# Patent

## Title
Polymer release system

## Abstract

A pharmaceutical composition for controlled release of an active substance, the composition being a matrix composition of: (a) a substantially water soluble or crystalline polymer, (b) an active substance, and optionally, (c) one or more pharmaceutically acceptable excipients having a water solubility of at least 1 mg/ml at ambient temperature. The matrix composition does not contain a water dispersible or water soluble surface active agent that has at least one domain, which is compatible with the polymer in the matrix composition, and which substantially eliminates water diffusion between the interface between the polymer crystals.

## Background
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
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.
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.
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.
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 ilpophilic 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.
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.
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.
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.
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
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,

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 toast 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.

    
    


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
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.
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
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 feast 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 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.

    
    


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
Matrix Composition
The pharmaceutical composition according to the invention comprises 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.
    
    


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
Polymers
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.
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.
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.
Polyethylene glycols (which when the molecular weight is above about 20,000 is denoted polyethylene oxides) are mixtures of condensation polymers of ethylene glycol.
The average molecular weight (MW) can be calculated from the following equation

MW=(56.110×2)/hydroxyl number

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.
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.
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.
Alternatively 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.
Active Substances
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.
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.
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.
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.).
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.
Examples of specific active substances suitable for use in a composition of the invention are:
Carvedilol, morphine, diclofenac, nifedipine, calcitonin, rivastigmine, methylphenidate, fluoroxetine, rosiglitazone, prednison, prednisolone, codeine, ethylmorphine, dextromethorphan, noscapine, pentoxiverine, acetylcysteine, bromhexine, epinephrine, isoprenaline, orciprenaline, ephedrine, fenoterol, rimiterol, ipratroplum, cholinetheophyllinate, proxiphylline, bechlomethasone, budesonide, deslanoside, digoxin, digitoxin, disopyramide, proscillaridin, chinidine, procainamide, mexiletin, flecainide, alprenolol, proproanolol, nadolol, pindolol, oxprenolol, labetalol, timolol, atenolol, pentaeritrityltetranitrate, isosorbiddinitrate, isosorbidmononitrate, niphedipin, phenylamine, verapamil, diltiazem, cyclandelar, nicotinylalcholhol, inositoinicotinate, 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, methylscopolamine, oxiphencyclimine, probanteline, terodilin, sennaglycosides, sagradaextract, dantron, bisachodyl, sodiumplcosulfat, etulos, diphenolxylate, loperamide, salazosulfapyridine, pyrvin, mebendazol, dimeticon, ferrofumarate, ferrosuccinate, ferritetrasemisodium, cyanochobalamine, folid acid heparin, heparin co-factor, diculmarole, warfarin, streptokinase, urokinase, factor VIII, factor IX, vitamin K, thiopeta, busulfan, chlorambucil, cyclophosphamid, melfalan, carmustin, mercatopurin, thioguanin, azathioprin, cytarabin, vinblastin, vinchristin, vindesin, procarbazine, dacarbazine, lomustin, estramustin, tenlposide, etoposide, cisplatin, amsachrin, aminogluthetimid, phosphestrol, medroxiprogresterone, hydroxiprogesterone, megesterol, noretisteron, tamoxiphen, ciciosporin, 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, glibenciamid, phenobarbital, methyprylon, pyrityldion, meprobamat, chlordiazepoxid, diazepam, nitrazepam, oxazepam, dikaiiumclorazepat, 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, cyclizine, dimenhydinate, meclozine, prometazine, thiethylperazine, metoclopramide, scopolamine, phenobarbital, phenytoine, ethosuximide, primidone, carbamazepine, chlonazepam, orphenadrine, atropine, bensatropine, biperiden, metixene, procylidine, 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, cyclophenile, 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, metformin, insulin, calcitonin, glucagons-like peptide-1, or combinations thereof.
The active substance can be in various forms, such as uncharged molecules, molecular complexes, crystalline forms, amorphous farm, 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, quaternary 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.
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.
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.
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 classify 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.
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.
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.
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. 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 imperfecti. A pharmaceutical composition of the invention may also be used for the delivery of active agents in specialized carriers such as liposomes, cyclodextrines, 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, antiinflammatory agents, growth promoters and permittants, antifungals and antihelmintics.
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 term “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”.
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.
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.
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.
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.
Pharmaceutically Acceptable Excipients
Diffusion and Dissolution Adjusters
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.
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.
The active substance release data may be analysed using Eq. 1 and Eq. 2 where Mt/Moo 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.




  
    
      
        
          
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        =
        
          n
          ·
          
            C
            d
          
          ·
          k
          ·
          
            t
            
              n
              -
              1
            
          
        
      
    
    
      
        (
        
          Eq
          .
          
