WO2013037396A1

WO2013037396A1 - Solution of polymer in api for a solid dosage form

Info

Publication number: WO2013037396A1
Application number: PCT/EP2011/065779
Authority: WO
Inventors: Daniel Bar-Shalom; Kaisa Naelapää; André H. ERIKSSON; Johan BOETKER; Jukka Rantanen
Original assignee: Bioneer A/S; Københavns Universitet
Priority date: 2011-09-12
Filing date: 2011-09-12
Publication date: 2013-03-21

Abstract

The present invention relates to dosage forms, in particular solid dosage forms providing a sustained release, such as an approximately zero order release, of an active pharmaceutical ingredient ("API"). Stable solutions for dosage forms may be made by heating a mixture of an API and a polymer above the melting point of the API rather than the melting point of the polymer. Thereby a polymer dispersed homogenously in the active substance may be obtained.

Description

SOLUTION OF POLYMER IN API FOR A SOLID DOSAGE FORM

The present invention relates to dosage forms, in particular solid dosage forms providing a sustained release, such as an approximately zero order release, of an active pharmaceutical ingredient ("API"). TECHNICAL BACKGROUND

A system comprising polyethylenglycol ("PEG") and API is known to provide a sustained release.

The European patent EP 0 406 315 Bl discloses a composition for controlled delivery of an active substance into an aqueous phase by erosion at a substantially constant rate, comprising a matrix of crystalline polyethylene glycol polymer, a non-ionic emulsifier, and at least one active substance, wherein the active substance may be substantially homogenously dispersed in the crystalline polymer matrix.

G. R. Lloyd et al. (Eur. J. Pharm. Biopharm. 48, 59-65(1999)) described mixtures of PEG 4000 and Paracetamol heated at 70 or 100°C, and solubility studies were undertaken. SUMMARY OF THE INVENTION

A problem with the known systems is the stability of the respective APIs in the relevant polymers. The known system is typically manufactured by mixing a polymer with an API, and heating the mixture to just above the glass transition temperature, Tg, or less commonly, the melting point, Tm, of the polymer. The expression Tg/Tm is used to denote the glass transition temperature or the melting point, whichever is lower, for the relevant entity. Often, but not always, Tg will be relevant for amorphous polymers, while Tm will be relevant for common, crystalline APIs. For mixtures or solid solutions it may be difficult to distinguish between Tg and Tm, inter alia because a mixture may be partly crystalline and partly amorphous. It has now surprisingly been discovered that the usual solubility limit of API in polymer may be exceeded by increasing the temperature of the mixture to above the melting point (or alternatively glass transition temperature) of the API, allowing formation of a solution of polymer in API. The melting point of the API, e.g. Gabapentin, is usually higher than the glass transition temperature of the suitable polymers.

It has been a problem to manufacture polymer solutions in solid form comprising a high content of API. The inventors of the present invention has surprisingly discovered that stable solid systems may be made by heating a mixture of API and polymer to or above Tg/Tm of the API rather than the Tg/Tm of the polymer. Thereby a polymer dispersed homogenously in the active substance may be obtained.

According to an aspect, the present invention concerns a method for manufacturing a solid homogenous mixture for a dosage form comprising at least one active pharmaceutical ingredient (API) and at least one polymer, said method comprising the steps of: i. Providing a mixture of said polymer and said API, said mixture being heated above the melting point or glass transition temperature of said API; and ii. Cooling said mixture.

Mixtures of polymer and API are known under such names as solid solutions, solid dispersions, and eutectic compositions. Here, the term "homogenous mixtures" will be used, whether the mixtures comprise one or more regions of solid solution, solid dispersion and/or eutectic composition.

The mixture of step (i) may be provided by a) heating the API, and subsequently mixing the API with the polymer; or b) by mixing the API and the polymer and heating the obtained mixture; or c) by combining a) and b).

The mixture is heated to or above the melting point or the glass transition temperature, whichever is lower, of the API, but. The heating softens or melts or liquefies the API sufficiently to allow formation of a homogenous mixture of API and polymer. Also, it is advantageous that the mixture of API and polymer is mixed after heating above the melting point or glass transition temperature of both the API and the polymer.

