US20040234602A1

US20040234602A1 - Polymer release system

Info

Publication number: US20040234602A1
Application number: US10/490,308
Authority: US
Inventors: Gina Fischer; Daniel Bar-Shalom; Lillian Slot; Anne-Marie Lademann; Christine Jensen
Original assignee: Individual
Current assignee: Egalet AS
Priority date: 2001-09-21
Filing date: 2002-09-23
Publication date: 2004-11-25
Also published as: EP1429739A1; US8617605B2; US20140120164A1; US20080254122A1; EP2957281A1; US9694080B2; WO2003024429A1

Abstract

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

Description

FIELD OF THE INVENTION

The present invention relates to a novel method for controlling the release of a therapeutically, prophylactically and/or diagnostically active substance from a pharmaceutical composition into an aqueous medium. The pharmaceutical composition is a coated matrix composition in which the matrix composition comprises a) polymer or a mixture of polymers, b) an active substance and, optionally, c) one or more pharmaceutically acceptable excipients. In a specific embodiment, the polymer is a substantially water soluble or crystalline polymer or a mixture of substantially water soluble and/or crystalline polymers. The coating remains intact during the release phase and may thereafter crumble and/or erode. Furthermore, the coating covers the matrix composition in such a manner that only a specific surface area of the matrix composition is subject to erosion in an aqueous medium, i.e. the surface area from which the active substance is release is kept substantial constant during the time period

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 lipophilic and which has a melting point that is lower than the polymer used in the polymeric matrix composition. The presence of such a substance (e.g. like PEG 400 monostearate or PEG 2000 monostearate) has been contemplated to function as a so-called repair medium. Such a repair medium has a substantially hydrophilic domain, which gives it affinity to the (crystalline) polymeric phase, thereby filling in domains between grains and cracks in the polymer matrix and reducing the water affinity of these domains and in the polymer matrix itself. Water diffusion in the interface between the polymer crystals is thereby substantially eliminated, thus substantially limiting diffusion of water into the composition to the surface layer of the matrix, so that erosion of the composition is predominantly effected by the dissolving action of the aqueous phase on a surface or surfaces of the composition exposed to the aqueous medium. In other words a repair medium seems to prevent the diffusion of water in the polymer matrix composition.

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 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

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

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.

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.

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.

Altematively to a polymer of a polyglycol type as described above other polymers may be suitable for use in the matrix composition a). Thus, in other embodiments of the invention, the polymer is selected from one or more of the following polymers: water soluble natural polymers such as glucomannan, galactan, glucan, polygalacturonic acid, polyxylane, polygalactomannans, rhanogalacturonan, polyxyloglycan, arabinogalactan, and starch; water soluble polymers such as PVA, PVB, methocel, Eudragit L methyl ester and PHPV; biodegradable polymers such as PHA, and PLA; hydrogels, such as olyacrylic amid, and dextran; copolymers such as polylactic acid with polyglycolic acid; and others such as alginate and pectins including low methylated or methoxylated pectins.

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, ipratropium, cholinetheophyllinate, proxiphylline, bechlomethasone, budesonide, deslanoside, digoxine, digitoxin, disopyramide, proscillaridin, chinidine, procainamide, mexiletin, flecainide, alprenolol, proproanolol, nadolol, pindolol, oxprenolol, labetalol, timolol, atenolol, pentaeritrityltetranitrate, isosorbiddinitrate, isosorbidmononitrate, niphedipin, phenylamine, verapamil, diltiazem, cyclandelar, nicotinylalcholhol, inositolnicotinate, alprostatdil, etilephrine, prenalterol, dobutamine, dopamine, dihydroergotamine, guanetidine, betanidine, methyldopa, reserpine, guanfacine, trimethaphan, hydralazine, dihydralazine, prazosine, diazoxid, captopril, nifedipine, enalapril, nitroprusside, bendroflumethiazide, hydrochlorthiazide, metychlothiazide, polythiazide, chlorthalidon, cinetazon, clopamide, mefruside, metholazone, bumetanide, ethacrynacide, spironolactone, amiloride, chlofibrate, nicotinic acid, nicheritrol, brompheniramine, cinnarizine, dexchlorpheniramine, clemastine, antazoline, cyproheptadine, proethazine, cimetidine, ranitidine, sucralfat, papaverine, moxaverine, atropin, butylscopolamin, emepron, glucopyrron, hyoscyamine, mepensolar, methyiscopolamine, oxiphencyclimine, probanteline, tero dilin, sennaglycosides, sagradaextract, dantron, bisachodyl, sodiumpicosulfat, etulos, diphenolxylate, loperamide, salazosulfapyridine, pyrvin, mebendazol, dimeticon, ferrofumarate, ferrosuccinate, ferritetrasemisodium, cyanochobalamine, folid acid heparin, heparin co-factor, diculmarole, warfarin, streptokinase, urokinase, factor Vil, factor IX, vitamin K, thiopeta, busulfan, chlorambucil, cyclophosphamid, melfalan, carmustin, mercatopurin, thioguanin, azathioprin, cytarabin, vinblastin, vinchristin, vindesin, procarbazine, dacarbazine, lomustin, estramustin, teniposide, etoposide, cisplatin, amsachrin, aminogluthetimid, phosphestrol, medroxiprogresterone, hydroxiprogesterone, megesterol, noretisteron, tamoxiphen, ciclosporin, sulfosomidine, bensylpenicillin, phenoxymethylpenicillin, dicloxacillin, cloxacillin, flucoxacillin, ampicillin, amoxicillin, pivampicillin, bacampicillin, piperacillin, mezlocillin, mecillinam, pivmecillinam, cephalotin, cephalexin, cephradin, cephadroxil, cephaclor, cefuroxim, cefotaxim, ceftazidim, cefoxitin, aztreonam, imipenem, cilastatin, tetracycline, lymecycline, demeclocycline, metacycline, oxitetracycline, doxycycline, chloramphenicol, spiramycin, fusidic acid, lincomycin, clindamycin, spectinomycin, rifampicin, amphotericin B, griseofulvin, nystatin, vancomycin, metronidazole, tinidazole, trimethoprim, norfloxacin, salazosulfapyridin, aminosalyl, isoniazid, etambutol, nitrofurantoin, nalidixic acid, metanamine, chloroquin, hydroxichloroquin, tinidazol, ketokonazol, acyclovir, interferon idoxuridin, retinal, tiamin, dexpantenol, pyridoxin, folic acid, ascorbic acid, tokoferol, phytominadion, phenfluramin, corticotropin, tetracosactid, tyrotropin, somatotoprin, somatrem, vasopressin, lypressin, desmopressin, oxytocin, chloriongonadotropin, cortison, hydrocortisone, fluodrocortison, prednison, prednisolon, fluoximesteron, mesterolon, nandrolon, stanozolol, oximetolon, cyproteron, levotyroxin, liotyronin, propylthiouracil, carbimazol, tiamazol, dihydrotachysterol, alfacalcidol, calcitirol, insulin, tolbutamid, chlorpropamid, tolazamid, glipizid, glibenclamid, phenobarbital, methyprylon, pyrityldion, meprobamat, chlordiazepoxid, diazepam, nitrazepam, oxazepam, dikaliumclorazepat, lorazepam, flunitrazepam, alprazolam, midazolam, hydroxizin, chlometiazol, propionmazine, alimemazine, chlorpromazine, levomepromazine, acetophenazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, dixyrazine, thiodirazine, periciazin, chloprothixene, zuclopentizol, flupentizol, thithixen, haloperidol, trimipramin, opipramol, chlomipramin, desipramin, lofepramin, amitriptylin, nortriptylin, protriptylin, maptrotilin, caffeine, cinnarizine, cydizine, dimenhydinate, meclozine, prometazine, thiethylperazine, metodopramide, scopolamine, phenobarbital, phenytoine, ethosuximide, primidone, carbamazepine, chlonazepam, orphenadrine, atropine, bensatropine, biperiden, metixene, procyilidine, levodopa, bromocriptin, amantadine, ambenon, pyridostigmine, synstigmine, disulfiram, morphine, codeine, pentazocine, buprenorphine, pethidine, phenoperidine, phentanyl, methadone, piritramide, dextropropoxyphene, ketobemidone, acetylsalicylic acid, phenazone, phenylbutazone, azapropazone, piroxicam, ergotamine, dihydroergotamine, cyproheptadine, pizitifen, flumedroxon, allopurinol, probenecid, sodiummaurothiomalate auronofin, penicillamine, estradiol, estradiolvalerianate, estriol, ethinylestradiol, dihydrogesteron, lynestrenol, medroxiprogresterone, noretisterone, cydophenile, clomiphene, levonorgestrel, mestranol, ornidazol, tinidazol, ekonazol, chlotrimazol, natamycine, miconazole, sulbentin, methylergotamine, dinoprost, dinoproston, gemeprost, bromocriptine, phenylpropanolamine; sodiumchromoglicate, azetasolamide, dichlophenamide, betacarotene, naloxone, calciumfolinate, in particular clonidine, thephylline, dipyradamol, hydrochlothiazade, scopolamine, indomethacine, furosemide, potassium chloride, morphine, ibuprofen, salbutamol, terbutalin, sulfonylurea, mefformin, insulin, calcitonin, glucagons-like peptide-1, or combinations thereof.

The active substance can be in various forms, such as uncharged molecules, molecular complexes, crystalline forms, amorphous form, polymorphous form, solvates, anhydrates, pharmacologically acceptable salts such as a hydrochloride, hydrobromide, sulfate, laurylate, palmitate, phosphate, nitrite, nitrate, borate, acetate, maleate, tartrate, oleate, and salicylate. For acidic active substance, salts of metals, amines amino acids or organic cations, quatemary ammoniums, can be used. Derivatives of active substances such as esters, ethers and amides which have solubility characteristics suitable for use herein can be used alone or mixed with other drugs. After release of the derivative from the drug delivery system it may be converted by enzymes, hydrolysed by body pH or other metabolic processes to the parent drug or to another biologically active form.

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 dassify dispersed system. A colloidal dispersion is when the dispersed phase has a particle size between about 1 and about 1000 nm and a coarsely dispersion has a mean particle size of at least about 1000 nm and a molecular dispersion has a particle size below about 1 nm. Combinations between the various states are very likely and the most dominating character can be determined by X-ray diffraction spectra or differential thermoanalysis.

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 imperfect. A pharmaceutical composition of the invention may also be used for the delivery of active agents in specialized carriers such as liposomes, cydodextrines, nanoparticles, micelles and fats.

A further use for which a composition of the invention is suited is the delivery of active substances to animals. Examples of such active substances for veterinary use are antiparasitics, corticosteroids, antibiotics, antiimflammatory agents, growth promoters and permittants, antifungals and antihelmintics.

A pharmaceutical composition of the invention is designed to release the active substance in a controlled manner such as by a zero order release mechanism. Accordingly, the composition is especially suitable for a controlled release of an active substance. In the present context the tern “controlled release” is used to designate a release a desired rate during a predetermined release period. Terms like “modified”, “delayed”, “sustained”, “prolonged”, “extended” etc. release are in the present context synonyms to the term “controlled release”.