            
          
          ⁢
          2
        
        )
      
    
  




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.














time dependence of solute


Diffusinal release
Overall Solute diffusion
release


Exponent (n)
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Alternatively 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 add etc.
Examples of suitable organic acids include acetic acid/ethanoic acid, adipic acid, angelic acid, ascorbic acid/vitamin C, carbamic acid, cinnamic add, citramalic acid, formic acid, fumaric add, gallic add, 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.
Examples of suitable inorganic acids include pyrophosphoric, glycerophosphoric, phosphoric such as ortho and meta phosphoric, boric acid, hydrochloric acid, and sulfuric acid.
Examples of suitable inorganic compounds include aluminium.
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.
Examples of inorganic bases include aluminium oxide such as, e.g., aluminium oxide trihydrate, alumina, sodium hydroxide, potassium hydroxide, calcium carbonate, ammonium carbonate, ammonium hydroxide, KOH and the like.
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.
A suitable inorganic salt for use in a matrix composition of the invention is sodium chloride, potassium chloride, calcium chloride, magnesium chloride etc.
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 isapoi husk, veegum, glycollate, magnesium stearate, calcium stearate, stearic acid, talc, titanium dioxide, silicium dioxide, days, croscarmellose, gums, agar etc.
Other Ingredients in the Matrix Composition
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.
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.
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 add, 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 hydrogencarbonate/tartaric 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.
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.
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.
Examples of suitable fillers are also dextrin, sucralfate, calcium hydroxyl-apatite, calcium phosphates and fatty acid salts such as magnesium stearate.
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.
In order to soften the carrier system, a plasticiser may be incorporated in the composition. A suitable plasticizer is selected from the group consisting of phosphate esters; phthalate esters; amides; mineral oils; fatty acids 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 mono-glycerides, nitrobenzene, carton 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-butylphenoxy)ethanol, beta-(p-teft-butylphenoxyethyl)acetate, bis(beta-p-tert-buthylphenoxydiethyl)ether, camphor, Cumar W-1, Cumar MH-1, Cumar V-1, diamyl phthalate, (diamylphenoxy) ethanol, diphenyl oxide, technical hydroabletyl alcohol, beckolin, benzene hexahydrochloride, Clorafin 40, Piccolastic A-5, Piccalastic A-25, Flexol B-400, Glycerol alfa-methyl alfa-phenyl ether, chlorinated naphthalene, HB-40, monoamylphthalate. Nevillac 10 o-nitrodiphenyl and Paracril 26.
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 add 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 ihiodipropionate), pyranon (maltol), and vitamin E (tocopherol, D-α-tocopherol, DL-α-tocopherol, tocopheryl acetate, d-α-tocopheryl acetate, di-α-tocopheryl acetate. However, other anti-oxidative agents known in the art may be used according to the present invention.
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. Remington's Pharmaceutical 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 copolymers. 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.
The release modifier enables a difference in release of the active substance/erosion of the matrix dependant on pH.
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.
In order to achieve a higher plasma concentration 5-10 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.
Specific examples of compositions with different shapes and sizes are:
















Batch
Length [mm]
Diameter [mm]
Vol [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













Batch
Length [mm]
Vol [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.
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.
However, minor corrections in the calculated area for the additional strength formulations may be necessary in case the erosion rate (length of the eroded matrix/time 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.
For instance, the present according to the present invention, the results from Examples 1 to 4 demonstrates that

















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.
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.
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.
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.
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 mm2 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 mm3 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.
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 mm2 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
Other designs according to the present invention for a 25 mg Carvedilol having a volume of 159 mm3 includes:

    Surface area (one end) of 27.17 mm2 and 5.85 mm length
    Surface area (one end) of 25.00 mm2 and 6.40 mm length


Designs for a 50 mg Carvedilol having a volume of 318 mm3 includes:

    Surface area (one end) of 45 mm2 and 7 mm length
    Surface area (one end) of 50 mm2 and 6.4 mm length
    Surface area (one end) of 55 mm2 and 5.6 mm length


Designs for a 12.5 mg Carvedilol having a having a volume of 79.5 mm3 includes

    Surface area (one end) 0113.6 mm2 and 5.85 mm length


Designs for a 6.25 mg Carvedilol having a volume of 39.75 mm3 includes:

    Surface area (one end) of 6.8 mm2 and 5.85 mm length


Such small formulations may be prepared with a thicker shell for patient compliance reasons. The final size of alt 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.
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).
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.
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 filter 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.
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.
The coating may also be an enteric coating employing methacrylates, a co-polymer of methacrylate-galactomannan etc.
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.
These coatings comprise:

    
    
        (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;

and at least one of:

        (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;
        (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
        (d) a filler, e.g. selected from conventional tablet or capsule excipients such as diluents, binders, lubricants and disintegrants.
    