In important embodiments, the API is in crystalline form prior to heating in step (i); this is often the case with water soluble APIs, cf. e.g. those tested in the examples presented herein. However, as shown in Example 2, the method of the invention has resulted in the formation of an amorphous form of the API in the resulting homogenous mixture; an important embodiment hence includes that the homogenous mixture obtained after step (ii) comprises the API in an amorphous form even though the API prior to step (i) is crystalline. In a related embodiment, the homogenous mixture obtained after step (ii) also comprises the API in crystalline form.

The polymer is a pharmaceutically acceptable polymer.

An active pharmaceutical ingredient (API) may be any ingredient, which provides a desired therapeutic or prophylactic effect, or an ingredient, which serves a diagnostic purpose.

The API may e.g. be a molecule, such as a molecule with low MW, a polypeptide, or the API may be a polymer, such as a protein. The API should not decompose or irreversibly change crystal structure to an undesired crystal form upon the necessary heating. Similarly, the API should not react with the polymer to produce an undesired product upon the necessary heating.

The polymer would usually have a melting point lower than the melting point of the API, but in certain situations a polymer with melting point above the melting point of the API may be suitable.

Initial experiments indicate that this approach allows manufacture of a system of API and polymer in any desired ratio, without affecting the properties of the API, for a large number of different APIs. This system allows improved control of the release of the API in the system and for higher drug load of the resulting solid solution. Accordingly, the dissolution rate may be controlled by erosion of API in an aqueous solution.

Further envisioned advantages associated with the present invention are improved stability and/or enhanced control of the release characteristics of the mixtures of API and polymer. Mixtures of the invention may have a different release profile than the API alone.

It is speculated that the present invention may provide solid dispersions of polymer in API as opposed to solid dispersions of API in polymer.

According to an aspect, the present invention concerns a dosage form comprising a homogenous mixture obtainable according to the invention.

According to an aspect, the present invention concerns a pharmaceutical composition comprising a dosage form according to the invention. LEGENDS TO THE FIGURES

Fig. 1 shows the result of a DSC experiment, the first heating of a mixture of Soluplus ("SP") and Paracetamol ("P"). The weight ratio of SP: P is 3: 1.

Fig. 2 shows the result of a DSC experiment, the second heating of the mixture of Fig. 1. Fig. 3 shows the result of a DSC experiment, the first heating of a mixture of Soluplus and Paracetamol. The weight ratio of SP: P is 1 : 1.

Fig. 4 shows the result of a DSC experiment, the second heating of the mixture of Fig. 3.

Fig. 5 shows the result of a DSC experiment, the first heating of a mixture of Soluplus and Paracetamol. The weight ratio of SP: P is 1 : 3. Fig. 6 shows the result of a DSC experiment, the second heating of the mixture of Fig. 5.

Fig. 7a shows a DSC thermogram of pure guaifenesin and Soluplus^®.

Fig. 7b shows diffractograms of pure crystalline guaifenesin and amorphous Soluplus^®, and compositions prior and after heating.

Fig. 8a shows a DSC thermogram of freshly prepared guaifenesin and Soluplus^® composition. Fig. 8b shows diffractrograms of guaifenesin and Soluplus^® composition (90 : 10) at different temperatures and guaifenesin reference spectrum.

DETAILED DISCLOSURE

According to an embodiment, the present invention concerns a method, wherein the mixture of API and polymer is heated to a temperature selected among 120-310°C, 130-300°C, 140- 290°C, 150-280°C, 160-270°C, 170-260°C, 180-250°C, 190-240°C, 200-230°C, 210-220°C, and above 110°C.

According to an embodiment, the present invention concerns a method, wherein the mixture of API and polymer is mixed after heating the API above the melting point of the API. According to an embodiment, the present invention concerns a method, wherein the obtained homogenous mixture is solid after the cooling (ii).

The cooling rate may have influence on the obtained product, in particular on the release rate of the API. Without being bound by any theory, the release rate of the API may be related to the size of the domains or particles in the material, which may be related to the cooling speed.

According to an embodiment, the present invention concerns a method, wherein more than one polymer is used, such as a mixture of polymers.

