US20040234602A1 - Polymer release system - Google Patents

Polymer release system Download PDF

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US20040234602A1
US20040234602A1 US10490308 US49030804A US2004234602A1 US 20040234602 A1 US20040234602 A1 US 20040234602A1 US 10490308 US10490308 US 10490308 US 49030804 A US49030804 A US 49030804A US 2004234602 A1 US2004234602 A1 US 2004234602A1
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method according
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Gina Fischer
Daniel Bar-Shalom
Lillian Slot
Anne-Marie Lademann
Christine Jensen
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Egalet AS
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Egalet AS
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    • 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
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38Cellulose; Derivatives thereof
    • 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
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • 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
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0002Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0087Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0092Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules, nanotubes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2031Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2095Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/286Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2009Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic 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
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2027Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating

Abstract

A method for controlling the release of at least one therapeutically, prophylactically and/or diagnostically active substance into an aqueous medium by erosion of at least one surface of a pharmaceutical composition. The method comprises adjusting the concentration and/or the nature of the ingredients making up the matrix composition in such a manner so as to obtain an approximately zero order release of the active substance from the pharmaceutical composition when subject to an in vitro dissolution test as described herein. The composition comprises i) a matrix composition comprising a) a polymer or a mixture of polymers that may be substantially water soluble and/or crystalline, b) an active substance and, optionally, c) one or more pharmaceutically acceptable excipients, and ii) a coating. Typical polymers are PEO. The coating comprises a first cellulose derivative which is substantially insoluble in the aqueous medium, and at least one of a) a second cellulose derivative which is soluble or dispersible in water, b) a plasticizer, and c) a filler. The active ingredient may be carvedilol. Stable solid dispersions of active substances having low water solubility are also disclosed.

Description

    FIELD OF THE INVENTION
  • The present invention relates to a novel method for controlling the release of a therapeutically, prophylactically and/or diagnostically active substance from a pharmaceutical composition into an aqueous medium. The pharmaceutical composition is a coated matrix composition in which the matrix composition comprises a) polymer or a mixture of polymers, b) an active substance and, optionally, c) one or more pharmaceutically acceptable excipients. In a specific embodiment, the polymer is a substantially water soluble or crystalline polymer or a mixture of substantially water soluble and/or crystalline polymers. The coating remains intact during the release phase and may thereafter crumble and/or erode. Furthermore, the coating covers the matrix composition in such a manner that only a specific surface area of the matrix composition is subject to erosion in an aqueous medium, i.e. the surface area from which the active substance is release is kept substantial constant during the time period [0001]
  • The method is based on the finding that it is possible to control the release from such a composition by ensuring that the release predominantly takes place by erosion. In order to ensure erosion based release, a balance must be obtained between the diffusion rate of water into the matrix composition and the dissolution rate of the matrix composition. [0002]
  • The invention also relates to a pharmaceutical composition, which provides zero order release based on controlling the balance between matrix erosion rate and diffusion rate in the matrix. [0003]
  • DETAILED DESCRIPTION OF THE INVENTION
  • During the last decades many different systems for modifying the release of an active drug substance from a pharmaceutical composition have been developed. Most of them aim at obtaining a zero or a first order release rate of the active substance from the composition. Zero order release rate (i.e. constant release of the active substance with time) seems to be very difficult to obtain from a pharmaceutical composition. The present invention is based on a polymeric matrix composition, which is construed to deliver the active substance in a zero order release manner. The present invention is a further development based on the Applicant's previously described drug delivery systems, see e.g. EP-B-0 406 315, EP-B-0 493 513, EP-B-0 740 310 and WO 99/51208 the disclosure of which is hereby incorporated by reference. [0004]
  • In particular, it has surprisingly been found that it is possible to obtain zero order release from a polymeric matrix composition without any content of a water dispersible or water soluble surface active agent or a mixture of such surface active agents which has at least one domain which is compatible with the polymer in the polymer matrix composition and at least one other domain which is substantially lipophilic and which has a melting point that is lower than the polymer used in the polymeric matrix composition. The presence of such a substance (e.g. like PEG 400 monostearate or PEG 2000 monostearate) has been contemplated to function as a so-called repair medium. Such a repair medium has a substantially hydrophilic domain, which gives it affinity to the (crystalline) polymeric phase, thereby filling in domains between grains and cracks in the polymer matrix and reducing the water affinity of these domains and in the polymer matrix itself. Water diffusion in the interface between the polymer crystals is thereby substantially eliminated, thus substantially limiting diffusion of water into the composition to the surface layer of the matrix, so that erosion of the composition is predominantly effected by the dissolving action of the aqueous phase on a surface or surfaces of the composition exposed to the aqueous medium. In other words a repair medium seems to prevent the diffusion of water in the polymer matrix composition. [0005]
  • However, in certain cases, the present inventors have observed that inclusion of a water soluble surface active agent has a negative impact on the mobility and/or stability of a composition. [0006]
  • However, the present inventors have found that it is possible to obtain a zero order release from a polymer matrix composition although water may be able to diffuse into the matrix. When water diffuse into the polymer matrix composition a resulting boundary layer (or swelling layer) can be formed at the surface of the matrix composition, which is exposed to the aqueous medium. In general the diffusion of an active substance through such a boundary layer is important for the release of an active substance and, accordingly, the thickness of the boundary layer is important for the release rate. However, the present inventors have found that it is possible to eliminate or substantially eliminate the impact of the boundary layer on the release rate of the active substance from a polymer matrix composition by ensuring that the thickness of the boundary layer is relatively small and/or that the release of the active substance from a polymer matrix composition is governed by erosion of the composition and the diffusion of the active substance through the boundary layer, if any, has no or only a small impact on the overall release rate. [0007]
  • The present inventors have found that when water is allowed to diffuse into a polymer matrix composition zero order release is obtained when the release rate is governed or controlled by erosion of a constant surface area per time unit. In order to ensure that the erosion of the polymer matrix composition is the predominant release mechanism, the inventors have found that it is necessary to provide a polymer matrix composition which has properties that ensures that the diffusion rate of water into the polymer matrix composition substantially corresponds to the dissolution rate of the polymer matrix composition into the aqueous medium. Thus, by adjusting the nature and amount of constituents contained in the polymer matrix composition along this line the present inventors have obtained polymer matrix compositions, which release the active substance by a zero order release mechanism. The compositions employed are coated in such a manner that at least one surface is exposed to the aqueous medium and this surface has a substantially constant or controlled surface area during erosion. In the present context controlled surface area relates to a predetermined surface area typically predicted from the shape of the coat of the unit dosage system. It may have a simple uniform cylindrical shape or the cylindrical form can have one or more tapered ends in order to decrease (or increase) the initial release period. [0008]
  • Accordingly, the present invention provides a method for controlling the release of at least one therapeutically, prophylactically and/or diagnostically active substance into an aqueous medium by erosion of at least one surface of a pharmaceutical composition comprising [0009]
  • i) a matrix composition comprising a) a polymer or a mixture of polymers, b) an active substance and, optionally, c) one or more pharmaceutically acceptable excipients, and [0010]
  • ii) a coating having at least one opening exposing at the one surface of said matrix, the coating comprising [0011]
  • a) a first cellulose derivative which has thermoplastic properties and which is substantially insoluble in the aqueous medium in which the composition is to be used, and at least one of [0012]
  • b) a second cellulose derivative which is soluble or dispersible in water, [0013]
  • c) a plasticizer, and [0014]
  • d) a filler, [0015]
  • the method comprising adjusting the concentration and/or the nature of the ingredients making up the matrix composition in such a manner that the diffusion rate of the aqueous medium into the matrix composition corresponds to about 100%±30% such as, e.g. about 100%±25%, about 100%±20%, about 100%±15% or about 100%±10% or about 100% of the dissolution rate of the matrix composition so as to obtain a zero order release of at least about 60% w/w such as, e.g. at least about 65% w/w at least about 70% w/w, at least about 75% w/w, at least about 80% w/w, at least about 85% w/w, at least about 90% w/w, at least about 95% w/w or at least about 97 or 98% w/w of the active substance from the pharmaceutical composition when subject to an in vitro dissolution test as described herein. [0016]
  • In a specific embodiment, the polymer is a substantially water soluble or crystalline polymer or a mixture of substantially water soluble and/or crystalline polymers [0017]
  • By use of such a method it is possible already during the developmental work to test various polymer matrix compositions with respect to diffusion rate of water into the composition and to dissolution rate of the polymer matrix composition in an aqueous medium. Based on such results adjustment of e.g. the concentration and/or nature of the individual constituents in the composition may be performed until the diffusion rate balance the dissolution rate. In such a manner, a relatively simple instrument has been provided in order to ensure a zero order-release rate from the final composition. [0018]
  • In another aspect, the invention relates to a pharmaceutical composition for controlled release of at least one therapeutically, prophylactically and/or diagnostically active substance into an aqueous medium by erosion of at least one surface of the composition, the composition comprising [0019]
  • i) a matrix composition comprising a) a polymer or a mixture of polymers, b) an active substance and, optionally, c) one or more pharmaceutically acceptable excipients, and [0020]
  • ii) a coating having at least one opening exposing at the one surface of said matrix, the coating comprising [0021]
  • a) a first cellulose derivative which has thermoplastic properties and which is substantially insoluble in the aqueous medium in which the composition is to be used, [0022]
  • and at least one of [0023]
  • b) a second cellulose derivative which is soluble or dispersible in water, [0024]
  • c) a plasticizer, and [0025]
  • d) a filler, [0026]
  • and the concentration and/or the nature of the ingredients making up the matrix composition has been adjusted in such a manner that the diffusion rate of the aqueous medium into the matrix composition corresponds to about 100%±30% such as, e.g. about 100%±25%, about 100%±20%, about 100%±15% or about 100%±10% or about 100% of the dissolution rate of the matrix composition so as to obtain a zero order release of at least about 60% w/w such as, e.g. at least about 65% w/w at least about 70% w/w, at least about 75% w/w, at least about 80% w/w, at least about 85% w/w, at least about 90% w/w, at least about 95% w/w or at least about 97 or 98% w/w of the active substance from the pharmaceutical composition when subject to an in vitro dissolution test as described herein. [0027]
  • In a specific embodiment, the polymer is a substantially water soluble or crystalline polymer or a mixture of substantially water soluble and/or crystalline polymers [0028]
  • Matrix Composition
  • The pharmaceutical composition according to the invention comprises a matrix composition comprising [0029]
  • a) a polymer or a mixture of polymers, [0030]
  • b) an active substance and, optionally, [0031]
  • c) one or more pharmaceutically acceptable excipients. [0032]
  • In a specific embodiment, the polymer is a substantially water soluble or crystalline polymer or a mixture of substantially water soluble and/or crystalline polymers [0033]
  • Polymers [0034]
  • The substantially water soluble or crystalline polymer or a mixture of substantially water soluble and/or crystalline polymers (in the following denoted: “the polymer”) typically comprises a polyglycol, e.g. in the form of a homopolymer and/or a copolymer. Suitable polymers for use in a composition according to the invention are polyethylene oxides and/or block copolymers of ethylene oxide and propylene oxide. Polyethylene oxides which are suitable for use in the matrix composition are those having a molecular weight of from about 20,000 daltons, such as, e.g., from about 20,000 to about 700,000 daltons, from about 20,000 to about 600,000 daltons, from about 35,000 to about 500,000 daltons, from about 35,000 to about 400,000 daltons, from about 35,000 to about 300,000 daltons, from about 50,000 to about 300,000 daltons, such as, e.g. about 35,000 daltons, about 50,000 daltons, about 75,000 daltons, about 100,000 daltons, about 150,000 daltons, about 200,000 daltons, about 250,000 daltons, about 300,000 daltons or about 400,000 daltons. [0035]
  • A particular suitable polyethylene oxide is one, which in itself has a suitable balance between the diffusion rate of water into the polymer and a dissolution rate of the polymer. Suitable examples are polyethylene oxides having a molecular weight of about 35,000 daltons, about 50,000 daltons, about 100,000 daltons, about 200,000 daltons, about 300,000 daltons and about 400,000. [0036]
  • Typical block copolymers of ethylene oxide and propylene oxide may comprise up to about 30% w/w of the propylene oxide based block, and has a molecular weight of about 5,000 daltons, typically about 5,000 to about 30,000 daltons such as, e.g. from about 8,000 to about 15,000 daltons. [0037]
  • Polyethylene glycols (which when the molecular weight is above about 20,000 is denoted polyethylene oxides) are mixtures of condensation polymers of ethylene glycol. [0038]
  • The average molecular weight (MW) can be calculated from the following equation MW=(56,110×2)/hydroxyl number [0039]
  • Where the hydroxyl number is defined as the number indicating the amount in mg of potassium hydroxide, which is equivalent to the acetic acid, which, by acetylation, is bound by 1 g of a substance. [0040]
  • Mixtures of PEO with different average molecular weights can be used in order to obtain a PEO with a desirable average molecular weight. It is important to note that in such cases it is necessary to use the PEO, which have MW closest to the desired molecular weight. The individual amount of the two PEO necessary to obtain a PEO with a desired MW can be calculated from the hydroxyl number and the equation given above. [0041]
  • The polymer may have a melting point, which is above the body temperature of the human or animal in which the composition is to be used. Thus, the polymer(s) employed in the matrix composition will suitably have a melting point of about 20-120° C. such as, e.g. from about 30 to about 100° C. or from about 40 to about 80° C. [0042]
  • Altematively to a polymer of a polyglycol type as described above other polymers may be suitable for use in the matrix composition a). Thus, in other embodiments of the invention, the polymer is selected from one or more of the following polymers: water soluble natural polymers such as glucomannan, galactan, glucan, polygalacturonic acid, polyxylane, polygalactomannans, rhanogalacturonan, polyxyloglycan, arabinogalactan, and starch; water soluble polymers such as PVA, PVB, methocel, Eudragit L methyl ester and PHPV; biodegradable polymers such as PHA, and PLA; hydrogels, such as olyacrylic amid, and dextran; copolymers such as polylactic acid with polyglycolic acid; and others such as alginate and pectins including low methylated or methoxylated pectins. [0043]
  • Active Substances [0044]
  • A pharmaceutical composition according to the invention comprises one or more active substances, i.e. substances, which are therapeutically, prophylactically, diagnostically and/or biologically active substance. The term “active substance” as used herein broadly includes any compound, or mixture thereof, that can be delivered from the composition to produce a beneficial result. The active and beneficial agents include pesticides, herbicides, germicides, biocides, algicides, rodenticides, fungicides, insecticides, antioxidants, plant hormone promoters, plant growth inhibitors, preservatives, disinfectants, sterilization agents, catalysts, chemical reactants, fermentation agents, food supplements, nutrients, cosmetics, therapeutically active substances (drugs), vitamins, sex sterilants, fertility inhibitors, fertility promoters, air purifiers, microorganism attenuators, ecological agents and other agents that benefit the environment in which they are used. [0045]
  • In the present context the term “drug substance” includes any physiologically or pharmacologically active substance that produces a localized or systemic effect in animals, in particular in mammals, including humans and primates. Other animals include domestic household, sport or farm animals such as sheep, goats, cattle, horses and pigs, laboratory animals such as mice, rats and guinea pigs, fishes, avians, reptiles and zoo animals. The term “therapeutically, prophylactically and/or diagnostically active substance” includes the term drug substance within its meaning. [0046]
  • In the present context, the term “ecological agent” denotes a non-therapeutic substance that has a biological effect on plants or animals in the environment. An ecological agent may be a pesticide, such as an insecticides or herbicide, a fertilizer a pheromone, a plant growth hormone or the like. [0047]
  • The active substance or substances included in a pharmaceutical composition of the invention may be selected from many therapeutic categories, in particular from substances which may advantageously be administered orally, rectally, vaginally, or administered to a body cavity (e.g. the urinary bladder, kidney pelvis, the gall bladder, the uterus, a central nervous system cavity, infectious/malignant/post-operative cavities, etc.). [0048]
  • Examples of such substances are hypnotics, sedatives, tranquilizers, anti-convulsants, muscle relaxants, analgesics, anti-inflammatory, anaesthetics, anti-spasmodics, anti-ulcer-agents, anti-parasitics, anti-microbials, anti-fungal, cardiovascular agents, diuretics, cytostatics, anti-neoplastic agents, anti-viral agents, anti-glaucoma agents, anti-depressants, sympathomimetics, hypoglycaemics, diagnostic agents, anti-cough, physic energizers, anti-parkinson agents, local anesthetics, muscle contractants, anti-malarials, hormonal agents, contraceptives, anorexic, anti-arthritic, anti-diabetic, anti-hypertensive, anti-pyretic, anti-cholingergic, bronchodilator, central nervous system, inotropic, vasodilator, vasoconstrictor, decongestant, hematine, iron salts and complexes, electrolyte supplement, germicidal, parasympathetolytic, parasympathethomimetic, antiemetic, psychostimulant, vitamin, beta-blockers, H-2 blocker, beta-2 agonist, counterirritants, coagulating modifying agents, stimulants, anti-hormones, drug-antagonists, lipid-regulating agents, uricosurics, cardiac glycosides, ergots and derivatives thereof, expectorants, muscle-relaxants, anti-histamines, purgatives, contrastmaterials, radiopharmaceuticals, imaging agents, anti-allergic agents. [0049]
  • Examples of specific active substances suitable for use in a composition of the invention are: [0050]
  • Carvedilol, morphine, diclofenac, nifedipine, calcitonin, rivastigmine, methylphenidate, fluoroxetine, rosiglitazone, prednison, prednisolone, codeine, ethylmorphine, dextromethorphan, noscapine, pentoxiverine, acetylcysteine, bromhexine, epinephrine, isoprenaline, orciprenaline, ephedrine, fenoterol, rimiterol, ipratropium, cholinetheophyllinate, proxiphylline, bechlomethasone, budesonide, deslanoside, digoxine, digitoxin, disopyramide, proscillaridin, chinidine, procainamide, mexiletin, flecainide, alprenolol, proproanolol, nadolol, pindolol, oxprenolol, labetalol, timolol, atenolol, pentaeritrityltetranitrate, isosorbiddinitrate, isosorbidmononitrate, niphedipin, phenylamine, verapamil, diltiazem, cyclandelar, nicotinylalcholhol, inositolnicotinate, alprostatdil, etilephrine, prenalterol, dobutamine, dopamine, dihydroergotamine, guanetidine, betanidine, methyldopa, reserpine, guanfacine, trimethaphan, hydralazine, dihydralazine, prazosine, diazoxid, captopril, nifedipine, enalapril, nitroprusside, bendroflumethiazide, hydrochlorthiazide, metychlothiazide, polythiazide, chlorthalidon, cinetazon, clopamide, mefruside, metholazone, bumetanide, ethacrynacide, spironolactone, amiloride, chlofibrate, nicotinic acid, nicheritrol, brompheniramine, cinnarizine, dexchlorpheniramine, clemastine, antazoline, cyproheptadine, proethazine, cimetidine, ranitidine, sucralfat, papaverine, moxaverine, atropin, butylscopolamin, emepron, glucopyrron, hyoscyamine, mepensolar, methyiscopolamine, oxiphencyclimine, probanteline, tero dilin, sennaglycosides, sagradaextract, dantron, bisachodyl, sodiumpicosulfat, etulos, diphenolxylate, loperamide, salazosulfapyridine, pyrvin, mebendazol, dimeticon, ferrofumarate, ferrosuccinate, ferritetrasemisodium, cyanochobalamine, folid acid heparin, heparin co-factor, diculmarole, warfarin, streptokinase, urokinase, factor Vil, factor IX, vitamin K, thiopeta, busulfan, chlorambucil, cyclophosphamid, melfalan, carmustin, mercatopurin, thioguanin, azathioprin, cytarabin, vinblastin, vinchristin, vindesin, procarbazine, dacarbazine, lomustin, estramustin, teniposide, etoposide, cisplatin, amsachrin, aminogluthetimid, phosphestrol, medroxiprogresterone, hydroxiprogesterone, megesterol, noretisteron, tamoxiphen, ciclosporin, sulfosomidine, bensylpenicillin, phenoxymethylpenicillin, dicloxacillin, cloxacillin, flucoxacillin, ampicillin, amoxicillin, pivampicillin, bacampicillin, piperacillin, mezlocillin, mecillinam, pivmecillinam, cephalotin, cephalexin, cephradin, cephadroxil, cephaclor, cefuroxim, cefotaxim, ceftazidim, cefoxitin, aztreonam, imipenem, cilastatin, tetracycline, lymecycline, demeclocycline, metacycline, oxitetracycline, doxycycline, chloramphenicol, spiramycin, fusidic acid, lincomycin, clindamycin, spectinomycin, rifampicin, amphotericin B, griseofulvin, nystatin, vancomycin, metronidazole, tinidazole, trimethoprim, norfloxacin, salazosulfapyridin, aminosalyl, isoniazid, etambutol, nitrofurantoin, nalidixic acid, metanamine, chloroquin, hydroxichloroquin, tinidazol, ketokonazol, acyclovir, interferon idoxuridin, retinal, tiamin, dexpantenol, pyridoxin, folic acid, ascorbic acid, tokoferol, phytominadion, phenfluramin, corticotropin, tetracosactid, tyrotropin, somatotoprin, somatrem, vasopressin, lypressin, desmopressin, oxytocin, chloriongonadotropin, cortison, hydrocortisone, fluodrocortison, prednison, prednisolon, fluoximesteron, mesterolon, nandrolon, stanozolol, oximetolon, cyproteron, levotyroxin, liotyronin, propylthiouracil, carbimazol, tiamazol, dihydrotachysterol, alfacalcidol, calcitirol, insulin, tolbutamid, chlorpropamid, tolazamid, glipizid, glibenclamid, phenobarbital, methyprylon, pyrityldion, meprobamat, chlordiazepoxid, diazepam, nitrazepam, oxazepam, dikaliumclorazepat, lorazepam, flunitrazepam, alprazolam, midazolam, hydroxizin, chlometiazol, propionmazine, alimemazine, chlorpromazine, levomepromazine, acetophenazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, dixyrazine, thiodirazine, periciazin, chloprothixene, zuclopentizol, flupentizol, thithixen, haloperidol, trimipramin, opipramol, chlomipramin, desipramin, lofepramin, amitriptylin, nortriptylin, protriptylin, maptrotilin, caffeine, cinnarizine, cydizine, dimenhydinate, meclozine, prometazine, thiethylperazine, metodopramide, scopolamine, phenobarbital, phenytoine, ethosuximide, primidone, carbamazepine, chlonazepam, orphenadrine, atropine, bensatropine, biperiden, metixene, procyilidine, levodopa, bromocriptin, amantadine, ambenon, pyridostigmine, synstigmine, disulfiram, morphine, codeine, pentazocine, buprenorphine, pethidine, phenoperidine, phentanyl, methadone, piritramide, dextropropoxyphene, ketobemidone, acetylsalicylic acid, phenazone, phenylbutazone, azapropazone, piroxicam, ergotamine, dihydroergotamine, cyproheptadine, pizitifen, flumedroxon, allopurinol, probenecid, sodiummaurothiomalate auronofin, penicillamine, estradiol, estradiolvalerianate, estriol, ethinylestradiol, dihydrogesteron, lynestrenol, medroxiprogresterone, noretisterone, cydophenile, clomiphene, levonorgestrel, mestranol, ornidazol, tinidazol, ekonazol, chlotrimazol, natamycine, miconazole, sulbentin, methylergotamine, dinoprost, dinoproston, gemeprost, bromocriptine, phenylpropanolamine; sodiumchromoglicate, azetasolamide, dichlophenamide, betacarotene, naloxone, calciumfolinate, in particular clonidine, thephylline, dipyradamol, hydrochlothiazade, scopolamine, indomethacine, furosemide, potassium chloride, morphine, ibuprofen, salbutamol, terbutalin, sulfonylurea, mefformin, insulin, calcitonin, glucagons-like peptide-1, or combinations thereof. [0051]
  • The active substance can be in various forms, such as uncharged molecules, molecular complexes, crystalline forms, amorphous form, polymorphous form, solvates, anhydrates, pharmacologically acceptable salts such as a hydrochloride, hydrobromide, sulfate, laurylate, palmitate, phosphate, nitrite, nitrate, borate, acetate, maleate, tartrate, oleate, and salicylate. For acidic active substance, salts of metals, amines amino acids or organic cations, quatemary ammoniums, can be used. Derivatives of active substances such as esters, ethers and amides which have solubility characteristics suitable for use herein can be used alone or mixed with other drugs. After release of the derivative from the drug delivery system it may be converted by enzymes, hydrolysed by body pH or other metabolic processes to the parent drug or to another biologically active form. [0052]
  • The active substance may be dissolved and/or dispersed in the polymer matrix. In those cases, where the active substance is dispersed in the matrix, it is present in any of its crystalline, polymorphous or amorphous forms or mixtures thereof. [0053]
  • In specific embodiments, the active substance may at least partially be present in solid form in the dispersion, i.e. some of the active substance may be dissolved in the polymer (such as, e.g., polyethylene oxide)provided that at least a part is still present on solid form. [0054]
  • In the pharmaceutical technology (and in the present context), the term “solid dispersion” also embraces semi-solid dispersions. By the term is understood the finely dispersed distribution of one or more solids, e.g. an active substance like morphine, in an inert solid or semi-solid carrier. The active substance may be present in molecular dispersed form, i.e. as a solid solution, in fine crystalline dispersed form, in a glassy amorphous phase or dispersed as a fine amorphous powder. Eutectic mixtures, i.e. crystalline structures of active substances and carriers are also encompassed in the definition of “solid dispersions”. Normally, the mean particle size is used to dassify dispersed system. A colloidal dispersion is when the dispersed phase has a particle size between about 1 and about 1000 nm and a coarsely dispersion has a mean particle size of at least about 1000 nm and a molecular dispersion has a particle size below about 1 nm. Combinations between the various states are very likely and the most dominating character can be determined by X-ray diffraction spectra or differential thermoanalysis. [0055]
  • In specific aspects of the present invention some of the active substance may be present in a molecular dispersion such as, e.g., in the form of a solid or semi-solid solution. [0056]
  • In a specific aspect of the invention, a composition comprises an active substance that at least partially is present in amorphous form with a mean particle size of at least about 0.01 μm such as, e.g., from about 0.01 μm to about 500 μm, from about 0.05 μm to about 500 μm, from about 0.1 μm to about 500 μm, from about 0.5 μm to about 500 μm, about 1 μm to about 500 μm, typically from about 0.5 μm to about 300 μm, more typically from about 1 μm to about 200 μm, especially from about 1 μm to about 100 μm. [0057]
  • A pharmaceutical composition of the invention may in addition be suitable for the delivery of polypeptides, for example hormones, enzymes such as lipases, proteases, carbohydrates, amylases, lactoferrin, lactoperoxidases, lysozymes, nanoparticles, etc., and antibodies. The composition may also be employed for the delivery of microorganisms, either living, attenuated or dead, for example bacteria, e.g. gastrointestinal bacteria such as streptococci, e.g. [0058] S. faecium, Bacillus spp. such as B. subtilis and B. licheniformis, lactobacteria, Aspergillus spp., bifidogenic factors, or viruses such as indigenous vira, enterovira, bacteriophages, e.g. as vaccines, and fungi such as baker's yeast, Saccharomyces cerevisiae and fungi imperfect. A pharmaceutical composition of the invention may also be used for the delivery of active agents in specialized carriers such as liposomes, cydodextrines, nanoparticles, micelles and fats.
