MXPA06005102A - Non-tabletted, chewable, individually dosed administration forms - Google Patents

Abstract

Non-tabletted, individually dosed administration forms comprising a composition of at least one pharmaceutically active substance dissolved or dispersed within a matrix material comprising a mixture of at least 0,2%by weight of a gelatine, at least one stabilising agent and at least one water-soluble alcohol and/or water as a solvent, which composition is plastic at elevated temperature, characterised in that:the stabilising agent is selected from the group consisting of (i) esters of glycerine and fatty acids;(ii) products resulting from the alcoholysis / esterification reaction of such esters of glycerine and fatty acids with polyethylenglycols;and, in that the stabilising agent has a melting point in the range of 42°C to 63°C, in that water is present in an amount not greater than 46%by weight of the composition.

Description

METHODS OF ADMINISTRATION MASTICABLE, NOT COMPRESSED DOSED INDIVIDUALLY FIELD OF THE INVENTION The invention relates to administration forms individually dosed for pharmaceutically active compounds consisting of an uncompressed chewable gel composition packaged in blister or cavities, to a process for the manufacture of said dosage forms individually, to forms administration dosages individually that can be obtained by the aforementioned method and the use of a stabilizing agent to improve the ease of extraction of the blister or cavity composition. BACKGROUND OF THE INVENTION Chewable release systems, such as chewing gums, are a very desirable mode for the oral administration of pharmaceutically active compounds. A disadvantage of chewing gums is that they generally comprise a gum base insoluble in water that remains in the mouth and that must be discarded. In addition, many active compounds may have affinity with the gum base making accurate dosing difficult. British patent application No. 2 009 597 describes antacid compositions in the form of chewable gel REF .: 171942 and swallowable. The compositions described herein are obtained by dispersing an antacid in a solution comprising water, a carbohydrate or polyhydric alcohol as a consistency agent and a sufficient amount of gelling agent to cause the liquid dispersion to harden into a self-supporting gel after cool. In a preferred embodiment, the still liquid dispersion can be poured before being cooled in unit dose molds for oral dosing and allowed to harden. This procedure no longer requires separate forming and packaging of the solid forms of administration. The form is provided in a particulate manner, during the packaging operation by simple application of the softened composition to a substrate with the desired shape followed by solidification. This results in an improvement in the economic performance of the entire manufacturing process. The international patent application WO 87/00429 describes opacified gelatin compositions and processes for their manufacture. The compositions comprise fats, fatty oils or fatty derivatives to improve the light stability of the dyes used to color the gelatin compositions. The specification discloses that all fats, fatty oils or fatty derivatives of natural or synthetic origin, as well as partially hydrogenated products, can be used, provided they are physiologically safe. Brief description of the invention The authors of the present invention have now discovered that the use of gelatin as a gelling agent for the manufacture of non-compressed, masticatory compositions such as those described in the state of the art leads to compositions which, as they age, present often the problem that they can not be easily removed from the package in which they have been formed without leaving residues in the package. The problem of leaving residues in the package after the extraction of the gelatinous composition is particularly pronounced when the compositions comprise high amounts of alkaline ingredients since said ingredients tend to destabilize the gelatin matrix. The problem is also particularly pronounced when the shape of the package has edges or portions with small radius of curvature. The inventors have solved this problem by incorporating a matrix material comprising a mixture comprising gelatin, at least one water-soluble alcohol and / or water as solvent and at least one stabilizing agent selected from the group consisting of esters of glycerin and fatty acids and the products resulting from the reaction of alcoholysis / esterification of said esters of glycerin and fatty acids with polyethylene glycolsthe stabilizing agent having a melting point in the range of 42 ° C to 63 ° C. This results in individually dosed, uncompressed administration forms comprising a composition of at least one pharmaceutically active substance dispersed or dissolved in the matrix material. the plastic composition being at elevated temperature. Said administration forms can be extracted from the package without leaving residues. In a preferred embodiment of the present invention, only one stabilizing agent is incorporated into the matrix material. The composition of the present invention comprises, as essential ingredients, at least one pharmaceutically active substance, gelatin present in an amount of at least 0.2% by weight of the composition, at least one stabilizing agent as described above, and less an alcohol soluble in water and / or water as a solvent, the water being present in an amount not higher than 46% by weight of the composition. It may also comprise consistency agents imparting texture and body to the final gel and other optional components such as preservatives, antioxidants, antifoaming agents, sweeteners, taste masking agents, colorants and flavors. In a preferred embodiment of the present invention, only one stabilizing agent is used.