According to an embodiment, the present invention concerns a method, wherein the polymer is a substantially water soluble crystalline polymer.

According to an embodiment, the present invention concerns a method, wherein the polymer is polyglycol.

According to an embodiment, the present invention concerns a method, wherein the polymer is a homopolymer and/or copolymer and/or graft polymer, e.g. Soluplus. According to an embodiment, the present invention concerns a method, wherein the polymer is selected among polyethylene glycol (PEG), polyethylene oxide (PEO) and a block copolymer of ethylene oxide and propylene oxide.

According to an embodiment, the present invention concerns a method, wherein the polymer is a block copolymer comprising up to about 30% by weight of propylene oxide based block, and has a molecular weight of above about 5000 daltons, typically about 5000 to about 30.000 daltons, more typically about 8000 to about 15.000 daltons.

According to an embodiment, the present invention concerns a method, wherein the polymer is PEG with a molecular weight of about 2.000 - 500.000, preferably 5.000 - 100.000, more preferred 10.000 - 50.000, preferably 20.000 - 35.000 daltons. According to an embodiment, the present invention concerns a method, wherein the polymer or mixture of polymers has a melting point of about 20 - 120°C, typically about 30 - 100°C, preferably about 40 - 80°C. According to an embodiment, the present invention concerns a dosage form providing sustained release of the API.

According to an embodiment, the present invention concerns a dosage form providing zero order release or approximately zero order release of the API. The term zero order release means that during the time of release, equal amounts of API is released per time unit. The term approximately zero order release refers to the case wherein the release varies from zero order release, but the variation is sufficiently small not to affect the therapeutic, prophylactic or diagnostic purpose of the dosage form adversely.

According to an embodiment, the invention provides a dosage form wherein the

approximately zero order release obeys that a constant amount of said first and/or second

API is released per hour, allowing a deviation from zero order release of 20%, more preferred 15%, preferably 10%, more preferred 5% per hour.

By deviation from zero order release is meant a release varying from a point on a linear line through the beginning and final points for the desired zero order release. All ratios and percentages are in weight/weight unless otherwise stated.

According to an embodiment, the invention provides a dosage form, wherein the deviation from zero order release is less than 20%, preferably 10%, more preferred 5% per hour; from the time when 30%, preferably 20%, more preferred 10% of said first and/or second API is released; until 70%, preferably 80%, more preferred 90% of the total amount of said API is released.

According to an embodiment, the present invention concerns a dosage form comprising at least 40%, preferably at least 50%, more preferred at least 60%, preferably at least 70%, more preferred at least 80%, preferably at least 90%, more preferred at least 95% API.

According to an embodiment, the present invention concerns a pharmaceutical composition, comprising at least two different solid dosage forms, wherein at least one is according to the invention, wherein one of said solid dosage forms has a melting point or glass transition temperature which is lower than the lower of the melting point and glass transition temperature of the other solid dosage form. This allows the pharmaceutical composition to be manufactured by injection molding, by firstly melting the solid dosage form having the higher Tg/Tm, cooling it; and subsequently melting the solid dosage form having the lower Tg/Tm without melting the solid dosage form having the higher Tg/Tm. Polymers which may be used for the present invention may include, but are not limited to, Polyethylene glycol (PEG), which are polymers of ethylene oxide; Polyvinylpyrrolidone (PVP); Polyvinylalcohol (PVA), crospovidone (PVP-CL); polyvinylpyrrolidone-polyvinylacetate copolymer (PVP-PVA); Cellulose derivatives, such as methylcellulose (MC),

hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), and other semi- synthetic celluloses; Celluloseacetatephthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP); Carboxymethylethylcellulose (CMEC); Polyacrylates, polymethacrylates; Urea; Sugar, polyols and their polymers; Mannitol, Sorbitol; Chitosan, chitosan glutamate; Succinic acid, citric acid; as well as mixtures of any of these.