  • A further use for which a composition of the invention is suited is the delivery of active substances to animals. Examples of such active substances for veterinary use are antiparasitics, corticosteroids, antibiotics, antiimflammatory agents, growth promoters and permittants, antifungals and antihelmintics. [0059]
  • A pharmaceutical composition of the invention is designed to release the active substance in a controlled manner such as by a zero order release mechanism. Accordingly, the composition is especially suitable for a controlled release of an active substance. In the present context the tern “controlled release” is used to designate a release a desired rate during a predetermined release period. Terms like “modified”, “delayed”, “sustained”, “prolonged”, “extended” etc. release are in the present context synonyms to the term “controlled release”. [0060]
  • In an embodiment of the invention, the active substance is a pharmaceutically active powder. The powder typically has a particle size of from about 0.1 μm to about 500 μm, typically from about 0.5 μm to about 300 μm, more typically from about 1 μm to about 200 μm, especially from about 5 μm to about 100 μm. [0061]
  • A pharmaceutical composition according to the invention is—due to the possibility of designing the composition in such a manner that i) a zero order release is obtained and ii) a controlled release during a predetermined time period is obtained—suitable for use for water soluble as well as slightly soluble or insoluble active substances. However, it is contemplated that a composition is also suitable for use when the at least one therapeutically, prophylactically and/or diagnostically active substance has a solubility of at the most about 3 mg/ml such as, e.g. at the most about 1 mg/ml, at the most about 0.1 mg/ml, at the most about 0.05 mg/ml such as, e.g. at the most about 0.001 mg/ml in water at ambient temperature and/or a prolonged release of the active substance is desired in order to obtain i) a prolonged residence time within the body after administration, ii) a reduced peak plasma concentration in order to avoid peak related side effects, iii) reduced frequency of administration in order e.g. to obtain a better patient compliance, etc. [0062]
  • To this end it seems that substantially hydrophobic active substances tend to result in a decrease in the erosion rate of the matrix composition. Substantially hydrophilic or water-soluble active substances seem to have the opposite effect, i.e. they tend to result in a faster erosion of the matrix. [0063]
  • The at least one therapeutically, prophylactically and/or diagnostically active substance will suitably be present in an amount of up to about 70%, typically up to about 60% or up to about 50%, by weight of the matrix composition. An active substance content of about 60% is contemplated to be the maximum content, which still allows for a sufficient content of the polymer and, when relevant, the pharmaceutically acceptable excipient in the composition. The active substance may, on the other hand, be present in the composition in much smaller amounts, depending on the nature and potency of the active substance in question. [0064]
  • Pharmaceutically Acceptable Excipients
  • Difussion and Dissolution Adjusters [0065]
  • As already discussed above, it is important that a composition according to the invention releases at least most of the active substance by a zero order release mechanism. One aspect of research about controlled-release delivery systems involves designing a system, which produces steady-state plasma drug levels. The release of active substance from such systems is also referred to as zero-order drug release kinetics. To meet this objective, numerous design variations have been attempted, and their major controlling mechanisms include diffusion/dissolution. [0066]
  • The release rate of a dissolved or dispersed active substance from a polymeric matrix composition introduced in a specific environment, strongly depends on the nature of the diffusion and sorption processes involving the polymer/environment system and the polymer/active substance system. [0067]
  • The active substance release data may be analysed using Eq. 1 and Eq. 2 where M[0068] t/M is the fractional drug release, t is the release time, k is a kinetic constant characteristics of the drug/polymer system, Cd is the tracer loading concentration and n is an exponent which characterisers the mechanism of release of the tracers. M t M = k · t n ( Eq . 1 ) M t A · t = n · C d · k · t n - 1 ( Eq . 2 )
    Figure US20040234602A1-20041125-M00001
  • Clearly, a desirable mechanism for many applications is that which leads to n=1. This characterizes zero-order behaviour. The table below summarizes the general dependence of n on the diffusion mechanism. [0069]
    time dependence of
    Diffusinal release Overall Solute solute release
    Exponent (n) diffusion mechanism rate (dMt/dt)
    0.5 t−0.5 Fickian diffusion
    0.5 < n < 1.0 Anomalous (non Fickian) tn−1
    diffusion
    1.0 Case II Transport Zero-order (time
    independent) release
    n > 1.0 Super Case II transport tn−1
  • In the case of PEO matrices, the solubility of the polymer can alter the characteristics of the penetrated layer, leading to different behaviours in systems presenting different dissolution features. To control the release of the active agent, there should be a balance between diffusion of the active agent and solubilization of the polymer matrix. The diffusivity of the drug through the matrix, the swelling of the polymer, and its solubilization rate may be biased by changing the molecular weight of the polymer or blending polymer fractions with different molecular weights. [0070]
  • In the following is given examples on suitable excipients that may be added in order to adjust the balance between diffusion and dissolution so as to obtain zero order release rate. The pharmaceutically acceptable excipients suitable for establishing the above-mentioned desired balance, are in the present context also denoted DDAs (Diffusion and Dissolution Adjusters). [0071]
  • Thus, the matrix composition may also comprise one or more pharmaceutically acceptable excipients (DDAs). The function of the at least one pharmaceutically acceptable excipient is to establish the desired balance between on the one hand the diffusion rate of water into the matrix composition and on the other hand the dissolution rate of the matrix composition in an aqueous medium such as, e.g., water. As explained above, a zero order release rate is obtained if that the diffusion rate of the aqueous medium into the matrix composition corresponds to about 100%±30% such as, e.g. about 100%±25%, about 100%±20%, about 100%±15% or about 100%±10% or about 100% of the dissolution rate of the matrix composition. By the term “zero order release” is meant that the release takes place so as to obtain a zero order release of at least about 60% w/w such as, e.g. at least about 65% w/w, at least about 70% w/w, at least about 75% w/w, at least about 80% w/w, at least about 85% w/w, at least about 90% w/w, at least about 95% w/w or at least about 97 or 98% w/w of the active substance from the pharmaceutical composition when subject to an in vitro dissolution test as described herein. [0072]
  • In general a test for diffusion of water into the matrix composition and a test for the dissolution of the matrix composition in an aqueous medium are performed using a matrix composition having the desired shape and being prepared analogous to the matrix composition in the final composition. This means that when the final composition is prepared by e.g. injection moulding then the matrix composition to be tested with respect to diffusion and dissolution behaviour is also prepared by injection moulding. [0073]
  • There may be cases where it is not necessary to adjust the matrix composition by adding a pharmaceutically acceptable excipient. Such cases are e.g. when the polymer employed in itself has the desired properties with respect to diffusion of water and dissolution of polymer. [0074]
  • In the experimental section herein examples are given showing that it has been possible to obtain the desired zero order release when a pharmaceutically acceptable excipients has been incorporated into the matrix composition. [0075]
  • Without being bound by any theory it is contemplated that in those cases where a slightly or insoluble active substance is employed then it may be necessary to circumvent the effect from the active substance (with respect to diffusion and/or dissolution of the matrix composition) by adding a very soluble pharmaceutically acceptable excipient. Accordingly, it is contemplated that when the at least one therapeutically, prophylactically and/or diagnostically active substance has a solubility of at the most about 3 mg/ml such as, e.g. at the most about 1 mg/ml, at the most about 0.1 mg/ml, at the most about 0.05 mg/ml such as, e.g. at the most about 0.001 mg/ml in water at ambient temperature then the pharmaceutically acceptable excipient, if present, typically has a solubility of at least 1 mg/ml such as, e.g. at least about 3 mg/ml, at least about 5 mg/ml, at least about 10 mg/ml, at least about 25 mg/ml or at least about 50 mg/ml in water at ambient temperature. [0076]
  • Vice versa, it is contemplated that in those cases where a very soluble active substance is employed then it may be necessary to circumvent the effect from the active substance (with respect to diffusion and/or dissolution of the matrix composition) by adding a slightly or insoluble pharmaceutically acceptable excipient. Accordingly, it is contemplated that when the at least one therapeutically, prophylactically and/or diagnostically active substance has a solubility of at least about 3 mg/ml such as, e.g., at least about 5 mg/ml, at least about 10 mg/ml, at least about 20 mg/ml, at least about 50 mg/ml or at least about 100 mg/ml in water at ambient temperature, then the pharmaceutically acceptable excipients typically has a solubility of at the most about 3 mg/ml such as, e.g., at the most about 1 mg/ml, at the most about 0.1 mg/ml, at the most about 0.05 mg/ml such as, e.g. at the most about 0.001 mg/ml in water at ambient temperature. [0077]
  • There may situations, however, where it also may be suitable to incorporate water-soluble substances (and/or water-insoluble substances) as DDA's irrespective of the solubility of the active substance. [0078]
  • Furthermore, in those cases where the active substance employed has a low solubility in acidic medium, it is contemplated that an inorganic or organic base or substance having an alkaline reaction in aqueous environment is employed as a DDA. [0079]
  • Analogous, in those cases where the active substance employed has a low solubility in alkaline medium, it is contemplated that an inorganic or organic acid or substance having an acidic reaction in aqueous environment is employed as a DDA. [0080]
  • However, other factors than the solubility in water play a role in the erosion process and therefore there may be situations where such factors dominate the solubility factor and then the above-given combinations may be of minor importance. [0081]
  • Suitable pharmaceutically acceptable excipients (DDAs) may be selected from the group consisting of inorganic acids, inorganic bases, inorganic salts, organic acids or bases and pharmaceutically acceptable salts thereof, saccharides, oligosaccharides, polysaccharides, and cellulose and cellulose derivatives. [0082]
  • Altematively or additionally, a suitable pharmaceutically acceptable excipient is a mono-, di-, oligo, polycarboxylic acid or amino acids such as, e.g. acetic acid, succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, sorbic acid etc., aspartic acid, glutamic acid etc. [0083]
  • Examples of suitable organic acids include acetic acid/ethanoic acid, adipic acid, angelic acid, ascorbic acid/vitamin C, carbamic acid, cinnamic acid, citramalic acid, formic acid, fumaric acid, gallic acid, gentisic acid, glutaconic acid, glutaric acid, glyceric acid, glycolic acid, glyoxylic acid, lactic acid, levulinic acid, malonic acid, mandelic acid, oxalic acid, oxamic acid, pimelic acid, and pyruvic acid. [0084]
  • Examples of suitable inorganic acids include pyrophosphoric, glycerophosphoric, phosphoric such as ortho and meta phosphoric, boric acid, hydrochloric acid, and sulfuric acid. [0085]
  • Examples of suitable inorganic compounds include aluminium. [0086]
  • Examples of organic bases are p-nitrophenol, succinimide, benzenesulfonamide, 2-hydroxy-2cyclohexenone, imidazole, pyrrole, diethanolamine, ethyleneamine,tris (hydroxymethyl) aminomethane, hydroxylamine and derivates of amines, sodium citrate, aniline, hydrazine. [0087]
  • Examples of inorganic bases include aluminium oxide such as, e.g., aluminium oxide trihydrate, alumina, sodium hydroxide, potassium hydroxide, calcium carbonate, ammonium carbonate, ammnonium hydroxide, KOH and the like. [0088]
  • Suitable pharmaceutically acceptable salts of an organic acid is e.g. an alkali metal salt or an alkaline earth metal salt such as, e.g. sodium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate etc., potassium phosphate, potassium dihydrogenphosphate, potassium hydrogenphosphate etc., calcium phosphate, dicalcium phosphate etc., sodium sulfate, potassium sulfate, calcium sulfate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, calcium carbonate, magnesium carbonate etc., sodium acetate, potassium acetate, calcium acetate, sodium succinate, potassium succinate, calcium succinate, sodium citrate, potassium citrate, calcium citrate, sodium tartrate, potassium tartrate, calcium tartrate etc. [0089]
  • A suitable inorganic salt for use in a matrix composition of the invention is sodium chloride, potassium chloride, calcium chloride, magnesium chloride etc. [0090]
  • Examples of such excipients are glucose and other monosaccharides, ribose, arabinose, xylose, lyxose, allose, altrose, inosito, glucose, sorbitol, mannose, gulose, idose, galactose, talose, mannitol, fructose, lactose, sucrose, and other disaccharides, dextrin, dextran or other polysaccharides, amylose, xylan, cellulose and cellulose derivatives such as, e.g. microcrystalline cellulose, methyl cellulose, ethyl cellulose, ethylhydroxyethyl cellulose, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxymethylpropyl cellulose, hydroxypropylmethyl cellulose, amylopectin, pectin, starch, sodium starch etc., kaolin, bentonit, acacia, alginic acid, sodium alginate, calcium alginate, gelatin, dextrose, molasses, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husk, veegum, glycollate, magnesium stearate, calcium stearate, stearic acid, talc, titanium dioxide, silicium dioxide, clays, croscarmellose, gums, agar etc. [0091]
  • Other Ingredients in the Matrix Composition [0092]
  • The matrix composition may also contain other excipients as well, e.g. in order to improve the technical properties of the matrix composition so that it may be easier to produce or in order to improve the stability of the composition. [0093]
  • A suitable pharmaceutically acceptable excipient for use in a matrix composition of the invention may be selected from the group consisting of fillers, diluents, disintegrants, glidants, pH-adjusting agents, viscosity adjusting agents, solubility increasing or decreasing agents, osmotically active agents and solvents. [0094]
  • Suitable excipients include conventional tablet or capsule excipients. These excipients may be, for example, diluents such as dicalcium phosphate, calcium sulfate, lactose or sucrose or other disaccharides, cellulose, cellulose derivatives, kaolin, mannitol, dry starch, glucose or other monosaccharides, dextrin or other polysaccharides, sorbitol, inositol or mixtures thereof; binders such as acacia, sodium alginate, starch, gelatin, saccharides (including glucose, sucrose, dextrose and lactose), molasses, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husk, carboxymethylcellulose, methylcellulose, veegum, larch arabolactan, polyethylene glycols, ethylcellulose, water, alcohols, waxes, polyvinylpyrrolidone such as, e.g., PVP K90 (may be used to improve mixing of the polymer with the other ingredients) or mixtures thereof; lubricants such as talc, magnesium stearate, calcium stearate, staeric acid, hydrogenated vegetable oils, sodium benzoate, sodium chloride, leucine, carbowax 4000, magnesium lauryl sulfate, colloidal silicon dioxide and mixtures thereof, disintegrants such as starches, clays, cellulose derivatives including crosscarmellose, gums, aligns, various combinations of hydrogencarbonates with weak acids (e.g. sodium hydrogencarbonateitartaric acid or citric acid) crosprovidone, sodium starch glycolate, agar, cation exchange resins, citrus pulp, veegum HV, bentonite. or mixtures thereof; volatile solvents such as alcohols, including aqueous alcohols, petroleum benzine, acetone, ether or mixtures thereof; plasticizers such as sorbitol and glycerine; and others such as cocoa butter, polyethylene glycols, e.g. with a molecular weight of about 1,000-500,000 daltons, typically about 1,000-100,000 daltons, more typically 1,000-50,000 daltons, especially about 1,000-10,000 daltons, in particular about 1,500-5,000 daltons, and mixtures thereof, hydrogenated vegetable oils, glycerinated gelatin or mixtures thereof. [0095]
  • The matrix composition may in addition include a cellulose derivative, e.g. a cellulose derivative selected from the group consisting of methylcellulose, carboxymethylcellulose and salts thereof, microcrystalline cellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose and hydroxymethylpropylcellulose. Of these cellulose derivatives, hydroxypropylmethylcellulose and methylcellulose are preferred for incorporation in the matrix composition. [0096]
  • Furthermore, the matrix composition may comprise one or more agents selected from the group consisting of sweetening agents, flavouring agents and colouring agents, in order to provide an elegant and palatable preparation. Examples of colouring agents are water soluble FD&C dyes and mixtures thereof with corresponding lakes and direct compression sugars such as Di-Pac from Amstar. In addition, coloured dye migration inhibitors such as tragacanth, acacia or attapulgite talc may be added. Specific examples include calcium carbonate, chromium-cobalt-aluminium oxide, ferric ferrocyanide, ferric oxide, iron ammonium citrate, iron (III) oxide hydrated, iron oxides, magnesium carbonate, titanium dioxide. [0097]
  • Examples of suitable fillers are also dextrin, sucralfate, calcium hydroxyl-apatite, calcium phosphates and fatty acid salts such as magnesium stearate. [0098]
  • The filler may be added in an amount so that the combination of the filler and the active substance comprises up to about 60%, typically up to about 50%, by weight of the first composition. [0099]
  • In order to soften the carrier system, a plasticziser may be incorporated in the composition. A suitable plasticizer is selected from the group consisting of phosphate esters; phthalate esters; amides; mineral oils; fatty adds and esters; fatty alcohols, vegetable oils and hydrogenated vegetable oils including acetylated hydrogenated cottonseed glyceride and acetylated hydrogenated soybean oil glycerides; acetyl tributyl citrate, acetyl triethyl citrate, Castor oil, diacetylated monoglycerides, dipropylene glycol salicylate glycerin, glyceryl cocoate, mono- and di-acetylated monoglycerides, nitrobenzene, carbon disulfide, β-naphtyl salicylate, phthalyl glycolate, diocyl phthalate; sorbitol, sorbitol glyceryl tricitrate; sucrose octaacetate; a-tocopheryl polyethylene glycol succinate, phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters; fatty alcohols; and vegetable oils, fatty alcohols including cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol and myristyl alcohol; methyl abietate, acetyl tributyl citrate, acetyl triethyl citrate, diisooctyl adipate, amyl oleate, butyl ricinoleate, benzyl benzoate, butyl and glycol esters of fatty acids, butyl diglycol carbonate, butyl oleate, butyl stearate, di(beta-methoxyethyl) adipate, dibutyl sebacate, dibutyl tartrate, diisobutyl adipate, dihexyl adipate, triethylene glycol di(beta-ethyl butyrate), polyethylene glycol di(2-ethyl hexoate), diethylene glycol monolaurate, monomeric polyethylene ester, hydrogenated methyl ester of rosin, methoxyethyl oleate, butoxyethyl stearate, butyl phthalyl butyl glycolate, glycerol tributyrate, triethylene glycol dipelargonate, beta-(p-tert-amyl phenoxy)ethanol, beta(p-tert-butytphenoxy)ethanol, beta-(p-teft-butytphenoxyethyl)acetate, bis(beta-p-tert-buthylphenoxydiethyl) ether, camphor, Cumar W-1, Cumar MH-1, Cumar V-1, diamyl phthalate, (diamylphenoxy) ethanol, diphenyl oxide, technical hydroabietyl alcohol, beckolin, benzene hexahydrochlonde, Clorafin 40, Piccolastic A-5, Piccalastic A-25, Flexol B400, Glycerol alfa-methyl alfa-phenyl ether, chlorinated naphthalene, HB-40, monoamylphthalate. Nevillac 10 o-nitrodiphenyl and Paracril 26. [0100]
  • Preferred anti-oxidative agents include TPGS due to surfactant properties, BHA, BHT, t-butyl hydroquinone, calcium ascorbate, gallic acid, hydroquinone, maltol, octyl gallate, sodium bisulfite, sodium metabisulfite, tocopherol and derivates thereof, citric acid, tartaric acid, and ascorbic acid. Other antioxidants include trivalent phosphorous like e.g phosphite, phenolic antioxidants, hydroxylamines, lactones such as substituted benzofuranones. Hindered phenols, thiosynergists and/or hindered amines are useful for the long-term stability for polymers, whereas the following antioxidants are suitable for use also in situation where the active substance is subject to oxidation: acids (ascorbic acid, erythorbic acid, etidronic acid, gallic acid, hypophosphorous acid, nordihydroguairetic acid, propionic acid etc.), phenols (e.g. BHA, BHT, t-butyl hydroquinone, dodecyl gallate, octyl gallate, 1,3,5-trihydroxybenzene), organic and inorganic salts (calcium ascorbate, sodium ascorbate, sodium bisulphite, sodium metabisulfite, sodium sulfite, potassium bisulphite, potassium metabisulphite), esteres (calcium ascorbate, dilauryl thiodipropionate, dimyristyl thiodipropionate, distearyl thiodipropionate), pyranon (maltol), and vitamin E (tocopherol, D-α-tocopherol, DL-α-tocopherol, tocopheryl acetate, d-α-tocopheryl acetate, dl-α-tocopheryl acetate. However, other anti-oxidative agents known in the art may be used according to the present invention. [0101]
  • pH Dependant Release
  • In some situations it may be convenient that the composition releases the active substance in a pH dependant manner. As described in e.g. WO 99/51208 a pH dependant release can be obtained by inclusion of a so-called release rate modifier. The release rate modifier is preferably selected from materials conventionally used in the pharmaceutical industry to produce enteric coatings. A number of different types of compounds suitable for use as enteric coatings are known in the art; see e.g. [0102] Remington's Pharmmaceutical Sciences, 18th Edition, 1990. Release modifiers may in particular be selected from one of three general classes, namely cellulose derivatives, methacrylic acid polymers and modified gelatine compounds. Preferred release modifiers include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate, as well as methacrylic acid copolyrmers. Modified gelatine compounds include gelatine treated with e.g. formaldehyde or glutaraldehyde.
  • Examples of commercially available polymers suitable as release modifiers are EUDRAGIT® L and EUDRAGIT® S, available from Röhm GmbH, Germany, and enteric coating agents available from Shin-Etsu Chemical Co., Japan. The release modifier will typically be present in the composition in an amount of about 0.1-10%, based on the weight of the matrix, preferably about 0.5-4%, e.g. about 1-3%, such as about 1.5-2.0%. If desired, a suitable mixture of more than one release modifier may be used in order to obtain a desired release profile in any given composition. [0103]
  • The release modifier enables a difference in release of the active substance/erosion of the matrix dependant on pH. [0104]
  • Shape
  • The geometric form of the composition is important for the obtainment of the above-mentioned controlled zero order. Thus, in a preferred version of the invention, the pharmaceutical composition of the invention has a geometric shape, which enables a substantially constant surface area to become exposed during erosion of the matrix. [0105]
  • In order to achieve a higher plasma concentration 510 hours after administration it is contemplated that a shape is suitable that exposes an increasing surface area during the first 1-3 hours and then exposes a constant surface area. Examples of such shapes are given in FIG. 1B. [0106]
  • Specific examples of compositions with different shapes and sizes are: [0107]
    Length Diameter Vol
    Batch [mm] [mm] [mm3]
    01-0034-042 7.5 5.05 150
    01-0035-042 6.0 5.64 150
    01-0043-042 9.0 4.6 150
  • The following table describes formulations having a cylindrical form and oval openings in both ends [0108]
    Length Vol
    Batch [mm] [mm3] Longest/shortest diameter [mm]
    01-0075-042 6.0 150 8.74 3.64
    01-0076-042 7.5 150 7.82 3.21
  • The coated compositions obtained were open at two opposite ends. The area for an open end is calculates as the volume/length of the cylindrical formulations. [0109]
  • The different strengths of the pharmaceutical composition are then prepared based on a desired specific formulation, which has shown the desired release duration. The release period is then secured by keeping the same length in each strength formulation. Simply by decreasing or increasing the exposed area with the same fold as the desired increase or decrease, respectively, in the desired strength compared to the strength of the basis formulation different. In other words, the ratio between the amount of active substance and surface area of the original basis formulation is constant in each individual strength formulation. [0110]
  • However, minor corrections in the calculated area for the additional strength formulations may be necessary in case the erosion rate (length of the eroded matrixitime unit) is dependent on the size of the area indicating non-linearity. However such non-linearity may be tested by measuring the erosion rate individually with two different exposed areas of the same matrix composition. In case the formulations show different dissolution rates, the ratio between the areas and the rates may be calculated. [0111]
  • For instance, the present according to the present invention, the results from Examples 1 to 4 demonstrates that [0112]
    Round 7.5 mm 5.05 mm diameter 8 hours 0.94 mm/h
    Round 9 mm 4.6 mm diameter 9 hours 1.00 mm/h
    Oval 6 mm 8.74/3.64 mm diam. 5.33 hours 1.12 mm/h
    Oval 7.5 mm 7.82/3.21 mm diam. 6.49 hours 1.15 mm/h
  • Accordingly the release rate of the present matrix formulation is increased with decreased area. The ratio between the two rates is 0.94:1 and not 1:1 The ratio between the areas is 1.1:1 for the round formulations. [0113]
  • These factors can be used to adjust the area and/or the length of the specific desired new strength when exactly the same matrix is preferred in different pharmaceutical strengths. [0114]
  • Such increase in dissolution rate with decreasing exposed area may be an advantage as it is expected that smaller areas in vivo may result in relative slower release. [0115]
  • In vitro, it is believed that when the area is decreased, the physical factors of the dissolution parameters, (paddle rotation speed) might have a decreased erosion effect on the surface area bearing in mind the present shape of the formulation is a tube where the coat or wall of the tube remains intact during the erosion process. [0116]
  • The observation from the results mentioned above may relate to the low solubility of carvedilol at high pH values. With smaller diameters, more shell wall is present per mm[0117] 2 surface to protect de formulation from diffusion of the buffer solution.