DETAILED DESCRIPTION OF THE INVENTION In a preferred embodiment of the present invention a single stabilizing agent is incorporated into the composition of the matrix. Consistency agents suitable for the present invention are sugars such as glucose, sucrose and fructose, sugar alcohols such as sorbitol, mannitol and maltitol and polysaccharides such as starch, cellulose and functionalized cellulose derivatives. To ensure consumer acceptability it is preferred that the individually dosed, uncompressed administration forms of the present invention have compositions that do not show plastic deformation at temperatures below 37 ° C. Gelatin is a protein obtained by extraction of raw materials animals that contain collagen such as skin and bones that have been previously treated by acid or alkaline process. Commercially available gelatin typically contains 84-92% proteins, 0.1-2% salts, the balance being water. Commercially available gelatins are classified according to the raw material from which they were obtained and according to their ability to gel, which is usually measured as the Bloom strength or degree of the gel. Although all types of gelatin can be used for the manufacture of the individually dosed administration forms of the present invention, it has been found that gelatins with a Bloom range of between 140 and 270 degrees Bloom, preferably 180 to 250 degrees Bloom provide a composition with an optimal acceptance by the consumer in terms of palatability. The gelatins obtained by alkaline treatment are generally preferred with respect to those obtained by acid treatment. It is preferred that the compositions of the present invention comprise gelatin in an amount greater than 0.2% by weight of the composition, more preferably an amount greater than 1% by weight and still more preferably an amount greater than 5% by weight of the composition. The stabilizing agent of the present invention is selected from the group consisting of esters of glycerin and fatty acids and the products originated from the alcoholysis / esterification reaction of such esters of glycerin and fatty acids with polyethylene glycols, which have a point of Examples of such stabilizing agents are mono-, di-, and tri-esters of glycerin with fatty acids and mixtures thereof, preferably, the glycerin diesters with fatty acids. Preferred fatty acids are those selected from the group consisting of saturated or unsaturated fatty acids with 10 to 20 carbon atoms, preferably with 16 to 18 carbon atoms. Examples of fatty acids of this type are lauric, oleic, linolenic, linoleic, palmitic and stearic. An example of a preferred commercially available ester is the Estol ® 3745 GDS T2 from Uniqema. Other examples of stabilizing agents are the products of the alcoholysis / esterification reaction of the glycerin esters and fatty acids mentioned above. Preferred examples are the reaction products of alcoholysis / esterification of hydrogenated palm kernel oil or hydrogenated palm oil with polyethylene glycol (PEG 1500) such as Gelucire ® 44/14 and Gelucire ® 50/13 from Gattefossé. In one embodiment of the invention, the stabilizer is present in an amount greater than 1% by weight of the formulation. In one embodiment of the present invention the solvent or solvents present in the composition are used in an amount of at least 10% by weight, more preferably greater than 25% by weight and still more preferably greater than 50% by weight of the composition. In a preferred embodiment of the invention the composition comprises more than 46% by weight of the composition of at least one water-soluble alcohol. In another embodiment of the present invention the amount of water of the compositions present is not greater than 46% by weight, preferably not more than 35% by weight, more preferably not more than 25% by weight and still more preferably not more than 15% by weight of the composition. The compositions of the present invention comprise at least one pharmaceutically active substance that is dispersed or dissolved in the matrix material when it is in the molten state. The pharmaceutically active substance need not be in any specific form for its successful incorporation into the molten matrix material, in particular, it is not required and it is also not preferred that the pharmaceutically active substance be provided as a component of a fibrous support matrix prepared by a process of rapid flow. In another embodiment of the present invention, uncompressed, individually dosed administration forms comprise more than 18% by weight of a pharmaceutically active substance. Suitable pharmaceutically active substances that can be contained in the individually dosed administration forms of the present invention can vary widely and