Polymers which may be used for the present invention may be known under various names, including, but not limited to, carbowaxes; 1,2-ethanediol, homopolymers; ethylene glycol, homopolymers; ethylene oxide, polymers; ethylene polyoxide; lutrol; oxyethylene polymer; polyethylene oxide polymers; poly(ethyleneoxide)s; polyhdroxyethylene; polyoxyethylene; polyoxyethylenediol; poly(oxyethylene) glycols; and poly(vinyl oxide).

Polymers suitable for use in the present invention include polymers able to act as a matrix polymer for solid solutions, such as copolymers.

An example of a suitable polymer is a polymer specifically designed for hot melt extrusion technology, such as the polymer known under the trade name Soluplus ("SP"). SP is a graft polymer made from PEG 6000, vinylcaprolactam and vinylacetate. Thus it comprises hydrophilic elements, lipophilic elements and sites for drug complexation. SP is able to act as a matrix polymer for solid solutions, and it is capable of solubilizing poorly-water soluble drugs in aqueous media.

According to an embodiment, an emulsifying agent may be included in the mixtures of the present invention. Suitable emulsifiers may include Sodium lauryl sulphate (SLS), Tween 80 (a polyethylene sorbitan fatty acid ester); Alkali dodecylsulphate surfactant; Bile salts and their derivatives, cholic acid, deoxycholic acid, lithocholic acid; Cholesterol, and Cholesterol esters. According to an embodiment, the invention provides a dosage form, further comprising at least one excipient selected among antiadherents, binders, coatings, disintegrants, fillers, diluents, flavours, colours, lubricants, glidants, preservatives, sorbents, and sweeteners.

According to an embodiment, the present invention concerns a dosage form, comprising an excipient selected among starch, lactose, magnesium stearate, microcrystalline cellulose, stearic acid, calcium phosphate, glycerol monostearate, sucrose, polyvinylpyrrolidone, gelatin, methylcellulose, sodium carboxymethylcellulose, sorbitol, mannitol, polyethylene glycol, dicalcium phosphate, calcium sulfate, lactose or sucrose or other disaccharides, cellulose, cellulose derivatives, kaolin, dry starch, other raonosaccharides, dextrin or other polysaccharides, inositol or mixtures thereof; binders such as acacia, sodium alginate, starch, gelatin, saccharides (including 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 or mixtures thereof; lubricants such as talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, sodium benzoate, sodium chloride, leucine, carbowax 4000, magnesium lauryl sulfate, colloidal silicon dioxide and mixtures thereof; swellable polymers, including but not limited to, crosslinked

polymethacrylate and polyacrylate polymers derivatized with hydroxyalkyl and/or ionizable acidic or basic functional groups, and their respective salt forms; crosslinked

polyvinylpyrrolidone; crosslinked polyvinyl alcohols; poly(ethylene oxide)s;

polymethacrylamides and polyacrylamides; derivatized or modified cellulosic polymers such as crosslinked sodium carboxymethylcellulose, crosslinked hydroxypropylcellulose, starch graft copolymers, crosslinked hydroxypropylmethylcellulose, crosslinked dextrans and agarose, and microcrystalline cellulose; carboxymethylamide; and polyelectrolytes. Examples of disintegrants comprise, but are not limited to, starches, clays, cellulose derivatives including croscarmellose, gums, algins, various combinations of

hydrogencarbonates with weak acids (e.g. sodium hydrogencarbonate/tartaric acid or citric acid) crospovidone, sodium starch glycolate, agar, cation exchange resins, citrus pulp, veegum HV, natural sponge, bentonite or mixtures there of; 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, and mixtures thereof, hydrogenated vegetable oils, glycerinated gelatin or mixtures thereof.

Furthermore, a dosage form of the invention 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 and 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.

Further guidance on pharmaceutically acceptable excipients may be found in the FDA inactive ingredient database available on the Internet.