    


The use of a plasticizer will often be desirable in order to improve the processability 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.
Other suitable plasticizers appear from EP-B-0 746 310 to which reference is made.
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.
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 1-6 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.
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.
The controlled release of the active substance is caused by erosion at a substantially constant rate of a surface or surfaces of the composition
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 infer 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.
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.
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.
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.
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.
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.
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.
Stability
In order to improve the stability of a composition according to the invention, the composition may optionally comprise a stabilizing agent.
In the present context, the terms “stability” and “stabilizing agent” are employed to encompass one or more of the following:
Stability with respect to the final composition:

    i) stability with respect to the physical stability of the composition (appearance, color, strength, etc
    ii) stability with respect to in vitro dissolution behaviour of the active substance from the composition


Stability of the Individual Components:

    iii) stability with respect to the chemical stability of the active substance (degradation of the active substance to other—normally—unwanted products)
    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.
    v) physical and chemical stability of the pharmaceutically acceptable polymer employed as component ii).


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.
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.
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 amorphous 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)
i) being at least one therapeutically, prophylactically and/or diagnostically active substance, which at least partially is in an amorphous form.
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.
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).
In a further aspect, the invention relates to compositions as described above.
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.
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.
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 lake 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.
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).
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.
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.
Suitable qualities include PEO 200,000 NF or LF from Dow Chemicals.
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.
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 formaldehyde sulfoxylate, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives, sulfides, phosphine etc. Other suitable antioxidants are described herein.
Another measure to reduce any oxidation during processing is to employ nitrogen purges during manufacturing.
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 production 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.
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.
For further details reference is made to the experimental section herein.
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.



The invention is further illustrated in the figures and in the following non-limiting examples.
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.
FIG. 2 is the results from pilot study of Example 5.
FIG. 3 shows the DSC of carvedilol as starting material and a peak is observed corresponding to that carvedilol is employed in crystalline form.
FIG. 4-5 are the DSCs of PEO 200,000 and citric acid, respectively, and show that the substances are employed as crystals.
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).
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 pattern.
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.
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 10 et al. J. Pharm. Sci. 11 Suppl. 2 (2000) pp S73-S80.
FIGS. 10A-10B show the dissolution profile relating to a composition of Example B denoted 0069; the dissolution has been determined after 26 days storage at 30° 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, =2 mm and d=7.5 mm
FIG. 12 is the dissolution profile from the composition of Example 9.
FIG. 13 (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.
FIG. 15 shows the plasma concentration vs. time profile for the clinical study in phase II reported in Example 11.



METHODS
Diffusion/Dissolution Studies
Method for Determination of Dissolution Rate of the Matrix
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.
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.
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.
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.
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.
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.
The test proceeds as follows: Place 1 plug incorporated into the glass tube in a vessel—optionally with a water soluble dye (e.g. Cu2+) 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.
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.
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 add 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.
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.
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.
Example of Coat Composition


    
    
        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.
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.
The following table describes formulations having a cylindrical form and circular openings in both ends.
















Batch
Length [mm]
Diameter [mm]
Vol [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













Batch
Length [mm]
Vol [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.
Example 1
Preparation of a Pharmaceutical Composition Comprising Carvedilol as an Active Substance
A composition (plug batch No. 01-004-5-042), formulation batch No. 01-0034 042 according to the invention was prepared from the following ingredients:












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.
The composition was subjected to the dissolution test described above. The following results were obtained:











Time (h)
dissolved carvedilol (% 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 dissolution profile corresponds to a zero order release of carvedilol from the composition.
Example 2
Preparation of an Oval Shaped Pharmaceutical Composition Comprising Carvedilol as an Active Substance
A composition (batch No. 01-0076-042) according to the invention was prepared from the following ingredients:














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 contains 50 mg carvedilol. The composition was 7.5 mm long and had an oval cross sectional shape.
The composition was subjected to the dissolution test described above. The following results were obtained:











Time (h)
dissolved carvedilol (% 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.
Example 3
Preparation of a Pharmaceutical Composition Comprising Carvedilol as an Active Substance
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:














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.
The composition was subjected to the dissolution test described above. The following results were obtained:











Time (h)
dissolved carvedilol (% 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.
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:














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.
The composition was subjected to the dissolution test described above. The following results were obtained:











Time (h)
dissolved carvedilol (% 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.
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:














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.
The composition was subjected to the dissolution test described above. The following results were obtained:
Dissolved carvedilol (% w/w of the coated composition) from hour 1 to 15 hours











Time (h)
dissolved carvedilol (% 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.
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.
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.
Carvedilol is registered for the following indications:

    Hypertension
    Chronic cardiac insufficiency
    Angina pectoris


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.
The expected advantages offered by the Carvedilol Egalet® compared to the immediate release formulation include:

    
    
        i) Reduced standard deviation and thus, a more predictable concentration in plasma.
        ii) A dose regimen with lower frequency of administration and thereby potentially improvement of patient compliance.
    