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

Difussion 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 M _t/M_∞ is the fractional drug release, t is the release time, k is a kinetic constant characteristics of the drug/polymer system, C_dis the tracer loading concentration and n is an exponent which characterisers the mechanism of release of the tracers.

\begin{matrix} \frac{M_{t}}{M_{\infty}} = k \cdot t^{n} & (Eq . 1) \\ \frac{\partial M_{t}}{A \cdot \partial t} = n \cdot C_{d} \cdot k \cdot t^{n - 1} & (Eq . 2) \end{matrix}

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
Diffusinal release	Overall Solute	solute release
Exponent (n)	diffusion mechanism	rate (dM_t/d_t)

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.

Altematively or additionally, a suitable pharmaceutically acceptable excipient is a mono-, di-, oligo, polycarboxylic acid or amino acids such as, e.g. acetic acid, succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, sorbic acid etc., aspartic acid, glutamic acid etc.

Examples of suitable organic acids include acetic acid/ethanoic acid, adipic acid, angelic acid, ascorbic acid/vitamin C, carbamic acid, cinnamic acid, citramalic acid, formic acid, fumaric acid, gallic acid, gentisic acid, glutaconic acid, glutaric acid, glyceric acid, glycolic acid, glyoxylic acid, lactic acid, levulinic acid, malonic acid, mandelic acid, oxalic acid, oxamic acid, pimelic acid, and pyruvic acid.

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, ammnonium 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 isapol husk, veegum, glycollate, magnesium stearate, calcium stearate, stearic acid, talc, titanium dioxide, silicium dioxide, clays, 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 acid, hydrogenated vegetable oils, sodium benzoate, sodium chloride, leucine, carbowax 4000, magnesium lauryl sulfate, colloidal silicon dioxide and mixtures thereof, disintegrants such as starches, clays, cellulose derivatives including crosscarmellose, gums, aligns, various combinations of hydrogencarbonates with weak acids (e.g. sodium hydrogencarbonateitartaric acid or citric acid) crosprovidone, sodium starch glycolate, agar, cation exchange resins, citrus pulp, veegum HV, bentonite. or mixtures thereof; volatile solvents such as alcohols, including aqueous alcohols, petroleum benzine, acetone, ether or mixtures thereof; plasticizers such as sorbitol and glycerine; and others such as cocoa butter, polyethylene glycols, e.g. with a molecular weight of about 1,000-500,000 daltons, typically about 1,000-100,000 daltons, more typically 1,000-50,000 daltons, especially about 1,000-10,000 daltons, in particular about 1,500-5,000 daltons, and mixtures thereof, hydrogenated vegetable oils, glycerinated gelatin or mixtures thereof.

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 plasticziser may be incorporated in the composition. A suitable plasticizer is selected from the group consisting of phosphate esters; phthalate esters; amides; mineral oils; fatty adds and esters; fatty alcohols, vegetable oils and hydrogenated vegetable oils including acetylated hydrogenated cottonseed glyceride and acetylated hydrogenated soybean oil glycerides; acetyl tributyl citrate, acetyl triethyl citrate, Castor oil, diacetylated monoglycerides, dipropylene glycol salicylate glycerin, glyceryl cocoate, mono- and di-acetylated monoglycerides, nitrobenzene, carbon disulfide, β-naphtyl salicylate, phthalyl glycolate, diocyl phthalate; sorbitol, sorbitol glyceryl tricitrate; sucrose octaacetate; a-tocopheryl polyethylene glycol succinate, phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters; fatty alcohols; and vegetable oils, fatty alcohols including cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol and myristyl alcohol; methyl abietate, acetyl tributyl citrate, acetyl triethyl citrate, diisooctyl adipate, amyl oleate, butyl ricinoleate, benzyl benzoate, butyl and glycol esters of fatty acids, butyl diglycol carbonate, butyl oleate, butyl stearate, di(beta-methoxyethyl) adipate, dibutyl sebacate, dibutyl tartrate, diisobutyl adipate, dihexyl adipate, triethylene glycol di(beta-ethyl butyrate), polyethylene glycol di(2-ethyl hexoate), diethylene glycol monolaurate, monomeric polyethylene ester, hydrogenated methyl ester of rosin, methoxyethyl oleate, butoxyethyl stearate, butyl phthalyl butyl glycolate, glycerol tributyrate, triethylene glycol dipelargonate, beta-(p-tert-amyl phenoxy)ethanol, beta(p-tert-butytphenoxy)ethanol, beta-(p-teft-butytphenoxyethyl)acetate, bis(beta-p-tert-buthylphenoxydiethyl) ether, camphor, Cumar W-1, Cumar MH-1, Cumar V-1, diamyl phthalate, (diamylphenoxy) ethanol, diphenyl oxide, technical hydroabietyl alcohol, beckolin, benzene hexahydrochlonde, Clorafin 40, Piccolastic A-5, Piccalastic A-25, Flexol B400, Glycerol alfa-methyl alfa-phenyl ether, chlorinated naphthalene, HB-40, monoamylphthalate. Nevillac 10 o-nitrodiphenyl and Paracril 26.

Preferred anti-oxidative agents include TPGS due to surfactant properties, BHA, BHT, t-butyl hydroquinone, calcium ascorbate, gallic acid, hydroquinone, maltol, octyl gallate, sodium bisulfite, sodium metabisulfite, tocopherol and derivates thereof, citric acid, tartaric acid, and ascorbic acid. Other antioxidants include trivalent phosphorous like e.g phosphite, phenolic antioxidants, hydroxylamines, lactones such as substituted benzofuranones. Hindered phenols, thiosynergists and/or hindered amines are useful for the long-term stability for polymers, whereas the following antioxidants are suitable for use also in situation where the active substance is subject to oxidation: acids (ascorbic acid, erythorbic acid, etidronic acid, gallic acid, hypophosphorous acid, nordihydroguairetic acid, propionic acid etc.), phenols (e.g. BHA, BHT, t-butyl hydroquinone, dodecyl gallate, octyl gallate, 1,3,5-trihydroxybenzene), organic and inorganic salts (calcium ascorbate, sodium ascorbate, sodium bisulphite, sodium metabisulfite, sodium sulfite, potassium bisulphite, potassium metabisulphite), esteres (calcium ascorbate, dilauryl thiodipropionate, dimyristyl thiodipropionate, distearyl thiodipropionate), pyranon (maltol), and vitamin E (tocopherol, D-α-tocopherol, DL-α-tocopherol, tocopheryl acetate, d-α-tocopheryl acetate, dl-α-tocopheryl acetate. However, other anti-oxidative agents known in the art may be used according to the present invention.

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 Pharmmaceutical Sciences, 18^thEdition, 1990. Release modifiers may in particular be selected from one of three general classes, namely cellulose derivatives, methacrylic acid polymers and modified gelatine compounds. Preferred release modifiers include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate, as well as methacrylic acid copolyrmers. Modified gelatine compounds include gelatine treated with e.g. formaldehyde or glutaraldehyde.

Examples of commercially available polymers suitable as release modifiers are EUDRAGIT® L and EUDRAGIT® S, available from Röhm GmbH, Germany, and enteric coating agents available from Shin-Etsu Chemical Co., Japan. The release modifier will typically be present in the composition in an amount of about 0.1-10%, based on the weight of the matrix, preferably about 0.5-4%, e.g. about 1-3%, such as about 1.5-2.0%. If desired, a suitable mixture of more than one release modifier may be used in order to obtain a desired release profile in any given composition.

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 510 hours after administration it is contemplated that a shape is suitable that exposes an increasing surface area during the first 1-3 hours and then exposes a constant surface area. Examples of such shapes are given in FIG. 1B.

Specific examples of compositions with different shapes and sizes are:



	Length	Diameter	Vol
Batch	[mm]	[mm]	[mm³]

01-0034-042	7.5	5.05	150
01-0035-042	6.0	5.64	150
01-0043-042	9.0	4.6	150

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



	Length	Vol
Batch	[mm]	[mm³]	Longest/shortest diameter [mm]

01-0075-042	6.0	150	8.74	3.64
01-0076-042	7.5	150	7.82	3.21

The coated compositions obtained were open at two opposite ends. The area for an open end is calculates as the volume/length of the cylindrical formulations.

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 matrixitime unit) is dependent on the size of the area indicating non-linearity. However such non-linearity may be tested by measuring the erosion rate individually with two different exposed areas of the same matrix composition. In case the formulations show different dissolution rates, the ratio between the areas and the rates may be calculated.

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 mm ²surface to protect de formulation from diffusion of the buffer solution.

In a still further embodiment, a formulation as disclosed in Batch 084 (12% load, 6 mm oval, 150 mm ³corresponding 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 mm ²and 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 mm ³includes:

Surface area (one end) of 27.17 mm ²and 5.85 mm length

Surface area (one end) of 25.00 mm ²and 6.40 mm length

Designs for a 50 mg Carvedilol having a volume of 318 mm ³includes:

Surface area (one end) of 45 mm ²and 7 mm length

Surface area (one end) of 50 mm ²and 6.4 mm length

Surface area (one end) of 55 mm ²and 5.6 mm length

Designs for a 12,5 mg Carvedilol having a volume of 79.5 mm ³includes

Surface area (one end) of 13.6 mm ²and 5.85 mm length

Designs for a 6.25 mg Carvedilol having a volume of 39.75 mm ³includes:

Surface area (one end) of 6.8 mm ²and 5.85 mm length

Such small formulations may be prepared with a thicker shell for patient compliance reasons. The final size of all the formulations may be adjusted simply with adjusting the thickness of the shell for example by selecting the overall size of the 12.5 mg formulation.

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 filler in the coating will be determined in each particular case according to the characteristics, e.g. erosion rate and size, of the matrix comprising the active substance.

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 inorder to improve the processibility of the ethylcellulose or the first cellulose derivative. The plasticizer may also be a non-ionic surfactant, e.g. a non-ionic surfactant selected from the group consisting of diacetylated monoglycerides, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monooleate, glyceryl monostearate, propylene glycol monostearate, macrogol esters, macrogol stearate 400, macrogol stearate 2000, polyoxyethylene 50 stearate, macrogol ethers, cetomacrogol 1000, lauromacrogols, nonoxinols, octocinols, tyloxapol, poloxamers, polyvinyl alcohols, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate and sucrose esters; nitrobenzene, carbon disulfide, β-naphtyl salicylate, phthalyl glycolate, dioctyl phthalate.

Other suitable plasticizers appear from EP-B0 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 1-4 times a day, normally 1-4 times daily such as 1-3 times, 1-2 times or 1 times daily. The technology may also provide compositions for administration only once or twice daily. In the present context the term “once daily” is intended to mean that it is only necessary to administer the pharmaceutical composition once a day in order to obtain a suitable therapeutic and/or prophylactic response; however, any administration may comprise co-administration of more than one dosage unit, such as, e.g. 2-4 dosage units if the amount of active substance required may not be formulated in only one composition or if a composition of a smaller size is preferred.

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 inter alia depend on the amount of active substance to be released for it to exert the desired effect, as well as on the overall dosage of the active substance contained in the matrix. The substance of which the matrix is composed and the distribution of the active substance in the matrix may therefore be selected according to one or more of these criteria to ensure the desired level of release of the active substance.

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) stablility 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

Stablility of the individual components:

iii) stablility 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 amorphos state it is often necessary to provide suitable conditions in the composition for improved stability as well as to provide suitable storage conditions. Irrespective of the release mechanism of the active substance from the composition, the present inventors have found that—when active substances with a low water solubility is employed—a suitable stable pharmaceutical compositions for oral use is a composition comprising a solid dispersion of component i) and ii)

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 take place (unless the substance is degraded to insoluble products etc.). A dissolved system may therefore be regarded as a stable system. However, in practice the situation is often much more complex and it is normally necessary to stabilize even dissolved system by use of different methods.