  • In a still further embodiment, a formulation as disclosed in Batch 084 (12% load, 6 mm oval, 150 mm[0118] 3 corresponding to 25 mg) having a erosion time of 5.6 hours and a length of 6 mm resulting in a dissolution rate of approximately 1 mm/h (1.06 mm/h calculated) may be used for the preparation of dosages of 12.5 mg and 6,25 mg simply decreasing the area of batch 084 by a factor 2 and 4 respectively. Furthermore, a 50 mg may be prepared by increasing the area with a factor 2 and in case the size of the formulation is being bigger than desired, the load may be increased. Consequently, if the load is increased to 18% from 12%, the area is increased 1.5 in order to provide a 50 mg formulation.
  • In a further embodiment of the invention the design of a formulation may be made based on the dissolution of a different formulation. If the desired rate is corresponding to the 6 mm oval formulation as used in the clinical study disclosed herein having a dissolution rate of 1 mm/h and the basis formulation has a dissolution rate of 1.08. The calculated length would be 5.55 mm and the exposed area may be adjusted accordingly to have the desired content. [0119]
  • Accordingly, preferred designs of a formulation wherein the dissolution rate is 1.08 in a oval 6 mm shape with a surface area of 25 mm[0120] 2 and a load of Carvedilol and wherein the desired dissolution duration is 5.5 hours is a formulation having a length of 5.5 mm
  • The surface areas may be adjusted to the desired content of active substance as illustrated above [0121]
  • Other designs according to the present invention for a 25 mg Carvedilol having a volume of 159 mm[0122] 3 includes:
  • Surface area (one end) of 27.17 mm[0123] 2 and 5.85 mm length
  • Surface area (one end) of 25.00 mm[0124] 2 and 6.40 mm length
  • Designs for a 50 mg Carvedilol having a volume of 318 mm[0125] 3 includes:
  • Surface area (one end) of 45 mm[0126] 2 and 7 mm length
  • Surface area (one end) of 50 mm[0127] 2 and 6.4 mm length
  • Surface area (one end) of 55 mm[0128] 2 and 5.6 mm length
  • Designs for a 12,5 mg Carvedilol having a volume of 79.5 mm[0129] 3 includes
  • Surface area (one end) of 13.6 mm[0130] 2 and 5.85 mm length
  • Designs for a 6.25 mg Carvedilol having a volume of 39.75 mm[0131] 3 includes:
  • Surface area (one end) of 6.8 mm[0132] 2 and 5.85 mm length
  • Such small formulations may be prepared with a thicker shell for patient compliance reasons. The final size of all the formulations may be adjusted simply with adjusting the thickness of the shell for example by selecting the overall size of the 12.5 mg formulation. [0133]
  • Coating
  • The pharmaceutical composition may thus have the shape of a cylindrical rod, which is provided with a coating, which is substantially insoluble in and impermeable to fluids such as body fluids during the intended release period, the coating having an opening at one or both ends. Polymers useful as coatings are preferably those, which are possible to process by extrusion, solution or in the form of a dispersion. Most preferred are those, which are available in a food grade or a pharmaceutical grade quality. Examples of such polymers are cellulose acetate, polyamide, polyethylene, polyethylene terephthalate, polypropylenem polyurethane, polyvinyl acetate, polyvinyl chloride, silicone rubber, latex, polyhydroxybutyrate, polyhydroxyvalerate, teflon, polylactic acid or polyglycolic acid and copolymers thereof, copolymers such as ethylene vinyl acetate (EVA), styrene-butadienestyrene (SBS) and styrene-isoprene-styrene (SIS). [0134]
  • The coating may also be a coating, which is substantially soluble in and permeable to fluids such as body fluids during the intended release period provided that the coating dissolves so much slower than the matrix composition that the coating remains intact until the matrix has eroded and released the active substance. Examples of suitable polymers include polyols as described herein. [0135]
  • The coating may further comprise any of the above-mentioned matrix materials in a form, which erodes at a substantially slower rate than the rest of the matrix. The coating may thus comprise a matrix of one or more substantially water soluble crystalline polymers and, optionally, a non-ionic emulsifier, the coating being one which is eroded in the aqueous phase at a substantially slower rate than the matrix composition comprising the active substance, whereby a substantially constant area of the matrix composition comprising the active substance is exposed during erosion of the matrix composition, and whereby the coating is substantially eroded upon erosion of the matrix composition comprising the active substance. Such a coating will be designed so that its longitudinal erosion rate is substantially the same as the longitudinal erosion rate of the matrix, whereby the matrix and the coating will erode longitudinally towards the centre of the composition at substantially the same rate. Thus, when the matrix composition has been completely eroded by the aqueous medium, the coating will also be substantially completely eroded. A matrix composition having such a coating has the obvious advantage of being completely biodegraded upon release of the active substance. Such a coating will typically be a combination of a polyethylene glycol and a mixture of, for example, polyethylene glycol 400 monostearate or another non-ionic emulsifier, and may also include a filler. The content of the mixture of non-ionic emulsifiers and the filler in the coating will be determined in each particular case according to the characteristics, e.g. erosion rate and size, of the matrix comprising the active substance. [0136]
  • In an embodiment of the invention, the coating is one, which disintegrates or crumbles after erosion of the matrix. A coating of this type will remain intact as long as it is supported by the matrix containing the active substance, but it lacks the ability to remain intact after erosion of the matrix, because it then disintegrates or crumbles, so that it will not remain in e.g. a human or animal for any significant amount of time after the complete erosion of the matrix and the release of the active substance. [0137]
  • The coating may also be an enteric coating employing methacrylates, a co-polymer of methacrylate-galactomannan etc. [0138]
  • In an interesting embodiment, the controlled release composition of the invention further comprises a coating having at least one opening exposing at least one surface of the matrix, the coating being one which crumbles and/or erodes upon exposure to the aqueous medium at a rate which is equal to or slower than the rate at which the matrix erodes in the aqueous medium, allowing exposure of said surface of the matrix to the aqueous medium to be controlled. Coatings of this type are described in WO 95/22962, to which reference is made and which is incorporated herein by reference. [0139]
  • These coatings comprise: [0140]
  • (a) a first cellulose derivative which has thermoplastic properties and which is substantially insoluble in the aqueous medium in which the composition is to be used, e.g. an ethylcellulose such as ethylcellulose having an ethoxyl content in the range of 44.5-52.5%, or cellulose acetate, cellulose propionate or cellulose nitrate; [0141]
  • and at least one of: [0142]
  • (b) a second cellulose derivative which is soluble or dispersible in water, e.g. a cellulose derivative selected from the group consisting of methylcellulose, carboxymethylcellulose and salts thereof, cellulose acetate phthalate, microcrystalline cellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose and hydroxymethylpropylcellulose; [0143]
  • (c) a plasticizer, e.g. selected from the group consisting of phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters thereof with polyethylene glycol, glycerin or sugars; fatty alcohols and ethers thereof with polyethylene glycol, glycerin or sugars; and vegetable oils; or a non-ionic surfactant; and [0144]
  • (d) a filler, e.g. selected from conventional tablet or capsule excipients such as diluents, binders, lubricants and disintegrants. [0145]
  • The use of a plasticizer will often be desirable inorder to improve the processibility of the ethylcellulose or the first cellulose derivative. The plasticizer may also be a non-ionic surfactant, e.g. a non-ionic surfactant selected from the group consisting of diacetylated monoglycerides, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monooleate, glyceryl monostearate, propylene glycol monostearate, macrogol esters, macrogol stearate 400, macrogol stearate 2000, polyoxyethylene 50 stearate, macrogol ethers, cetomacrogol 1000, lauromacrogols, nonoxinols, octocinols, tyloxapol, poloxamers, polyvinyl alcohols, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate and sucrose esters; nitrobenzene, carbon disulfide, β-naphtyl salicylate, phthalyl glycolate, dioctyl phthalate. [0146]
  • Other suitable plasticizers appear from EP-B0 746 310 to which reference is made. [0147]
  • Pharmaceutical Composition
  • As mentioned above a pharmaceutical composition according to the invention is a coated matrix composition from which the active substance is released in by a zero order release mechanism. [0148]
  • A composition according to the invention containing a drug substance is typically for oral administration and may be in the form of a tablet or a capsule or in the form of a multiple unit dosage form. Due to the possibility of controlling the release rate of the active substance the composition may be adapted for oral administration 1-4 times a day, normally 1-4 times daily such as 1-3 times, 1-2 times or 1 times daily. The technology may also provide compositions for administration only once or twice daily. In the present context the term “once daily” is intended to mean that it is only necessary to administer the pharmaceutical composition once a day in order to obtain a suitable therapeutic and/or prophylactic response; however, any administration may comprise co-administration of more than one dosage unit, such as, e.g. 2-4 dosage units if the amount of active substance required may not be formulated in only one composition or if a composition of a smaller size is preferred. [0149]
  • The dosage of the active substance depends on the particular substance, the age, weight condition etc. of the human or animal that will be treated with the composition etc. All such factors are well known to a person skilled in the art. [0150]
  • The controlled release of the active substance is caused by erosion at a substantially constant rate of a surface or surfaces of the composition [0151]
  • The rate at which the active substance is released from the matrix is a predetermined rate, i.e. a rate, which is controllable over a certain period of time. The release rate required in each particular instance may inter alia depend on the amount of active substance to be released for it to exert the desired effect, as well as on the overall dosage of the active substance contained in the matrix. The substance of which the matrix is composed and the distribution of the active substance in the matrix may therefore be selected according to one or more of these criteria to ensure the desired level of release of the active substance. [0152]
  • Due to the controlled release of the active substance obtainable from the pharmaceutical composition of the invention, it is possible to obtain a substantially constant rate of release of the active substance over a specific period of time, corresponding to the dosage necessary for the treatment in question, so that adherence to a strict dosage regimen, e.g. requiring administration of a drug at set intervals up to several times a day, may be dispensed with. [0153]
  • Furthermore, it is possible to include two or more different active substances in the pharmaceutical composition of the invention, and the two or more different active substances may be adapted to be released at different concentrations and/or intervals, thus making it easier for patients to follow a prescribed regimen. [0154]
  • An additional advantage of a pharmaceutical composition of the invention, compared to other known controlled release compositions, is that it may be produced by relatively simple and inexpensive methods. [0155]
  • Furthermore, a pharmaceutical composition according to the invention allows for the incorporation of high concentrations of the active substance relative to the size of the delivery system. This is obviously a great advantage, notably when the composition is to be used for the delivery of a therapeutically, prophylactically and/or diagnostically active substance, since it allows for the delivery of the required amount of the active substance without the size of the composition being unnecessarily large. In addition, sparingly soluble or non-soluble active substances may be readily incorporated into a composition of the invention. A composition of the invention may thus be used for the delivery of, for example, sparingly soluble or non-soluble pharmaceutical powders which can otherwise be difficult to administer. [0156]
  • As mentioned above, the release of the active substance from the pharmaceutical composition corresponds to a substantially zero order release determined by in vitro dissolution test according to USP. The substantially zero order release is obtained in a time period of at least 1 hours such as, e.g. at least 2 hours, at least 3 hours, at least 4 hours or at least 5 hours, or in a time period of at least 5 hours such as, e.g. at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours or at least 10 hours. [0157]
  • Multiple Units Composition
  • The pharmaceutical composition according to the invention may furthermore be used in the preparation of a multiple units pharmaceutical composition, e.g. in the form of a capsule or tablet. A multiple units pharmaceutical composition is a composition, which comprises a multiplicity of individual units in such a form that the individual units will be made available upon disintegration of the composition, typically a capsule or tablet, in the stomach of humans or animals ingesting said composition. Thus, in this case, at least some of the individual units in said multiple units pharmaceutical composition will consist of the composition of the invention, the individual units being of a size, which allows them to be incorporated into such a composition. [0158]
  • Stability
  • In order to improve the stability of a composition according to the invention, the composition may optionally comprise a stabilizing agent. [0159]
  • In the present context, the terms “stability” and “stabilizing agent” are employed to encompass one or more of the following: [0160]
  • Stability with respect to the final composition: [0161]
  • i) stablility with respect to the physical stability of the composition (appearance, color, strength, etc [0162]
  • ii) stability with respect to in vitro dissolution behaviour of the active substance from the composition [0163]
  • Stablility of the individual components: [0164]
  • iii) stablility with respect to the chemical stability of the active substance (degradation of the active substance to other—normally—unwanted products) [0165]
  • iv) stability with respect to the form the active substance has in the composition; normally, the active substance is dissolved (molecularly dispersed) in the polymer as a solid dispersion. In such cases precipitation or otherwise formation of crystals of the active substance in the composition is an indication of a stability problem. [0166]
  • v) physical and chemical stability of the pharmaceutically acceptable polymer employed as component ii). [0167]
  • Normally, stability is considered under specific storage and test conditions. In the present context, a stable composition is a composition that does not change (with respect to a specific property) more than 20% within a time period of at least 2 weeks (when physical parameters are considered) or a period of at least 3 months (when chemical parameters are considers). Specific conditions appear from the patent claims herein. [0168]
  • Many crystalline, therapeutically active substances have a very slight solubility in aqueous medium such as, e.g., body fluids. It is well known that changing a crystalline compound into its amorphous state will substantially increase the aqueous solubility of the compound. The amorphous state of an active substance may be obtained by melting the active substance, holding it in the molten state for a certain period of time and then cooling it to an amorphous solid. Such a method is especially suitable for active substances that can produce stable amorphous solids and which are not degraded by the heating step. [0169]
  • Accordingly, for active substances having a very low water solubility (e.g. at the most about 3 mg/ml as defined herein) it may be appropriate to present the active substance at least partly on amorphous form in the composition. However, due to the inherent instability of the amorphos state it is often necessary to provide suitable conditions in the composition for improved stability as well as to provide suitable storage conditions. Irrespective of the release mechanism of the active substance from the composition, the present inventors have found that—when active substances with a low water solubility is employed—a suitable stable pharmaceutical compositions for oral use is a composition comprising a solid dispersion of component i) and ii) [0170]
  • i) being at least one therapeutically, prophylactically and/or diagnostically active substance, which at least partially is in an amorphous form, [0171]
  • ii) being a pharmaceutically acceptable polymer that has plasticizing properties and which has a melting point or melting interval of a temperature of at the most 200° C., and, optionally, a stabilizing agent. [0172]
  • Typically, the at least one therapeutically, prophylactically and/or diagnostically active substance has a water solubility of at the most 3 mg/ml at 25° C. such as, e.g. at the most about 2 mg/ml, at the most about 1 mg/ml, and the concentration of the active substance in the composition corresponds to a concentration of at the most the saturated concentration in component ii) at a temperature corresponding to the melting point or the lowest end point of the melting interval of component ii) optionally together with component iii). [0173]
  • In a further aspect, the invention relates to compositions as described above. [0174]
  • To this end, the present inventors have found that it is of utmost importance in order to obtain a stable composition that the active ingredient is present in the solid dispersion in a suitable concentration that makes it possible to prevent formation of any unwanted precipitates during storage under normal conditions. In the present context it is especially of interest to avoid formation of crystals of the active substance. [0175]
  • Normally supersaturated systems (i.e. systems wherein the concentration of a given substance in a medium is larger than the solubility in the medium) are instable systems that after a certain time period will lead to precipitation of the substance in the medium. [0176]
  • In a saturated system, which is a stable system, an equilibrium between solid and dissolved substance will take place. In systems where the active substance is present in dissolved form and the concentration of the substance is well below the solubility normally no change with respect to formation of precipitates will take place (unless the substance is degraded to insoluble products etc.). A dissolved system may therefore be regarded as a stable system. However, in practice the situation is often much more complex and it is normally necessary to stabilize even dissolved system by use of different methods. [0177]
  • An important feature of the invention is that the active substance is converted to and stabilized in its amorphous form as a solid dispersion. The amorphous state and/or the solid dispersion is stabilized either by a very careful choice of the concentration of the active substance in the composition and/or by addition of suitable stabilizing agents acting by stabilizing one or more of the conditions mentioned above under items i) to v). [0178]
  • In a specific embodiment, the pharmaceutically acceptable polymer employed as component ii) is a polyethylene oxide having a molecular weight of at least about 20,000 in crystalline and/or amorphous form or a mixture such polymers. More details on suitable polymers are disclosed herein. The solubility of a particular active substance in PEO depends inter alia on the quality and the molecular weight of the PEO employed. Thus, in order to determine a suitable concentration of the active substance in a composition of the invention it is necessary to determine the solubility of the active substance in the PEO (or other polymers employed) in question. The solubility is normally determined at a temperature that corresponds to the melting or softening point of the PEO in question and the solubility determined is the saturation solubility. A person skilled in the art knows how to determine the solubility of a specific substance in a specific polymer. [0179]
  • Normally, when preparing a composition according to the invention heating is employed for an injection moulding process. During heating it has been observed that PEO in various qualities forms free radicals that results in the formation of inter alia formaldehyde and formic acid. These products may often lead to further degradation e.g. of the active substance present in the composition and it is therefore necessary to take the necessary precautions in this respect. Oxidative free radicals degradation by hydroperoxides can be catalysed by certain transition metal ions, especially those of copper, cobalt and manganese. Thus, employment of PEO qualities devoid of or only containing a very small amount of such transition metal ions may improve stability. Another possibility is to use component ii) in a quality that ensures that free radicals formed, if any, do not significantly increase the degradation of the active substance in the composition. Such a quality could e.g. be a quality containing an antioxidant that functions by preventing the formation of free radical during heating or by scavenging any free radicals formed. Another possibility is to add such antioxidant to the formulation before any heating takes place. [0180]
  • Suitable qualities include PEO 200,000 NF or LF from Dow Chemicals. [0181]
  • A composition according to the invention may therefore further comprise one or more antioxidants that inhibits the formation of peroxides and/or inactivates any peroxides present. [0182]
  • Suitable antioxidants for use includes beta-caroten (a vitamin A precursor), ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, sodium metabisulfite, propyl gallate, sodium formaldehylde sulfoxylate, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives, sulfides, phosphine etc. Other suitable antioxidants are described herein. [0183]
  • Another measure to reduce any oxidation during processing is to employ nitrogen purges during manufacturing. [0184]
  • Preparation
  • The delivery system as well as the first composition of the invention may be produced by various methods which are either known per se in the pharmaceutical industry or which, for example, are used in the productiori of polymer-based materials, depending upon the desired embodiment and the materials employed in the composition in question. As mentioned above, one advantage of the composition according to the invention is that it may be produced by methods, which are relatively simple and inexpensive. [0185]
  • A pharmaceutical composition may be produced by, for example, co-extrusion of the coating with the matrix composition and the active substance, extrusion and dip coating, injection moulding and dip coating, or by extrusion or injection moulding and solvent coating by spraying or dipping. [0186]
  • For further details reference is made to the experimental section herein. [0187]
  • Method for Controlling the Release
  • As mentioned above, the invention also relates to a method for controlling the release of a therapeutically, prophylactically and/or diagnostically active substance from a pharmaceutical composition. To this end all details and particulars described above under the composition aspect applies mutatis mutandi to the method aspect and any other aspect. [0188]
  • The invention is further illustrated in the figures and in the following non-limiting examples. [0189]
  • FIG. 1 is a plug holder suitable for use when determining diffusion and dissolution rate. A stopper on the right seals the plug holder, and,the swelling layer is formed on the left side on the plug. [0190]
  • FIG. 2 is the results from pilot study of Example 5. [0191]
  • FIG. 3 shows the DSC of carvedilol as starting material and a peak is observed corresponding to that carvedilol is employed in crystalline form. [0192]
  • FIG. 4-5 are the DSCs of PEO 200,000 and citric acid, respectively, and show that the substances are employed as crystals. [0193]
  • FIG. 6 shows that PEO+citric acid only has one peak indicating that citric acid is present on amorphous or dissolved form or possible in a different crystalline form. Carvedilol when admixed with PEO and citric acid maintain at least some of its crystallinity (no heating has taken place). [0194]
  • FIG. 7 shows DSC's of compositions according to the invention. No peak is present for carvedilol indicating the carvedilol is present in amorphous form. Storage of the compositions as mentioned above for about 1 month did not show any substantial difference in the DSC pattem. [0195]
  • FIG. 8 shows the dissolution profile relating to a composition of Example 8 denoted 0069; the dissolution has been determined in FaSSIF medium (cf. Dressmann et al. J. Pharm. Sci. 11 Suppl. 2 (2000) pp S73-S80. [0196]
  • FIG. 9 shows the dissolution profile relating to a composition of Example 8 denoted 0069; the dissolution has been determined in FeSSIF medium (cf. Dressmann et al. J. Pharm. Sci. 11 Suppl. 2 (2000) pp S73-S80. [0197]
  • FIG. 10 shows the dissolution profile relating to a composition of Example 8 denoted 0069; the dissolution has been determined after 26 days storage at 30°[0198] 0 C. and 60% RH.
  • FIG. 11 is a suitable shape for an opioid composition. Suitable values are e.g. a=3 mm, b=4.5 mm, c=1.5 mm and d=9 mm; a=3 mm, b=4.6 mm, c=2 mm and d=9 mm; a=2.3 mm, b=5.3 mm, c=1.5 mm and d=7.5 mm; or a=3.4 mm, b=5.1 mm, c=2 mm and d=7.5 mm [0199]
  • FIG. 12 is the dissolution profile from the composition of Example 9. [0200]
  • FIG. 13 ([0201] 1A, 1B, 2A and 2B) shows the dissolution profiles from the compositions of Example 10.
  • FIG. 14 shows the plasma concentration vs. time profile for the clinical study on healthy volunteers reported in Example 11. [0202]
  • FIG. 15 shows the plasma concentration vs. time profile for the clinical study in phase II reported in Example 11. [0203]
  • Methods Diffusion/Dissolution Studies
  • Method for Determination of Dissolution Rate of the Matrix [0204]
  • A composition according to the invention has properties that ensure that the diffusion rate of water into the polymer matrix substantially corresponds to the dissolution rate of the polymer matrix composition into the aqueous medium. In the following is given a simple method to test these conditions. [0205]
  • The polymers that are suitable for use according to the present invention and which are sufficiently hydrophilic are water-soluble. When contacted with water, a sharp advancing waterfront divides the intact and not penetrated matrix from a swollen front. Under stationary conditions, a constant thickness surface layer is formed by the swollen polymer and by a high concentration of polymer in solution. [0206]
  • In fact, once the hydrodynamic external conditions are defined, a stationary state is reached where the rate of penetration of the moving boundary equals the rate of removal of the polymer at the external surface. [0207]
  • The time lapse until the quasi-stationary state is reached is called swelling time. At steady state, the dissolution rate is constant and can be defined equally by either the velocity of the retracting front of the polymer or the velocity of the front separating the pure penetrate and the liquid dissolving sublayer. Thus, both fronts are synchronized. [0208]
  • When the dissolution rate equals the penetration rate (i.e. the diffusion rate) a constant thickness surface layer should be observed. The dissolving layer evolution during water conditioning should reflect the different dissolution characteristics of the materials employed. The surface layer thickness is measured as a function of time. [0209]
  • In order to measure the diffusion rates of water, samples may be prepared in the form of plugs fitting to the sample holder (e.g. 2 mm, 4 mm, 6 mm, 7.5 mm and 12 mm long and preferable with the same shape and volume as the desired dosage unit). The sample holder is prepared by translucent glass in a tubular shape and with noticeable marks indicated with a specific distance. [0210]
  • The test proceeds as follows: Place 1 plug incorporated into the glass tube in a vessel—optionally with a water soluble dye (e.g. Cu[0211] 2+)—and the plug/glass tube is placed in a dissolution apparatus e.g. according to monograph: USP 24, page 1941-1950, which is hereby incorporated by reference (see FIG. 1). By employment of the USP method it is possible to determine the diffusion rate as well as the dissolution rate in the same experiment. The copper ions are blue-coloured so they are visually detectable and due to the metric scale on the tube, the diffusion rate can be calculated (unit is length/time). The dissolution rate is determined by determining the amount of substance (e.g. active substance) released and at the same time determining the length of the matrix composition that has been eroded. Thus, the dissolution rate is also in length/time units. As the dissolution profile easily can be obtained from the data measured, a simple means for the determination of whether the release follows zero order is to investigate the dissolution profile and see whether linearity is present.