    


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 Cmax, 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.
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”.
According to the American Physician's Desk Reference (PDR) 2000, Carvedilol should be prescribed twice daily for all indications.
According to the German Drug Listing (Role 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.
According to “Drugs, Fact and Comparison”, 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.
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.
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.







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.
01. Bioavailability


    
    
        a) Rate and extent of absorption
        b) Fluctuations in drug concentration
        c) Variability arising from the formulation
        d) Dose proportionality
        e) Risk of unexpected release characteristics

2. Factors influencing the performance of a modified drug formulation

        f) GI function
        g) Diurnal rhythm

3. Stereoisomers

Ad a-c Absorption, Fluctuations and Variability:

    
    


These characteristics are described by the pharmacokinetic studies already conducted and will be further confirmed in studies planned.
a. Absorption
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.
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. Fluctuations
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 C24 h, which will correspond to Cmin in a once daily dosing, is 2.5 times as high.
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.
c. Variability
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%.
There are no indications that the variability will be higher than for the immediate release formulation.
d. Dose Proportionality:
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.
e. Dose Dumping:
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.
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.
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.
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.
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.
f. GI Function:
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.
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.
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.
The absorption of Carvedilol Egalet® in patients with 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.
g. Diurnal Rhythms
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.
3. Stereoisomers
Carvedilol is a racemic mixture of R(+) and S(−)—enantiomers: S(−), which is a potent β1 and β2 antagonist and α-adrenoceptor antagonist and R(+), which has 1/100 of the beta effect and the same α effect as the S(−). The pharmacokinetics of these is described both in healthy volunteers and in patients with cardiac insufficiency.
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 t1⁄2 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.
Pharmacokinetics
The development of Carvedilol Egalet® has involved investigational pilot studies on healthy volunteers. No full-scale studies have been performed up to now.
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.
Pilot Phase I studies
Completed Pharmacokinetic Studies
The pharmacokinetic studies on Carvedilol Egalet® listed in Table 1 are part of the development work to obtain preliminary information on the pharmacokinetics.







TABLE 1







Completed pilot pharmacokinetic studies, listed chronologically











Study


Doses
No. of


No.
Design
Treatment
(mg)a
subjects














Pilot test I
Single-dose PK:
Single-
C Egalet:
6



Open-label, 2-armed, parallel
dose
25 mg



group

C IR: 25 mg



(Carvedilol Egalet ® vs. Carvedilol



IR)


Pilot test
Single-dose PK:
Single-
C Egalet:
6


II
Open-label, 2-armed, parallel
dose
50 mg



group

C IR: 50 mg



(Carvedilol Egalet ® vs. Carvedilol



IR)


Pre-Pilot I
Single-dose PK:
Single-
C Egalet:
2



Open-label, Carvedilol Egalet ®
dose
50 mg


Pre-Pilot
Single-dose PK:
Single-
C Egalet:
2


II
Open-label, Carvedilol Egalet ®
dose
50 mg


Pre-Pilot
Single-dose PK:
Single-
C Egalet:
2


III
Open-label, Carvedilol Egalet ®
dose
37.5 mg


Pre-Pilot
Single-dose:
Single-
C Egalet:
2


IV
Collection of excreted shells
dose
50 mg


Pilot test
Single-dose PK:
Single-
C Egalet:
6


III
Open-label, 4-way cross-over study
dose
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
Single-dose PK:
Single-
C Egalet:
10


Test IV
Open-label, 4-way cross-over
dose
50 mg o.d.



(3 different shapes of Carvedilol

C IR: 50 mg



Egalet ® vs. Carvedilol IR)

o.d.


Pilot
Single-dose PK:
Single-
C Egalet:
10


Test V
Open-label, 4-way cross-over
dose
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.
The formulations tested in these studies showed a prolonged release of Carvedilol with reduced Cmax and measurable plasma concentrations over 36 hours.
Results and Discussion—Pilot Pharmacokinetic Studies
The pilot phase I studios 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.
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. Cmax 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 71⁄2 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.
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



















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


71⁄2 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


71⁄2 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









Carvedilol IR in Fasting Subjects.

In the table is given relevant pharmacokinetic parameters from the pilot studies (see FIG. 1).
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:










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.
The composition was subjected to the dissolution test described above. The following results were obtained:











Time (hours)
% w/w release morphine 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.
Example 7
Preparation of a Composition of Carvedilol—DSC Measurements
A composition according to the invention was made from the following:
















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.
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.
Example 8
Compositions According to the Invention
This 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.
Abbreviations


    PEG: polyethylene glycol
    PEG ms: polyethylene glycol monostearat
    HPMCP HP 50: hydroxypropyl methylcellulose pthalate (HP 50 is grade)
    TPGS: α-tocopheryl polyethylene glycol succinate
    Polymer System


















Desired Release time 12



Matrix
%
hours in 12 mm long 



Ingredient
w/w
tubular tablet. Result


















EC-042-011
PEO 200 000
86
No zero-order release in 


25 mg Carvedilol
Carvedilol
14
acid 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.),



PEG 2000 ms
5
no 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. 