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 formaldehylde sulfoxylate, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives, sulfides, phosphine etc. Other suitable antioxidants are described herein.

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 productiori of polymer-based materials, depending upon the desired embodiment and the materials employed in the composition in question. As mentioned above, one advantage of the composition according to the invention is that it may be produced by methods, which are relatively simple and inexpensive.

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 pattem.

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 et al. J. Pharm. Sci. 11 Suppl. 2 (2000) pp S73-S80.

FIG. 10 shows the dissolution profile relating to a composition of Example 8 denoted 0069; the dissolution has been determined after 26 days storage at 30° 0 C. and 60% RH.

FIG. 11 is a suitable shape for an opioid composition. Suitable values are e.g. a=3 mm, b=4.5 mm, c=1.5 mm and d=9 mm; a=3 mm, b=4.6 mm, c=2 mm and d=9 mm; a=2.3 mm, b=5.3 mm, c=1.5 mm and d=7.5 mm; or a=3.4 mm, b=5.1 mm, c=2 mm and d=7.5 mm

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 [0204]
A composition according to the invention has properties that ensure that the diffusion rate of water into the polymer matrix substantially corresponds to the dissolution rate of the polymer matrix composition into the aqueous medium. In the following is given a simple method to test these conditions. [0205]
The polymers that are suitable for use according to the present invention and which are sufficiently hydrophilic are water-soluble. When contacted with water, a sharp advancing waterfront divides the intact and not penetrated matrix from a swollen front. Under stationary conditions, a constant thickness surface layer is formed by the swollen polymer and by a high concentration of polymer in solution. [0206]
In fact, once the hydrodynamic external conditions are defined, a stationary state is reached where the rate of penetration of the moving boundary equals the rate of removal of the polymer at the external surface. [0207]
The time lapse until the quasi-stationary state is reached is called swelling time. At steady state, the dissolution rate is constant and can be defined equally by either the velocity of the retracting front of the polymer or the velocity of the front separating the pure penetrate and the liquid dissolving sublayer. Thus, both fronts are synchronized. [0208]
When the dissolution rate equals the penetration rate (i.e. the diffusion rate) a constant thickness surface layer should be observed. The dissolving layer evolution during water conditioning should reflect the different dissolution characteristics of the materials employed. The surface layer thickness is measured as a function of time. [0209]
In order to measure the diffusion rates of water, samples may be prepared in the form of plugs fitting to the sample holder (e.g. 2 mm, 4 mm, 6 mm, 7.5 mm and 12 mm long and preferable with the same shape and volume as the desired dosage unit). The sample holder is prepared by translucent glass in a tubular shape and with noticeable marks indicated with a specific distance. [0210]
The test proceeds as follows: [0211] 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. [0212]
When the dissolution rate equals the penetration rate a constant thickness surface layer is observed. The different dissolving layers in different matrices obtained during the water contact, reflect the different dissolution characteristics of the matrix. The thickness of the surface layer as a function of time is then compared. The specific aqueous medium may be selected individually. [0213]

Dissolution Test

Dissolution tests were performed in accordance with the [0214] USP 24, NF 19, (711) Dissolution, Apparatus 2 equipped with a paddle. The dissolution medium was 0.1 N hydrochloric acid during the first 120 min, which was then substituted with a buffer solution pH 6.8. The volume of the dissolution medium was 1000 ml and the rotation speed of the paddle was 120 rpm during the first 120 min and then 50 rpm. Samples were withdrawn at suitable time intervals and analyzed for content of active substance by means of UV spectrometry at a wavelength of 284 nm.

EXAMPLES

A General Method for the Preparation of a Controlled Release Composition is Described Below

Preparation of the Matrix Composition

An accurate amount of the polymer (i.e. in the examples below: the polyethylene oxide) is loaded into a MTI mixer followed by an accurate amount of the active substance and of the pharmaceutically acceptable excipients(s), if any. The mixing is performed at 2050/1450 rpm and at a time period of 10 min+4 min+short final spinning. At the start of the mixing the temperature is about 19° C. (the first time period) and the final temperature of the mixture is about 52° C. (the second and third time period). The mixture is then allowed to cool to room temperature and is ready to be fed into an injection moulding machine. [0215]

Preparation of the Coating Composition

The coating composition was prepared by first adding the hydroxymethylcellulose then cetostearyl alcohol, and finally the titanium dioxide to an MTI-Mixer at a temperature about 21° C. After mixing for nearly 9 min at 1000 rpm (I: 0.9 A) the mixer was stopped (temperature about 46° C.) and the adhered material manually incorporated into the mixture. The mixture was left to cool for about 10 minutes. The mixing is then finalized with a short high-speed mix in order to minimize lumps formation. The mixture was then allowed to cool to room temperature, after which it had a suitable consistency for being fed into an injection moulding machine. [0216]

Example of Coat Composition

[0217]

Batch: 58-014-01-013

amount Weight

% Batch Material (g) (g) step

79 991207-A Ethocel 632 632 1

20 990426-B Cetylstearyl Alkohol 160 160.1 2

1 97051301 TiO ₂ 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 [0218] 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. [0219]
The following table describes formulations having a cylindrical form and circular openings in both ends. [0220]

Length Diameter Vol

Batch [mm] [mm] [mm³]

01-0034-042 7.5 5.05 150

01-0035-042 6.0 5.64 150

01-0043-042 9.0 4.6 150
The following table describes formulations having a cylindrical form and oval openings in both ends [0221]

Length Vol

Batch [mm] [mm³] Longest/shortest diameter [mm]

01-0075-042 6.0 150 8.74 3.64

01-0076-042 7.5 150 7.82 3.21
The coated compositions obtained were open at two opposite ends. The area for an open end is calculates as the volume/length of the cylindrical formulations. [0222]

Example 1

Preparation of a Pharmaceutical Composition Comprising Carvedilol as an Active Substance

A composition (plug batch No. 01-0045-042), formulation batch No. 01-0034 042 according to the invention was prepared from the following ingredients: [0223]

No Raw materials Reference:

1 PEO 200,000 S-Ega40200; USP24-NF19 2000 p. 2497

2 Carvedilol Ph. Eur. 3rd Ed. 2000 p.359

3 Citric Acid Ph. Eur. 3rd Ed. 1997 p.645

Matrix % w/w

Polyethylene oxide 64.6

Carvedilol (Cipla) 30

Citric acid 5.4
The coating and the matrix were prepared as described above. One dosage form contains 50 mg carvedilol. The composition was 7.5 mm long. [0224]
The composition was subjected to the dissolution test described above. The following results were obtained: [0225]

dissolved carvedilol

Time (h) (% w/w of the coated composition)

0 0

1 14.1

2 27.1

3 39.3

4 49.9

5 60.7

6 72.5

7 85.0

8 99.7
The solution profile corresponds to a zero order release of carvedilol from the composition. [0226]

Example 2

Preparation of an Oval Shaped Pharmaceutical Composition Comprising Carvedilol as an Active Substance

A complsition (batch No. 01-0076-042) according to the invention was prepared from the following ingredients: [0227]

Matrix % w/w

Polyethylene oxide 64.6

Carvedilol (Cipla) 30

Citric acid 5.4
The coating and the matrix were prepared as described above. One dosis form contain 50 mg carvedilol. The composition was 7.5 mm long and had an oval cross sectional shape. [0228]
The composition was subjected to the dissolution test described above. The following results were obtained: [0229]

dissolved carvedilol

Time (h) (% w/w of the coated composition)

0 0

1 15.9

2 30.1

3 46.2

4 62.2

5 77.61

6 92.4
The dissolution profile corresponds to a zero order release of carvedilol from the composition. [0230]

Example 3

Preparation of a Pharmaceutical Composition Comprising Carvedilol as an Active Substace

A composition (plug batch No. 01-0044-042, dosage unit batch No. 01-0043 042) according to the invention was prepared from the following ingredients: [0231]

Matrix % w/w

Polyethylene oxide 64.6

Carvedilol (Cipla) 30

Citric acid 5.4
The coating and the matrix were prepared as described above. One dosage form contains 50 mg carvedilol. The composition was 9 mm long. [0232]
The composition was subjected to the dissolution test described above. The following results were obtained: [0233]

dissolved carvedilol

Time (h) (% w/w of the coated composition)

0 0

1 13.2

2 22.5

3 33.2

4 44.7

5 56.2

6 67.0

7 77.2

8 88.1

9 98.6
The dissolution profile corresponds to a zero order release of carvedilol from the composition. [0234]

Example 4

A composition (batch No. 01-0075-042) according to the invention was prepared from the following ingredients: [0235]

Matrix % w/w

Polyethylene oxide 64.6

Carvedilol (Cipla) 30

Citric acid 5.4
The coating and the matrix were prepared as described above. One dosage unit form contains 50 mg carvedilol. The composition was 6 mm long and had an oval shape. [0236]
The composition was subjected to the dissolution test described above. The following results were obtained: [0237]

dissolved carvedilol

Time (h) (% w/w of the coated composition)

0 0

1 17.0

2 35.1

3 55.1

4 74.7

5 93.8
The dissolution profile corresponds to a zero order release of carvedilol from the composition. [0238]

Example 4A

A composition (batch No. EC-042-211) according to the invention was prepared from the following ingredients: [0239]

Matrix % w/w

Polyethylene oxide 86

Carvedilol (Cipla) 14
The coating and the matrix were prepared as described above. One dosage unit form contains 25 mg carvedilol. The composition was 12 mm long and had circular end surfaces. [0240]
The composition was subjected to the dissolution test described above. The following results were obtained: [0241]

Dissolved carvedilol (% w/w of the coated composition) from hour 1 to 15 hours



		dissolved carvedilol
	Time (h)	(% w/w of the coated composition)

	1	12.4
	2	21.6
	3	29.2
	4	35.4
	5	40.0
	6	44.5
	7	49.4
	8	54.3
	9	59.4
	10	64.6
	11	70.6
	12	75.5
	13	79.8
	14	84.1
	15	88.7
	16	92.6
	17	94.6

The dissolution profile corresponds to a zero order release of carvedilol from the composition. [0243]

Example 5

Pilot Phase I Studies in Health Volunteers Employing Carvedilol Compositions According to the Invention