The APIs for use in a dosage form of the invention comprises, but are not limited to, hypnotics, sedatives, tranquilizers, anti-convulsants, musclerelaxants, analgesics,

antiinflammatory, anesthetics, anti-spasmodics, anti-ulcer-agents, anti-parasitics, antimicrobials, anti-fungal, cardiovascular agents, diuretics, cytostatics, anti-neoplastic agents, anti-viral agents, antiglaucoma agents, anti-depressants, sympathomimetics,

hypoglycaemics, diagnostic agents, anticough, physic energizers, anti-parkinson agents, local anesthetics, muscle contractants, antimalarials, hormonal agents, contraceptives, anorexic, anti-arthritic, anti-diabetic, antihypertensive, anti-pyretic, anti-cholingergic, bronchodilator, central nervous system, inotropic, vasodilator, vasoconstrictor, decongestant, hematinic, electrolyte supplement, germicidal, parasympathetolytic, parasymphatethomimetic, antiemetic, psychostimulant, vitamin, betablockers, H-2 blocker, beta-2 agonist,

counterirritants, coagulating modifying agents, stimulants, anti-hormones, API-antagonists, lipid-regulating agents, uricosurics, cardiac glycosides, ergot and derivatives thereof, expectorants, muscle relaxants, anti-histamines, purgatives, contrastmaterials,

radiopharmaceuticals, imaging agents, anti-allergic agents, ion channel inhibitors and activators.

Examples of specific active substances comprise, but are not limited to, codeine,

ethylmorphine, dextromethorphan, noscapine, pentoxiverine, acetylcysteine, bromhexine, epinephrine, isoprenaline, orciprenaline, ephedrine, fenoterol, riiterol, 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, inositolnico-tinate, alprostatdil, etilephrine, prenalterol, dobutamine, dopamine, dihydroergotamine, guanetidine, betanidine, meth Idopa, reserpine, guanfacine, trimethaphan, hydralazine, dihydralazine, prazosine, diazoxid, captopril, nifedipine, enalapril, nitroprusside, bendroflumethiaziede,

hydrochlorthiazide, metychlothiazide, polythiazide, chlorthalidon, cinetazon, clopamide, mefruside, metholazone, bumetanide, ethacrynacide, spironolactone, amiloride, chlofibrate, nicotinic acid, nicheritrol, brompheniramine, cinnarizine, dexchlorpheniramine, clemastine, antazoline, cyproheptadine, promethazine, cimetidine, ranitidine, sucralfat, papaverine, moxaverine, atropin, butylscopolamin, emepron, glucopyrron, hyoscyamine, mepensolar, methylscopolamine, oxiphencyclimine, probanteline, terodilin, sennaglycosides,

sagradaextract, dantron, bisachodyl, sodiumpicosulfat, etulos, diphenoxylate, loperamide, salazosulfapyridine, pyrvin, mebendazol, dimeticon, ferrofumarate, ferrosuccinate, ferritetrasemisodium, cyanochobalamine, folic acid heparin, heparin co-factor, diculmarole, warfarin, streptokinase, urokinase, factor VIII, factor IX, vitamin K, thiotepa, busulfan, chlorambucil, cyclophosphamid, melfalan, carmustin, mercaptopurin, thioguanin, azathioprin, cytarabin, vinblastin, vinchristin, vindesin, procarbazine, dacarbazine, lomustin, estramustin, teniposide, etoposide, cisplatin, amsachrin, aminogluthetimid, phosphestrol,

medroxiprogresterone, hydroxiprogresterone, megesterol, noretisteron, tamoxiphen, ciclosporin, sulfisomidine, bensylpenicillin, phenoxymethylpenicillin, dicloxacillin, cloxacillin, flucloxacillin, ampicillin, amoxicillin, pivampicillin, bacampicillin, piperacillin, ezlocillin, 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,

metenamine, chloroquin, hydroxichloroquin, tinidazol, ketokonazol, acyclovir, interferon idoxuridin, retinol, tiamin, dexpantenol, pyridoxin, folic acid, ascorbic acid, tokoferol, phytominadion, phenfluramin, corticotropin, tetracosactid, tyrotropin, somatotropin, somatrem, vasopressin, lypressin, desmopressin, oxytocin, chloriongonadotropin, cortison, hydrocortison, fludrocortison, 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, oxazepa, dikaliumchlorazepat, lorazepam, flunitrazepam, alprazolam, midazolam, hydroxizin, chlomethiazol, propionmazine, alimemazine, chlorpromazine, levomepromazine, acetophenazine, fluphenazine,