25 mg Carvedilol
Carvedilol
14
After 2-3 month storage 



PEG 2000 ms
16
(18° C.-22° C.),





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
4
Release time after 15 h.



cellulose

No zero-order release.



(Natrosol)





HPMCP HP 50
3



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 


50 mg Carvedilol
Carvedilol
32
medium. Precipitation of





carvedilol


EC-042-051
PEO 200.000
68
No release in buffer 


50 mg Carvedilol
Carvedilol
32
medium. 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















Matrix
%



Batch No.
Ingredient
w/w





















Desired Release time 12 hours





in 12 mm long tubular tablet.





Result


EC-042-045
PEO 200.000
47
Release time was too short.


50 mg
PEG 2000 ms
16
Zero-order release, release


Carvedilol
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
PEG 2000 ms
16
short. Faster release in acid


Carvedilol
Carvedilol
32
than in buffer



Succinic Acid
5



EC-042-066
PEO 200.000
58
Zero-order,


50 mg
PEG 2000 ms
5
release time 12 h. Faster


Carvedilol
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
32
Release in acid medium faster


Carvedilol
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
32
medium.


Carvedilol
PEG 2000 ms
3




Starch (corn)
20




Citric Acid
5



EC-042-081
PEG 35.000
42
Zero-order release, release


50 mg
PEO 600.000
21
time 16 h. Matrix was left in


Carvedilol
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
PEO 600.000
19
Release time >18 h.


Carvedilol
Carvedilol
32




PEG 2000 ms
5




Citric Acid
5



EC-042-083
PEO 600.000
10
Zero-order release. Release


50 mg
PEO 200.000
69
time >18 h.


Carvedilol
Carvedilol
16
Matrix left in the shell.



Citric Acid
5
PEO 600.000 delayed the





release.





Conclusion


EC-042-047
PEO 200.000
63
Zero-order, release time 14 h.


50 mg
Carvedilol
32



Carvedilol
Citric Acid
5



EC-042-049
PEO 200.000
63
Succinic acid could be used


50 mg
Carvedilol
32
instead of citric acid as


Carvedilol
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
32
small. Same slope in acid


Carvedilol
Citric Acid
2.5
and buffer was not observed.


EC-042-054
PEO 200.000
58
Amount of citric acid too


50 mg
Carvedilol
32
high. Same slope in acid and


Carvedilol
Citric Acid
10
buffer was not observed.


EC-042-073
PEO 200.000
61
Almost zero-order release.


50 mg
Carvedilol
32
Release in acid faster than in


Carvedilol
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
16
time 14 h. Comparable with


Carvedilol
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
8
time 14 h. Comparable with


Carvedilol
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
16
medium was increased when


Carvedilol
Citric Acid
5
Citric Acid/Carv Increased


EC-042-080
PEG 35.000
63
PEG 35000 increased the


50 mg
Carvedilol
32
release in acid medium.


Carvedilol
Citric Acid
5
Undesired


EC-042-084
PEO 200.000
74
Almost zero-order, release


50 mg
Carvedilol
16
time 13 h. Aluminium lactate


Carvedilol
Citric Acid
5
reduced the release in acid



Aluminum lactate
5
medium.









Addition of Zink Sulphate















Matrix
%



Batch No.
Ingredient
w/w
Conclusion


















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















Matrix
%



Batch No.
Ingredient
w/w
Conclusion


















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









Polymer















Batch

Matrix
%



No.
Formulation
Ingredient
w/w
Conclusion



















042-
50 mg
PEO 100.000
74.8
The dissolution profile


130
Carvedilol
Carvedilol
24
shows zero-order release.




Potassium Sulfite
0.2





Sucrose
0.5





BHT
0.5



042-
50 mg
PEO 200.000 LF
76
The dissolution profile


149
Carvedilol
Carvedilol
24
shows zero-order release,






however different slope






between acid and buffer.









Organic Antioxidants















Batch

Matrix




No.
Formulation
Ingredient
% w/w
Conclusion



















042-
50 mg
PEO 200.000
75.9
Diminishes degradation


115
Carvedilol
Carvedilol
24
of PEO 200.000 and




Ascorbic acid
0.1
Carvedilol. The






dissolution profile shows






zero-order release.


042-
50 mg
PEO 100.000
75.9
Diminishes degradation


116
Carvedilol
Carvedilol
24
of PEO 100.000 and




Ascorbic acid
0.1
Carvedilol. The






dissolution profile shows






zero-order release.


042-
50 mg
PEO 200.000
72.3
Diminishes degradation


133
Carvedilol
Carvedilol
24
of PEO 200.000 and




Potassium 
0.2
Carvedilol. The




Sulfite

dissolution profile shows




Salicylic acid
3
zero-order release.




BHT
0.5



042-
50 mg
PEO 200.000
74.7
The increased dosage of


135
Carvedilol
Carvedilol
24
BHT did not produce any




Potassium
0.2
significant change in the




Metabisulfite

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-
50 mg
PEO 200.000
74.6
The increased dosage of


136
Carvedilol
Carvedilol
24
BHT did not produce any




Potassium
0.2
significant change in the




Metabisulfite

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-
50 mg
PEO 200.000
64.765
The increased dosage of


141
Carvedilol
Carvedilol
24
BHT did not produce any




Potassium
0.2
significant change in the




Metabisulfite

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















Batch

Matrix
%



No.
Formulation
Ingredient
w/w
Conclusion



















042-
50 mg
PEO 200.000
75.9
Diminishes degradation of


117
Carvedilol
Carvedilol
24
PEO 200.000 and




Potassium
0.1
Carvedilol. The




Metabisulfite

dissolution profile shows






zero-order release.


042-
50 mg
PEO 200.000
72.3
Diminishes degradation of


133
Carvedilol
Carvedilol
24
PEO 200.000 and




Potassium
0.2
Carvedilol. The




Metabisulfite

dissolution profile shows




Salicylic acid
3
zero-order release.




BHT
0.5



042-
50 mg
PEO 200.000
74.8
Diminishes degradation of


134
Carvedilol
Carvedilol
24
PEO 200.000 and




Potassium
0.2
Carvedilol. The




Metabisulfite

dissolution profile shows




BHT
1
zero-order release.









6. Sugars















Batch

Matrix




No.
Formulation
Ingredient
% w/w
Conclusion



















042-
50 mg
PEO 200.000
75.8
The dissolution profile


118
Carvedilol
Carvedilol
24
shows zero-order




Potassium
0.1
release.




Sulfite






Sucrose
0.1



042-
50 mg
PEO 200.000
70.9
Production cancelled, the


120
Carvedilol
Carvedilol
24
Concentrasion of




Potassium
0.1
Sucrose to hight for the




Sulfite

selected process




Sucrose
5.0
parameters. May be






produced with increased






temperature


042-
50 mg
PEO 200.000
65.9
Carvedilol precipitated


121
Carvedilol
Carvedilol
24
when standing.




Potassium
0.1





Sulfite






Mannitol
10



042-
50 mg
PEO 200.000
73.3
Concentration of Sucrose


122
Carvedilol
Carvedilol
24
to high for the selected




Potassium
0.2
process parameters. May




Sulfite

be produced with




Sucrose
2
increased temperature.




BHT
0.5



042-
50 mg
PEO 200.000
71.8
The concentration was


123
Carvedilol
Carvedilol
24
too high and resulted in




Potassium
0.2
process problems.




Sulfite

Production cancelled.




Sucrose
3.5





BHT
0.5



042-
50 mg
PEO 200.000
74.8
The dissolution profile


129
Carvedilol
Carvedilol
24
shows zero-order




Potassium
0.2
release.




Sulfite






Sucrose
0.5





BHT
0.5



042-
50 mg
PEO 100.000
74.8
The dissolution profile


130
Carvedilol
Carvedilol
24
shows zero-order




Potassium
0.2
release.




Sulfite






Sucrose
0.5





BHT
0.5



042-
50 mg
PEO 200.000
59.8
Mannitol did not produce


137
Carvedilol
Carvedilol
24
the expected result,




Potassium
0.2
because Carvedilol




Metabisulfite

precipitated when




BHT
1
standing.




Mannitol
15



042-
50 mg
PEO 200.000
64.765
Carvedilol precipitated


141
Carvedilol
Carvedilol
24
after standing




Potassium
0.2
approximately one week.




Metabisulfite






BHT
1





Sorbitol
10





HCl
0.035









Increase in Hydrogen Bondings















Batch

Matrix
%



No.
Formulation
Ingredient
w/w
Conclusion



















042-
50 mg
PEO 200.000
74.8
Carvedilol


128
Carvedilol
Carvedilol
24
precipitated




Potassium
0.2
after standing




Metabisulfite

approximately




2-amino-
0.5
one week.




2(hydroxymethyl)1,3

Dissolution




ropandiol

profile shows




BHT
0.5
zero-order






release.


042-
50 mg
PEO 200.000
74.3
Dissolution


131
Carvedilol
Carvedilol
24
profile shows




Potassium
0.2
zero-order




Metabisulfite

release.




Klucel
1





BHT
0.5



042-
50 mg
PEO 200.000
74
The dissolution


142
Carvedilol
Carvedilol
24
profile is




PVP K90
2
zero-order.


042-
50 mg
PEO 200.000
71
Dissolution not


143-
Carvedilol
Carvedilol
24
zero-order.


02-

Sorbitol
5



001






042-
50 mg
PEO 200.000
73
Dissolution not


144
Carvedilol
Carvedilol
24
zero-order.




Cyclodextrin
3



042-
50 mg
PEO 200.000
69
Dissolution not


145
Carvedilol
Carvedilol
24
zero-order . . .




Cyclodextrin
7



042-
50 mg
PEO 200.000
64.765
Dissolution


141
Carvedilol
Carvedilol
24
profile does not




Potassium
0.2
show zero-order




Metabisulfite

release, possibly




BHT
1
due to the amount




Sorbitol
10
of BHT.




HCl
0.035



042-
50 mg
PEO 200.000
72
The dissolution


148
Carvedilol
Carvedilol
24.1
profile does not




Potassium
0.2
show zero-order




Metabisulfite

release possibly




BHT
1
due to the




KH2PO4
0.32
amount of BHT.




HCl
0.61





PVP K90
1.7



042-
50 mg
PEO 200.000
68.5
Test of


153
Carvedilol
Carvedilol
24
granulation




Potassium
0.2
method




Metabisulfite






BHT
0.5





KH2PO4
0.20





H3PO4
4.6





PVP K90
2.0









Examples disclosing Formulation Nos 68 to 84.

    6 mm oval shaped formulations 150 mm2















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%);
Carv/acid*: 4.6


Meta-Phosphoric acid*
Carv/HPO3: 10.9)


(5.2%);



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
Dry mixing: H3PO4(s) in 40 g PEO. Rest of PEO mixed


PEO 200.000(LF)
with carv. + antioxidants. Mixed all. Mix kept dry.


Carv. (18.0%),
pH 5.71


PM (0.2%),
Appearance after production: White


BHT (0.5%);
Dissolution: Cancelled due to crystallization


Ortho-Phosphoric acid
Carv/acid**: 5


(3.6%);



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%);
Carv/acid*: 3.3


Meta-Phosphoric acid*
Carv/HPO3: 7.9)


(3.6%);



PVP K90 (2.0%)





*The Meha Phosphoric acid comprises 42.1% HPO3 and 54.4%(NaPO3)6


**Ortho Phosphoric acid comprises 86% H3PO4)






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.
When TPGS is included in the composition, TPGS and PEO are premixed by adding melted TPGS to PEO followed by mixing.
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:










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.
The composition was subjected to the dissolution test described above. The following results were obtained:














% w/w release morphine sulfate



Time (hours)
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.
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.













Composition (% w/w)













No.
Length/mm
PEO 200.000
Morphine Sulphate
TPGS
AlO2, 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





a150 mm3/20 mm2


b137 mm3/diameter 5 mm


c150 mm3/16.67 mm2


d150 mm3/16.67 mm2






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.
In the following is given the data for the dissolution profiles of each composition:
Composition 2A (see FIG. 13-2A):













% 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)














% 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)














% 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)














% 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.
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).
16 healthy male volunteers aged 20 to 40 who had given their written informed consent were included in the study.
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.
The compositions tested were those described in Example 2 above. The dose given corresponds to 30 mg morphine sulphate.
The results of the study are shown in FIG. 14. In FIG. 14 is also included data for a comparative composition, Dolcontin. The results indicate that the shape as well as the size of the composition are important.
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.

## Claims

1. A pharmaceutical composition for controlled release of at least one therapeutically active substance into an aqueous medium by erosion of at least one surface of the composition, wherein:
the composition is provided in a dosage form consisting of a single erodible matrix having a coating, wherein:
the single erodible matrix comprises:
(a) one or more polyethylene oxides, wherein the average molecular weight of the one or more polyethylene oxides present in the matrix is from about 200,000 daltons to about 400,000 daltons,
(b) a block copolymer of ethylene oxide and propylene oxide,
(c) a therapeutically active substance, and,
(d) one or more pharmaceutically acceptable excipients selected from the group consisting of cellulose derivatives, release modifiers, and antioxidants, and
the coating has at least one opening exposing at least one surface of said matrix, the coating being insoluble in and impermeable to body fluids,
wherein any matrix surface exposed to an aqueous medium erodes at a substantially constant rate, so that a zero order release is obtained of at least about 60% w/w of the active substance from the pharmaceutical composition over a time period of at least 4 hours when subject to an in vitro dissolution test according to USP 24, NF 19, 711 Dissolution, employing Apparatus 2 equipped with a paddle and wherein aqueous medium is able to diffuse into the matrix with a diffusion rate of 100±30% of the dissolution rate of the matrix in aqueous medium when tested according to USP 24, page 1941-1950.

2. The composition of claim 1, wherein the one or more polyethylene oxides have an average molecular weight of from about 200,000 daltons to about 300,000 daltons.