Carvedilol has emerged as one of the important and promising drugs for cardiovascular diseases including hypertension and congestive heart failure, and results in a noticeable improvement of survival rates in patients with chronic cardiac insufficiency. To further optimize the treatment, Carvedilol Egalet® has been developed as a once daily composition. [0244]
Carvedilol is currently marketed as an immediate release formulation only in 3,125 mg, 6,25 mg, 12,5 mg, 25 mg and 50 mg tablets. Only the 6,25 mg and 25 mg application form is available throughout the EU whilst of the other strengths some are missing in certain member states. A 25 mg immediate release application form may be used as a reference. [0245]
Carvedilol is registered for the following indications: [0246]
Hypertension [0247]
Chronic cardiac insufficiency [0248]
Angina pectoris [0249]
Carvedilol Egalet® is developed for long-term treatment of hypertension and is therefore developed for a maintenance dosage. However, the present invention encompasses other dosages where a controlled delivery is desired. [0250]
The expected advantages offered by the Carvedilol Egalet® compared to the immediate release formulation include: [0251]
i) Reduced standard deviation and thus, a more predictable concentration in plasma. [0252]
ii) A dose regimen with lower frequency of administration and thereby potentially improvement of patient compliance. [0253]
For patients with cardiac insufficiency, it is recommended to take Carvedilol with a meal to delay absorption and thereby avoid adverse reactions. Carvedilol Egalet® offers the advantage of reduced C[0254] _max, even if taken fasting. (Latest studies CL-EG-pilot-1 and CL-EG-pilot-02 shows that C_maxis only slightly as high as for 25 mg Carvedilol IR).
Patients with hypertension have a well-described low compliance, presumably because there are no recognizable symptoms connected with the condition. Compliance with a once-daily regimen is higher and therefore offers a therapeutic advantage. Recommendations for the use of Carvedilol vary between countries. [0255]
An evaluation of Carvedilol in “Drugs” from 1997 lists in the summary under Dosage and Administration “A dosage of Carvedilol 12.5 mg once daily for 2 days, increased to 25 mg daily thereafter and increased to 50 mg once daily after 2 weeks if necessary, is recommended for patients with mild to moderate hypertension”. [0256]
According to the American Physician's Desk Reference (PDR) 2000, Carvedilol should be prescribed twice daily for all indications. [0257]
According to the German Drug Listing (Rote Liste 2001 for Dilatrend®), Carvedilol should be prescribed twice daily for cardiac insufficiency and angina pectoris, and once to twice daily for hypertension with a maximum dose of 2×25 mg. [0258]
According to “Drugs, Fact and Compariso”, Carvedilol is prescribed twice daily for hypertension. In all countries, the maximum daily dose is 25 mg b.i.d., and it is against this dose and frequency that Carvedilol Egalet is tested herein. [0259]

Composition of Carvedilol Egalet

In the development work on Carvedilol Egalet®, different compositions of matrix have been tested, i.e. the load of drug has been varied. [0260]

In Table 1 below is given the final composition of the coated composition used in the pilot studies. The individual composition employed in Pilot tests III, Iv and V corresponds to the compositions of Examples 1-4.

TABLE 1


Composition of Carvedilol Egalet ®

			Reference
			to
Ingredients	Percentage	Function	standards

Active substance
Carvedilol
	32%	Active compound	Cipla
Excipients
Citric Acid
	5%	Matrix	Ph. Eur.
Polyethylene Oxide	63%	Matrix	USP
(PEO 200000)
Ethylcellulose	79%	Shell	Ph. Eur
Ceto-stearyl alcohol	19.8%	Shell	Ph. Eur
Titanium dioxide
	1%	Shell	Ph. Eur
Ferro Oxide

	0,2%	Colouring	USP

Pharmacodynamics

There are several pharmacodynamics issues to be described for the Carvedilol Egalet®. The following is a list of issues and the considerations regarding their testing. [0262]
01. Bioavailability [0263]
a) Rate and extent of absorption [0264]
b) Fluctuations in drug concentration [0265]
c) Variability arising from the formulation [0266]
d) Dose proportionality [0267]
e) Risk of unexpected release characteristics [0268]
2. Factors influencing the performance of a modified drug formulation [0269]
f) GI function [0270]
g) Diumal rhythm [0271]
3. Stereoisomers [0272]
Ad a-c Absorption, fluctuations and variability: [0273]
These characteristics are described by the pharmacokinetic studies already conducted and will be further confirmed in studies planned. [0274]
a. Absorption [0275]
There is no literature on slow release formulations of Carvedilol. One study has been identified on in-vivo absorption of Carvedilol formulated in timed-release capsules. This study by Nolte et al found absorption throughout the GI tract, correlating with the absolute absorption areas of the different parts of the intestinal tract. They found a relatively high absorption of Carvedilol in the large intestine, amounting to approximately 10% of the total absorption. [0276]
This supports the findings from the pilot studies performed on the Carvedilol Egalet®, where the plasma curves show that Carvedilol is being absorbed throughout the GI tract, including the colon, and that the absorption in the colon is present, but considerably reduced compared to earlier in the GI tract. b. [0277]
Fluctuations [0278]
To evaluate fluctuations in plasma concentration, comparison should be made between plasma profiles from the same concentration given. Data from pilot study IV and V on [0279] Carvedilol IR 50 mg compared to Carvedilol Egalet® 50 mg shows that Cmax for the Carvedilol Egalet® is reduced approximately 50%, whereas the C24h, which will correspond to Cmin in a once daily dosing, is 2,5 times as high.
In the studies, the Carvedilol IR has been given in a single dose. Patients will be taking Carvedilol IR b.i.d., wherefore peak/trough ratio should be measured for this dose regimen. This will be done in the steady state studies. [0280]
c. Variability [0281]
In published literature the variability of Carvedilol is very high, with standard deviations of >50%. The study with the highest number of subjects, i.e. 44 shows a SD of 70%. [0282]
There are no indications that the variability will be higher than for the immediate release formulation. [0283]
d. Dose proportionality: [0284]
At this point it is only planned to market one dose of Carvedilol Egalet®, and no investigations into dose proportionality are planned. Literature describes dose linearity for Carvedilol in the range of 6,25-50 mg. [0285]
e. Dose dumping: [0286]
Carvedilol is being released from the Egalet tablet by the erosion of the matrix from the exposed surfaces only as the coat prevents contact to the aqueous medium of the intestines. Accordingly, release of all of the Carvedilol at one time is not possible. [0287]
A further advantage of the injection moulding of shell and matrix in one process step is that the shell and the matrix reach a high degree of adherence. [0288]
An uncoated and thus unprotected matrix has been investigated through dissolution tests, which show that release time in-vitro for a freely exposed Carvedilol matrix from a 9 mm Egalet® is about two hours. Accordingly, the coating actively prevents release due to the limited exposed area. [0289]
In addition, the in-vivo-in-vitro correlation of the Egalet® has been described to some extend through scintigraphy. 2 hours in vitro release in the stomach will correspond to at least 3 hours in vivo, and will not be below 2 hours. Thus any dose dumping would be of less severity than seen after intake of 50 mg conventional immediate release tablet. [0290]
The immediate release tablet has been investigated as 50 mg o.d. in several clinical studies, but is associated to an increased number of adverse events, compared to lower doses, due to the increased trough-peak ratio. [0291]
f. GI function: [0292]
GI transit time may influence the release rate. A very fast transit time where the tablet is excreted before the content is fully released, will result in a decreased AUC. This is a well-described issue for slow release products. [0293]
For the Carvedilol Egalet® the effect of GI transit time can be clearly demonstrated because the non-degradable shell can be collected. When all Carvedilol is released with normal transit times, remaining Carvedilol can be found in the shells with decreased transit time. This has been documented in findings from pilot study III. [0294]
As release rate is constant for any given formulation, release time is depending on the length of the Egalet® tablet. For the matrix formulation, which releases at the rate of 1 mm/hour in in-vitro dissolution, tablets of 9 mm have shown complete release with normal transit time. [0295]
The absorption of Carvedilol Egalet® in patients with [0296] Morbus Crohn and Collitis ulcerosa has not been investigated. Until that is performed, the use of the product in the patient population is contraindicated.
The effect of food will be evaluated in a traditional PK study. Preliminary information on food effect will be obtained in a pilot study on 10 volunteers. [0297]
9. Diumal rhythms [0298]
Carvedilol has been shown to preserve the diurnal rhythm of blood pressure; there are no reasons to believe that a slow release formulation will influence this rhythm differently than the IR formulation. This will be explored in the phase II study, where ambulatory BP will be measured for 24 hours. [0299]
3. Stereoisomers [0300]
Carvedilol is a racemic mixture of R(+) and S(−)-enantiomers: S(−), which is a potent β1 and β2 antagonist and a-adrenoceptor antagonist and R(+), which has 1/100 of the beta effect and the same a effect as the S(−). The pharmacokinetics of these is described both in healthy volunteers and in patients with cardiac insufficiency. [0301]
Theoretically, the plasma profiles of the enantiomers seen after intake of the Carvedilol Egalet® could be different from the one seen after Carvedilol immediate release, given that the t½ of the two are different (9.6 h for R(+) and 22.1 h for S(−)). In steady state, however, the plasma profiles are similar to that of Carvedilol, and it is not expected that the blood pressure lowering effect will be different for the Carvedilol Egalet® than for the Carvedilol IR. [0302]

Pharmacokinetics

The development of Carvedilol Egalet® has involved investigational pilot studies on healthy volunteers. No full-scale studies have been performed up to now. [0303]
Different formulations of Carvedilol Egalet® have been tested and through this work the final formulation has been identified, and a strategy was planned for the clinical testing programme. [0304]

Pilot Phase I Studies

Completed Pharmacokinetic Studies

The pharnacokinetic studies on Carvedilol Egalet® listed in Table 1 are part of the development work to obtain preliminary information on the pharmacokinetics.

TABLE 1


Completed pilot pharmacokinetic studies, listed chronologically

Study			Doses	No. of
No.	Design	Treatment	(mg)^a	subjects

Pilot test	Single-dose PK:	Single-dose	C Egalet:	6
I	Open-label, 2-armed, parallel		25 mg
	group		C IR: 25 mg
	(Carvedilol Egalet ® vs. Carvedilol IR)
Pilot test	Single-dose PK:	Single-dose	C Egalet:	6
II	Open-label, 2-armed, parallel		50 mg
	group		C IR: 50 mg
	(Carvedilol Egalet ® vs. Carvedilol IR)
Pre-Pilot	Single-dose PK:	Single-dose	C Egalet:	2
I	Open-label, Carvedilol Egalet ®		50 mg
Pre-Pilot	Single-dose PK:	Single-dose	C Egalet:	2
II	Open-label, Carvedilol Egalet ®		50 mg
Pre-Pilot	Single-dose PK:	Single-dose	C Egalet:	2
III	Open-label, Carvedilol Egalet ®		37.5 mg
Pre-Pilot	Single-dose:	Single-dose	C Egalet:	2
IV	Collection of excreted shells		50 mg
Pilot test	Single-dose PK:	Single-dose	C Egalet:	6
III	Open-label, 4-way cross-over study		25 mg/
	(3 doses Carvedilol Egalet ® vs.		37.5 mg/
	Carvedilol IR)		50 mg o.d.
			C IR:
			37.5 mg
			b.i.d.
Pilot Test	Single-dose PK:	Single-dose	C Egalet:	10
IV	Open-label, 4-way cross-over		50 mg o.d.
	(3 different shapes of Carvedilol		C IR: 50 mg
	Egalet ® vs. Carvedilol IR)		o.d.
Pilot Test	Single-dose PK:	Single-dose	C Egalet:	10
V	Open-label, 4-way cross-over		50 mg o.d.
	(2 different shapes of Carvedilol		C IR: 50 mg
	Egalet ® vs. Carvedilol IR)		o.d.
	As a final fixed sequence arm; the
	chosen shape of Carvedilol Egalet ®
	in fed subjects

In all studies, the investigational products were administered orally as tablets. [0306]
The formulations tested in these studies showed a prolonged release of Carvedilol with reduced C[0307] _maxand measurable plasma concentrations over 36 hours.