perphenazine, prochlorperazine, trifluoperazine, dixyrazi- ne, thioridazine, periciazin, chloprothixene, zuclopentizol, flupentizol, thithixen, haloperidol, trimipramin, opipramol, chlomipramin, desipramin, lofepramin, amitriptylin, nortriptylin, protriptylin, maptrotilin, caffeine, cinnarizine, cyclizine, dimenhydinate, meclozine, pro etazine, thiethylperazine, metoclopramide, scopolamine, phenobarbital, phenytoine, ethosuximide, primidone, carbamazepine, chlonazepam, orphenadrine, atropine, bensatropine, biperiden, metixene, procylidine, levodopa, bromocriptin, amantadine, ambenon, pyridostigmine, synstigmine, disulfiram, morphine, codeine, pentazocine, buprenorphine, pethidine, phenoperidine, phentanyl, methadone, piritramide, dextropropoxyphene, ketobemidone, acetylsalicylic acid, phenazone, phenylbutazone, azapropazone, piroxicam, ergotamine, dihydroergotamine, cyproheptadine, pizitifen, flumedroxon, allopurinol, probenecid, sodiummaurothiomalate auronofin, penicillamine, estradiol, estradiolvalerianate, estriol, ethinylestradiol,

dihydrogesteron, lynestrenol, medroxiprogresterone, noretisterone, cyclophenile, clomiphene, levonorgestrel, mestranol, ornidazol, tinidazol, ekonazol, chlotrimazol, natamycine, miconazole, sulbentin, methylergotamine, dinoprost, dinoproston, gemeprost, bromocriptine, phenylpropanolamine, sodium-chromoglicate, azetazolamide, dichlophenamide, betacarotene, naloxone, calciumfolinate, in particular clonidine, theophlline, dipyradamol,

hydrochlorthiazide, scopolamine, indomethacine, furosemide, potassium chloride, morphine, ibuprofen, salbutamol, terbutalin. The active pharmaceutical ingredients can be in various forms, such as uncharged molecules, molecular complexes, a pharmacologically acceptable salt such as a hydro-chloride, hydrobromide, sulfate, laurylate, palmitate, phosphate, nitrite, nitrate, borate, acetate, maleate, tartrate, oleate, and salicylate. For acid active pharmaceutical ingredients, salts of metals, amines amino acids or organic cations, quaternary ammonium, can be used.

Derivatives of active pharmaceutical ingredients such as esters, ethers and amides which have solubility characteristics suitable for use herein can be used alone or mixed with other active pharmaceutical ingredients. After release of the derivative from the composition it may be converted by enzymes, hydrolyzed by body pH or other metabolic processes to the parent active pharmaceutical ingredients or to another biologically active form. The dosage form is in addition suitable for the delivery of polypeptides, for example hormones such as growth 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. The composition may also be used for the delivery of active agents in specialized carriers such as liposomes, cyclodextrines, nanoparticles, micelles and fats. A further use for which the dosage form of the invention is suited is the delivery of active substances to animals. Examples of such active substances for veterinary use are

antiparasitics, corticosteroids, antibiotics, antiinflammatory agents, growth promoters and permittants, antifungals and antihelmintics.

Mixtures of the invention may be produced by simple heating and mixing. It is also contemplated that the mixtures may be produced using conventional thermoplastic equipment such as extrusion, injection molding, or calendaring. Dosage forms of the invention may be produced in the thermoplastic process itself or by further processing the product obtained with a thermoplastic process by, for example, filling particles into capsules or compressing them into tablets or by first milling the mixture produced with a e.g. a thermoplastic process and then using the resulting powder to manufacture the tablets or fill capsules.

All cited references are incorporated by reference.

The accompanying Figures and Examples are provided to explain rather than limit the present invention. It will be clear to the person skilled in the art that aspects, embodiments and claims of the present invention may be combined.

EXAM PLE 1

Preparation of Soluplus in Paracetamol solid system

The API Paracetamol was heated to above its melting point. The polymer Soluplus was added to the molten Paracetamol and thorough mixing undertaken. The mixture was cooled and solidified, before being milled. Tablets were manufactured by direct compression of the milled mass.