3. The composition of claim 1, wherein the cellulose derivative is selected from the group consisting of microcrystalline cellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose and hydroxymethylpropylcellulose.

4. The composition of claim 1, wherein the cellulose derivative is selected from the group consisting of hydroxypropylmethylcellulose and methyl cellulose.

5. The composition of claim 1, wherein the cellulose derivative is hydroxypropylmethylcellulose.

6. The composition according to claim 1, wherein the release modifier is selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and methacrylic acid copolymers.

7. The composition according to claim 1, wherein the release modifier is selected from the group consisting of methacrylic acid copolymers.

8. The composition according to claim 1, wherein the release modifier is selected from the group of methacrylic acid copolymers consisting of methacrylic acid-methyl methacrylate (1:1) and methacrylic acid-methyl methacrylate (1:2) methacrylic acid copolymers.

9. The composition according to claim 1, wherein the release modifier is selected from methacrylic acid-methyl methacrylate (1:1) methacrylic acid copolymers.

10. The composition of claim 1, wherein the antioxidant is selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), t-butyl hydroquinone, 1,3,5-trihydroxybenzene , calcium ascorbate, sodium ascorbate, gallic acid, dodecyl gallate, octyl gallate, hydroquinone, maltol, sodium sulfite, sodium bisulfite, sodium metabisulfite, citric acid, tartaric acid, ascorbic acid, erythorbic acid, etidronic acid, phosphite, hypophosphorous acid, nordihydroguairetic acid, propionic acid, potassium bisulphite, potassium metabisulphite, dilauryl thiodipropionate, dimyristyl thiodipropionate, distearyl thiodipropionate, tocopherols, tocopheryl acetates, beta-carotene, ascorbyl palmitate, propyl gallate, sodium formaldehyde sulfoxylate, sodium thiosulfate, sulfur dioxide, tocopherol hemisuccinate.

11. The composition of claim 1, wherein the antioxidant is selected from the group consisting of BHA and BHT.

12. The composition of claim 1, wherein the antioxidant is BHT.

13. The composition of claim 1, wherein the coating comprises one or more polymers selected from the group consisting of cellulose acetate, polyimide, polyethylene, polyethylene terephthalate, polypropylene, polyurethane, polyvinyl acetate, polyvinyl chloride, silicone rubber, latex, polyhydroxybutyrate, polyhydroxyvalerate, teflon, polylactic acid or polyglycolic acid and copolymers thereof, ethylene vinyl acetate (EVA), styrene-butadienestyrene (SBS) and styrene-isoprene-styrene (SIS).

14. The composition of claim 1, wherein the coating comprises one or more polylactic acid polymers.

15. The composition of claim 13, wherein the coating further comprises one or more water-soluble crystalline polymers.

16. The composition of claim 1, having a cylindrical shape optionally with one or more tapered ends.

17. The composition of claim 1, wherein at least a part of the active substance is in amorphous form.

18. The composition of claim 1, wherein at least a part of the active substance is in the form of a pharmaceutically active powder.

19. The composition of claim 18, wherein the powder is comprised of particles with a particle size of from about 0.1 μm to about 500 μm.

20. The composition of claim 1, wherein at least part of the active substance is present in the form of a solid dispersion.

21. The composition of claim 1, wherein at least part of the active substance is present as a molecular dispersion.

22. The composition of claim 1, wherein the coating does not completely crumble or disintegrate before the matrix has completely eroded.

23. A method for administering a therapeutically active substance, comprising orally administering a composition according to claim 1 to a patient in need thereof.

24. A pharmaceutical composition for controlled release of at least one therapeutically active substance into an aqueous medium by erosion of at least one surface of the composition, wherein:
the composition is provided in a dosage form consisting of a single erodible matrix having a coating, wherein:
the single erodible matrix consists essentially of:
(a) one or more polyethylene oxides, wherein the average molecular weight of the one or more polyethylene oxides present in the matrix is from about 200,000 daltons to about 400,000 daltons,
(b) a block copolymer of ethylene oxide and propylene oxide,
(c) a therapeutically active substance, and
(d) one or more pharmaceutically acceptable excipients selected from the group consisting of cellulose derivatives, release modifiers, and antioxidants, and
the coating has at least one opening exposing at least one surface of said matrix, the coating being insoluble in and impermeable to body fluids,
wherein any matrix surface exposed to an aqueous medium erodes at a substantially constant rate, so that a zero order release is obtained of at least about 60% w/w of the active substance from the pharmaceutical composition over a time period of at least 4 hours when subject to an in vitro dissolution test according to USP 24, NF 19, 711 Dissolution, employing Apparatus 2 equipped with a paddle and wherein aqueous medium is able to diffuse into the matrix with a diffusion rate of 100±30% of the dissolution rate of the matrix in aqueous medium when tested according to USP 24, page 1941-1950.