Results and Discussion—Pilot Pharmacokinetic Studies

The pilot phase I studies completed up to now clearly indicates that it is possible to produce a slow release Carvedilol Egalet® with a PK profile required of a once daily formulation. [0308]
In pilot test III, the influence of the length of the Egalet® tablet on the release characteristics was described. In pilot test IV, Egalet® tablets with 3 different diameters and lengths has been tested. In vitro dissolution tests indicated that an increased diameter would not influence the speed of erosion and pilot IV and V has confirmed this. C[0309] _maxis increasing proportionally to the increasing surface area exposed of the Egalet. Tmax does not differ between the formulations. The mean of the plasma concentrations measured for the 6 mm Carvedilol Egalet 50 mg is reduced due to an unexpected high number of subjects having a fast transit time in that treatment group; 6 of 10 subjects excreted the Egalet before hour 24.
In pilot study V, two of the same lengths of Carvedilol Egalet® as in pilot test IV were tested, but in a different oval shape, and compared to Carvedilol immediate release. Preliminary data assessment supports the conclusion from pilot study IV that Cmax increases with increasing diameter of the Egalet®. When comparing data for the round Egalet in pilot IV to the “easy-to-swallow” oval shaped Egalet in pilot V, for the 6 mm and the 7½ mm lengths respectively, and the exposed matrix area being constant, there are no observed difference by the change of shape. To obtain preliminary information on the effect of food on Carvedilol Egalet®, the 6 mm Egalet formulation was tested after a standard, high-fat meal, according to guidelines. The first 3 arms of the study were randomised and the last, the fed, was a fixed sequence arm. The data results from the last sequence have not been received yet and full data analysis for pilot study V has thus not been completed. [0310]
The composition, the [0311] 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

7½ mm 10 355 88 37.8 10.3 3.8 4

6 mm 10 336 76 37.4 9.1 2.9 4

IR 10 433 100 105.5 5.8 1.9 1

CL-EG-02 (oval egalet)

IR 10 444 100 95.8 6.6 2.4 1

7½ mm 10 344 76 33.2 9.0 5.0 4

6 mm 10 421 97 41.7 11.8 4.8 4

6 mm + food 10 362 80 39.0 10.9 3.9 3
In the table is given relevant pharmacokinetic parameters from the pilot studies (see FIG. 1). [0312]

Example 6

Preparation of a Morphine Containing Controlled Release Composition According to the Invention

A composition (batch No. 01-0112-066) according to the invention was prepared from the following ingredients: [0313]

Matrix

Polyethylene oxide 200,000 83.5% w//w

Morphine sulfate 16.5% w/w
The coating and the matrix were prepared as described above. The composition was 9 mm long and had elliptic formed surfaces. [0314]
The composition was subjected to the dissolution test described above. The following results were obtained: [0315]

% w/w release morphine

Time (hours) sulfate from the composition

1 19.48

2 33.64

3 44.22

4 55.59

5 70.11

6 80.70

7 91.30

8 96.65
The release corresponds to a zero order release. [0316]

Example 7

Preparation of a Composition of Carvedilol—DSC Measurements

A composition according to the invention was made from the following: [0317]

PEO 200,000 67% w/w

Carvedilol

28% w/w

Citric acid

5% w/w
The composition was made according to the general process described herein. [0318]
All starting materials as well as a mixture of PEO 200,000 and citric acid was subject to differential scanning caliometry measurements (thermal measurement). The final composition was also investigated at [0319] 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

Composition According to the Invention

The example illustrates the invention and gives a number of different compositions according to the invention. In the right hand column is given comments to the individual compositions with respect to the impact on the composition of the ingredients employed and with respect to the dissolution profile obtained. [0320]

Abbreviations:



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

		Desired Release time
Matrix	%
12 hours in 12 mm long
Ingredient	w/w	tubular tablet. Result

Polymer system

EC-042-011	PEO	200 000	86	No zero-order release in acid
25 mg Carvedilol	Carvedilol		14	medium, release time after
			17 h.
EC-042-013	PEO 200 000	50	No zero-order release,
25 mg Carvedilol	Carvedilol		14	release time after 14 h.
	Lactose	24
	Klucel	5
	PEG 2000 ms	7
EC-042-014	PEO 200 000	81	Released after 14 h. After 1
25 mg Carvedilol	Carvedilol		14	month (18-22° C.), no
	PEG 2000 ms	5	release in buffer.
EC-042-015	PEO 200 000	81	Release time after more
25 mg Carvedilol	Carvedilol		14	than 20 h. Matrix left in
	HPMCP HP 50	5	the shell.
EC-042-016	PEO 200 000	76	Release time after 16 h.
25 mg Carvedilol	Carvedilol		14	Matrix left in the shell.
	PEG 2000 ms	5
	HPMCP HP 50	5
EC-042-020	PEO 200 000	81	Released after 12 h. Almost
25 mg Carvedilol	Carvedilol		14	zero-order.
	PEG 2000 ms	5
EC-042-024	PEO 200 000	70	Released after 11 h. After 2-3
25 mg Carvedilol	Carvedilol		14	month storage (18° C.-22° C.),
	PEG 2000 ms	16	no release in buffer.
EC-042-025	PEO 200 000	65	Release time increased but
25 mg Carvedilol	Carvedilol		14	HPMCP did not lower the
	PEG 2000 ms	14	release rate in acid medium.
	Hydroxyethyl cellulose	4	Release time after 15 h.
	(Natrosol)	3	No zero-order release.
	HPMCP HP 50
EC-042-030	PEO 200 000	52	No zero order release.
50 mg Carvedilol	Carvedilol		32
	PEG 2000 ms	16
EC-042-031	PEO 600 000	52	No zero order release.
50 mg Carvedilol	Carvedilol		32
	PEG 2000 ms	16
EC-042-034	PEO 45.000	70	No zero-order release, the
25 mg Carvedilol	PEG 2000 ms	14	matrix swell.
	Carvedilol	16
EC-042-037	PEO 200.000	52	No zero-order release.
50 mg Carvedilol	Carvedilol		32	Release time 14-16 h.
	PEG 2000 ms	16	Carvedilol precipitated in
			buffer medium.
EC-042-039	PEO 200.000	52	No zero order release,
50 mg Carvedilol	Carvedilol		32	release time > 25 h.
	PEG 2000 ms	6	Starch increased the release
	Starch
	10	time
EC-042-042	PEO 200.000	43	Too low release rate,
50 mg Carvedilol	Carvedilol		32	Carbomer 974 dereased the
	PEG 2000 ms	10	release time
	Carbomer 974	15
EC-042-043	PEO 200.000	47	Too low release rate,
50 mg Carvedilol	Carvedilol		32	Carbomer 974 dereased the
	PEG 2000 ms	16	release time
	Carbomer 974	5
EC-042-044	PEO 200.000	55	Too low release.
50 mg Carvedilol	Carvedilol		32	Carbomer decreased the
	PEG 2000 ms	10	release.
	Carbomer 974	3
EC-042-048	PEO 200.000	68	No release in buffer medium.
50 mg Carvedilol	Carvedilol		32	Precipitation of carvedilol
EC-042-051	PEO 200.000	68	No release in buffer medium.
50 mg Carvedilol	Carvedilol		32	Precipitation of carvedilol
EC-042-052	PEO 200.000	84	Almost zero-order release.
25 mg Carvedilol	Carvedilol		16	Release time 15 h.
			Formulation was unstable.

Acidic stabilizicers

EC-042-045	PEO 200.000	47	Release time was too short.
50 mg Carvedilol	PEG 2000 ms	16	Zero-order release, release
	Carvedilol	32	time 11 h Faster release in
	Citric Acid	5	acid than in buffer
EC-042-050	PEO 200.000	47	Zero-order, release time too
50 mg Carvedilol	PEG 2000 ms	16	short. Faster release in acid
	Carvedilol
	32	than in buffer
	Succinic Acid
	5
EC-042-066	PEO 200.000	58	Zero-order,
50 mg Carvedilol	PEG 2000 ms	5	release time 12 h. Faster
	Carvedilol
	32	release in acid than in buffer
	Citric Acid
	5
EC-042-069	PEO 200.000	40	No zero-order release.
50 mg Carvedilol	Carvedilol		32	Release in acid medium faster
	PEG 2000 ms	3	than in buffer. Some matrix
	Pectin
	20	was still left in the matrix.
	Citric Acid	5	Pectin delayed release
EC-042-070	PEO 200.000	40	No release in buffer
50 mg Carvedilol	Carvedilol		32	medium.
	PEG 2000 ms	3
	Starch (com)	20
	Citric Acid	5
EC-042-081	PEG 35.000	42	Zero-order release, release
50 mg Carvedilol	PEO 600.000	21	time 16 h. Matrix was left in
	Carvedilol	32	the shell. PEO 600.000
	Citric Acid	5	delayed the release
EC-042-082	PEG 35.000	39	No zero-order release.
50 mg Carvedilol	PEO 600.000	19	Release time > 18 h.
	Carvedilol	32
	PEG 2000 ms	5
	Citric Acid	5
EC-042-083	PEO 600.000	10	Zero-order release. Release
50 mg Carvedilol	PEO 200.000	69	time > 18 h.
	Carvedilol	16	Matrix left in the shell.
	Citric Acid	5	PEO 600.000 delayed the
			release.

Matrix	%
Ingredient	w/w	Conclusion

EC-042-047	PEO 200.000	63	Zero-order, release time
50 mg Carvedilol	Carvedilol		32	14 h.
	Citric Acid	5
EC-042-049	PEO 200.000	63	Succinic acid could be used
50 mg Carvedilol	Carvedilol		32	instead of citric acid as
	Succinic Acid	5	release time and release
			pattern were the same.
EC-042-053	PEO 200.000	65.5	Amount of citric acid too
50 mg Carvedilol	Carvedilol		32	small. Same slope in acid
	Citric Acid	2.5	and buffer was not observed.
EC-042-054	PEO 200.000	58	Amount of citric acid too
50 mg Carvedilol	Carvedilol		32	high. Same slope in acid and
	Citric Acid	10	buffer was not observed.
EC-042-073	PEO 200.000	61	Almost zero-order release.
50 mg Carvedilol	Carvedilol		32	Release in acid faster than in
	Citric Acid	5	buffer. Matrix left in the shell.
	Tristearin	2
EC-042-077	PEO 200.000	81.5	Zero-order release, release
25 mg Carvedilol	Carvedilol		16	time 14 h. Comparable with
	Citric Acid	2.5	50 mg carvedilol EC-042-047
EC-042-078	PEO 200.000	90.75	Zero-order release, release
12.5 mg Carvedilol	Carvedilol		8	time 14 h. Comparable with
	Citric Acid	1.25	50 mg and 25 mg EC-042-047
			and EC-042-077
EC-042-079	PEO 200.000	79	Release profile in acid
25 mg Carvedilol	Carvedilol		16	medium was increased when
	Citric Acid	5	Citric Acid/Carv increased
EC-042-080	PEG 35.000	63	PEG 35000 increased
50 mg Carvedilol	Carvedilol		32	the release in acid
	Citric Acid
	5	medium. Undesired
EC-042-084	PEO 200.000	74	Almost zero-order, release
50 mg Carvedilol	Carvedilol		16	time 13 h. Aluminium lactate
	Citric Acid
	5	reduced the release in acid
	Aluminum lactate
	5	medium.