  • Agitation is provided, and the length of the front of matrix is measured at desired time intervals as a function of time. The measurement may be a simple visual identification of the marks on the glass tube. [0212]
  • When the dissolution rate equals the penetration rate a constant thickness surface layer is observed. The different dissolving layers in different matrices obtained during the water contact, reflect the different dissolution characteristics of the matrix. The thickness of the surface layer as a function of time is then compared. The specific aqueous medium may be selected individually. [0213]
  • Dissolution Test
  • Dissolution tests were performed in accordance with the USP 24, NF 19, (711) Dissolution, Apparatus 2 equipped with a paddle. The dissolution medium was 0.1 N hydrochloric acid during the first 120 min, which was then substituted with a buffer solution pH 6.8. The volume of the dissolution medium was 1000 ml and the rotation speed of the paddle was 120 rpm during the first 120 min and then 50 rpm. Samples were withdrawn at suitable time intervals and analyzed for content of active substance by means of UV spectrometry at a wavelength of 284 nm. [0214]
  • EXAMPLES A General Method for the Preparation of a Controlled Release Composition is Described Below Preparation of the Matrix Composition
  • An accurate amount of the polymer (i.e. in the examples below: the polyethylene oxide) is loaded into a MTI mixer followed by an accurate amount of the active substance and of the pharmaceutically acceptable excipients(s), if any. The mixing is performed at 2050/1450 rpm and at a time period of 10 min+4 min+short final spinning. At the start of the mixing the temperature is about 19° C. (the first time period) and the final temperature of the mixture is about 52° C. (the second and third time period). The mixture is then allowed to cool to room temperature and is ready to be fed into an injection moulding machine. [0215]
  • Preparation of the Coating Composition
  • The coating composition was prepared by first adding the hydroxymethylcellulose then cetostearyl alcohol, and finally the titanium dioxide to an MTI-Mixer at a temperature about 21° C. After mixing for nearly 9 min at 1000 rpm (I: 0.9 A) the mixer was stopped (temperature about 46° C.) and the adhered material manually incorporated into the mixture. The mixture was left to cool for about 10 minutes. The mixing is then finalized with a short high-speed mix in order to minimize lumps formation. The mixture was then allowed to cool to room temperature, after which it had a suitable consistency for being fed into an injection moulding machine. [0216]
  • Example of Coat Composition
  • [0217]
    Batch: 58-014-01-013
    amount Weight
    % Batch Material (g) (g) step
    79 991207-A Ethocel 632 632 1
    20 990426-B Cetylstearyl Alkohol 160 160.1 2
    1 97051301 TiO2 8 8.0 3
    100 total 800 800.1
  • The final dosage units may be prepared according to two different methods. In one method, the coat and the matrix moulded individually followed by a manually incorporation of the moulded matrix plug into the moulded coat. The moulding machine used is an Arburg Allrounder 220 S 250/60. [0218]
  • In the second method, the coat and matrix are moulded in one process where the coat is moulded in a first step and the matrix is moulded directly into the coat in a second step. The moulding machine used is Arburg Allrounder 420 V 800-60/35. [0219]
  • The following table describes formulations having a cylindrical form and circular openings in both ends. [0220]
    Length Diameter Vol
    Batch [mm] [mm] [mm3]
    01-0034-042 7.5 5.05 150
    01-0035-042 6.0 5.64 150
    01-0043-042 9.0 4.6 150
  • The following table describes formulations having a cylindrical form and oval openings in both ends [0221]
    Length Vol
    Batch [mm] [mm3] Longest/shortest diameter [mm]
    01-0075-042 6.0 150 8.74 3.64
    01-0076-042 7.5 150 7.82 3.21
  • The coated compositions obtained were open at two opposite ends. The area for an open end is calculates as the volume/length of the cylindrical formulations. [0222]
  • Example 1 Preparation of a Pharmaceutical Composition Comprising Carvedilol as an Active Substance
  • A composition (plug batch No. 01-0045-042), formulation batch No. 01-0034 042 according to the invention was prepared from the following ingredients: [0223]
    No Raw materials Reference:
    1 PEO 200,000 S-Ega40200; USP24-NF19 2000 p. 2497
    2 Carvedilol Ph. Eur. 3rd Ed. 2000 p.359
    3 Citric Acid Ph. Eur. 3rd Ed. 1997 p.645
    Matrix % w/w
    Polyethylene oxide 64.6
    Carvedilol (Cipla) 30
    Citric acid 5.4
  • The coating and the matrix were prepared as described above. One dosage form contains 50 mg carvedilol. The composition was 7.5 mm long. [0224]
  • The composition was subjected to the dissolution test described above. The following results were obtained: [0225]
    dissolved carvedilol
    Time (h) (% w/w of the coated composition)
    0 0
    1 14.1
    2 27.1
    3 39.3
    4 49.9
    5 60.7
    6 72.5
    7 85.0
    8 99.7
  • The solution profile corresponds to a zero order release of carvedilol from the composition. [0226]
  • Example 2 Preparation of an Oval Shaped Pharmaceutical Composition Comprising Carvedilol as an Active Substance
  • A complsition (batch No. 01-0076-042) according to the invention was prepared from the following ingredients: [0227]
    Matrix % w/w
    Polyethylene oxide 64.6
    Carvedilol (Cipla) 30
    Citric acid  5.4
  • The coating and the matrix were prepared as described above. One dosis form contain 50 mg carvedilol. The composition was 7.5 mm long and had an oval cross sectional shape. [0228]
  • The composition was subjected to the dissolution test described above. The following results were obtained: [0229]
    dissolved carvedilol
    Time (h) (% w/w of the coated composition)
    0 0
    1 15.9
    2 30.1
    3 46.2
    4 62.2
    5 77.61
    6 92.4
  • The dissolution profile corresponds to a zero order release of carvedilol from the composition. [0230]
  • Example 3 Preparation of a Pharmaceutical Composition Comprising Carvedilol as an Active Substace
  • A composition (plug batch No. 01-0044-042, dosage unit batch No. 01-0043 042) according to the invention was prepared from the following ingredients: [0231]
    Matrix % w/w
    Polyethylene oxide 64.6
    Carvedilol (Cipla) 30
    Citric acid 5.4
  • The coating and the matrix were prepared as described above. One dosage form contains 50 mg carvedilol. The composition was 9 mm long. [0232]
  • The composition was subjected to the dissolution test described above. The following results were obtained: [0233]
    dissolved carvedilol
    Time (h) (% w/w of the coated composition)
    0 0
    1 13.2
    2 22.5
    3 33.2
    4 44.7
    5 56.2
    6 67.0
    7 77.2
    8 88.1
    9 98.6
  • The dissolution profile corresponds to a zero order release of carvedilol from the composition. [0234]
  • Example 4 Preparation of a Pharmaceutical Composition Comprising Carvedilol as an Active Substance
  • A composition (batch No. 01-0075-042) according to the invention was prepared from the following ingredients: [0235]
    Matrix % w/w
    Polyethylene oxide 64.6
    Carvedilol (Cipla) 30
    Citric acid 5.4
  • The coating and the matrix were prepared as described above. One dosage unit form contains 50 mg carvedilol. The composition was 6 mm long and had an oval shape. [0236]
  • The composition was subjected to the dissolution test described above. The following results were obtained: [0237]
    dissolved carvedilol
    Time (h) (% w/w of the coated composition)
    0 0
    1 17.0
    2 35.1
    3 55.1
    4 74.7
    5 93.8
  • The dissolution profile corresponds to a zero order release of carvedilol from the composition. [0238]
  • Example 4A Preparation of a Pharmaceutical Composition Comprising Carvedilol as an Active Substance
  • A composition (batch No. EC-042-211) according to the invention was prepared from the following ingredients: [0239]
    Matrix % w/w
    Polyethylene oxide 86
    Carvedilol (Cipla) 14
  • The coating and the matrix were prepared as described above. One dosage unit form contains 25 mg carvedilol. The composition was 12 mm long and had circular end surfaces. [0240]
  • The composition was subjected to the dissolution test described above. The following results were obtained: [0241]
  • Dissolved carvedilol (% w/w of the coated composition) from hour 1 to 15 hours [0242]
    dissolved carvedilol
    Time (h) (% w/w of the coated composition)
    1 12.4
    2 21.6
    3 29.2
    4 35.4
    5 40.0
    6 44.5
    7 49.4
    8 54.3
    9 59.4
    10 64.6
    11 70.6
    12 75.5
    13 79.8
    14 84.1
    15 88.7
    16 92.6
    17 94.6
  • The dissolution profile corresponds to a zero order release of carvedilol from the composition. [0243]
  • Example 5 Pilot Phase I Studies in Health Volunteers Employing Carvedilol Compositions According to the Invention
  • Carvedilol has emerged as one of the important and promising drugs for cardiovascular diseases including hypertension and congestive heart failure, and results in a noticeable improvement of survival rates in patients with chronic cardiac insufficiency. To further optimize the treatment, Carvedilol Egalet® has been developed as a once daily composition. [0244]
  • Carvedilol is currently marketed as an immediate release formulation only in 3,125 mg, 6,25 mg, 12,5 mg, 25 mg and 50 mg tablets. Only the 6,25 mg and 25 mg application form is available throughout the EU whilst of the other strengths some are missing in certain member states. A 25 mg immediate release application form may be used as a reference. [0245]
  • Carvedilol is registered for the following indications: [0246]
  • Hypertension [0247]
  • Chronic cardiac insufficiency [0248]
  • Angina pectoris [0249]
  • Carvedilol Egalet® is developed for long-term treatment of hypertension and is therefore developed for a maintenance dosage. However, the present invention encompasses other dosages where a controlled delivery is desired. [0250]
  • The expected advantages offered by the Carvedilol Egalet® compared to the immediate release formulation include: [0251]
  • i) Reduced standard deviation and thus, a more predictable concentration in plasma. [0252]
  • ii) A dose regimen with lower frequency of administration and thereby potentially improvement of patient compliance. [0253]
  • For patients with cardiac insufficiency, it is recommended to take Carvedilol with a meal to delay absorption and thereby avoid adverse reactions. Carvedilol Egalet® offers the advantage of reduced C[0254] max, even if taken fasting. (Latest studies CL-EG-pilot-1 and CL-EG-pilot-02 shows that Cmax is only slightly as high as for 25 mg Carvedilol IR).
  • Patients with hypertension have a well-described low compliance, presumably because there are no recognizable symptoms connected with the condition. Compliance with a once-daily regimen is higher and therefore offers a therapeutic advantage. Recommendations for the use of Carvedilol vary between countries. [0255]
  • An evaluation of Carvedilol in “Drugs” from 1997 lists in the summary under Dosage and Administration “A dosage of Carvedilol 12.5 mg once daily for 2 days, increased to 25 mg daily thereafter and increased to 50 mg once daily after 2 weeks if necessary, is recommended for patients with mild to moderate hypertension”. [0256]
  • According to the American Physician's Desk Reference (PDR) 2000, Carvedilol should be prescribed twice daily for all indications. [0257]
  • According to the German Drug Listing (Rote Liste 2001 for Dilatrend®), Carvedilol should be prescribed twice daily for cardiac insufficiency and angina pectoris, and once to twice daily for hypertension with a maximum dose of 2×25 mg. [0258]
  • According to “Drugs, Fact and Compariso”, Carvedilol is prescribed twice daily for hypertension. In all countries, the maximum daily dose is 25 mg b.i.d., and it is against this dose and frequency that Carvedilol Egalet is tested herein. [0259]
  • Composition of Carvedilol Egalet
  • In the development work on Carvedilol Egalet®, different compositions of matrix have been tested, i.e. the load of drug has been varied. [0260]
  • In Table 1 below is given the final composition of the coated composition used in the pilot studies. The individual composition employed in Pilot tests III, Iv and V corresponds to the compositions of Examples 1-4. [0261]
    TABLE 1
    Composition of Carvedilol Egalet ®
    Reference
    to
    Ingredients Percentage Function standards
    Active substance
    Carvedilol 32% Active compound Cipla
    Excipients
    Citric Acid  5% Matrix Ph. Eur.
    Polyethylene Oxide 63% Matrix USP
    (PEO 200000)
    Ethylcellulose 79% Shell Ph. Eur
    Ceto-stearyl alcohol 19.8%   Shell Ph. Eur
    Titanium dioxide  1% Shell Ph. Eur
    Ferro Oxide 0,2%  Colouring USP
  • Pharmacodynamics
  • There are several pharmacodynamics issues to be described for the Carvedilol Egalet®. The following is a list of issues and the considerations regarding their testing. [0262]
  • 01. Bioavailability [0263]
  • a) Rate and extent of absorption [0264]
  • b) Fluctuations in drug concentration [0265]
  • c) Variability arising from the formulation [0266]
  • d) Dose proportionality [0267]
  • e) Risk of unexpected release characteristics [0268]
  • 2. Factors influencing the performance of a modified drug formulation [0269]
  • f) GI function [0270]
  • g) Diumal rhythm [0271]
  • 3. Stereoisomers [0272]
  • Ad a-c Absorption, fluctuations and variability: [0273]
  • These characteristics are described by the pharmacokinetic studies already conducted and will be further confirmed in studies planned. [0274]
  • a. Absorption [0275]
  • There is no literature on slow release formulations of Carvedilol. One study has been identified on in-vivo absorption of Carvedilol formulated in timed-release capsules. This study by Nolte et al found absorption throughout the GI tract, correlating with the absolute absorption areas of the different parts of the intestinal tract. They found a relatively high absorption of Carvedilol in the large intestine, amounting to approximately 10% of the total absorption. [0276]
  • This supports the findings from the pilot studies performed on the Carvedilol Egalet®, where the plasma curves show that Carvedilol is being absorbed throughout the GI tract, including the colon, and that the absorption in the colon is present, but considerably reduced compared to earlier in the GI tract. b. [0277]
  • Fluctuations [0278]
  • To evaluate fluctuations in plasma concentration, comparison should be made between plasma profiles from the same concentration given. Data from pilot study IV and V on Carvedilol IR 50 mg compared to Carvedilol Egalet® 50 mg shows that Cmax for the Carvedilol Egalet® is reduced approximately 50%, whereas the C24h, which will correspond to Cmin in a once daily dosing, is 2,5 times as high. [0279]
  • In the studies, the Carvedilol IR has been given in a single dose. Patients will be taking Carvedilol IR b.i.d., wherefore peak/trough ratio should be measured for this dose regimen. This will be done in the steady state studies. [0280]
  • c. Variability [0281]
  • In published literature the variability of Carvedilol is very high, with standard deviations of >50%. The study with the highest number of subjects, i.e. 44 shows a SD of 70%. [0282]
  • There are no indications that the variability will be higher than for the immediate release formulation. [0283]
  • d. Dose proportionality: [0284]
  • At this point it is only planned to market one dose of Carvedilol Egalet®, and no investigations into dose proportionality are planned. Literature describes dose linearity for Carvedilol in the range of 6,25-50 mg. [0285]
  • e. Dose dumping: [0286]
  • Carvedilol is being released from the Egalet tablet by the erosion of the matrix from the exposed surfaces only as the coat prevents contact to the aqueous medium of the intestines. Accordingly, release of all of the Carvedilol at one time is not possible. [0287]
  • A further advantage of the injection moulding of shell and matrix in one process step is that the shell and the matrix reach a high degree of adherence. [0288]
  • An uncoated and thus unprotected matrix has been investigated through dissolution tests, which show that release time in-vitro for a freely exposed Carvedilol matrix from a 9 mm Egalet® is about two hours. Accordingly, the coating actively prevents release due to the limited exposed area. [0289]
  • In addition, the in-vivo-in-vitro correlation of the Egalet® has been described to some extend through scintigraphy. 2 hours in vitro release in the stomach will correspond to at least 3 hours in vivo, and will not be below 2 hours. Thus any dose dumping would be of less severity than seen after intake of 50 mg conventional immediate release tablet. [0290]
  • The immediate release tablet has been investigated as 50 mg o.d. in several clinical studies, but is associated to an increased number of adverse events, compared to lower doses, due to the increased trough-peak ratio. [0291]
  • f. GI function: [0292]
  • GI transit time may influence the release rate. A very fast transit time where the tablet is excreted before the content is fully released, will result in a decreased AUC. This is a well-described issue for slow release products. [0293]
  • For the Carvedilol Egalet® the effect of GI transit time can be clearly demonstrated because the non-degradable shell can be collected. When all Carvedilol is released with normal transit times, remaining Carvedilol can be found in the shells with decreased transit time. This has been documented in findings from pilot study III. [0294]
  • As release rate is constant for any given formulation, release time is depending on the length of the Egalet® tablet. For the matrix formulation, which releases at the rate of 1 mm/hour in in-vitro dissolution, tablets of 9 mm have shown complete release with normal transit time. [0295]
  • The absorption of Carvedilol Egalet® in patients with [0296] Morbus Crohn and Collitis ulcerosa has not been investigated. Until that is performed, the use of the product in the patient population is contraindicated.
  • The effect of food will be evaluated in a traditional PK study. Preliminary information on food effect will be obtained in a pilot study on 10 volunteers. [0297]
  • 9. Diumal rhythms [0298]
  • Carvedilol has been shown to preserve the diurnal rhythm of blood pressure; there are no reasons to believe that a slow release formulation will influence this rhythm differently than the IR formulation. This will be explored in the phase II study, where ambulatory BP will be measured for 24 hours. [0299]
  • 3. Stereoisomers [0300]
  • Carvedilol is a racemic mixture of R(+) and S(−)-enantiomers: S(−), which is a potent β1 and β2 antagonist and a-adrenoceptor antagonist and R(+), which has 1/100 of the beta effect and the same a effect as the S(−). The pharmacokinetics of these is described both in healthy volunteers and in patients with cardiac insufficiency. [0301]
  • Theoretically, the plasma profiles of the enantiomers seen after intake of the Carvedilol Egalet® could be different from the one seen after Carvedilol immediate release, given that the t½ of the two are different (9.6 h for R(+) and 22.1 h for S(−)). In steady state, however, the plasma profiles are similar to that of Carvedilol, and it is not expected that the blood pressure lowering effect will be different for the Carvedilol Egalet® than for the Carvedilol IR. [0302]
  • Pharmacokinetics
  • The development of Carvedilol Egalet® has involved investigational pilot studies on healthy volunteers. No full-scale studies have been performed up to now. [0303]
  • Different formulations of Carvedilol Egalet® have been tested and through this work the final formulation has been identified, and a strategy was planned for the clinical testing programme. [0304]
  • Pilot Phase I Studies Completed Pharmacokinetic Studies
  • The pharnacokinetic studies on Carvedilol Egalet® listed in Table 1 are part of the development work to obtain preliminary information on the pharmacokinetics. [0305]
    TABLE 1
    Completed pilot pharmacokinetic studies, listed chronologically
    Study Doses No. of
    No. Design Treatment (mg)a subjects
    Pilot test Single-dose PK: Single-dose C Egalet: 6
    I Open-label, 2-armed, parallel 25 mg
    group C IR: 25 mg
    (Carvedilol Egalet ® vs. Carvedilol IR)
    Pilot test Single-dose PK: Single-dose C Egalet: 6
    II Open-label, 2-armed, parallel 50 mg
    group C IR: 50 mg
    (Carvedilol Egalet ® vs. Carvedilol IR)
    Pre-Pilot Single-dose PK: Single-dose C Egalet: 2
    I Open-label, Carvedilol Egalet ® 50 mg
    Pre-Pilot Single-dose PK: Single-dose C Egalet: 2
    II Open-label, Carvedilol Egalet ® 50 mg
    Pre-Pilot Single-dose PK: Single-dose C Egalet: 2
    III Open-label, Carvedilol Egalet ® 37.5 mg
    Pre-Pilot Single-dose: Single-dose C Egalet: 2
    IV Collection of excreted shells 50 mg
    Pilot test Single-dose PK: Single-dose C Egalet: 6
    III Open-label, 4-way cross-over study 25 mg/
    (3 doses Carvedilol Egalet ® vs. 37.5 mg/
    Carvedilol IR) 50 mg o.d.
    C IR:
    37.5 mg
    b.i.d.
    Pilot Test Single-dose PK: Single-dose C Egalet: 10
    IV Open-label, 4-way cross-over 50 mg o.d.
    (3 different shapes of Carvedilol C IR: 50 mg
    Egalet ® vs. Carvedilol IR) o.d.
    Pilot Test Single-dose PK: Single-dose C Egalet: 10
    V Open-label, 4-way cross-over 50 mg o.d.
    (2 different shapes of Carvedilol C IR: 50 mg
    Egalet ® vs. Carvedilol IR) o.d.
    As a final fixed sequence arm; the
    chosen shape of Carvedilol Egalet ®
    in fed subjects
  • In all studies, the investigational products were administered orally as tablets. [0306]
  • The formulations tested in these studies showed a prolonged release of Carvedilol with reduced C[0307] max and measurable plasma concentrations over 36 hours.
  • Results and Discussion—Pilot Pharmacokinetic Studies
  • The pilot phase I studies completed up to now clearly indicates that it is possible to produce a slow release Carvedilol Egalet® with a PK profile required of a once daily formulation. [0308]
  • In pilot test III, the influence of the length of the Egalet® tablet on the release characteristics was described. In pilot test IV, Egalet® tablets with 3 different diameters and lengths has been tested. In vitro dissolution tests indicated that an increased diameter would not influence the speed of erosion and pilot IV and V has confirmed this. C[0309] max is increasing proportionally to the increasing surface area exposed of the Egalet. Tmax does not differ between the formulations. The mean of the plasma concentrations measured for the 6 mm Carvedilol Egalet 50 mg is reduced due to an unexpected high number of subjects having a fast transit time in that treatment group; 6 of 10 subjects excreted the Egalet before hour 24.
  • In pilot study V, two of the same lengths of Carvedilol Egalet® as in pilot test IV were tested, but in a different oval shape, and compared to Carvedilol immediate release. Preliminary data assessment supports the conclusion from pilot study IV that Cmax increases with increasing diameter of the Egalet®. When comparing data for the round Egalet in pilot IV to the “easy-to-swallow” oval shaped Egalet in pilot V, for the 6 mm and the 7½ mm lengths respectively, and the exposed matrix area being constant, there are no observed difference by the change of shape. To obtain preliminary information on the effect of food on Carvedilol Egalet®, the 6 mm Egalet formulation was tested after a standard, high-fat meal, according to guidelines. The first 3 arms of the study were randomised and the last, the fed, was a fixed sequence arm. The data results from the last sequence have not been received yet and full data analysis for pilot study V has thus not been completed. [0310]
  • The composition, the Carvedilol Egalet® 6 mm, is a composition, for which we aim at showing an AUC equivalent to the marketed twice-daily formulation. Preliminary data assessment from pilot study V shows for the 6 mm oval Egalet an AUC of 97,7% of the [0311]
    AUC C C C t
    (0-36 h) rel. max (12 h) (24 h) max
    Formulation n h*ng/ml AUC % ng/ml ng/ml ng/ml hours
    CL-EG-01 (round egalet)
    9 mm 10 285 70 26.7 7.1 4.2 3
    7½ mm 10 355 88 37.8 10.3 3.8 4
    6 mm 10 336 76 37.4 9.1 2.9 4
    IR 10 433 100 105.5 5.8 1.9 1
    CL-EG-02 (oval egalet)
    IR 10 444 100 95.8 6.6 2.4 1
    7½ mm 10 344 76 33.2 9.0 5.0 4
    6 mm 10 421 97 41.7 11.8 4.8 4
    6 mm + food 10 362 80 39.0 10.9 3.9 3
  • In the table is given relevant pharmacokinetic parameters from the pilot studies (see FIG. 1). [0312]
  • Example 6 Preparation of a Morphine Containing Controlled Release Composition According to the Invention
  • A composition (batch No. 01-0112-066) according to the invention was prepared from the following ingredients: [0313]
    Matrix
    Polyethylene oxide 200,000 83.5% w//w
    Morphine sulfate 16.5% w/w
  • The coating and the matrix were prepared as described above. The composition was 9 mm long and had elliptic formed surfaces. [0314]
  • The composition was subjected to the dissolution test described above. The following results were obtained: [0315]
    % w/w release morphine
    Time (hours) sulfate from the composition
    1 19.48
    2 33.64
    3 44.22
    4 55.59
    5 70.11
    6 80.70
    7 91.30
    8 96.65
  • The release corresponds to a zero order release. [0316]
  • Example 7 Preparation of a Composition of Carvedilol—DSC Measurements
  • A composition according to the invention was made from the following: [0317]
    PEO 200,000 67% w/w
    Carvedilol 28% w/w
    Citric acid  5% w/w
  • The composition was made according to the general process described herein. [0318]
  • All starting materials as well as a mixture of PEO 200,000 and citric acid was subject to differential scanning caliometry measurements (thermal measurement). The final composition was also investigated at time 0 and 1 month after storage at 25° C./60% RH and 40° C./70% RH. The results are shown in FIGS. 3-7. [0319]
  • Example 8 Composition According to the Invention
  • The example illustrates the invention and gives a number of different compositions according to the invention. In the right hand column is given comments to the individual compositions with respect to the impact on the composition of the ingredients employed and with respect to the dissolution profile obtained. [0320]
  • Abbreviations: [0321]
    PEG: polyethylene glycol
    PEG ms: polyethylene glycol monostearat
    HPMCP HP 50: hydroxypropyl methylcellulose pthalate (HP 50 is grade)
    TPGS: α-tocopheryl polyethylene glycol succinate
    Desired Release time
    Matrix % 12 hours in 12 mm long
    Ingredient w/w tubular tablet. Result
    Polymer system
    EC-042-011 PEO 200 000 86 No zero-order release in acid
    25 mg Carvedilol Carvedilol 14 medium, release time after
    17 h.