generally represent any stable drug combination. Descriptive categories and specific examples include: a) ANTI-ACIDS: i) Inorganic or organic aluminum salts such as for example aluminum allantoinate, aluminum aminoacetate, aluminum phosphate, aluminum silicate, aluminum glycopheptanoate, or polygalacturonate aluminum. ii) Inorganic or organic salts of bismuth such as for example bismuth aluminate, bismuth carbonate, bismuth silicate, bismuth subcarbonate or bismuth citrate. iii) Inorganic or organic calcium salts such as calcium phosphate or calcium aminoacetate, iv) Inorganic or organic magnesium salts such as magnesium carbonate, magnesium basic carbonate, magnesium phosphate or magnesium silicate. v) Oxides and hydroxides such as aluminum oxide, algeldrate (aluminum hydroxide), magnesium or calcium oxides or hydroxides, vi) Mixed aluminum and sodium salts such as silicate, mixed aluminum and magnesium salts such as hydrotalcite ( basic carbonate of aluminum and magnesium), the almagate (basic carbonate of aluminum and magnesium) or magaldrate (basic sulfate of aluminum and magnesium), mixed bismuth and magnesium salts such as magnesium silicate and magnesium aluminosilicates such as simaldrate or almasylate vii) Bicarbonates such as sodium or potassium viii) Glycine ix) Alginic acid and its salts and mixtures thereof b) ACTIVE PRINCIPLES FOR PEPTIC ULCER AND GASTROESOPHAGEAL REFLECTION Ranitidine *, Nizatidine, Famotidine, Cimetidine, Roxatidine, Pifatidine, Roxatidine, Sufotidine, Lafutidine, Osutidine, Pantoprazole, Omeprazole, Lansoprazole, Esomeprazole, Rabeprazole, Esaprazole, Pariprazole, Aripiprazole, Leminoprazole, Amoxicillin, Trospectomycin, Clarithromycin, Zinc Acetone, Ceraxate, Rotraxate, Dosmalfate, Flavalfate, Sucralfate, Bismuth salts such as citrate or subsalicylate, Triletide, Dicloguamine, Sulfoxazine, Rioprostil, Ritipenem, Trimoprostilo, Benexato, Pramipida, Misoprostol, Alaptide, Proglumide, Azuletil, Trepenone, Polienfosfatidilcolina, Plaunotol, Troxipida, Midoriamin, Ecabet, Quinotolast, Sulglicotide, Nitazoxanide, Revaprazan, and mixtures thereof c) ACTIVE PRINCIPLES FOR FUNCTIONAL GASTROINTESTINAL DISORDERS; PROPULSIVES Metoclopramide, Cinitapride, Cleboprida, Cisapride, Zacopride, Mosapride, Itopride, Prucalopride, Domperidone, Ecabapide, Calcium Polycarbophil, Tegaserod, and mixtures thereof d) LAXANTS Sennatin, Sennosides A + B, Glycerol, Picosulfate, Lactitol, Bisacodyl, Polyethylene glycol , Láctulose, Basic magnesium carbonate, and mixtures thereof.) OBJECTIVE PRODUCTS Orlistat, Amfebutamone, Bupropion, Diethylpropion, Sibutramine, Fluoxetine, Metaraminol, Mazindol, Chorionic gonadotropin, Phentermine, Metamfetamine, Fendimetrazine, Benzfetamine, Phenylpropanolamine, Fenproporex, and mixtures thereof f) DIGESTIVES; ENZYMATIC PREPARATIONS Amylase, Cellulase, Lactase, Lipase, and mixtures thereof g) VITAMINS Mixtures of vitamins, mixtures of trace elements, and mixtures thereof h) APPETITE STIMULANTS Pizotifen, Cryptoheptadine, Carnitine, Stolimine, and mixtures thereof ) ANTITROMBÓTIC AGENTS; INHIBITORS OF PLAQUETARIA AGGREGATION Ditazole, Acetylsalicylic acid, Trifusal, Epoprostenol, Eptifibatide, Heparin, Clopidrogel, Dipiridamol, Abciximab, Ticlopidine, Dalteparin, Danaparoid, Warfarin, Fenindione, Dicumarol, Epoprostenol, Enoxaparin, Nadroparin, Antithrombin III, Indobufen, Parnaparin, Tinzaparin , Dermatan, Desirudin, Reviparin, Thrombomodulin, Bivalirudin, Ardeparin, Lepirudin, Tifacogin, Fondaparin, Fenprocoumon, Certoparin, Bemiparin, Idraparinux, Acenoculenol, Gabexate, Sulodexide, Defibrotide, Isbogrel, Cilostazol, Ciprostene, Ataprost, Sulotroblan, Taprostene, Chlorochromen, Picotamide, Alprostadil, Sulfinpyrazone, Beraprost, Daltroban, Variprost, Satrigel, Sarpogrelate, Tirofiban, 'Ecraprost, Lamifiban, Lefradafiban, Xemilofiban, Policosinol, Roxifiban, Lotrafiban, Sibrafiban, Alnidofibatide, Orbofiban, Argatroban, Ticlomarol, and mixtures thereof j) ANTIANEMIC PREPARATIONS TRIVALENT IRON PREPARATIONS Ferritina, Pro ferric teinsuccinate, ferric dextran, and mixtures thereof k) ANTIARRÍMICOS Quinidina, Esmolol, Pirmenol, Acecainide, Pilsicainide, Recainam, Penticainide, Flecainide, Adenosine, Lidocaine, Metoprolol, Propranolol, Nadolol, Oxprenolol, Phenytoin, Acebutolol, Sotalol, Carteolol, Medigoxin, Procainamide, Bretilio, Amiodarone, Disopyramide, Mexiletine, Moracizine, Tocainide, Propafenone, Barucainide, Alprenolol, Otenzepad, Verapamil, Diprafenone, Etacizin, Bidisomide, Arotinolol, Cibenzoline, Tiracizine, Pindolol, Diltiazem, Atenolol, Dofetilide, Tedisamil, Sematilide, Sotalol, Almokalant, Nifekalant, Ibutilide, Landiolol, Dronedarone, Talinolol, Tecadenoson, Digoxin, Indenolol, Prajmalio, Aprindin, Bunaftin, Butobendin, Loraxin, