuse-deterrent pharmaceutical compositions of opioids and other drugs
US20090297617A1 (en) * 2002-07-05 2009-12-03 Collegium Pharmaceuticals Inc. Abuse-deterrent pharmaceutical compositions of opioids and other drugs
US9248195B2 (en) 2002-07-05 2016-02-02 Collegium Pharmaceutical, Inc. Abuse-deterrent pharmaceutical compositions of opioids and other drugs
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US20100260834A1 (en) * 2004-06-12 2010-10-14 Collegium Pharmaceutical, Inc. Abuse-deterrent drug formulations
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US20050281748A1 (en) * 2004-06-12 2005-12-22 Collegium Pharmaceutical, Inc. Abuse-deterrent drug formulations
US8758813B2 (en) 2004-06-12 2014-06-24 Collegium Pharmaceutical, Inc. Abuse-deterrent drug formulations
US8940729B1 (en) * 2007-05-22 2015-01-27 Pisgah Laboratories, Inc. Abuse deterrent and anti-dose dumping pharmaceutical salts useful for the treatment of attention deficit/hyperactivity disorder
US20110159090A1 (en) * 2007-08-13 2011-06-30 Inspirion Delivery Technologies, Llc Abuse resistant drugs, method of use and method of making
US20110159089A1 (en) * 2007-08-13 2011-06-30 Inspirion Delivery Technologies, Llc Abuse resistant drugs, method of use and method of making
US20110150971A1 (en) * 2007-08-13 2011-06-23 Inspirion Delivery Technologies, Llc Abuse resistant drugs, method of use and method of making
US20110150991A1 (en) * 2007-08-13 2011-06-23 Inspirion Delivery Technologies, Llc Abuse resistant drugs, method of use and method of making
US7955619B2 (en) 2007-08-13 2011-06-07 Inspirion Delivery Technologies, Llc Abuse resistant drugs, method of use and method of making
US20110076325A1 (en) * 2007-08-13 2011-03-31 Abuse Deterrent Pharmaceutical, Llc Abuse resistant drugs, method of use and method of making
US20110150970A1 (en) * 2007-08-13 2011-06-23 Inspirion Delivery Technologies, Llc Abuse resistant drugs, method of use and method of making
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US20100307542A1 (en) * 2009-06-05 2010-12-09 Kraft Foods Global Brands Llc Method of Reducing Surface Oil on Encapsulated Material
US20100310726A1 (en) * 2009-06-05 2010-12-09 Kraft Foods Global Brands Llc Novel Preparation of an Enteric Release System
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US8859003B2 (en) 2009-06-05 2014-10-14 Intercontinental Great Brands Llc Preparation of an enteric release system
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US9012507B2 (en) 2011-01-12 2015-04-21 Thetis Pharmaceuticals Llc Lipid-lowering antidiabetic agent
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