Release experiment

It was surprisingly observed that the paracetamol ("APAP") was slowly released from tablets produced by direct compression of the obtained milled mass, while the API Paracetamol taken alone usually dissolves fast in water.

The length of the release period was increased with increasing concentration of Soluplus. A cylindrical tablet, 10 mm in diameter, 6 mm in height, consisting of 15% (w/w) Soluplus in Paracetamol released for more than 24 hours, while a tablet with 7% (w/w) Soluplus in Paracetamol released for 8 hours. The release was approximately zero-order. Differential Scanning Calorimetrv (DSO experiments

DSC experiments were conducted using intimate mixtures of the polymer Soluplus and the API Paracetamol. After mixing, a first DSC experiment was conducted, heating the mixture. Subsequently, the mixture was cooled, ant a second DSC experiment was conducted, heating the mixture. By comparing the two experiments, effects of the first heating and cooling procedure became apparent.

Fig. 1 shows the result of a DSC experiment, the first heating of a mixture of Soluplus ("SP") and Paracetamol ("P"). The weight ratio of SP: P is 3: 1 and Fig. 2 shows the result of a DSC experiment, the second heating of the mixture of Fig. 1.

In Fig. 1, a peak at around 70°C, consistent with the Tg of Soluplus, and another peak at around 163°C, lower than the peak expected at 170°C for Paracetamol, was observed. After cooling and upon reheating the lower Tg has shifted to around 85°C (cf. Fig. 2), indicating a solution (with corresponding raising of Tg/Tm), while the higher peak is absent, indicating that there is no crystalline Paracetamol present.

Fig. 3 shows the result of a DSC experiment, the first heating of a mixture of Soluplus and Paracetamol. The weight ratio of SP: P is 1 : 1 and Fig. 4 shows the result of a DSC experiment, the second heating of the mixture of Fig. 3.

In Fig. 3, a peak at around 70°C, consistent with the Tg of Soluplus, and another peak at around 171°C, as expected for Paracetamol, was observed. After cooling and upon reheating the lower Tg has again shifted to around 85°C (cf. Fig. 4), indicating a solution (with corresponding raising of Tg/Tm) and a higher peak appears around 163°C, which may indicate that a co-crystal of SP and P has formed.

Fig. 5 shows the result of a DSC experiment, the first heating of a mixture of Soluplus and Paracetamol. The weight ratio of SP: P is 1 : 3 and Fig. 6 shows the result of a DSC experiment, the second heating of the mixture of Fig. 5.

Similar results as those found from Figs. 1 + 2 and 3+4 are seen in Fig. 5 and Fig. 6. The higher peak may be indicating a larger amount of co-crystal.

EXAMPLE 2

Preparation of Soluplus in Guaifenesin solid system

Guaifenesin (solubility of approx. 50mg/ml) has previously been formulated using a minimal amount of Soluplus^® as a polymeric excipient. Instead of dissolving the drug in the polymer (Drug-In-Polymer, DIP), the polymer was in the present experiment dissolved in the molten drug (Polymer-In-Drug, PID). Preparation of the samples was performed by heating guaifenesin above its melting point (~80°C) and adding Soluplus^® 10%, w/w basis. DSC, XRPD (X-ray powder diffraction), VT- XRPD (variable temperature X-ray powder diffraction) and dissolution testing were performed on the prepared samples. The starting material (guaifenesin powder) exhibited a melting point onset at 78°C and a mid point at 82°C (Fig. 7a). The Soluplus^® compound did not exhibit any thermal events. XRPD was subsequently performed and the diffractograms of the starting material (guaifenesin), amorphous Soluplus^® and physical mixture as well of the melted PID sample are shown in Fig. 7b. The guaifenesin present in the melted PID sample recrystallized as a mixture of the original form and a new polymorphic modification.

The guaifenesin and Soluplus^® PID sample exhibited two melting events (Fig. 8a). The first melting event had an onset at 65°C and the second onset was at 73-75°C. It is furthermore noted that the mid point of the second melting event was at 78-80°C.