Addition of Zink Sulphate

EC-042-085	PEO 200.000	77.5	Zero-order release, release
25 mg Carvedilol	Carvedilol		16	time 14 h.
	Citric Acid	5	Zink Sulphate decreased
	Zink Sulphate	1.5	release in acid compared to
			buffer.
EC-042-086	PEO 200.000	74.5	Zero-order release, release
25 mg Carvedilol	Carvedilol		16	time 14 h.
	Citric Acid	5	Zink Sulphate decreased
	Zinc Sulphate	4.5	release in acid compared to
			buffer
EC-042-087	PEO 200.000	79.5	Zero-order release, release
25 mg Carvedilol	Carvedilol		16	time 13 h. Zink Sulphate
	Citric Acid	2.5	decreased release in acid
	Zinc Sulphate
	2

Polymer with inorganic ingredients

EC-042-040	PEO 200.000	52	No release in buffer medium.
50 mg Carvedilol	PEG 2000 ms	6	See also EC-042-037, not
	Carvedilol	32	comprising SiO2
	SiO2
	10

Batch		Matrix	%
No.	Formulation	Ingredient	w/w	Conclusion

Polymer

042-130	50 mg Carvedilol	PEO 100.000	74.8	The dissolution profile
		Carvedilol
	24	shows zero-order release.
		Potassium Sulfite	0.2
		Sucrose	0.5
		BHT	0.5
042-149	50 mg Carvedilol	PEO 200.000 LF	76	The dissolution profile
		Carvedilol
	24	shows zero-order release,
				however different slope
				between acid and buffer.

Organic antioxidants

042-115	50 mg Carvedilol	PEO 200.000	75.9	Diminishes degradation
		Carvedilol
	24	of PEO 200.000 and
		Ascorbic acid	0.1	Carvedilol. The
				dissolution profile shows
				zero-order release.
042-116	50 mg Carvedilol	PEO 100.000	75.9	Diminishes degradation
		Carvedilol
	24	of PEO 100.000 and
		Ascorbic acid	0.1	Carvedilol. The
				dissolution profile shows
				zero-order release.
042-133	50 mg Carvedilol	PEO 200.000	72.3	Diminishes degradation
		Carvedilol
	24	of PEO 200.000 and
		Potassium Sulfite	0.2	Carvedilol. The
		Salicylic acid	3	dissolution profile shows
		BHT	0.5	zero-order release.
042-135	50 mg Carvedilol	PEO 200.000	74.7	The increased dosage of
		Carvedilol	24	BHT did not produce any
		Potassium		significant change in the
		Metabisulfite	0.2	level of impurities caused
		BHT	1	by PEO 200.000
		Gentisic acid	0.1	compred to 0.5% BHT
				The dissolution profile
				does not show zero-order
				release.
042-136	50 mg Carvedilol	PEO 200.000	74.6	The increased dosage of
		Carvedilol	24	BHT did not produce any
		Potassium		significant change in the
		Metabisulfite	0.2	level of impurities caused
		BHT	1	by PEO 200.000
		Gentisic acid	0.2	compatred to 0.5% BHT
				The dissolution profile
				does not show zero-order
				release.
042-141	50 mg Carvedilol	PEO 200.000	64.765	The increased dosage of
		Carvedilol	24	BHT did not produce any
		Potassium		significant change in the
		Metabisulfite	0.2	level of impurities caused
		BHT	1	by PEO 200.000
		Sorbitol	10	compared to 0.5% BHT
		HCl	0.035	The dissolution profile
				does not show zero-order
				release.

2.3 Inorganic antioxidants

042-117	50 mg Carvedilol	PEO 200.000	75.9	Diminishes degradation of
		Carvedilol	24	PEO 200.000 and
		Potassium		Carvedilol. The
		Metabisulfite	0.1	dissolution profile shows
				zero-order release.
042-133	50 mg Carvedilol	PEO 200.000	72.3	Diminishes degradation of
		Carvedilol	24	PEO 200.000 and
		Potassium		Carvedilol. The
		Metabisulfite	0.2	dissolution profile shows
		Salicylic acid	3	zero-order release.
		BHT	0.5
042-134	50 mg Carvedilol	PEO 200.000	74.8	Diminishes degradation of
		Carvedilol	24	PEO 200.000 and
		Potassium		Carvedilol. The
		Metabisulfite	0.2	dissolution profile shows
		BHT	1	zero-order release.

6. Sugars

042-118	50 mg Carvedilol	PEO 200.000	75.8	The dissolution profile
		Carvedilol
	24	shows zero-order release.
		Potassium Sulfite	0.1
		Sucrose	0.1
042-120	50 mg Carvedilol	PEO 200.000	70.9	Production cancelled, the
		Carvedilol	24	Concentrasion of
		Potassium Sulfite	0.1	Sucrose to hight for the
		Sucrose	5.0	selected process
				parameters. May be
				produced with increased
				temperature
042-121	50 mg Carvedilol	PEO 200.000	65.9	Carvedilol precipitated
		Carvedilol	24	when standing.
		Potassium Sulfite	0.1
		Mannitol	10
042-122	50 mg Carvedilol	PEO 200.000	73.3	Concentration of Sucrose
		Carvedilol
	24	to high for the selected
		Potassium Sulfite	0.2	process parameters. May
		Sucrose
	2	be produced with
		BHT	0.5	increased temperature.
042-123	50 mg Carvedilol	PEO 200.000	71.8	The concentration was
		Carvedilol	24	too high and resulted in
		Potassium Sulfite	0.2	process problems.
		Sucrose	3.5	Production cancelled.
		BHT	0.5
042-129	50 mg Carvedilol	PEO 200.000	74.8	The dissolution profile
		Carvedilol
	24	shows zero-order
		Potassium Sulfite	0.2	release.
		Sucrose	0.5
		BHT	0.5
042-130	50 mg Carvedilol	PEO 100.000	74.8	The dissolution profile
		Carvedilol
	24	shows zero-order
		Potassium Sulfite	0.2	release.
		Sucrose	0.5
		BHT	0.5
042-137	50 mg Carvedilol	PEO 200.000	59.8	Mannitol did not produce
		Carvedilol	24	the expected result,
		Potassium		because Carvedilol
		Metabisulfite	0.2	precipitated when
		BHT	1	standing.
		Mannitol	15
042-141	50 mg Carvedilol	PEO 200.000	64.765	Carvedilol precipitated
		Carvedilol	24	after standing
		Potassium		approximately one week.
		Metabisulfite	0.2
		BHT	1
		Sorbitol	10
		HCl	0.035

Increase in hydrogen bondings

042-128	50 mg Carvedilol	PEO 200.000	74.8	Carvedilol precipitated
		Carvedilol	24	after standing
		Potassium		approximately one week.
		Metabisulfite	0.2	Dissolution profile shows
		2-amino-		zero-order release.
		2(hydroxymethyl)1,3
		ropandiol	0.5
		BHT	0.5
042-131	50 mg Carvedilol	PEO 200.000	74.3	Dissolution profile shows
		Carvedilol	24	zero-order release.
		Potassium
		Metabisulfite	0.2
		Klucel	1
		BHT	0.5
042-142	50 mg Carvedilol	PEO 200.000	74	The dissolution profile is
		Carvedilol	24	zero-order.
		PVP K90	2
042-143-	50 mg Carvedilol	PEO 200.000	71	Dissolution not zero-
02-001		Carvedilol	24	order.
		Sorbitol	5
042-144	50 mg Carvedilol	PEO 200.000	73	Dissolution not zero-
		Carvedilol	24	order.
		Cyclodextrin	3
042-145	50 mg Carvedilol	PEO 200.000	69	Dissolution not zero-
		Carvedilol	24	order.
		Cyclodextrin	7
042-141	50 mg Carvedilol	PEO 200.000	64.765	Dissolution profile does
		Carvedilol	24	not show zero-order
		Potassium		release, possibly due to
		Metabisulfite	0.2	the amount of BHT.
		BHT	1
		Sorbitol	10
		HCl	0.035
042-148	50 mg Carvedilol	PEO 200.000	72	The dissolution profile
		Carvedilol	24.1	does not show zero-order
		Potassium		release possibly due to
		Metabisulfite	0.2	the amount of BHT.
		BHT	1
		KH₂PO₄	0.32
		HCl	0.61
		PVP K90	1.7
042-153	50 mg Carvedilol	PEO 200.000	68.5	Test of granulation
		Carvedilol
	24	method
		Potassium
		Metabisulfite	0.2
		BHT	0.5
		KH₂PO₄	0.20
		H₃PO₄	4.6
		PVP K90	2.0

Examples disclosing Formulation Nos 68 to 84. [0322]

6 mm oval shaped formulations 150 mm ²



0068	Dry mixing with solid phosphoric acid.
PEO 200.000,	pH 7.27
Carv.(24.0%),	Base line Dissolution zero-order, erosion time 7 hours, not
PM (0.2%),	complete dissolution at hour 8, matrix on bottom of vessel
BHT(0.5%);
Meta-Phosphoric acid*	Carv/acid*: 4.6
(5.2%);	Carv/HPO3: 10.9)
PVP K90 (2.0%)
0069	Dry mixing: Acid(s) and PEO mixed in mortar. Blended and
PEO 200.000 81.7%	crushed. All mixed. Mix kept dry.
Carv.(12.0%),	pH 7.27
PM (0.2%),	Appearance of tablets after production:
BHT(0.5%);	Transparent yellowish
Meta-Phosphoric acid*	Baseline Dissolution, zero-order, erosion time 6.5 hours,
(3.6%)	complete dissolution at hour 7
PVP K90 (2.0%)	Dissolution in simulated fasted and fed media zero-order
	(FIGS. 8 and 9)
	Carv/acid*: 3.3
	Carv/HPO3: 7.9)
	Appearance/Dissolution after 26 days storage at
	30° C./60% Rh:
	Transparent yellowish/Zero-order erosion time 6 hours,
	complete dissolution after 6.5 hours (FIG. 10)
Not produced	Carvedilol/acid ratio 3.3* (7.9 based on HO3P)
PEO 200.000 LF83.7%	Exptected values:
Carv.(12.0%),	pH about 6
PM (0.2%),	Appearance of tablets transparent yellowish
BHT(0.5%);	Dissolution, zero-order
Meta-Phosphoric acid*
(3.6%)(42.1% HO3P)
0070	Dry mixing: H3PO4(s) in PEO. Then mixed with rest. Mix
PEO 200.000,	kept dry.
Carv.(24.0%),	pH 5.93
PM (0.2%),	Appearance after production: White
BHT(0.5%);	Baseline Dissolution: Carvedilol.not released in buffer due
Ortho-Phosphoric acid	to crystallization.
(4.4%);	Carvedilol/acid**: 5.45
PVP K90 (2.0%)
Composition	Dry mixing: H3PO4(s) in PEO. Then mixed with rest. Mix
0073	kept dry.
PEO 200.000 (LF),	pH 3.23
Carv. (18.0%),	Appearance after production: Transparent yellowish,
PM (0.2%),	Dissolution:
BHT(0.5%);	Dissolution, zero-order, erosion time 6 hours, complete
Ortho-Phosphoric acid	dissolution at hour 6.5
(4.5%);	Carv/acid**: 4
PVP K90 (2.0%)	Appearance: After 1-2 weeks storage white
0075
PEO 200.000(LF)	Dry mixing: H3PO4(s) in 40 g PEO. Rest of PEO mixed
Carv. (18.0%),	with carv. + antioxidants. Mixed all. Mix kept dry.
PM (0.2%),	pH 5.71
BHT(0.5%);	Appearance after production: White
Ortho-Phosphoric acid	Dissolution: Cancelled due to crystallization
(3.6%);	Carv/acid**: 5
PVP K90 (2.0%)
0083	Dry mixing: Powders mixed and H3PO4 (I) mixed in some
PEO 200.000(LF),	of the powders. All mixed. Mix kept dry. pH in mixture 3.84
Carv. (12.0%),	Appearance after production: White
PM (0.2%),	Dissolution: Cancelled due to crystallization
BHT(0.5%);	Carv/acid**: 5
Ortho-Phosphoric acid
(2.4%);
PVP K90 (2.0%)
0084	pH 3.23 (mixture)
PEO 200.000 (LF),	Appearance after production: Transparent yellowish,
Carv. (12.0%),	Dissolution: Zero-order, erosion time 6 hours, complete
PM (0.2%),	dissolution at hour 6.5
BHT(0.5%);
Meta-Phosphoric acid*	Carv/acid*: 3.3
(3.6%);	Carv/HPO3: 7.9)
PVP K90 (2.0%)