    EC-042-013 PEO 200 000 50 No zero-order release,
    25 mg Carvedilol Carvedilol 14 release time after 14 h.
    Lactose 24
    Klucel 5
    PEG 2000 ms 7
    EC-042-014 PEO 200 000 81 Released after 14 h. After 1
    25 mg Carvedilol Carvedilol 14 month (18-22° C.), no
    PEG 2000 ms 5 release in buffer.
    EC-042-015 PEO 200 000 81 Release time after more
    25 mg Carvedilol Carvedilol 14 than 20 h. Matrix left in
    HPMCP HP 50 5 the shell.
    EC-042-016 PEO 200 000 76 Release time after 16 h.
    25 mg Carvedilol Carvedilol 14 Matrix left in the shell.
    PEG 2000 ms 5
    HPMCP HP 50 5
    EC-042-020 PEO 200 000 81 Released after 12 h. Almost
    25 mg Carvedilol Carvedilol 14 zero-order.
    PEG 2000 ms 5
    EC-042-024 PEO 200 000 70 Released after 11 h. After 2-3
    25 mg Carvedilol Carvedilol 14 month storage (18° C.-22° C.),
    PEG 2000 ms 16 no release in buffer.
    EC-042-025 PEO 200 000 65 Release time increased but
    25 mg Carvedilol Carvedilol 14 HPMCP did not lower the
    PEG 2000 ms 14 release rate in acid medium.
    Hydroxyethyl cellulose 4 Release time after 15 h.
    (Natrosol) 3 No zero-order release.
    HPMCP HP 50
    EC-042-030 PEO 200 000 52 No zero order release.
    50 mg Carvedilol Carvedilol 32
    PEG 2000 ms 16
    EC-042-031 PEO 600 000 52 No zero order release.
    50 mg Carvedilol Carvedilol 32
    PEG 2000 ms 16
    EC-042-034 PEO 45.000 70 No zero-order release, the
    25 mg Carvedilol PEG 2000 ms 14 matrix swell.
    Carvedilol 16
    EC-042-037 PEO 200.000 52 No zero-order release.
    50 mg Carvedilol Carvedilol 32 Release time 14-16 h.
    PEG 2000 ms 16 Carvedilol precipitated in
    buffer medium.
    EC-042-039 PEO 200.000 52 No zero order release,
    50 mg Carvedilol Carvedilol 32 release time > 25 h.
    PEG 2000 ms 6 Starch increased the release
    Starch 10 time
    EC-042-042 PEO 200.000 43 Too low release rate,
    50 mg Carvedilol Carvedilol 32 Carbomer 974 dereased the
    PEG 2000 ms 10 release time
    Carbomer 974 15
    EC-042-043 PEO 200.000 47 Too low release rate,
    50 mg Carvedilol Carvedilol 32 Carbomer 974 dereased the
    PEG 2000 ms 16 release time
    Carbomer 974 5
    EC-042-044 PEO 200.000 55 Too low release.
    50 mg Carvedilol Carvedilol 32 Carbomer decreased the
    PEG 2000 ms 10 release.
    Carbomer 974 3
    EC-042-048 PEO 200.000 68 No release in buffer medium.
    50 mg Carvedilol Carvedilol 32 Precipitation of carvedilol
    EC-042-051 PEO 200.000 68 No release in buffer medium.
    50 mg Carvedilol Carvedilol 32 Precipitation of carvedilol
    EC-042-052 PEO 200.000 84 Almost zero-order release.
    25 mg Carvedilol Carvedilol 16 Release time 15 h.
    Formulation was unstable.
    Acidic stabilizicers
    EC-042-045 PEO 200.000 47 Release time was too short.
    50 mg Carvedilol PEG 2000 ms 16 Zero-order release, release
    Carvedilol 32 time 11 h Faster release in
    Citric Acid 5 acid than in buffer
    EC-042-050 PEO 200.000 47 Zero-order, release time too
    50 mg Carvedilol PEG 2000 ms 16 short. Faster release in acid
    Carvedilol 32 than in buffer
    Succinic Acid 5
    EC-042-066 PEO 200.000 58 Zero-order,
    50 mg Carvedilol PEG 2000 ms 5 release time 12 h. Faster
    Carvedilol 32 release in acid than in buffer
    Citric Acid 5
    EC-042-069 PEO 200.000 40 No zero-order release.
    50 mg Carvedilol Carvedilol 32 Release in acid medium faster
    PEG 2000 ms 3 than in buffer. Some matrix
    Pectin 20 was still left in the matrix.
    Citric Acid 5 Pectin delayed release
    EC-042-070 PEO 200.000 40 No release in buffer
    50 mg Carvedilol Carvedilol 32 medium.
    PEG 2000 ms 3
    Starch (com) 20
    Citric Acid 5
    EC-042-081 PEG 35.000 42 Zero-order release, release
    50 mg Carvedilol PEO 600.000 21 time 16 h. Matrix was left in
    Carvedilol 32 the shell. PEO 600.000
    Citric Acid 5 delayed the release
    EC-042-082 PEG 35.000 39 No zero-order release.
    50 mg Carvedilol PEO 600.000 19 Release time > 18 h.
    Carvedilol 32
    PEG 2000 ms 5
    Citric Acid 5
    EC-042-083 PEO 600.000 10 Zero-order release. Release
    50 mg Carvedilol PEO 200.000 69 time > 18 h.
    Carvedilol 16 Matrix left in the shell.
    Citric Acid 5 PEO 600.000 delayed the
    release.
    Matrix %
    Ingredient w/w Conclusion
    EC-042-047 PEO 200.000 63 Zero-order, release time
    50 mg Carvedilol Carvedilol 32 14 h.
    Citric Acid 5
    EC-042-049 PEO 200.000 63 Succinic acid could be used
    50 mg Carvedilol Carvedilol 32 instead of citric acid as
    Succinic Acid 5 release time and release
    pattern were the same.
    EC-042-053 PEO 200.000 65.5 Amount of citric acid too
    50 mg Carvedilol Carvedilol 32 small. Same slope in acid
    Citric Acid 2.5 and buffer was not observed.
    EC-042-054 PEO 200.000 58 Amount of citric acid too
    50 mg Carvedilol Carvedilol 32 high. Same slope in acid and
    Citric Acid 10 buffer was not observed.
    EC-042-073 PEO 200.000 61 Almost zero-order release.
    50 mg Carvedilol Carvedilol 32 Release in acid faster than in
    Citric Acid 5 buffer. Matrix left in the shell.
    Tristearin 2
    EC-042-077 PEO 200.000 81.5 Zero-order release, release
    25 mg Carvedilol Carvedilol 16 time 14 h. Comparable with
    Citric Acid 2.5 50 mg carvedilol EC-042-047
    EC-042-078 PEO 200.000 90.75 Zero-order release, release
    12.5 mg Carvedilol Carvedilol 8 time 14 h. Comparable with
    Citric Acid 1.25 50 mg and 25 mg EC-042-047
    and EC-042-077
    EC-042-079 PEO 200.000 79 Release profile in acid
    25 mg Carvedilol Carvedilol 16 medium was increased when
    Citric Acid 5 Citric Acid/Carv increased
    EC-042-080 PEG 35.000 63 PEG 35000 increased
    50 mg Carvedilol Carvedilol 32 the release in acid
    Citric Acid 5 medium. Undesired
    EC-042-084 PEO 200.000 74 Almost zero-order, release
    50 mg Carvedilol Carvedilol 16 time 13 h. Aluminium lactate
    Citric Acid 5 reduced the release in acid
    Aluminum lactate 5 medium.
    Addition of Zink Sulphate
    EC-042-085 PEO 200.000 77.5 Zero-order release, release
    25 mg Carvedilol Carvedilol 16 time 14 h.
    Citric Acid 5 Zink Sulphate decreased
    Zink Sulphate 1.5 release in acid compared to
    buffer.
    EC-042-086 PEO 200.000 74.5 Zero-order release, release
    25 mg Carvedilol Carvedilol 16 time 14 h.
    Citric Acid 5 Zink Sulphate decreased
    Zinc Sulphate 4.5 release in acid compared to
    buffer
    EC-042-087 PEO 200.000 79.5 Zero-order release, release
    25 mg Carvedilol Carvedilol 16 time 13 h. Zink Sulphate
    Citric Acid 2.5 decreased release in acid
    Zinc Sulphate 2
    Polymer with inorganic ingredients
    EC-042-040 PEO 200.000 52 No release in buffer medium.
    50 mg Carvedilol PEG 2000 ms 6 See also EC-042-037, not
    Carvedilol 32 comprising SiO2
    SiO2 10
    Batch Matrix %
    No. Formulation Ingredient w/w Conclusion
    Polymer
    042-130 50 mg Carvedilol PEO 100.000 74.8 The dissolution profile
    Carvedilol 24 shows zero-order release.
    Potassium Sulfite 0.2
    Sucrose 0.5
    BHT 0.5
    042-149 50 mg Carvedilol PEO 200.000 LF 76 The dissolution profile
    Carvedilol 24 shows zero-order release,
    however different slope
    between acid and buffer.
    Organic antioxidants
    042-115 50 mg Carvedilol PEO 200.000 75.9 Diminishes degradation
    Carvedilol 24 of PEO 200.000 and
    Ascorbic acid 0.1 Carvedilol. The
    dissolution profile shows
    zero-order release.
    042-116 50 mg Carvedilol PEO 100.000 75.9 Diminishes degradation
    Carvedilol 24 of PEO 100.000 and
    Ascorbic acid 0.1 Carvedilol. The
    dissolution profile shows
    zero-order release.
    042-133 50 mg Carvedilol PEO 200.000 72.3 Diminishes degradation
    Carvedilol 24 of PEO 200.000 and
    Potassium Sulfite 0.2 Carvedilol. The
    Salicylic acid 3 dissolution profile shows
    BHT 0.5 zero-order release.
    042-135 50 mg Carvedilol PEO 200.000 74.7 The increased dosage of
    Carvedilol 24 BHT did not produce any
    Potassium significant change in the
    Metabisulfite 0.2 level of impurities caused
    BHT 1 by PEO 200.000
    Gentisic acid 0.1 compred to 0.5% BHT
    The dissolution profile
    does not show zero-order
    release.
    042-136 50 mg Carvedilol PEO 200.000 74.6 The increased dosage of
    Carvedilol 24 BHT did not produce any
    Potassium significant change in the
    Metabisulfite 0.2 level of impurities caused
    BHT 1 by PEO 200.000
    Gentisic acid 0.2 compatred to 0.5% BHT
    The dissolution profile
    does not show zero-order
    release.
    042-141 50 mg Carvedilol PEO 200.000 64.765 The increased dosage of
    Carvedilol 24 BHT did not produce any
    Potassium significant change in the
    Metabisulfite 0.2 level of impurities caused
    BHT 1 by PEO 200.000
    Sorbitol 10 compared to 0.5% BHT
    HCl 0.035 The dissolution profile
    does not show zero-order
    release.
    2.3 Inorganic antioxidants
    042-117 50 mg Carvedilol PEO 200.000 75.9 Diminishes degradation of
    Carvedilol 24 PEO 200.000 and
    Potassium Carvedilol. The
    Metabisulfite 0.1 dissolution profile shows
    zero-order release.
    042-133 50 mg Carvedilol PEO 200.000 72.3 Diminishes degradation of
    Carvedilol 24 PEO 200.000 and
    Potassium Carvedilol. The
    Metabisulfite 0.2 dissolution profile shows
    Salicylic acid 3 zero-order release.
    BHT 0.5
    042-134 50 mg Carvedilol PEO 200.000 74.8 Diminishes degradation of
    Carvedilol 24 PEO 200.000 and
    Potassium Carvedilol. The
    Metabisulfite 0.2 dissolution profile shows
    BHT 1 zero-order release.
    6. Sugars
    042-118 50 mg Carvedilol PEO 200.000 75.8 The dissolution profile
    Carvedilol 24 shows zero-order release.
    Potassium Sulfite 0.1
    Sucrose 0.1
    042-120 50 mg Carvedilol PEO 200.000 70.9 Production cancelled, the
    Carvedilol 24 Concentrasion of
    Potassium Sulfite 0.1 Sucrose to hight for the
    Sucrose 5.0 selected process
    parameters. May be
    produced with increased
    temperature
    042-121 50 mg Carvedilol PEO 200.000 65.9 Carvedilol precipitated
    Carvedilol 24 when standing.
    Potassium Sulfite 0.1
    Mannitol 10
    042-122 50 mg Carvedilol PEO 200.000 73.3 Concentration of Sucrose
    Carvedilol 24 to high for the selected
    Potassium Sulfite 0.2 process parameters. May
    Sucrose 2 be produced with
    BHT 0.5 increased temperature.
    042-123 50 mg Carvedilol PEO 200.000 71.8 The concentration was
    Carvedilol 24 too high and resulted in
    Potassium Sulfite 0.2 process problems.
    Sucrose 3.5 Production cancelled.
    BHT 0.5
    042-129 50 mg Carvedilol PEO 200.000 74.8 The dissolution profile
    Carvedilol 24 shows zero-order
    Potassium Sulfite 0.2 release.
    Sucrose 0.5
    BHT 0.5
    042-130 50 mg Carvedilol PEO 100.000 74.8 The dissolution profile
    Carvedilol 24 shows zero-order
    Potassium Sulfite 0.2 release.
    Sucrose 0.5
    BHT 0.5
    042-137 50 mg Carvedilol PEO 200.000 59.8 Mannitol did not produce
    Carvedilol 24 the expected result,
    Potassium because Carvedilol
    Metabisulfite 0.2 precipitated when
    BHT 1 standing.
    Mannitol 15
    042-141 50 mg Carvedilol PEO 200.000 64.765 Carvedilol precipitated
    Carvedilol 24 after standing
    Potassium approximately one week.
    Metabisulfite 0.2
    BHT 1
    Sorbitol 10
    HCl 0.035
    Increase in hydrogen bondings
    042-128 50 mg Carvedilol PEO 200.000 74.8 Carvedilol precipitated
    Carvedilol 24 after standing
    Potassium approximately one week.
    Metabisulfite 0.2 Dissolution profile shows
    2-amino- zero-order release.
    2(hydroxymethyl)1,3
    ropandiol 0.5
    BHT 0.5
    042-131 50 mg Carvedilol PEO 200.000 74.3 Dissolution profile shows
    Carvedilol 24 zero-order release.
    Potassium
    Metabisulfite 0.2
    Klucel 1
    BHT 0.5
    042-142 50 mg Carvedilol PEO 200.000 74 The dissolution profile is
    Carvedilol 24 zero-order.
    PVP K90 2
    042-143- 50 mg Carvedilol PEO 200.000 71 Dissolution not zero-
    02-001 Carvedilol 24 order.
    Sorbitol 5
    042-144 50 mg Carvedilol PEO 200.000 73 Dissolution not zero-
    Carvedilol 24 order.
    Cyclodextrin 3
    042-145 50 mg Carvedilol PEO 200.000 69 Dissolution not zero-
    Carvedilol 24 order.
    Cyclodextrin 7
    042-141 50 mg Carvedilol PEO 200.000 64.765 Dissolution profile does
    Carvedilol 24 not show zero-order
    Potassium release, possibly due to
    Metabisulfite 0.2 the amount of BHT.
    BHT 1
    Sorbitol 10
    HCl 0.035
    042-148 50 mg Carvedilol PEO 200.000 72 The dissolution profile
    Carvedilol 24.1 does not show zero-order
    Potassium release possibly due to
    Metabisulfite 0.2 the amount of BHT.
    BHT 1
    KH2PO4 0.32
    HCl 0.61
    PVP K90 1.7
    042-153 50 mg Carvedilol PEO 200.000 68.5 Test of granulation
    Carvedilol 24 method
    Potassium
    Metabisulfite 0.2
    BHT 0.5
    KH2PO4 0.20
    H3PO4 4.6
    PVP K90 2.0
  • Examples disclosing Formulation Nos 68 to 84. [0322]
  • 6 mm oval shaped formulations 150 mm[0323] 2
    0068 Dry mixing with solid phosphoric acid.
    PEO 200.000, pH 7.27
    Carv.(24.0%), Base line Dissolution zero-order, erosion time 7 hours, not
    PM (0.2%), complete dissolution at hour 8, matrix on bottom of vessel
    BHT(0.5%);
    Meta-Phosphoric acid* Carv/acid*: 4.6
    (5.2%); Carv/HPO3: 10.9)
    PVP K90 (2.0%)
    0069 Dry mixing: Acid(s) and PEO mixed in mortar. Blended and
    PEO 200.000 81.7% crushed. All mixed. Mix kept dry.
    Carv.(12.0%), pH 7.27
    PM (0.2%), Appearance of tablets after production:
    BHT(0.5%); Transparent yellowish
    Meta-Phosphoric acid* Baseline Dissolution, zero-order, erosion time 6.5 hours,
    (3.6%) complete dissolution at hour 7
    PVP K90 (2.0%) Dissolution in simulated fasted and fed media zero-order
    (FIGS. 8 and 9)
    Carv/acid*: 3.3
    Carv/HPO3: 7.9)
    Appearance/Dissolution after 26 days storage at
    30° C./60% Rh:
    Transparent yellowish/Zero-order erosion time 6 hours,
    complete dissolution after 6.5 hours (FIG. 10)
    Not produced Carvedilol/acid ratio 3.3* (7.9 based on HO3P)
    PEO 200.000 LF83.7% Exptected values:
    Carv.(12.0%), pH about 6
    PM (0.2%), Appearance of tablets transparent yellowish
    BHT(0.5%); Dissolution, zero-order
    Meta-Phosphoric acid*
    (3.6%)(42.1% HO3P)
    0070 Dry mixing: H3PO4(s) in PEO. Then mixed with rest. Mix
    PEO 200.000, kept dry.
    Carv.(24.0%), pH 5.93
    PM (0.2%), Appearance after production: White
    BHT(0.5%); Baseline Dissolution: Carvedilol.not released in buffer due
    Ortho-Phosphoric acid to crystallization.
    (4.4%); Carvedilol/acid**: 5.45
    PVP K90 (2.0%)
    Composition Dry mixing: H3PO4(s) in PEO. Then mixed with rest. Mix
    0073 kept dry.
    PEO 200.000 (LF), pH 3.23
    Carv. (18.0%), Appearance after production: Transparent yellowish,
    PM (0.2%), Dissolution:
    BHT(0.5%); Dissolution, zero-order, erosion time 6 hours, complete
    Ortho-Phosphoric acid dissolution at hour 6.5
    (4.5%); Carv/acid**: 4
    PVP K90 (2.0%) Appearance: After 1-2 weeks storage white
    0075
    PEO 200.000(LF) Dry mixing: H3PO4(s) in 40 g PEO. Rest of PEO mixed
    Carv. (18.0%), with carv. + antioxidants. Mixed all. Mix kept dry.
    PM (0.2%), pH 5.71
    BHT(0.5%); Appearance after production: White
    Ortho-Phosphoric acid Dissolution: Cancelled due to crystallization
    (3.6%); Carv/acid**: 5
    PVP K90 (2.0%)
    0083 Dry mixing: Powders mixed and H3PO4 (I) mixed in some
    PEO 200.000(LF), of the powders. All mixed. Mix kept dry. pH in mixture 3.84
    Carv. (12.0%), Appearance after production: White
    PM (0.2%), Dissolution: Cancelled due to crystallization
    BHT(0.5%); Carv/acid**: 5
    Ortho-Phosphoric acid
    (2.4%);
    PVP K90 (2.0%)
    0084 pH 3.23 (mixture)
    PEO 200.000 (LF), Appearance after production: Transparent yellowish,
    Carv. (12.0%), Dissolution: Zero-order, erosion time 6 hours, complete
    PM (0.2%), dissolution at hour 6.5
    BHT(0.5%);
    Meta-Phosphoric acid* Carv/acid*: 3.3
    (3.6%); Carv/HPO3: 7.9)
    PVP K90 (2.0%)
  • A General Method for the Preparation of a Controlled Release Composition is Described Below for the Following Examples Preparation of the Matrix Composition
  • An accurate amount of the polymer (i.e. in the examples below: the polyethylene oxide) is loaded into a MTI mixer followed by an accurate amount of the active substance and of the pharmaceutically acceptable excipients(s), if any. The mixing is performed at 2000/1500 rpm and at a time period of from 10 min to 20 min. At the start of the mixing the temperature is about 19° C. and the final temperature of the mixture is about 40-43° C. The mixture is then allowed to cool to room temperature and is ready to be fed into an injection moulding machine. [0324]
  • When TPGS is included in the composition, TPGS and PEO are premixed by adding melted TPGS to PEO followed by mixing. [0325]
  • Example 9 Preparation of a Morphine Containing Controlled Release Composition According to the Invention
  • A composition (batch No. 01-0112-066) according to the invention was prepared from the following ingredients: [0326]
    Matrix
    Polyethylene oxide 200,000 83.5% w//w
    Morphine sulfate 16.5% w/w
  • The coating and the matrix were prepared as described above. The composition was 9 mm long and had elliptic formed surfaces. [0327]
  • The composition was subjected to the dissolution test described above. The following results were obtained: [0328]
    % w/w release morphine
    Time (hours) sulfate from the composition
    9 19.48
    10 33.64
    11 44.22
    12 55.59
    13 70.11
    14 80.70
    15 91.30
    16 96.65
  • The result is also shown in FIG. 12 and the release corresponds to a zero order release. [0329]
  • Example 10 Preparation of Morphine-containing Compositions According to the Invention
  • In the table below is given details on the composition of 4 different morphine compositions. The content of morphine sulphate in all compositions corresponds to 30 mg morphine sulphate. The volumes of the different compositions were the same, whereas the diameter of the open end surfaces varies. [0330]
    Composition (% w/w)
    PEO Morphine AlO2,
    No. Length/mm 200.000 Sulphate TPGS 3H2O Mannitol
    1B 7.5; Ellipsea 76.5 18.7 2.5 2.3
    2B 12; roundb 68.7 18.7 2.6 10.0
    2A 9; roundc 69.9 17.5 2.6 10.0
    1A 9; roundd 77.3 17.9 2.5 2.4
  • All compositions demonstrated 6 months accelerated stability at 40° C./75% RH and 12 months stability at 25° C./75% RH. In all compositions each single impurity is below 0.1% w/w. [0331]
  • In the following is given the data for the dissolution profiles of each composition: [0332]
  • Composition 2A (see FIG. 13-[0333] 2A):
    % active
    substance
    Time/h dissolved
    0.0 −0.36
    1.0 23.45 20.0
    2.0 41.3 35.2
    3.0 59.5 50.7
    4.0 75.93 64.7
    5.0 90.83 77.4
    6.0 107.34 91.5
    6.5 113.26 96.6
    7.0 116.67 99.4
    7.5 117.24 100
    8.0 117.28 100
  • Composition 2B (see FIG. 14-2B) [0334]
    % active
    substance
    Time/h dissolved
    0.0 −0.48
    1.0 19.22 16.9
    2.0 34.44 30.0
    3.0 44.3 39.0
    4.0 55.52 48.8
    5.0 66.13 58.2
    6.0 76.93 67.7
    7.0 87.19 76.7
    8.0 98.11 86.3
    9.0 109.04 96.0
    9.5 111.26 97.8
    10.0 112.63 99.1
    10.5 113.48 100
    11.0 113.66 100
  • Composition 1B (see FIG. 13-1B) [0335]
    % active
    substance
    Time/h dissolved
    0.0 −0.47
    1.0 30.15 23.7
    2.0 55.72 43.9
    3.0 77.54 61.1
    4.0 97.55 76.8
    5.0 117.57 92.6
    5.5 124.77 98.2
    6.0 126.89 100
    6.5 126.93 100
  • Composition 1A (see FIG. 13-1A) [0336]
    % active
    substance
    Time/h dissolved
    0.0 −0.423
    1.0 23.17 19.3
    2.0 40.47 33.8
    3.0 53.27 44.4
    4.0 67.13 56.0
    5.0 80.67 67.3
    6.0 101.23 84.4
    7.0 108.16 90.2
    7.5 114.53 95.6
    8.0 119.78 100
  • The results show that the use of mannitol or aluminiumoxide as a DDA leads to the desired zero order release of morphine sulphate from a composition according to the invention. The above-mentioned compositions were subject to a clinical study. The clinical study is reported in the following example. [0337]
  • Example 11 A Single Dose, Randomized, Cross-over, Pharmacokinetic Pilot Study on Four Different Morphine Compositions According to the Invention
  • The objectives were to study the pharmacokinetics of morphine after administration of four different morphine compositions according to the invention. The compositions had different shape and size and the DDAs employed in order to enable a zero order dissolution profile were different (mannitol and aluminium oxide, respectively). [0338]
  • 16 healthy male volunteers aged 20 to 40 who had given their written informed consent were included in the study. [0339]
  • The volunteers were screened up to three weeks prior to baseline. The first treatment was administered at the baseline visit and second treatment was administered after 2 weeks of wash out. Follow-up visits took place 30 days after the second study period. [0340]
  • The compositions tested were those described in Example 2 above. The dose given corresponds to 30 mg morphine sulphate. [0341]
  • The results of the study are shown in FIG. 14. In FIG. 14 is also included data for a comparitive composition, Dolcontin. The results indicate that the shape as well as the size of the composition are important. [0342]
  • Another clinical study has also been performed as a phase II, open, prospective, controlled study in patients with chronic pain. The study included 13 patients with chronic pain for any reason judged by the investigator as stable and in need of opioids analgesics. A composition according to the invention was tested and compared with a commercially available morphine containing composition, Dolcontin. The total morphine sulphate released from the composition according to the invention was about 20 mg (the dosage in Dolcontin was 30 mg). Although there was a difference in the amount administered, it was evident from the study that the therapeutic effect of a composition according to the invention was not different from Dolcontin, i.e. a reduction is the overall dose may be reduced by the use a zero order release composition. Moreover, the adverse effects reported were less compared to the Dolcontin composition, most likely due to the smaller amount of morphine sulphate administered. Another interesting feature is that during the study rescue medication was allowed and there was no difference in the intake of rescue medicine of patients administered with Dolcontin or with a composition according to the invention. FIG. 15 shows the plasma concentration versus time profiles from the study. [0343]

Claims (65)

  1. 1. A method for controlling the release of at least one therapeutically, prophylactically and/or diagnostically active substance into an aqueous medium by erosion of at least one surface of a pharmaceutical composition comprising
    i) a matrix composition comprising a) a substantially water soluble or crystalline polymer or a mixture of substantially water soluble and/or crystalline polymers, b) an active substance and, optionally, c) one or more pharmaceutically acceptable excipients, and
    ii) a coating having at least one opening exposing at the one surface of said matrix, the coating comprising
    a) a first cellulose derivative which has thermoplastic properties and which is substantially insoluble in the aqueous medium in which the composition is to be used and at least one of
    b) a second cellulose derivative which is soluble or dispersible in water,
    c) a plasticizer, and
    d) a filler, and wherein the diffusion rate of the aqueous medium into the matrix composition corresponds to about 100%±30% such as, e.g. about 100%±25%, about 100%±20%, about 100%±15% or about 100%±10% or about 100% of the dissolution rate of the matrix composition, and wherein any matrix surface exposed to the aqueous medium erodes so as to obtain a zero order release of at least about 60% w/w such as, e.g. at least about 65% w/w at least about 70% w/w, at least about 75% w/w, at least about 80% w/w, at least about 85% w/w, at least about 90% w/w, at least about 95% w/w or at least about 97 or 98% w/w of the active substance from the pharmaceutical composition when subject to an in vitro dissolution test as described herein.