VT-XRPD was subsequently employed and the PID sample was heated from 25 to 130°C. The diffractograms for the PID (guaifenesin and Soluplus^®, 90: 10) composition showed unique reflections at 25°C up to 50°C (shown by 4 boxes in Fig. 8b, 25 C and 50 C). However, when heated up to 75°C the diffractogram for the sample (Fig. 8b, 75 C) was essentially the same as the guaifenesin reference sample (Fig. 8b, Reference) indicating the melting of a new polymorphic form of guaifenesin. Furthermore, continued heating of the sample resulted in the characteristic amorphous halo for a molten PID.

Based on the DSC and VT-XRPD data it can be concluded that cooling of molten guaifenesin in the presence of Soluplus^® (PID technology) results in a formation of a new polymorphic form of guaifenesin.

Further investigation of this system is initiated in order to obtain an increased understanding of solid dispersion interactions.

Claims

1. Method for manufacturing a solid homogenous mixture for a dosage form comprising at least one active pharmaceutical ingredient (API) and at least one polymer, said method comprising the steps of: i. Providing a mixture of said polymer and said API, said mixture being heated above the melting point or glass transition temperature of said API; and ii. Cooling said mixture.

2. The method according to claim 1, where said mixture is being heated above the melting point or glass transition temperature of said polymer.

3. The method according to claim 1 or 2, wherein said mixture of API and polymer is mixed after heating the API above the melting point or glass transition temperature of the API.

4. The method according to any one of the preceding claims, wherein said mixture of API and polymer is mixed after heating the API above the melting point or glass transition

temperature of both the API and the polymer.

5. The method according to any one of the preceding claims, wherein the API is in crystalline form prior to heating in step (i).

6. The method according to any one of the preceding claims, wherein the homogenous mixture obtained after step (ii) comprises the API in an amorphous form.

7. The method according to claim 6, wherein the homogenous mixture obtained after step (ii) also comprises the API in crystalline form.

8. The method according to any one of the preceding claims, wherein the obtained homogenous mixture is solid after the cooling (ii).

9. The method according to any of the preceding claims, wherein more than one polymer is used, such as a mixture of polymers.

10. The method according to any of the preceding claims, wherein the polymer is a substantially water soluble crystalline polymer.

11. The method according to any of the preceding claims, wherein the polymer is polyglycol.

12. The method according to any of the preceding claims, wherein the polymer is a homopolymer and/or copolymer and/or graft polymer.

13. the method according to any of the preceding claims, wherein the polymer is selected among polyethylene glycol (PEG), polyethylene oxide (PEO) and a block copolymer of ethylene oxide and propylene oxide.

14. The method according to any of the preceding claims, wherein the polymer is a block copolymer comprising up to about 30% by weight of propylene oxide based block, and has a molecular weight of above about 5000 daltons, typically about 5000 to about 30.000 daltons, more typically about 8000 to about 15.000 daltons.

15. The method according to any of the preceding claims, wherein the polymer is PEG with a molecular weight of about 2.000 - 500.000, preferably 5.000 - 100.000, more preferred 10.000 - 50.000, preferably 20.000 - 35.000 daltons.

16. The method according to any of the preceding claims, wherein the polymer or mixture of polymers has a melting point of about 20 - 120°C, typically about 30 - 100°C, preferably about 40 - 80°C.

17. A dosage form comprising a homogenous mixture obtainable according to any of the preceding claims.

18. The dosage form according to claim 17, providing sustained release of said API.

19. The dosage form according to claim 17 or 18, providing zero order release or

approximately zero order release of said API.

20. The dosage form according to any of the claims 17-19, comprising at least 40%, preferably at least 50%, more preferred at least 60%, preferably at least 70%, more preferred at least 80%, preferably at least 90%, more preferred at least 95% API.

21. The method according to any one of claims 1- 16 or the dosage form according to any one of claims 17-20, wherein the API is guaifenesin.

22. A pharmaceutical composition comprising a dosage form according to any of the claims 17-21.

23. A pharmaceutical composition, comprising at least two different solid dosage forms, wherein at least one is according to any of the clams 17-21, wherein one of said solid dosage forms has a melting point which is lower than the melting point of the other solid dosage form.