A General Method for the Preparation of a Controlled Release Composition is Described Below for the Following Examples

Preparation of the Matrix Composition

An accurate amount of the polymer (i.e. in the examples below: the polyethylene oxide) is loaded into a MTI mixer followed by an accurate amount of the active substance and of the pharmaceutically acceptable excipients(s), if any. The mixing is performed at 2000/1500 rpm and at a time period of from 10 min to 20 min. At the start of the mixing the temperature is about 19° C. and the final temperature of the mixture is about 40-43° C. The mixture is then allowed to cool to room temperature and is ready to be fed into an injection moulding machine. [0324]
When TPGS is included in the composition, TPGS and PEO are premixed by adding melted TPGS to PEO followed by mixing. [0325]

Example 9

A composition (batch No. 01-0112-066) according to the invention was prepared from the following ingredients: [0326]

Matrix

Polyethylene oxide 200,000 83.5% w//w

Morphine sulfate 16.5% w/w
The coating and the matrix were prepared as described above. The composition was 9 mm long and had elliptic formed surfaces. [0327]
The composition was subjected to the dissolution test described above. The following results were obtained: [0328]

% w/w release morphine

Time (hours) sulfate from the composition

9 19.48

10 33.64

11 44.22

12 55.59

13 70.11

14 80.70

15 91.30

16 96.65
The result is also shown in FIG. 12 and the release corresponds to a zero order release. [0329]

Example 10

Preparation of Morphine-containing Compositions According to the Invention

In the table below is given details on the composition of 4 different morphine compositions. The content of morphine sulphate in all compositions corresponds to 30 mg morphine sulphate. The volumes of the different compositions were the same, whereas the diameter of the open end surfaces varies. [0330]

Composition (% w/w)

PEO Morphine AlO₂,

No. Length/mm 200.000 Sulphate TPGS 3H₂O Mannitol

1B 7.5; Ellipse^a 76.5 18.7 2.5 2.3

2B 12; round^b 68.7 18.7 2.6 10.0

2A 9; round^c 69.9 17.5 2.6 10.0

1A 9; round^d 77.3 17.9 2.5 2.4
All compositions demonstrated 6 months accelerated stability at 40° C./75% RH and 12 months stability at 25° C./75% RH. In all compositions each single impurity is below 0.1% w/w. [0331]
In the following is given the data for the dissolution profiles of each composition: [0332]
Composition 2A (see FIG. 13-[0333] 2A):

% active

substance

Time/h dissolved

0.0 −0.36

1.0 23.45 20.0

2.0 41.3 35.2

3.0 59.5 50.7

4.0 75.93 64.7

5.0 90.83 77.4

6.0 107.34 91.5

6.5 113.26 96.6

7.0 116.67 99.4

7.5 117.24 100

8.0 117.28 100

Composition 2B (see FIG. 14-2B)



	% active
	substance
Time/h	dissolved

0.0	−0.48
1.0	19.22	16.9
2.0	34.44	30.0
3.0	44.3	39.0
4.0	55.52	48.8
5.0	66.13	58.2
6.0	76.93	67.7
7.0	87.19	76.7
8.0	98.11	86.3
9.0	109.04	96.0
9.5	111.26	97.8
10.0	112.63	99.1
10.5	113.48	100
11.0	113.66	100

Composition 1B (see FIG. 13-1B) [0335]

% active

substance

Time/h dissolved

0.0 −0.47

1.0 30.15 23.7

2.0 55.72 43.9

3.0 77.54 61.1

4.0 97.55 76.8

5.0 117.57 92.6

5.5 124.77 98.2

6.0 126.89 100

6.5 126.93 100
Composition 1A (see FIG. 13-1A) [0336]

% active

substance

Time/h dissolved

0.0 −0.423

1.0 23.17 19.3

2.0 40.47 33.8

3.0 53.27 44.4

4.0 67.13 56.0

5.0 80.67 67.3

6.0 101.23 84.4

7.0 108.16 90.2

7.5 114.53 95.6

8.0 119.78 100
The results show that the use of mannitol or aluminiumoxide as a DDA leads to the desired zero order release of morphine sulphate from a composition according to the invention. The above-mentioned compositions were subject to a clinical study. The clinical study is reported in the following example. [0337]

Example 11

A Single Dose, Randomized, Cross-over, Pharmacokinetic Pilot Study on Four Different Morphine Compositions According to the Invention

The objectives were to study the pharmacokinetics of morphine after administration of four different morphine compositions according to the invention. The compositions had different shape and size and the DDAs employed in order to enable a zero order dissolution profile were different (mannitol and aluminium oxide, respectively). [0338]
16 healthy male volunteers aged 20 to 40 who had given their written informed consent were included in the study. [0339]
The volunteers were screened up to three weeks prior to baseline. The first treatment was administered at the baseline visit and second treatment was administered after 2 weeks of wash out. Follow-up visits took [0340] 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. [0341]
The results of the study are shown in FIG. 14. In FIG. 14 is also included data for a comparitive composition, Dolcontin. The results indicate that the shape as well as the size of the composition are important. [0342]
Another clinical study has also been performed as a phase II, open, prospective, controlled study in patients with chronic pain. The study included 13 patients with chronic pain for any reason judged by the investigator as stable and in need of opioids analgesics. A composition according to the invention was tested and compared with a commercially available morphine containing composition, Dolcontin. The total morphine sulphate released from the composition according to the invention was about 20 mg (the dosage in Dolcontin was 30 mg). Although there was a difference in the amount administered, it was evident from the study that the therapeutic effect of a composition according to the invention was not different from Dolcontin, i.e. a reduction is the overall dose may be reduced by the use a zero order release composition. Moreover, the adverse effects reported were less compared to the Dolcontin composition, most likely due to the smaller amount of morphine sulphate administered. Another interesting feature is that during the study rescue medication was allowed and there was no difference in the intake of rescue medicine of patients administered with Dolcontin or with a composition according to the invention. FIG. 15 shows the plasma concentration versus time profiles from the study. [0343]

Claims

1. A method for controlling the release of at least one therapeutically, prophylactically and/or diagnostically active substance into an aqueous medium by erosion of at least one surface of a pharmaceutical composition comprising

i) a matrix composition comprising a) a substantially water soluble or crystalline polymer or a mixture of substantially water soluble and/or crystalline polymers, b) an active substance and, optionally, c) one or more pharmaceutically acceptable excipients, and

a) a first cellulose derivative which has thermoplastic properties and which is substantially insoluble in the aqueous medium in which the composition is to be used and at least one of

b) a second cellulose derivative which is soluble or dispersible in water,

c) a plasticizer, and

d) a filler, and wherein the diffusion rate of the aqueous medium into the matrix composition corresponds to about 100%±30% such as, e.g. about 100%±25%, about 100%±20%, about 100%±15% or about 100%±10% or about 100% of the dissolution rate of the matrix composition, and wherein any matrix surface exposed to the aqueous medium erodes so as to obtain a zero order release of at least about 60% w/w such as, e.g. at least about 65% w/w at least about 70% w/w, at least about 75% w/w, at least about 80% w/w, at least about 85% w/w, at least about 90% w/w, at least about 95% w/w or at least about 97 or 98% w/w of the active substance from the pharmaceutical composition when subject to an in vitro dissolution test as described herein.

2. A method according to claim 1, wherein the polymer is a substantially water soluble or crystalline polymer or a mixture of substantially water soluble and/or crystalline polymers.

3. A method according to claim 1, wherein the matrix comprises a pharmaceutically acceptable excipient functioning as a diffusion and dissolution adjusting agent.

4. A method according to claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of inorganic acids, inorganic bases, inorganic salts, organic acids or bases and pharmaceutically acceptable salts thereof, saccharides, oligosaccharides, polysaccharides, and cellulose and cellulose derivatives.

5. A method according to claim 4, wherein the organic acid is a mono-, di-, oligo, polycarboxylic acid or an amino acid selected from the group consisting of acetic acid, ethanoic acid, succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, adipic acid, angelic acid, ascorbic acid/vitamin C, carbamic acid, cinnamic acid, citramalic acid, formic acid, fumaric acid, gallic acid, gentisic acid, glutaconic acid, glutaric acid, glyceric acid, glycolic acid, glyoxylic acid, lactic acid, levulinic acid, malonic acid, mandelic acid, oxalic acid, oxamic acid, pimelic acid pyruvic acid, aspartic acid , and glutamic acid.

6. A method according to claim 4, wherein the inorganic acid is selected from the group consisting of pyrophosphoric, glycerophosphoric, phosphoric such as ortho or meta phosphoric, boric acid, hydrochloric acid, and sulfuric acid.

7. A method according to claim 4, wherein the suitable inorganic compounds include aluminium.

8. A method according to claim 4, wherein the suitable organic bases are selected from the group consisting of p-nitrophenol, succinimide, benzenesulfonamide, 2-hydroxy-2cyclohexenone, imidazole, pyrrole, diethanolamine, ethyleneamine,tris (hydroxymethyl) aminomethane, hydroxylamine and derivates of amines, sodium citrate, aniline, and hydrazine.

9. A method according to claim 4, wherein the suitable inorganic bases are selected from the group consisting of aluminium oxide such as, e.g., aluminium oxide trihydrate, alumina, sodium hydroxide, potassium hydroxide, calcium carbonate, ammonium carbonate, ammnonium hydroxide, KOH and the like.

10. A method according to claim 4, wherein the pharmaceutically acceptable salt of an organic acid is e.g. an alkali metal salt or an alkaline earth metal salt selected from the group consisting of sodium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate, potassium phosphate, potassium dihydrogenphosphate, potassium hydrogenphosphate, calcium phosphate, dicalcium phosphate, sodium sulfate, potassium sulfate, calcium sulfate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, calcium carbonate, magnesium carbonate, sodium acetate, potassium acetate, calcium acetate, sodium succinate, potassium succinate, calcium succinate, sodium citrate, potassium citrate, calcium citrate, sodium tartrate, potassium tartrate, calcium tartrate, zinc gluconate, and zinc sulphate.

11. A method according to claim 4, wherein the inorganic salt is sodium chloride, potassium chloride, calcium chloride, or magnesium chloride etc.

12. A method according to claim 4, wherein the pharmaceutically acceptable excipient is selected from the group consisting of glucose and other monosaccharides, ribose, arabinose, xylose, lyxose, allose, altrose, inosito, glucose, sorbitol, mannose, gulose, idose, galactose, talose, mannitol, fructose, lactose, sucrose, and other disaccharides, dextrin, dextran or other polysaccharides, amylose, xylan, cellulose and cellulose derivatives such as, e.g. microcrystalline cellulose, methyl cellulose, ethyl cellulose, ethylhydroxyethyl cellulose, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxymethylpropyl cellulose, hydroxypropylmethyl cellulose, amylopectin, pectin, starch, sodium starch etc., kaolin, bentonit, acacia, alginic acid, sodium alginate, calcium alginate, gelatin, dextrose, molasses, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husk, veegum, glycollate, magnesium stearate, calcium stearate, stearic acid, talc, titanium dioxide, silicium dioxide, clays, croscarmellose, gums, and agar.

13. A method according to claim 1 further comprising a pharmaceutically acceptable excipient selected from the group consisting of fillers, diluents, disintegrants, glidants, pH-adjusting agents, viscosity adjusting agents, solubility increasing or decreasing agents, osmotically active agents and solvents.

14. A method according to claim 1, wherein the polymer matrix comprises a polyglycol.

15. A method according to claim 1, wherein the matrix comprises a homopolymer and/or a copolymer.

16. A method according claim 1, wherein the matrix comprises a polyethylene glycol, a polyethylene oxide and/or a block copolymer of ethylene oxide and propylene oxide including including poly(ethylene-glycol-b-(DL-lactic acid-co-glycolic acid)-b-ethylene glycol (PEG-PLGA PEG), poly((DL-lactic acid-co-glycolic acid)-g-ethylene glycol) (PLGA-g-PEG), and polyethylene oxide-polypropylene oxide (PEO-PPO).

17. A method according to claim 16, wherein the polyethylene glycol, a polyethylene oxide and/or a block copolymer of ethylene oxide and propylene oxide has a molecular weight of from about 20,000 daltons, such as, e.g., from about 20,000 to about 700,000 daltons, from about 20,000 to about 600,000 daltons, from about 35,000 to about 500,000 daltons, from about 35,000 to about 400,000 daltons, from about 35,000 to about 300,000 daltons, from about 50,000 to about 300,000 daltons, such as, e.g. about 35,000 daltons, about 50,000 daltons, about 75,000 daltons, about 100,000 daltons, about 150,000 daltons, about 200,000 daltons, about 250,000 daltons, about 300,000 daltons or about 400,000 daltons.

18. A method according to claim 16, wherein the block copolymer of ethylene oxide and propylene oxide comprises up to about 30% w/w of the propylene oxide based block, and has a molecular weight of about 5,000 daltons, typically about 5,000 to about 30,000 daltons such as, e.g. from about 8,000 to about 15,000 daltons.

19. A method according to claim 1, wherein the matrix comprises a polymer which has a melting point of about 20-120° C. such as, e.g. from about 30 to about 100° C. or from about 40 to about 80° C.

20. A method according to claim 1, wherein the active substance is present in the matrix composition in a concentration of from about 0.1 to about 98% w/w such as, e.g. at the most about 90% w/w, at the most about 85% w/w, at the most about 80% w/w, at the most about 75% w/w, at the most about 70% w/w, at the most about 65% w/w or at the most about 60% w/w.

21. A method according to claim 1, wherein the active substance is a substance for human or veterinary use, a vitamin or other nutritional supplement, a disinfectant, a deodorant or another substance to be administered continuously in an aqueous environment.

22. A method according to claim 1, wherein the active substance is present in the matrix at least partly on amorphous form.

23. A method according to claim 1, wherein the active substance is a pharmaceutically active powder.

24. A method according to claim 23, wherein the powder has a particle size of from about 0.1 μm to about 500 μm, typically from about 0.5 μm to about 300 μm, more typically from about 1 μm to about 200 μm, especially from about 5 μm to about 100 μm.

25. A method according to claim 1, wherein the at least one therapeutically, prophylactically and/or diagnostically active substance has a solubility of at the most about 3 mg/ml such as, e.g. at the most about 1 mg/ml, at the most about 0.1 mg/ml, at the most about 0.05 mg/ml such as, e.g. at the most about 0.001 mg/ml in water at ambient temperature.

26. A method according to claim 25, wherein the matrix composition comprises a pharmaceutically acceptable excipient which has a solubility of at least 1 mg/ml such as, e.g. at least about 3 mg/ml, at least about 5 mg/ml, at least about 10 mg/ml, at least about 25 mg/ml or at least about 50 mg/ml in water at ambient temperature.

27. A method according to claim 1, wherein the at least one therapeutically, prophylactically and/or diagnostically active substance has a solubility of at least about 3 mg/ml such as, e.g., at least about 5 mg/ml, at least about 10 mg/ml, at least about 20 mg/ml, at least about 50 mg/ml or at least about 100 mg/ml in water at ambient temperature.

28. A method according to claim 27, wherein the matrix composition comprises a pharmaceutically acceptable excipient, which has a solubility of at the most about 3 mg/ml such as, e.g., at the most about 1 mg/ml, at the most about 0.1 mg/ml, at the most about 0.05 mg/ml such as, e.g. at the most about 0.001 mg/ml in water at ambient temperature.

29. (Cancelled).

30. A method according to claim 1, wherein in the aqueous medium in which the composition is to be used, the coating does not completely crumble or erode before the matrix has completely eroded.

31. A method according claim 1, wherein said first cellulose derivative is a cellulose ether which, when heated, is shapeable by molding or extrusion, including injection molding, blow molding and compression molding.

32. A method according to claim 31 in which the cellulose ether comprises at least one ethylcellulose.

33. (Cancelled).

34. (Cancelled).

35. A method according to claim 1 in which said first cellulose derivative is selected from the group consisting of cellulose acetate, cellulose propionate and cellulose nitrate.

36. A method according to claim 1 in which said second cellulose derivative is selected from the group consisting of methylcellulose, carboxymethylcellulose and salts thereof, cellulose acetate phthalate, microcrystalline cellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, hydrocyethylcellylose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose and hydroxymethylpropylcellulose.

37. A method according to claim 36 in which said salt of carboxymethylcelllulose is selected from the group consisting of alkali metal and alkaline earth metal salts.

38. A method according to claim 1, in which said plasticizer is selected from the group consisting of phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters thereof with polyethylene glycol, glycerin or sugars; fatty alcohols and ethers thereof with polyethylene glycol, glycerin or sugars; vegetable oils and hydrogenated vegetable oils; nitrobenzene, carbon disulfide, β-naphtyl salicylate, phthalyl glycolate, and diocyl phthalate.

39. A method according to claim 38 in which said fatty alcohol is selected from the group consisting of cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol and myristyl alcohol.

40. A method according to claim 1 in which said plasticizer is a non-ionic surfactant.

41. A method according to claim 1, wherein the matrix composition does not contain polyethylene glycol 2000 monostearate or polyethylene glycol 400 monostearate.

42. (Cancelled).

43. (Cancelled).

44. (Cancelled).

45. (Cancelled).

46. (Cancelled).

47. A method according to claim 1, wherein the polymer is a polyethylene oxide having a molecular weight of at least 100,000 daltons and at the most 300,000 daltons.

48. A method according to claim 1, wherein the pharmaceutically acceptable excipient is present and is a mono-, di-, oligo or polycarboxylic acid selected from the group consistin of acetic acid, succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, and sorbic acid.

49. A method according to claim 1, wherein the pharmaceutically acceptable excipient is present and is selected from mannitol, xylitol, sorbitol and inositol.

50. A method according to claim 1, wherein the pharmaceutically acceptable excipient is an aluminium oxide.

51. A method according to claim 1, wherein comprising PEO 200,000 as polymer and mannitol and/or aluminium oxide as pharmaceutically acceptable excipient.

52. A method according to claim 1, wherein the pharmaceutically acceptable excipient is an inorganic acid such as phosphoric acid including ortho phosphoric acid and meta phosphoric acid.

53. 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

b) a second cellulose derivative which is soluble or dispersible in water,

c) a plasticizer, and

d) a filler,

and wherein the diffusion rate of the aqueous medium into the matrix composition corresponds to about 100%±30% such as, e.g. about 100%±25%, about 100%±20%, about 100%±15% or about 100%±10% or about 100% of the dissolution rate of the matrix composition, and wherein any matrix surface exposed to the aqueous medium erodes at a substantially constant rate, so as to obtain a zero order release of at least about 60% w/w such as, e.g. at least about 65% w/w at least about 70% w/w, at least about 75% w/w, at least about 80% w/w, at least about 85% w/w, at least about 90% w/w, at least about 95% w/w or at least about 97 or 98% w/w of the active substance from the pharmaceutical composition when subject to an in vitro dissolution test as described herein.

54. A stable controlled release pharmaceutical composition for oral use comprising a solid dispersion of component i) and ii)

i) at least one therapeutically, prophylactically and/or diagnostically active substance, which at least partially is in an amorphous form,

ii) a pharmaceutically acceptable polymer that has plasticizing properties and which has a melting point or melting interval of a temperature of at the most 200° C.,

and, optionally, iii) a stabilizing agent, wherein the at least one therapeutically, prophylactically and/or diagnostically active substance has a water solubility of at the most 3 mg/ml at 25° C. such as, e.g. at the most about 2 mg/ml, at the most about 1 mg/ml, and the concentration of the active substance in the composition corresponds to a concentration of at the most the saturated concentration in component ii) at a temperature corresponding to the melting point or the lowest end point of the melting interval of component ii) optionally together with component iii).

55. A composition according to claim 54, wherein component ii) is a polyethylene glycol and/or a polyethylene oxide having a molecular weight of at least about 20,000 in crystalline and/or amorphous form or a mixture such polymers.

56. A composition according to claim 54, wherein component ii) is of a quality that ensures that free radicals formed, if any, do not significantly increase the degradation of the active substance in the composition.

57. A composition according to claim 53 or 54 comprising a stabilizing agent.

58. A composition according to claim 54 comprising one or more antioxidants that inhibits the formation of peroxides and/or inactivates any peroxides present.

59. A composition according to claims 53 or 54, wherein the composition is stable with respect to physical stability.

60. A composition according to claims 53 or 54, wherein the composition is stable with respect to in vitro dissolution of the active substance from the composition.

61. A composition according to claim 60, wherein the composition is stable with respect to in vitro dissolution behaviour in such a manner that t₅₀%, i.e. the time for 50% w/w of the active substance to dissolve in a dissolution medium, differs at the most ±20% w/w such as, e.g., at the most ±15% w/w, at the most ±10% w/w, at the most ±7.5% w/w, at the most ±5% w/w, at the most ±2.5% w/w, at the most ±1.5% w/w or at the most 1% w/w when two compositions from the same batch is compared with a time difference of 2 weeks under similar storage and test conditions.

62. A composition according to claims 53 or 54, wherein the composition is stable with respect to chemical stability of the active substance.

63. A composition according to claim 62, wherein the concentration of the active substance in the composition decreases at the most 20% w/w such as, e.g. at the most 15% w/w, at the most 10% w/w, at the most 7.5% w/w or at the most 5% w/w when stored at room temperature for a time period of at least 3 months such as, e.g. 6 months, 12 months, 18 months or 24 months and a relative humidity of at the most 75% such as, e.g., at the most 70%, at the most 65%, at the most 60%, at the most 55%, at the most 50% or at the most 45%.

64. A composition according to claims 53 or 54 containing carvedilol as active substance in a concentration of at the most about 23% w/w such as, e.g., at the most about 22% w/w, at the most about 21% w/w or at the most about 20% w/w.

65. A composition according to claim 64 containing carvedilol as active substance and PEO 200,000 as component ii) and wherein the concentration of carvedilol in PEO 200,000 is at the most about 22% w/w, at the most about 21% w/w or at the most about 20% w/w.