  2. 2. A method according to claim 1, wherein the polymer is a substantially water soluble or crystalline polymer or a mixture of substantially water soluble and/or crystalline polymers.
  3. 3. A method according to claim 1, wherein the matrix comprises a pharmaceutically acceptable excipient functioning as a diffusion and dissolution adjusting agent.
  4. 4. A method according to claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of inorganic acids, inorganic bases, inorganic salts, organic acids or bases and pharmaceutically acceptable salts thereof, saccharides, oligosaccharides, polysaccharides, and cellulose and cellulose derivatives.
  5. 5. A method according to claim 4, wherein the organic acid is a mono-, di-, oligo, polycarboxylic acid or an amino acid selected from the group consisting of acetic acid, ethanoic acid, succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, adipic acid, angelic acid, ascorbic acid/vitamin C, carbamic acid, cinnamic acid, citramalic acid, formic acid, fumaric acid, gallic acid, gentisic acid, glutaconic acid, glutaric acid, glyceric acid, glycolic acid, glyoxylic acid, lactic acid, levulinic acid, malonic acid, mandelic acid, oxalic acid, oxamic acid, pimelic acid pyruvic acid, aspartic acid , and glutamic acid.
  6. 6. A method according to claim 4, wherein the inorganic acid is selected from the group consisting of pyrophosphoric, glycerophosphoric, phosphoric such as ortho or meta phosphoric, boric acid, hydrochloric acid, and sulfuric acid.
  7. 7. A method according to claim 4, wherein the suitable inorganic compounds include aluminium.
  8. 8. A method according to claim 4, wherein the suitable organic bases are selected from the group consisting of p-nitrophenol, succinimide, benzenesulfonamide, 2-hydroxy-2cyclohexenone, imidazole, pyrrole, diethanolamine, ethyleneamine,tris (hydroxymethyl) aminomethane, hydroxylamine and derivates of amines, sodium citrate, aniline, and hydrazine.
  9. 9. A method according to claim 4, wherein the suitable inorganic bases are selected from the group consisting of aluminium oxide such as, e.g., aluminium oxide trihydrate, alumina, sodium hydroxide, potassium hydroxide, calcium carbonate, ammonium carbonate, ammnonium hydroxide, KOH and the like.
  10. 10. A method according to claim 4, wherein the pharmaceutically acceptable salt of an organic acid is e.g. an alkali metal salt or an alkaline earth metal salt selected from the group consisting of sodium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate, potassium phosphate, potassium dihydrogenphosphate, potassium hydrogenphosphate, calcium phosphate, dicalcium phosphate, sodium sulfate, potassium sulfate, calcium sulfate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, calcium carbonate, magnesium carbonate, sodium acetate, potassium acetate, calcium acetate, sodium succinate, potassium succinate, calcium succinate, sodium citrate, potassium citrate, calcium citrate, sodium tartrate, potassium tartrate, calcium tartrate, zinc gluconate, and zinc sulphate.
  11. 11. A method according to claim 4, wherein the inorganic salt is sodium chloride, potassium chloride, calcium chloride, or magnesium chloride etc.
  12. 12. A method according to claim 4, wherein the pharmaceutically acceptable excipient is selected from the group consisting of glucose and other monosaccharides, ribose, arabinose, xylose, lyxose, allose, altrose, inosito, glucose, sorbitol, mannose, gulose, idose, galactose, talose, mannitol, fructose, lactose, sucrose, and other disaccharides, dextrin, dextran or other polysaccharides, amylose, xylan, cellulose and cellulose derivatives such as, e.g. microcrystalline cellulose, methyl cellulose, ethyl cellulose, ethylhydroxyethyl cellulose, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxymethylpropyl cellulose, hydroxypropylmethyl cellulose, amylopectin, pectin, starch, sodium starch etc., kaolin, bentonit, acacia, alginic acid, sodium alginate, calcium alginate, gelatin, dextrose, molasses, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husk, veegum, glycollate, magnesium stearate, calcium stearate, stearic acid, talc, titanium dioxide, silicium dioxide, clays, croscarmellose, gums, and agar.
  13. 13. A method according to claim 1 further comprising a pharmaceutically acceptable excipient selected from the group consisting of fillers, diluents, disintegrants, glidants, pH-adjusting agents, viscosity adjusting agents, solubility increasing or decreasing agents, osmotically active agents and solvents.
  14. 14. A method according to claim 1, wherein the polymer matrix comprises a polyglycol.
  15. 15. A method according to claim 1, wherein the matrix comprises a homopolymer and/or a copolymer.
  16. 16. A method according claim 1, wherein the matrix comprises a polyethylene glycol, a polyethylene oxide and/or a block copolymer of ethylene oxide and propylene oxide including including poly(ethylene-glycol-b-(DL-lactic acid-co-glycolic acid)-b-ethylene glycol (PEG-PLGA PEG), poly((DL-lactic acid-co-glycolic acid)-g-ethylene glycol) (PLGA-g-PEG), and polyethylene oxide-polypropylene oxide (PEO-PPO).
  17. 17. A method according to claim 16, wherein the polyethylene glycol, a polyethylene oxide and/or a block copolymer of ethylene oxide and propylene oxide has a molecular weight of from about 20,000 daltons, such as, e.g., from about 20,000 to about 700,000 daltons, from about 20,000 to about 600,000 daltons, from about 35,000 to about 500,000 daltons, from about 35,000 to about 400,000 daltons, from about 35,000 to about 300,000 daltons, from about 50,000 to about 300,000 daltons, such as, e.g. about 35,000 daltons, about 50,000 daltons, about 75,000 daltons, about 100,000 daltons, about 150,000 daltons, about 200,000 daltons, about 250,000 daltons, about 300,000 daltons or about 400,000 daltons.
  18. 18. A method according to claim 16, wherein the block copolymer of ethylene oxide and propylene oxide comprises up to about 30% w/w of the propylene oxide based block, and has a molecular weight of about 5,000 daltons, typically about 5,000 to about 30,000 daltons such as, e.g. from about 8,000 to about 15,000 daltons.
  19. 19. A method according to claim 1, wherein the matrix comprises a polymer which has a melting point of about 20-120° C. such as, e.g. from about 30 to about 100° C. or from about 40 to about 80° C.
  20. 20. A method according to claim 1, wherein the active substance is present in the matrix composition in a concentration of from about 0.1 to about 98% w/w such as, e.g. at the most about 90% w/w, at the most about 85% w/w, at the most about 80% w/w, at the most about 75% w/w, at the most about 70% w/w, at the most about 65% w/w or at the most about 60% w/w.
  21. 21. A method according to claim 1, wherein the active substance is a substance for human or veterinary use, a vitamin or other nutritional supplement, a disinfectant, a deodorant or another substance to be administered continuously in an aqueous environment.
  22. 22. A method according to claim 1, wherein the active substance is present in the matrix at least partly on amorphous form.
  23. 23. A method according to claim 1, wherein the active substance is a pharmaceutically active powder.
  24. 24. A method according to claim 23, wherein the powder has a particle size of from about 0.1 μm to about 500 μm, typically from about 0.5 μm to about 300 μm, more typically from about 1 μm to about 200 μm, especially from about 5 μm to about 100 μm.
  25. 25. A method according to claim 1, wherein the at least one therapeutically, prophylactically and/or diagnostically active substance has a solubility of at the most about 3 mg/ml such as, e.g. at the most about 1 mg/ml, at the most about 0.1 mg/ml, at the most about 0.05 mg/ml such as, e.g. at the most about 0.001 mg/ml in water at ambient temperature.
  26. 26. A method according to claim 25, wherein the matrix composition comprises a pharmaceutically acceptable excipient which has a solubility of at least 1 mg/ml such as, e.g. at least about 3 mg/ml, at least about 5 mg/ml, at least about 10 mg/ml, at least about 25 mg/ml or at least about 50 mg/ml in water at ambient temperature.
  27. 27. A method according to claim 1, wherein the at least one therapeutically, prophylactically and/or diagnostically active substance has a solubility of at least about 3 mg/ml such as, e.g., at least about 5 mg/ml, at least about 10 mg/ml, at least about 20 mg/ml, at least about 50 mg/ml or at least about 100 mg/ml in water at ambient temperature.
  28. 28. A method according to claim 27, wherein the matrix composition comprises a pharmaceutically acceptable excipient, which has a solubility of at the most about 3 mg/ml such as, e.g., at the most about 1 mg/ml, at the most about 0.1 mg/ml, at the most about 0.05 mg/ml such as, e.g. at the most about 0.001 mg/ml in water at ambient temperature.
  29. 29. (Cancelled).
  30. 30. A method according to claim 1, wherein in the aqueous medium in which the composition is to be used, the coating does not completely crumble or erode before the matrix has completely eroded.
  31. 31. A method according claim 1, wherein said first cellulose derivative is a cellulose ether which, when heated, is shapeable by molding or extrusion, including injection molding, blow molding and compression molding.
  32. 32. A method according to claim 31 in which the cellulose ether comprises at least one ethylcellulose.
  33. 33. (Cancelled).
  34. 34. (Cancelled).
  35. 35. A method according to claim 1 in which said first cellulose derivative is selected from the group consisting of cellulose acetate, cellulose propionate and cellulose nitrate.
  36. 36. A method according to claim 1 in which said second cellulose derivative is selected from the group consisting of methylcellulose, carboxymethylcellulose and salts thereof, cellulose acetate phthalate, microcrystalline cellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, hydrocyethylcellylose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose and hydroxymethylpropylcellulose.
  37. 37. A method according to claim 36 in which said salt of carboxymethylcelllulose is selected from the group consisting of alkali metal and alkaline earth metal salts.
  38. 38. A method according to claim 1, in which said plasticizer is selected from the group consisting of phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters thereof with polyethylene glycol, glycerin or sugars; fatty alcohols and ethers thereof with polyethylene glycol, glycerin or sugars; vegetable oils and hydrogenated vegetable oils; nitrobenzene, carbon disulfide, β-naphtyl salicylate, phthalyl glycolate, and diocyl phthalate.
  39. 39. A method according to claim 38 in which said fatty alcohol is selected from the group consisting of cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol and myristyl alcohol.
  40. 40. A method according to claim 1 in which said plasticizer is a non-ionic surfactant.
  41. 41. A method according to claim 1, wherein the matrix composition does not contain polyethylene glycol 2000 monostearate or polyethylene glycol 400 monostearate.
  42. 42. (Cancelled).
  43. 43. (Cancelled).
  44. 44. (Cancelled).
  45. 45. (Cancelled).
  46. 46. (Cancelled).
  47. 47. A method according to claim 1, wherein the polymer is a polyethylene oxide having a molecular weight of at least 100,000 daltons and at the most 300,000 daltons.
  48. 48. A method according to claim 1, wherein the pharmaceutically acceptable excipient is present and is a mono-, di-, oligo or polycarboxylic acid selected from the group consistin of acetic acid, succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, and sorbic acid.
  49. 49. A method according to claim 1, wherein the pharmaceutically acceptable excipient is present and is selected from mannitol, xylitol, sorbitol and inositol.
  50. 50. A method according to claim 1, wherein the pharmaceutically acceptable excipient is an aluminium oxide.
  51. 51. A method according to claim 1, wherein comprising PEO 200,000 as polymer and mannitol and/or aluminium oxide as pharmaceutically acceptable excipient.
  52. 52. A method according to claim 1, wherein the pharmaceutically acceptable excipient is an inorganic acid such as phosphoric acid including ortho phosphoric acid and meta phosphoric acid.
  53. 53. A pharmaceutical composition for controlled release of at least one therapeutically, prophylactically and/or diagnostically active substance into an aqueous medium by erosion of at least one surface of the composition, the composition comprising
    i) a matrix composition comprising a) a polymer or a mixture of polymers, b) an active substance and, optionally, c) one or more pharmaceutically acceptable excipients, and
    ii) a coating having at least one opening exposing at the one surface of said matrix, the coating comprising
    a) a first cellulose derivative which has thermoplastic properties and which is substantially insoluble in the aqueous medium in which the composition is to be used, and at least one of
    b) a second cellulose derivative which is soluble or dispersible in water,
    c) a plasticizer, and
    d) a filler,
    and wherein the diffusion rate of the aqueous medium into the matrix composition corresponds to about 100%±30% such as, e.g. about 100%±25%, about 100%±20%, about 100%±15% or about 100%±10% or about 100% of the dissolution rate of the matrix composition, and wherein any matrix surface exposed to the aqueous medium erodes at a substantially constant rate, so as to obtain a zero order release of at least about 60% w/w such as, e.g. at least about 65% w/w at least about 70% w/w, at least about 75% w/w, at least about 80% w/w, at least about 85% w/w, at least about 90% w/w, at least about 95% w/w or at least about 97 or 98% w/w of the active substance from the pharmaceutical composition when subject to an in vitro dissolution test as described herein.
  54. 54. A stable controlled release pharmaceutical composition for oral use comprising a solid dispersion of component i) and ii)
    i) at least one therapeutically, prophylactically and/or diagnostically active substance, which at least partially is in an amorphous form,
    ii) a pharmaceutically acceptable polymer that has plasticizing properties and which has a melting point or melting interval of a temperature of at the most 200° C.,
    and, optionally, iii) a stabilizing agent, wherein the at least one therapeutically, prophylactically and/or diagnostically active substance has a water solubility of at the most 3 mg/ml at 25° C. such as, e.g. at the most about 2 mg/ml, at the most about 1 mg/ml, and the concentration of the active substance in the composition corresponds to a concentration of at the most the saturated concentration in component ii) at a temperature corresponding to the melting point or the lowest end point of the melting interval of component ii) optionally together with component iii).
  55. 55. A composition according to claim 54, wherein component ii) is a polyethylene glycol and/or a polyethylene oxide having a molecular weight of at least about 20,000 in crystalline and/or amorphous form or a mixture such polymers.
  56. 56. A composition according to claim 54, wherein component ii) is of a quality that ensures that free radicals formed, if any, do not significantly increase the degradation of the active substance in the composition.
  57. 57. A composition according to claim 53 or 54 comprising a stabilizing agent.
  58. 58. A composition according to claim 54 comprising one or more antioxidants that inhibits the formation of peroxides and/or inactivates any peroxides present.
  59. 59. A composition according to claims 53 or 54, wherein the composition is stable with respect to physical stability.
  60. 60. A composition according to claims 53 or 54, wherein the composition is stable with respect to in vitro dissolution of the active substance from the composition.
  61. 61. A composition according to claim 60, wherein the composition is stable with respect to in vitro dissolution behaviour in such a manner that t50%, i.e. the time for 50% w/w of the active substance to dissolve in a dissolution medium, differs at the most ±20% w/w such as, e.g., at the most ±15% w/w, at the most ±10% w/w, at the most ±7.5% w/w, at the most ±5% w/w, at the most ±2.5% w/w, at the most ±1.5% w/w or at the most 1% w/w when two compositions from the same batch is compared with a time difference of 2 weeks under similar storage and test conditions.
  62. 62. A composition according to claims 53 or 54, wherein the composition is stable with respect to chemical stability of the active substance.
  63. 63. A composition according to claim 62, wherein the concentration of the active substance in the composition decreases at the most 20% w/w such as, e.g. at the most 15% w/w, at the most 10% w/w, at the most 7.5% w/w or at the most 5% w/w when stored at room temperature for a time period of at least 3 months such as, e.g. 6 months, 12 months, 18 months or 24 months and a relative humidity of at the most 75% such as, e.g., at the most 70%, at the most 65%, at the most 60%, at the most 55%, at the most 50% or at the most 45%.
  64. 64. A composition according to claims 53 or 54 containing carvedilol as active substance in a concentration of at the most about 23% w/w such as, e.g., at the most about 22% w/w, at the most about 21% w/w or at the most about 20% w/w.
  65. 65. A composition according to claim 64 containing carvedilol as active substance and PEO 200,000 as component ii) and wherein the concentration of carvedilol in PEO 200,000 is at the most about 22% w/w, at the most about 21% w/w or at the most about 20% w/w.
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Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040052754A1 (en) * 2000-11-14 2004-03-18 West Simon Michael Complexes of phosphate derivatives
US20040071777A1 (en) * 2000-12-22 2004-04-15 Laura Trespidi Solid dispersions of nitrate active principles
US20040096493A1 (en) * 2001-06-06 2004-05-20 West Simon Michael Formulation containing phopshate derivatives of electron transfer agents
US20040253318A1 (en) * 2001-07-27 2004-12-16 West Simon Michael Dermal therapy using phosphate derivatives of electron transfer agents
US20050089495A1 (en) * 2001-12-13 2005-04-28 West Simon M. Transdermal transport of compounds
US20050089569A1 (en) * 1998-04-03 2005-04-28 Bm Research A/S Controlled release composition
US20060099168A1 (en) * 2004-11-05 2006-05-11 Italo Corzani Polymeric compositions for sustained release of volatile materials
US20060241085A1 (en) * 2003-01-17 2006-10-26 West Simon M Compounds having anti-proliferative properties
US20060257459A1 (en) * 2002-08-09 2006-11-16 West Simon M Carrier
US20060281716A1 (en) * 2004-03-03 2006-12-14 West Simon M Alkaloid formulations
US20070003617A1 (en) * 2003-03-26 2007-01-04 Egalet A/S Morphine controlled release system
US20070042044A1 (en) * 2003-03-26 2007-02-22 Egalet A/S Matrix compositions for controlled delivery of drug substances
US20070135390A1 (en) * 2003-04-15 2007-06-14 West Micheal S Phosphate derivatives
US20070178152A1 (en) * 2005-11-04 2007-08-02 Shelton Michael C Carboxyalkylcellulose esters for administration of poorly soluble pharmaceutically active agents
US20080056235A1 (en) * 2006-08-31 2008-03-06 Syniverse Technologies, Inc. Cellular-to-VoIP call establishment systems, methods, devices, and computer software
US20080254122A1 (en) * 2001-09-21 2008-10-16 Egalet A/S Polymer release system
US20080254123A1 (en) * 2001-09-21 2008-10-16 Egalet A/S Morphine polymer release system
US20080268057A1 (en) * 2002-11-08 2008-10-30 Egalet A/S Controlled release carvedilol compositions
US20080292695A1 (en) * 2006-12-01 2008-11-27 Kristin Arnold Carvedilol forms, compositions, and methods of preparation thereof
US20090005348A1 (en) * 2005-12-23 2009-01-01 Vital Health Sciences Pty Ltd Compounds Having Cytokine Modulating Properties
US20090023778A1 (en) * 2005-04-28 2009-01-22 Eisai R&D Management Co., Ltd. Composition Containing Anti-Dementia Drug
US20090028935A1 (en) * 2006-12-01 2009-01-29 Kristin Arnold Carvedilol forms, compositions, and methods of preparation thereof
US20090036354A1 (en) * 2005-06-17 2009-02-05 Paul Gavin Carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
WO2009110004A1 (en) 2008-03-04 2009-09-11 Lupin Limited Stable pharmaceutical compositions qf carvedilol
US20090233881A1 (en) * 2005-03-03 2009-09-17 Vital Health Sciences Pty. Ltd Compounds having anti-cancer properties
US20090274759A1 (en) * 2005-06-03 2009-11-05 Egalet A/S Solid pharmaceutical composition with a first fraction of a dispersion medium and a second fraction of a matrix, the latter being at least partially first exposed to gastrointestinal fluids
US20090317473A1 (en) * 2008-06-20 2009-12-24 Naringrekar Gandha V Controlled-release formulations, method of manufacture, and use thereof
US20090317471A1 (en) * 2008-06-20 2009-12-24 Naringrekar Gandha V Controlled-release formulations, method of manufacture, and use thereof
US20100047340A1 (en) * 2008-08-20 2010-02-25 Board Of Regents, The University Of Texas System Hot-melt extrusion of modified release multi-particulates
US20100196427A1 (en) * 2009-01-30 2010-08-05 Nitec Pharma Ag Delayed-release glucocorticoid treatment of rheumatoid arthritis by improving signs and symptoms, showing major or complete clinical response and by preventing from joint damage
US20100203129A1 (en) * 2009-01-26 2010-08-12 Egalet A/S Controlled release formulations with continuous efficacy
US20100291205A1 (en) * 2007-01-16 2010-11-18 Egalet A/S Pharmaceutical compositions and methods for mitigating risk of alcohol induced dose dumping or drug abuse
US20110142905A1 (en) * 2008-08-14 2011-06-16 Bioneer A/S Coated tablets with remaining degradation surface over the time
US20110223244A1 (en) * 2010-03-09 2011-09-15 Elan Pharma International Limited Alcohol resistant enteric pharmaceutical compositions
US20120083734A1 (en) * 2009-05-18 2012-04-05 Encapson B.V. Balloon catheter comprising pressure sensitive microparticles
US8481565B2 (en) 2004-12-27 2013-07-09 Eisai R&D Management Co., Ltd. Method for stabilizing anti-dementia drug
US8652511B2 (en) 2010-03-30 2014-02-18 Phosphagenics Limited Transdermal delivery patch
US8920838B2 (en) 2006-08-03 2014-12-30 Horizon Pharma Ag Delayed-release glucocorticoid treatment of rheumatoid disease
US9005660B2 (en) 2009-02-06 2015-04-14 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
US9023394B2 (en) 2009-06-24 2015-05-05 Egalet Ltd. Formulations and methods for the controlled release of active drug substances
US9044402B2 (en) 2012-07-06 2015-06-02 Egalet Ltd. Abuse-deterrent pharmaceutical compositions for controlled release
US20160058868A1 (en) * 2013-04-24 2016-03-03 Temple University - Of The Commonwealth System Of Higher Education Solid dosage form containing arabinogalactan
US9561243B2 (en) 2011-03-15 2017-02-07 Phosphagenics Limited Composition comprising non-neutralised tocol phosphate and a vitamin A compound
US9642809B2 (en) 2007-06-04 2017-05-09 Egalet Ltd. Controlled release pharmaceutical compositions for prolonged effect
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate

Families Citing this family (22)

* 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
CA2446550C (en) 2001-05-11 2012-03-06 Endo Pharmaceuticals, Inc. Abuse-resistant controlled-release opioid dosage form
EP1639997A1 (en) 2002-04-05 2006-03-29 Euro-Celtique S.A. Matrix for sustained, invariant and independant release of active compounds
CN103288715A (en) 2002-06-27 2013-09-11 史密斯克莱.比奇曼(科克)有限公司 Carvedilol phosphate salts and/or solvates thereof, correspondinq compositions, and/or methods of treatment
US20050261355A1 (en) 2002-06-27 2005-11-24 Sb Pharmco Puerto Rico Inc., Carvedilol hydobromide
WO2004096182A1 (en) * 2003-04-30 2004-11-11 Ranbaxy Laboratories Limited Extended release matrix tablets of carvedilol
WO2005051383A1 (en) 2003-11-25 2005-06-09 Sb Pharmco Puerto Rico Inc. Carvedilol salts, corresponding compositions, methods of delivery and/or treatment
EP1604666A1 (en) 2004-06-08 2005-12-14 Euro-Celtique S.A. Opioids for the treatment of the Chronic Obstructive Pulmonary Disease (COPD)
EP2264162A1 (en) * 2005-07-02 2010-12-22 Arecor Limited Stable aqueous systems comprising proteins
CN102688241B (en) 2006-08-25 2017-04-12 普渡制药公司 Anti containing an opioid analgesic oral dosage form is tampered
JP5569398B2 (en) 2008-02-29 2014-08-13 フェッローサン メディカル ディバイス エー/エス Apparatus for facilitating hemostasis and / or wound healing
WO2010088911A1 (en) 2009-02-06 2010-08-12 Egalet A/S Pharmaceutical compositions resistant to abuse
CA2754853C (en) 2009-03-10 2015-04-28 Euro-Celtique S.A. Immediate release pharmaceutical compositions comprising oxycodone and naloxone
EP2547371A1 (en) 2010-03-15 2013-01-23 Ferrosan Medical Devices A/S A method for promotion of hemostasis and/or wound healing
CN102697744B (en) * 2012-05-29 2013-11-27 安吉东来药用辅料有限责任公司 Allose tablet excipient, medicinal tablet and method for preparing medicinal tablet
EP2825216B1 (en) 2012-06-12 2015-08-19 Ferrosan Medical Devices A/S Dry haemostatic composition
WO2014160155A3 (en) * 2013-03-14 2014-11-13 Endo Pharmaceuticals Solutions Inc. Implantable drug delivery compositions comprising non-polymeric sorption enhancers and methods of treatment thereof
CA2912357A1 (en) 2013-06-21 2014-12-24 Ferrosan Medical Devices A/S Vacuum expanded dry composition and syringe for retaining same
JP2016525138A (en) 2013-07-23 2016-08-22 ユーロ−セルティーク エス.エイ. The combination of oxycodone and naloxone for use in the treatment of pain in patients suffering from diseases increase the risk for diseases and / or Enterobacteriaceae migration results in pain and intestinal Disconnect bio cis
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
CA2955229A1 (en) 2014-07-17 2016-01-21 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4873080A (en) * 1983-06-08 1989-10-10 Dr. Karl Thomae Gmbh Oral anti-diabetic pharmaceutical compositions and the preparation thereof
US20020054911A1 (en) * 2000-05-11 2002-05-09 Boehringer Mannheim Pharmaceutical Corporation-Sm Ithkline Beckman Corporation, Limited Partnershi Novel oral dosage form for carvedilol
US6458772B1 (en) * 1909-10-07 2002-10-01 Medivir Ab Prodrugs
US6562375B1 (en) * 1999-08-04 2003-05-13 Yamanouchi Pharmaceuticals, Co., Ltd. Stable pharmaceutical composition for oral use
US20040151772A1 (en) * 2002-11-08 2004-08-05 Egalet A/S Controlled release carvedilol compositions
US6787156B1 (en) * 1994-02-23 2004-09-07 Bm Research A/S Controlled release composition

Family Cites Families (268)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2685553A (en) 1951-03-30 1954-08-03 Winthrop Stearns Inc Cement coated tablets
DE2010416B2 (en) 1970-03-05 1979-03-29 Hoechst Ag, 6000 Frankfurt
CA1018456A (en) 1972-06-26 1977-10-04 Hans Lowey Prolonged release lozenges
JPS5518694B2 (en) 1973-04-02 1980-05-21
US4034758A (en) 1975-09-08 1977-07-12 Alza Corporation Osmotic therapeutic system for administering medicament
DE2815926A1 (en) 1978-04-13 1979-10-18 Boehringer Mannheim Gmbh New carbazolyl (4) -oxy-propanolamine derivatives, processes for their preparation and medicines containing compounds
US4330338A (en) 1978-10-02 1982-05-18 Purdue Research Foundation Pharmaceutical coating composition, and preparation and dosages so coated
CA1146866A (en) * 1979-07-05 1983-05-24 Yamanouchi Pharmaceutical Co. Ltd. Process for the production of sustained release pharmaceutical composition of solid medical material
US4449983A (en) 1982-03-22 1984-05-22 Alza Corporation Simultaneous delivery of two drugs from unit delivery device
US4389393B1 (en) 1982-03-26 1985-10-22
GB2182559B (en) 1983-11-02 1989-10-25 Alza Corp Dispenser for delivering thermo-responsive composition
US4644984A (en) * 1983-12-12 1987-02-24 Abraham Samuel R Self service gas cap
US4844984A (en) 1984-03-19 1989-07-04 Alza Corporation Dispensing system with means for increasing delivery of beneficial agent from the system
JPH0246008B2 (en) 1984-06-01 1990-10-12 Takada Seiyaku Kk Nifuejipinjizokuseiseizainoseizohoho
GB8601389D0 (en) 1985-01-30 1986-02-26 Warner Lambert Co Treating pharmaceutical dosage forms
ES552145A0 (en) 1985-02-19 1988-01-01 Key Pharma Process for manufacturing a dosage unit for oral administration of potassium chloride.
US4898733A (en) 1985-11-04 1990-02-06 International Minerals & Chemical Corp. Layered, compression molded device for the sustained release of a beneficial agent
US4892742A (en) 1985-11-18 1990-01-09 Hoffmann-La Roche Inc. Controlled release compositions with zero order release
US4896733A (en) * 1986-05-22 1990-01-30 Flowmole Corporation Technique for providing an underground tunnel utilizing a powered boring device
US4824675A (en) 1987-07-13 1989-04-25 Alza Corporation Dispenser with movable matrix comprising a plurality of tiny pills
WO1989009066A1 (en) 1988-03-24 1989-10-05 Bukh Meditec A/S Controlled release composition
FI101344B1 (en) 1988-03-31 1998-06-15 Tanabe Seiyaku Co A process for preparing a preparation for which the controlled release of a pharmaceutically active agent
WO1990008536A1 (en) 1989-01-30 1990-08-09 Alza Corporation Dosage form for administering calcium antagonist
US5019396A (en) 1989-05-12 1991-05-28 Alza Corporation Delivery dispenser for treating cardiac arrhythmias
DK469989D0 (en) * 1989-09-22 1989-09-22 Bukh Meditec pharmaceutical preparation
DK0432607T3 (en) 1989-12-14 1996-04-29 Jagotec Ag Tablets with controlled release rate of the active substances
EP0435726B1 (en) 1989-12-29 1994-11-09 Bristol-Myers Squibb Company Capsule and caplet combination
US5102668A (en) 1990-10-05 1992-04-07 Kingaform Technology, Inc. Sustained release pharmaceutical preparation using diffusion barriers whose permeabilities change in response to changing pH
GB9025372D0 (en) 1990-11-22 1991-01-09 Nat Res Dev Pharmaceutical dosage forms
GB9101502D0 (en) 1991-01-23 1991-03-06 Controlled Therapeutics Sct Controlled release compositions
US5266331A (en) 1991-11-27 1993-11-30 Euroceltique, S.A. Controlled release oxycodone compositions
US5656295A (en) 1991-11-27 1997-08-12 Euro-Celtique, S.A. Controlled release oxycodone compositions
US5968551A (en) 1991-12-24 1999-10-19 Purdue Pharma L.P. Orally administrable opioid formulations having extended duration of effect
DK0652747T3 (en) 1992-07-29 1999-09-20 Gacell Lab Ab Morphine controlled release preparation
US5609885A (en) 1992-09-15 1997-03-11 Alza Corporation Osmotic membrane and delivery device
US6183778B1 (en) 1993-09-21 2001-02-06 Jagotec Ag Pharmaceutical tablet capable of liberating one or more drugs at different release rates
US5869097A (en) 1992-11-02 1999-02-09 Alza Corporation Method of therapy comprising an osmotic caplet
US5881926A (en) 1993-03-11 1999-03-16 Taro Pharmaceutical Industries, Ltd. Pharmaceutical compositions in semisolid form and a device for administration thereof
US5656291A (en) 1994-03-16 1997-08-12 Pharmacia & Upjohn Aktiebolag Controlled release preparation
US5614218A (en) 1993-03-30 1997-03-25 Pharmacia & Upjohn Aktiebolag Controlled release preparation
EP2263673A1 (en) 1993-07-01 2010-12-22 Euro-Celtique S.A. Opioid formulations having extended controlled release
US5879705A (en) 1993-07-27 1999-03-09 Euro-Celtique S.A. Sustained release compositions of morphine and a method of preparing pharmaceutical compositions
JPH07100191A (en) 1993-10-06 1995-04-18 Daikyo Yakuhin Kogyo Kk Sustained release suppository
US5478577A (en) 1993-11-23 1995-12-26 Euroceltique, S.A. Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level
US5419917A (en) 1994-02-14 1995-05-30 Andrx Pharmaceuticals, Inc. Controlled release hydrogel formulation
US7060293B1 (en) 1994-05-25 2006-06-13 Purdue Pharma Powder-layered oral dosage forms
US5411745A (en) 1994-05-25 1995-05-02 Euro-Celtique, S.A. Powder-layered morphine sulfate formulations
US6077533A (en) 1994-05-25 2000-06-20 Purdue Pharma L.P. Powder-layered oral dosage forms
US5460826A (en) 1994-06-27 1995-10-24 Alza Corporation Morphine therapy
US6491945B1 (en) 1994-09-16 2002-12-10 Alza Corporation Hydrocodone therapy
US5965161A (en) 1994-11-04 1999-10-12 Euro-Celtique, S.A. Extruded multi-particulates
EP0749300B1 (en) 1995-01-09 2009-10-14 J. Rettenmaier &amp; Söhne GmbH + Co. KG Pharmaceutical excipient having improved compressibility
US6117453A (en) * 1995-04-14 2000-09-12 Pharma Pass Solid compositions containing polyethylene oxide and an active ingredient
JP3161278B2 (en) 1995-04-26 2001-04-25 株式会社村田製作所 The dielectric ceramic composition
EP0835101B1 (en) 1995-06-27 2004-06-09 Takeda Chemical Industries, Ltd. Method of producing sustained-release preparation
GB9519363D0 (en) 1995-09-22 1995-11-22 Euro Celtique Sa Pharmaceutical formulation
US5741624A (en) * 1996-02-13 1998-04-21 Micron Technology, Inc. Method for reducing photolithographic steps in a semiconductor interconnect process
US6245351B1 (en) 1996-03-07 2001-06-12 Takeda Chemical Industries, Ltd. Controlled-release composition
EP0914097B1 (en) 1996-03-12 2002-01-16 Alza Corporation Composition and dosage form comprising opioid antagonist
KR100459747B1 (en) 1996-05-20 2005-01-27 오쓰까 세이야꾸 가부시키가이샤 Roger Asian treatments
US6348216B1 (en) 1996-06-10 2002-02-19 Knoll Pharmaceutical Company Ibuprofen and narcotic analgesic compositions
US6361794B1 (en) 1996-06-12 2002-03-26 Basf Corporation Method of making ibuprofen and narcotic analgesic composition
CA2262595C (en) 1996-08-15 2005-10-18 Losan Pharma Gmbh Easy to swallow oral medicament composition
US5948787A (en) 1997-02-28 1999-09-07 Alza Corporation Compositions containing opiate analgesics
US6046177A (en) 1997-05-05 2000-04-04 Cydex, Inc. Sulfoalkyl ether cyclodextrin based controlled release solid pharmaceutical formulations
CN1256085C (en) 1997-07-01 2006-05-17 美国辉瑞有限公司 Sertraline salts and substained-release dosage forms of sertraline
US6730326B2 (en) 1997-07-22 2004-05-04 Roche Diagnostics Gmbh Thermodynamically stable modification of 1-(4-carbazolyl-oxy-3[2-(2-methoxyphenoxy)-ethylamino]-2-propanol process for its preparation and pharmaceutical compositions containing it
US6607751B1 (en) 1997-10-10 2003-08-19 Intellipharamaceutics Corp. Controlled release delivery device for pharmaceutical agents incorporating microbial polysaccharide gum
US6066339A (en) 1997-10-17 2000-05-23 Elan Corporation, Plc Oral morphine multiparticulate formulation
US6375957B1 (en) 1997-12-22 2002-04-23 Euro-Celtique, S.A. Opioid agonist/opioid antagonist/acetaminophen combinations
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
FR2774910B1 (en) 1998-02-16 2001-09-07 Ethypharm Lab Prod Ethiques morphine sulfate microgranules, method for making and pharmaceutical preparations
US6245357B1 (en) * 1998-03-06 2001-06-12 Alza Corporation Extended release dosage form
US8524277B2 (en) 1998-03-06 2013-09-03 Alza Corporation Extended release dosage form
WO1999051208A1 (en) 1998-04-03 1999-10-14 Bm Research A/S Controlled release composition
US6350470B1 (en) 1998-04-29 2002-02-26 Cima Labs Inc. Effervescent drug delivery system for oral administration
US7906143B1 (en) 1998-10-05 2011-03-15 Intellipharmaceutics Corp Controlled release pharmaceutical delivery device and process for preparation thereof
US20080102121A1 (en) 1998-11-02 2008-05-01 Elan Pharma International Limited Compositions comprising nanoparticulate meloxicam and controlled release hydrocodone
US20080113025A1 (en) 1998-11-02 2008-05-15 Elan Pharma International Limited Compositions comprising nanoparticulate naproxen and controlled release hydrocodone
DE60042352D1 (en) * 1999-02-10 2009-07-23 Pfizer Prod Inc contain osmotic system for the administration of active substances, the solid amorphous dispersions
WO2000047236A8 (en) 1999-02-12 2001-04-19 Biostream Inc Matrices for drug delivery and methods for making and using the same
US6383471B1 (en) 1999-04-06 2002-05-07 Lipocine, Inc. Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents
FR2794646B1 (en) 1999-06-09 2001-09-21 Ethypharm Lab Prod Ethiques morphine sulfate microgranules process for the preparation and composition containing them
US6225343B1 (en) 1999-06-16 2001-05-01 Nastech Pharmaceutical Company, Inc. Compositions and methods comprising morphine gluconate
US6267985B1 (en) 1999-06-30 2001-07-31 Lipocine Inc. Clear oil-containing pharmaceutical compositions
US20030118641A1 (en) 2000-07-27 2003-06-26 Roxane Laboratories, Inc. Abuse-resistant sustained-release opioid formulation
US6534085B1 (en) 1999-09-23 2003-03-18 Bioresponse L.L.C. Phytochemicals for promoting weight loss
RU2230556C2 (en) 1999-10-29 2004-06-20 Эро-Селтик, С.А. Hydrocodon preparative sustained-release formulations
CA2392085A1 (en) * 1999-11-15 2001-05-25 Smithkline Beecham Corporation Carvedilol methanesulfonate
US6458824B1 (en) 1999-11-30 2002-10-01 Dainippon Pharmaceutical Co., Ltd. Solid preparation
US6352721B1 (en) 2000-01-14 2002-03-05 Osmotica Corp. Combined diffusion/osmotic pumping drug delivery system
US6491949B2 (en) 2000-01-14 2002-12-10 Osmotica Corp. Osmotic device within an osmotic device
US6378165B1 (en) 2000-02-17 2002-04-30 Emerson Electric Co. Pull handle with interlocking mounting mechanism for wet/dry vacuum appliance
US20010053791A1 (en) 2000-03-16 2001-12-20 Babcock Walter C. Glycogen phosphorylase inhibitor
DE60105996T2 (en) 2000-04-03 2006-03-09 F. Hoffmann-La Roche Ag Concentrated solutions of carvedilol
US20010036959A1 (en) 2000-04-03 2001-11-01 Gabel Rolf Dieter Carvedilol-hydrophilic solutions
US6488962B1 (en) 2000-06-20 2002-12-03 Depomed, Inc. Tablet shapes to enhance gastric retention of swellable controlled-release oral dosage forms
US6757558B2 (en) 2000-07-06 2004-06-29 Algodyne, Ltd. Objective pain measurement system and method
WO2002065834A8 (en) * 2000-10-24 2003-06-26 Smithkline Beecham Corp Novel formulations of carvedilol
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
DE60110192D1 (en) 2000-12-07 2005-05-25 Warner Lambert Company Llc Mor Method and system for gleichmä weight drug delivery
US6800668B1 (en) 2001-01-19 2004-10-05 Intellipharmaceutics Corp. Syntactic deformable foam compositions and methods for making
US20110104214A1 (en) 2004-04-15 2011-05-05 Purdue Pharma L.P. Once-a-day oxycodone formulations
DK2281555T3 (en) 2001-05-02 2016-06-06 Euro-Celtique S A Oxycodone for once daily administration
WO2002092078A1 (en) 2001-05-17 2002-11-21 Sun Pharamceutical Industries Limited Oral controlled release pharmaceutical composition for one-a-day therapy for the treatment and prophylaxis of cardiac and circulatory diseases
US7332182B2 (en) 2001-08-06 2008-02-19 Purdue Pharma L.P. Pharmaceutical formulation containing opioid agonist, opioid antagonist and irritant
US7144587B2 (en) 2001-08-06 2006-12-05 Euro-Celtique S.A. Pharmaceutical formulation containing opioid agonist, opioid antagonist and bittering agent
US7842307B2 (en) 2001-08-06 2010-11-30 Purdue Pharma L.P. Pharmaceutical formulation containing opioid agonist, opioid antagonist and gelling agent
US20030068375A1 (en) 2001-08-06 2003-04-10 Curtis Wright Pharmaceutical formulation containing gelling agent
EP1429744A1 (en) 2001-09-21 2004-06-23 Egalet A/S Morphine polymer release system
DK1429734T3 (en) 2001-09-21 2008-05-13 Egalet As Solid dispersions of carvedilol for the Controlled Release
US20040234602A1 (en) 2001-09-21 2004-11-25 Gina Fischer Polymer release system
EP1429724B1 (en) 2001-09-28 2013-11-06 McNeil-PPC, Inc. Dosage form containing a confectionery composition
US8017150B2 (en) 2002-04-11 2011-09-13 Monosol Rx, Llc Polyethylene oxide-based films and drug delivery systems made therefrom
US20070281003A1 (en) 2001-10-12 2007-12-06 Fuisz Richard C Polymer-Based Films and Drug Delivery Systems Made Therefrom
US8765167B2 (en) 2001-10-12 2014-07-01 Monosol Rx, Llc Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions
US8603514B2 (en) 2002-04-11 2013-12-10 Monosol Rx, Llc Uniform films for rapid dissolve dosage form incorporating taste-masking compositions
US7666337B2 (en) 2002-04-11 2010-02-23 Monosol Rx, Llc Polyethylene oxide-based films and drug delivery systems made therefrom
CA2466529C (en) 2001-11-09 2012-07-10 Farmatron Ltd. Solid, stabilized, prompt- and/or modified-release therapeutical systems for the oral administration of liquid active principles, excipients or foodstuffs
CA2474698C (en) 2002-02-08 2009-07-21 Alkermes Controlled Therapeutics, Inc. Polymer-based compositions for sustained release
JP4664595B2 (en) 2002-03-12 2011-04-06 ヤゴテック アーゲー Treatment system for controlling the release of active ingredient
CA2479350A1 (en) 2002-03-15 2003-09-25 Cypress Bioscience, Inc. Ne and 5-ht reuptake inhibitors for treating visceral pain syndromes
ES2327034T3 (en) 2002-03-26 2009-10-23 Euro-Celtique S.A. Gel compositions coated with sustained release.
US20060039958A1 (en) 2003-05-28 2006-02-23 Monosolrx, Llc. Multi-layer films having uniform content
ES2320435T3 (en) 2002-04-29 2009-05-22 Alza Corporation Method and dosage forms for the controlled administration of oxycodone.
US20050106249A1 (en) 2002-04-29 2005-05-19 Stephen Hwang Once-a-day, oral, controlled-release, oxycodone dosage forms
CA2487786A1 (en) 2002-05-31 2003-12-11 Alza Corporation Dosage forms and compositions for osmotic delivery of variable dosages of oxycodone
CA2489688A1 (en) 2002-06-26 2004-01-08 Alza Corporation Dosage forms for increasing the solubility and extending the release of drugs such as e.g. topiramate and phenyton
US6632832B1 (en) 2002-09-10 2003-10-14 Dabur Research Foundation Anti-cancer activity of carvedilol and its isomers
DE602004025159D1 (en) 2003-03-26 2010-03-04 Egalet As Matrix preparations for the controlled administration of drugs
US20040102476A1 (en) 2002-11-25 2004-05-27 Chan Tai Wah High concentration formulations of opioids and opioid derivatives
EP2218448B1 (en) 2002-12-13 2015-09-23 Durect Corporation Oral drug delivery system comprising high viscosity liquid carrier materials
WO2004056337A3 (en) 2002-12-18 2004-08-19 Pain Therapeutics Oral dosage forms with therapeutically active agents in controlled release cores and immediate release gelatin capsule coats
EP2301526B1 (en) 2003-03-26 2016-03-23 Egalet Ltd. Morphine controlled release system
US20040202717A1 (en) 2003-04-08 2004-10-14 Mehta Atul M. Abuse-resistant oral dosage forms and method of use thereof
CA2519556C (en) 2003-04-21 2011-01-18 Benjamin Oshlack Tamper resistant dosage form comprising co-extruded, adverse agent particles and process of making same
JP4790597B2 (en) 2003-04-24 2011-10-12 ヤゴテック アーゲー Delayed release tablets with a defined core geometry
US20060177507A1 (en) 2003-05-22 2006-08-10 Joaquina Faour Controlled release device containing lercanidipine
US8029822B2 (en) 2003-05-22 2011-10-04 Osmotica Kereskedelmi és Seolgáltató KFT Rupturing controlled release device having a preformed passageway
CN1812773B (en) 2003-05-28 2012-06-27 莫诺索尔克斯有限公司 Polyethylene oxide-based films and drug delivery systems made therefrom
US20060165790A1 (en) 2003-06-27 2006-07-27 Malcolm Walden Multiparticulates
ES2490598T3 (en) 2003-06-27 2014-09-04 Euro-Celtique S.A. multiparticulates
EP1646367A4 (en) 2003-07-21 2011-06-15 Nesher Solutions Ltd Gellan gum based oral controlled release dosage forms- a novel platform technology for gastric retention
US20070183980A1 (en) 2003-08-06 2007-08-09 Elisabeth Arkenau-Maric Dosage form that is safeguarded from abuse
US8075872B2 (en) 2003-08-06 2011-12-13 Gruenenthal Gmbh Abuse-proofed dosage form
DE10336400A1 (en) 2003-08-06 2005-03-24 Grünenthal GmbH Abuse-proofed dosage form
US20070048228A1 (en) 2003-08-06 2007-03-01 Elisabeth Arkenau-Maric Abuse-proofed dosage form
US20050053655A1 (en) 2003-09-05 2005-03-10 Pharmaceutical Industry Technology And Development Center Rapid disintegrating tablets (RDTs) for pharmaceutical use and method for preparing the same
JP2007505921A (en) 2003-09-19 2007-03-15 ペンウェスト ファーマシューティカルズ カンパニー Delayed release dosage form
KR20060120049A (en) 2003-09-26 2006-11-24 알자 코포레이션 Controlled release formulations of opioid and nonopioid analgesics
CA2541371C (en) 2003-10-03 2014-12-16 Atul M. Mehta Extended release formulations of opioids and method of use thereof
US7201920B2 (en) 2003-11-26 2007-04-10 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of opioid containing dosage forms
US8883204B2 (en) 2003-12-09 2014-11-11 Purdue Pharma L.P. Tamper resistant co-extruded dosage form containing an active agent and an adverse agent and process of making same
CN1905856A (en) 2003-12-23 2007-01-31 阿尔扎公司 Methods and dosage forms for increasing solubility of drug compositions for controlled delivery
DE10361596A1 (en) 2003-12-24 2005-09-29 Grünenthal GmbH A process for preparing a secured against misuse dosage form
US20050163837A1 (en) 2003-12-31 2005-07-28 Garth Boehm Rosiglitazone formulations
DE102004020220A1 (en) 2004-04-22 2005-11-10 Grünenthal GmbH A process for preparing a secured against misuse, solid dosage form
WO2005102286A1 (en) 2004-04-22 2005-11-03 Grünenthal GmbH Method for the production of an abuse-proof, solid form of administration
US7470232B2 (en) * 2004-05-04 2008-12-30 General Electric Company Method and apparatus for non-invasive ultrasonic fetal heart rate monitoring
DK1758557T3 (en) 2004-05-11 2011-10-24 Egalet Ltd Swellable dosage form comprising gellan gum
DK1765292T3 (en) 2004-06-12 2018-01-02 Collegium Pharmaceutical Inc Addiction-prevention drug formulations
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
EP1765298B1 (en) 2004-07-01 2012-10-24 Gruenenthal Gmbh Method for producing a solid dosage form, which is safeguarded against abuse, while using a planetary gear extruder
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
DE102004032103A1 (en) 2004-07-01 2006-01-19 Grünenthal GmbH Abuse-proofed, oral dosage form
WO2006026504A3 (en) 2004-08-27 2006-08-10 Jules S Jacob Mucoadhesive oral formulations of high permeability, high solubility drugs
WO2006030402A3 (en) 2004-09-17 2006-05-18 Ranbaxy Lab Ltd Dual compartment osmotic delivery device
US20080152595A1 (en) 2004-11-24 2008-06-26 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of orally administered pharmaceutical products
US20060110327A1 (en) 2004-11-24 2006-05-25 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of orally administered pharmaceutical products
US20060177380A1 (en) 2004-11-24 2006-08-10 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of orally administered pharmaceutical products
US20070231268A1 (en) 2004-11-24 2007-10-04 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of orally administered pharmaceutical products
DE102005005446A1 (en) 2005-02-04 2006-08-10 Grünenthal GmbH Unbreakable dosage forms with delayed release
FR2881652B1 (en) 2005-02-08 2007-05-25 Flamel Technologies Sa microparticulate oral pharmaceutical form anti-mesuage
WO2006088305A1 (en) 2005-02-15 2006-08-24 Chong Kun Dang Pharmaceutical Corp. Gastric-retentive controlled release mono-matrix tablet
US20060193911A1 (en) 2005-02-28 2006-08-31 Penwest Pharmaceuticals Co., Controlled release venlafaxine formulations
CA2599386A1 (en) 2005-03-28 2006-10-05 Orexo Ab New pharmaceutical compositions useful in the treatment of pain
GB0506982D0 (en) 2005-04-06 2005-05-11 Mw Encap Ltd Abuse resistant capsules
FR2889810A1 (en) 2005-05-24 2007-02-23 Flamel Technologies Sa An oral pharmaceutical composition, microparticulate, anti-measurement
CA2611081C (en) 2005-06-03 2016-05-31 Egalet A/S A drug delivery system for delivering active substances dispersed in a dispersion medium
US7883772B2 (en) 2005-06-24 2011-02-08 North Carolina State University High strength, durable fabrics produced by fibrillating multilobal fibers
WO2007002906A1 (en) 2005-06-29 2007-01-04 Alza Corporation Methods and dosage forms for reducing side effects of carbamate compounds
US8858993B2 (en) 2005-07-25 2014-10-14 Metrics, Inc. Coated tablet with zero-order or near zero-order release kinetics
US20080166407A1 (en) 2005-07-29 2008-07-10 Shalaby Shalaby W Solid oral formulations for combination therapy
WO2007030754A3 (en) 2005-09-09 2007-05-10 Monosolrx Llc Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions
DE202006014131U1 (en) 2005-10-31 2007-01-04 Alza Corp., Mountain View Oral dosage form useful for treating pain comprises an opioid and a dosing structure that provides extended release of the opioid in the presence of alcohol
US8652529B2 (en) 2005-11-10 2014-02-18 Flamel Technologies Anti-misuse microparticulate oral pharmaceutical form
WO2007082757A3 (en) 2006-01-18 2007-09-20 Idc Immunological Diagnostic A Test systems for the analysis of polypeptides and cells adhering to silicones
RU2433817C2 (en) 2006-01-21 2011-11-20 Эбботт Гмбх Унд Ко.Кг Medical form and method for delivery of habit-forming medical substances
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
FR2898056B1 (en) 2006-03-01 2012-01-20 Ethypharm Sa Tablets resistant to crushing intended to prevent the illicit diversion
EP1993519A4 (en) 2006-03-15 2011-12-21 Acura Pharmaceuticals Inc Methods and compositions for deterring abuse of orally administered pharmaceutical products
KR101495146B1 (en) 2006-03-16 2015-02-24 트리스 파마 인코포레이티드 Modified release formulations containing drug - ion exchange resin complexes
CA2647809C (en) 2006-03-24 2016-08-16 Auxilium Pharmaceuticals, Inc. Stabilized compositions containing alkaline labile drugs
US8465759B2 (en) 2006-03-24 2013-06-18 Auxilium Us Holdings, Llc Process for the preparation of a hot-melt extruded laminate
ES2626632T3 (en) 2006-05-09 2017-07-25 Mallinckrodt Llc Solid dosage forms modified zero order release
US20140010860A1 (en) 2006-05-12 2014-01-09 Isa Odidi Abuse and alcohol resistant drug composition
FR2901478B1 (en) 2006-05-24 2015-06-05 Flamel Tech Sa oral pharmaceutical form multimicroparticulate SUSTAINED RELEASE
US9023400B2 (en) 2006-05-24 2015-05-05 Flamel Technologies Prolonged-release multimicroparticulate oral pharmaceutical form
KR20090023729A (en) 2006-06-23 2009-03-05 엘란 파마 인터내셔널 리미티드 Compositions comprising nanoparticulate meloxicam and controlled release hydrocodone
JP2009541359A (en) 2006-06-23 2009-11-26 エラン・ファルマ・インターナショナル・リミテッド Composition comprising a nanoparticulate naproxen and controlled release hydrocodone
CN101534792B (en) 2006-08-04 2013-02-20 爱的发 Granule and orally disintegrating tablet comprising oxycodone
CN102688241B (en) 2006-08-25 2017-04-12 普渡制药公司 Anti containing an opioid analgesic oral dosage form is tampered
WO2008027442A3 (en) 2006-08-30 2008-10-16 Theraquest Biosciences Llc Abuse deterrent oral pharmaceutical formulations of opioid agonists and method of use
WO2008028047A3 (en) 2006-08-30 2008-11-27 Lab Internat Srl Bioadhesive film drug delivery system
JP5730572B2 (en) 2007-09-13 2015-06-10 シマ ラブス インク. Abuse-resistant formulation
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
US8329720B1 (en) 2007-05-22 2012-12-11 Pisgah Laboratories, Inc. Opioid salts and formulations exhibiting abuse deterrent and anti-dose dumping properties
US8211905B1 (en) 2007-05-22 2012-07-03 Pisgah Laboratories, Inc. Opioid salts and formulations exhibiting anti-abuse and anti-dose dumping properties
WO2008068471A1 (en) 2006-12-04 2008-06-12 Orexo Ab New non-abusable pharmaceutical composition comprising opioids
CA2674536C (en) 2007-01-16 2016-07-26 Egalet A/S Use of i) a polyglycol and ii) an active drug substance for the preparation of a pharmaceutical composition for i) mitigating the risk of alcohol induced dose dumping and/or ii) reducing the risk of drug abuse
DE102007011485A1 (en) 2007-03-07 2008-09-11 Grünenthal GmbH Dosage form with impeded abuse
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
EP2247283A2 (en) 2007-12-06 2010-11-10 Pain Therapeutics, Inc. Micronized opioid compositions, formulations and dosage forms and methods of making same
JP2011506319A (en) 2007-12-06 2011-03-03 デュレクト コーポレーション Pain, methods useful in the treatment of inflammation associated with an arthritic condition or chronic disease,
US8486448B2 (en) 2007-12-17 2013-07-16 Paladin Labs Inc. Misuse preventative, controlled release formulation
WO2009092601A1 (en) 2008-01-25 2009-07-30 Grünenthal GmbH Pharmaceutical dosage form
KR101094231B1 (en) 2008-02-18 2011-12-14 하나제약 주식회사 Sustained release solid formulations and methods of manufacturing the same
US8372432B2 (en) 2008-03-11 2013-02-12 Depomed, Inc. Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic
WO2009114648A1 (en) 2008-03-11 2009-09-17 Depomed Inc. Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic
US20110142905A1 (en) 2008-08-14 2011-06-16 Bioneer A/S Coated tablets with remaining degradation surface over the time
CN102159193B (en) 2008-09-18 2015-09-16 普渡制药公司 Comprising poly ([epsilon] -caprolactone) pharmaceutical dosage form
WO2010066034A8 (en) 2008-12-12 2010-08-19 Paladin Labs Inc. Narcotic drug formulations with decreased abuse potential
ES2509497T3 (en) 2008-12-16 2014-10-17 Paladin Labs Inc. Controlled release formulation to avoid misuse
CA2750400A1 (en) 2009-01-26 2010-07-29 Egalet A/S Controlled release formulations with continuous efficacy
CA2751667C (en) 2009-02-06 2016-12-13 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
WO2010088911A1 (en) 2009-02-06 2010-08-12 Egalet A/S Pharmaceutical compositions resistant to abuse
GB0909680D0 (en) 2009-06-05 2009-07-22 Euro Celtique Sa Dosage form
WO2010149169A3 (en) 2009-06-24 2011-06-16 Egalet A/S Controlled release formulations
US9056054B2 (en) 2009-06-25 2015-06-16 Elite Laboratories, Inc. Abuse resistant oral dosage forms
ES2560210T3 (en) 2009-07-22 2016-02-17 Grünenthal GmbH Dosage form resistant to manipulation for opiádes sensitive to oxidation
WO2011009602A1 (en) 2009-07-22 2011-01-27 Grünenthal GmbH Hot-melt extruded controlled release dosage form
CA2775890C (en) 2009-09-30 2016-06-21 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse
WO2011079074A1 (en) 2009-12-24 2011-06-30 Acura Phamaceuticals, Inc. Pharmaceutical compositions for deterring misuse, abuse, and diversion
US20110195989A1 (en) 2010-02-09 2011-08-11 Rudnic Edward M Controlled Release Formulations of Opioids
CA2812570A1 (en) 2010-09-24 2012-03-29 QRxPharma Ltd. Controlled release formulations of opioids
US20130022646A1 (en) 2010-02-09 2013-01-24 Rudnic Edward M Controlled Release Formulations of Opioids
CA2790108C (en) 2010-02-24 2016-05-31 Cima Labs Inc. Abuse-resistant formulations
US8529848B2 (en) 2010-06-28 2013-09-10 Ronald Danehy Systems and methods for transfer of liquid samples
WO2012028319A1 (en) 2010-09-02 2012-03-08 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
CN103179956A (en) 2010-09-02 2013-06-26 格吕伦塔尔有限公司 Tamper resistant dosage form comprising an anionic polymer
RU2607499C2 (en) 2010-09-02 2017-01-10 Грюненталь Гмбх Destruction-resistant dosage form containing anionic polymer
US20120202838A1 (en) 2010-11-04 2012-08-09 Abbott Laboratories Drug formulations
GB201020895D0 (en) 2010-12-09 2011-01-26 Euro Celtique Sa Dosage form
WO2012080833A3 (en) 2010-12-13 2012-09-07 Purdue Pharma L.P. Controlled release dosage forms
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
US20120321674A1 (en) 2011-02-17 2012-12-20 Michael Vachon Technology for Preventing Abuse of Solid Dosage Forms
US20120321716A1 (en) 2011-02-17 2012-12-20 Michael Vachon Technology for preventing abuse of solid dosage forms
KR101619579B1 (en) 2011-03-25 2016-05-10 퍼듀 퍼머 엘피 Controlled release pharmaceutical dosage forms
CA2839123A1 (en) 2011-07-29 2013-02-07 Grunenthal Gmbh Tamper-resistant tablet providing immediate drug release
KR20140053158A (en) 2011-07-29 2014-05-07 그뤼넨탈 게엠베하 Tamper-resistant tablet providing immediate drug release
EP2755640B1 (en) 2011-09-16 2017-07-26 Purdue Pharma LP Tamper resistant pharmaceutical formulations
EP2755638B1 (en) 2011-09-16 2016-06-01 Purdue Pharma LP Tamper resistant immediate release formulations
US20130090349A1 (en) 2011-10-06 2013-04-11 Grünenthal GmbH Tamper-resistant oral pharmaceutical dosage form comprising opioid agonist and opioid antagonist
EP2768537A2 (en) 2011-10-18 2014-08-27 Purdue Pharma LP Acrylic polymer formulations
KR20140096062A (en) 2011-11-17 2014-08-04 그뤼넨탈 게엠베하 Tamper-resistant oral pharmaceutical dosage form comprising a pharmacologically active ingredient, an opioid antagonist and/or aversive agent, polyalkylene oxide and anionic polymer
WO2013077851A1 (en) 2011-11-22 2013-05-30 Watson Pharmaceuticals, Inc. Immediate release abuse deterrent tablet
JP6144274B2 (en) 2011-12-09 2017-06-07 パーデュー、ファーマ、リミテッド、パートナーシップ Poly (epsilon - caprolactone) and pharmaceutical dosage forms containing polyethylene oxide
CN104394890B (en) 2012-03-23 2018-07-10 73制药公司 Of Pichia yeast biomass obtained natural biological composite powder, preparation and to their use as excipients
WO2014006004A1 (en) 2012-07-06 2014-01-09 Egalet Ltd. Abuse deterrent pharmaceutical compositions for controlled release
EP3003279A1 (en) 2013-05-29 2016-04-13 Grünenthal GmbH Tamper-resistant dosage form containing one or more particles
CA2913209A1 (en) 2013-05-29 2014-12-04 Grunenthal Gmbh Tamper resistant dosage form with bimodal release profile
CA2817728A1 (en) 2013-05-31 2014-11-30 Pharmascience Inc. Abuse deterrent immediate release formulation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6458772B1 (en) * 1909-10-07 2002-10-01 Medivir Ab Prodrugs
US4873080A (en) * 1983-06-08 1989-10-10 Dr. Karl Thomae Gmbh Oral anti-diabetic pharmaceutical compositions and the preparation thereof
US6787156B1 (en) * 1994-02-23 2004-09-07 Bm Research A/S Controlled release composition
US6562375B1 (en) * 1999-08-04 2003-05-13 Yamanouchi Pharmaceuticals, Co., Ltd. Stable pharmaceutical composition for oral use
US20020054911A1 (en) * 2000-05-11 2002-05-09 Boehringer Mannheim Pharmaceutical Corporation-Sm Ithkline Beckman Corporation, Limited Partnershi Novel oral dosage form for carvedilol
US20040151772A1 (en) * 2002-11-08 2004-08-05 Egalet A/S Controlled release carvedilol compositions

Cited By (82)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050089569A1 (en) * 1998-04-03 2005-04-28 Bm Research A/S Controlled release composition
US7883722B2 (en) 1998-04-03 2011-02-08 Egalet Ltd. Controlled release composition
US8173145B2 (en) 2000-11-14 2012-05-08 Vital Health Sciences Pty. Ltd. Formulation containing phosphate derivatives of electron transfer agents
US20040097472A1 (en) * 2000-11-14 2004-05-20 West Simon Michael Complexes of phosphate derivatives
US20100222305A1 (en) * 2000-11-14 2010-09-02 Simon Michael West Complexes of phosphate derivatives
US20040052754A1 (en) * 2000-11-14 2004-03-18 West Simon Michael Complexes of phosphate derivatives
US20040071777A1 (en) * 2000-12-22 2004-04-15 Laura Trespidi Solid dispersions of nitrate active principles
US20040096493A1 (en) * 2001-06-06 2004-05-20 West Simon Michael Formulation containing phopshate derivatives of electron transfer agents
US7648710B2 (en) 2001-06-06 2010-01-19 Vital Health Sciences Pty Ltd. Formulation containing phosphate derivatives of electron transfer agents
US20040253318A1 (en) * 2001-07-27 2004-12-16 West Simon Michael Dermal therapy using phosphate derivatives of electron transfer agents
US8008345B2 (en) 2001-07-27 2011-08-30 Vital Health Sciences Pty. Ltd. Dermal therapy using phosphate derivatives of electron transfer agents
US9694080B2 (en) 2001-09-21 2017-07-04 Egalet Ltd. Polymer release system
US8808745B2 (en) 2001-09-21 2014-08-19 Egalet Ltd. Morphine polymer release system
US9707179B2 (en) 2001-09-21 2017-07-18 Egalet Ltd. Opioid polymer release system
US8617605B2 (en) 2001-09-21 2013-12-31 Egalet Ltd. Polymer release system
US8609143B2 (en) 2001-09-21 2013-12-17 Egalet Ltd. Morphine polymer release system
US20080254122A1 (en) * 2001-09-21 2008-10-16 Egalet A/S Polymer release system
US20080254123A1 (en) * 2001-09-21 2008-10-16 Egalet A/S Morphine polymer release system
US20050089495A1 (en) * 2001-12-13 2005-04-28 West Simon M. Transdermal transport of compounds
US8841342B2 (en) 2002-08-09 2014-09-23 Vital Health Sciences Pty. Ltd. Carrier
US20060257459A1 (en) * 2002-08-09 2006-11-16 West Simon M Carrier
US8449914B2 (en) 2002-11-08 2013-05-28 Egalet Ltd. Controlled release carvedilol compositions
US20080268057A1 (en) * 2002-11-08 2008-10-30 Egalet A/S Controlled release carvedilol compositions
US20060241085A1 (en) * 2003-01-17 2006-10-26 West Simon M Compounds having anti-proliferative properties
US20110003774A1 (en) * 2003-01-17 2011-01-06 Vital Health Sciences Pty. Ltd. Compounds having anti-proliferative properties
US8298581B2 (en) 2003-03-26 2012-10-30 Egalet A/S Matrix compositions for controlled delivery of drug substances
US9375428B2 (en) 2003-03-26 2016-06-28 Egalet Ltd. Morphine controlled release system
US20100166866A1 (en) * 2003-03-26 2010-07-01 Egalet A/S Matrix compositions for controlled delivery of drug substances
US9884029B2 (en) 2003-03-26 2018-02-06 Egalet Ltd. Morphine controlled release system
US20070042044A1 (en) * 2003-03-26 2007-02-22 Egalet A/S Matrix compositions for controlled delivery of drug substances
US20070003617A1 (en) * 2003-03-26 2007-01-04 Egalet A/S Morphine controlled release system
US8877241B2 (en) 2003-03-26 2014-11-04 Egalet Ltd. Morphine controlled release system
US20070135390A1 (en) * 2003-04-15 2007-06-14 West Micheal S Phosphate derivatives
US20060281716A1 (en) * 2004-03-03 2006-12-14 West Simon M Alkaloid formulations
US8529947B2 (en) * 2004-03-03 2013-09-10 Vital Health Sciences Pty. Ltd. Alkaloid formulations
US20100209459A1 (en) * 2004-03-03 2010-08-19 Simon Michael West Alkaloid formulations
US20060099168A1 (en) * 2004-11-05 2006-05-11 Italo Corzani Polymeric compositions for sustained release of volatile materials
US8507527B2 (en) 2004-12-27 2013-08-13 Eisai R & D Management Co., Ltd. Method for stabilizing anti-dementia drug
US8481565B2 (en) 2004-12-27 2013-07-09 Eisai R&D Management Co., Ltd. Method for stabilizing anti-dementia drug
US20090233881A1 (en) * 2005-03-03 2009-09-17 Vital Health Sciences Pty. Ltd Compounds having anti-cancer properties
US20090023778A1 (en) * 2005-04-28 2009-01-22 Eisai R&D Management Co., Ltd. Composition Containing Anti-Dementia Drug
US20090274759A1 (en) * 2005-06-03 2009-11-05 Egalet A/S Solid pharmaceutical composition with a first fraction of a dispersion medium and a second fraction of a matrix, the latter being at least partially first exposed to gastrointestinal fluids
US20090036354A1 (en) * 2005-06-17 2009-02-05 Paul Gavin Carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
US9168216B2 (en) 2005-06-17 2015-10-27 Vital Health Sciences Pty. Ltd. Carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
US20070178152A1 (en) * 2005-11-04 2007-08-02 Shelton Michael C Carboxyalkylcellulose esters for administration of poorly soluble pharmaceutically active agents
US20090005348A1 (en) * 2005-12-23 2009-01-01 Vital Health Sciences Pty Ltd Compounds Having Cytokine Modulating Properties
US8920838B2 (en) 2006-08-03 2014-12-30 Horizon Pharma Ag Delayed-release glucocorticoid treatment of rheumatoid disease
US9504699B2 (en) 2006-08-03 2016-11-29 Hznp Limited Delayed-release glucocorticoid treatment of rheumatoid disease
US20080056235A1 (en) * 2006-08-31 2008-03-06 Syniverse Technologies, Inc. Cellular-to-VoIP call establishment systems, methods, devices, and computer software
US20090263478A1 (en) * 2006-12-01 2009-10-22 Kristin Arnold Carvedilol forms, compositions, and methods of preparation thereof
US20080292695A1 (en) * 2006-12-01 2008-11-27 Kristin Arnold Carvedilol forms, compositions, and methods of preparation thereof
US20090028935A1 (en) * 2006-12-01 2009-01-29 Kristin Arnold Carvedilol forms, compositions, and methods of preparation thereof
US20100291205A1 (en) * 2007-01-16 2010-11-18 Egalet A/S Pharmaceutical compositions and methods for mitigating risk of alcohol induced dose dumping or drug abuse
US9642809B2 (en) 2007-06-04 2017-05-09 Egalet Ltd. Controlled release pharmaceutical compositions for prolonged effect
WO2009110004A1 (en) 2008-03-04 2009-09-11 Lupin Limited Stable pharmaceutical compositions qf carvedilol
US8889728B2 (en) 2008-03-04 2014-11-18 Lupin Limited Stable pharmaceutical compositions of carvedilol
US20110005960A1 (en) * 2008-03-04 2011-01-13 Ashish Guha Stable pharmaceutical compositions of carvedilol
US7794750B2 (en) 2008-06-20 2010-09-14 Mutual Pharmaceutical Company, Inc. Controlled-release formulations, method of manufacture, and use thereof
US8632805B2 (en) 2008-06-20 2014-01-21 Mutual Pharmaceutical Company, Inc. Controlled-release formulations, method of manufacture, and use thereof
US20090317473A1 (en) * 2008-06-20 2009-12-24 Naringrekar Gandha V Controlled-release formulations, method of manufacture, and use thereof
US20090317471A1 (en) * 2008-06-20 2009-12-24 Naringrekar Gandha V Controlled-release formulations, method of manufacture, and use thereof
US20110142905A1 (en) * 2008-08-14 2011-06-16 Bioneer A/S Coated tablets with remaining degradation surface over the time
WO2010022193A3 (en) * 2008-08-20 2010-05-27 Board Of Regents, The University Of Texas System Hot-melt extrusion of modified release multi-particulates
CN102271661A (en) * 2008-08-20 2011-12-07 德克萨斯州立大学董事会 Melt extruded multiparticulates release
US9192578B2 (en) * 2008-08-20 2015-11-24 Board Of Regents, The University Of Texas System Hot-melt extrusion of modified release multi-particulates
US20100047340A1 (en) * 2008-08-20 2010-02-25 Board Of Regents, The University Of Texas System Hot-melt extrusion of modified release multi-particulates
US9827202B2 (en) 2008-08-20 2017-11-28 Board Of Regents, The University Of Texas System Hot-melt extrusion of modified release multi-particulates
US20100203129A1 (en) * 2009-01-26 2010-08-12 Egalet A/S Controlled release formulations with continuous efficacy
US20150150812A1 (en) * 2009-01-26 2015-06-04 Egalet Ltd. Controlled release formulations with continuous efficacy
US20100196427A1 (en) * 2009-01-30 2010-08-05 Nitec Pharma Ag Delayed-release glucocorticoid treatment of rheumatoid arthritis by improving signs and symptoms, showing major or complete clinical response and by preventing from joint damage
US9005660B2 (en) 2009-02-06 2015-04-14 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
US9358295B2 (en) 2009-02-06 2016-06-07 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
US20120083734A1 (en) * 2009-05-18 2012-04-05 Encapson B.V. Balloon catheter comprising pressure sensitive microparticles
US9023394B2 (en) 2009-06-24 2015-05-05 Egalet Ltd. Formulations and methods for the controlled release of active drug substances
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
US20110223244A1 (en) * 2010-03-09 2011-09-15 Elan Pharma International Limited Alcohol resistant enteric pharmaceutical compositions
US8652511B2 (en) 2010-03-30 2014-02-18 Phosphagenics Limited Transdermal delivery patch
US9314527B2 (en) 2010-03-30 2016-04-19 Phosphagenics Limited Transdermal delivery patch
US9561243B2 (en) 2011-03-15 2017-02-07 Phosphagenics Limited Composition comprising non-neutralised tocol phosphate and a vitamin A compound
US9549899B2 (en) 2012-07-06 2017-01-24 Egalet Ltd. Abuse deterrent pharmaceutical compositions for controlled release
US9044402B2 (en) 2012-07-06 2015-06-02 Egalet Ltd. Abuse-deterrent pharmaceutical compositions for controlled release
US20160058868A1 (en) * 2013-04-24 2016-03-03 Temple University - Of The Commonwealth System Of Higher Education Solid dosage form containing arabinogalactan

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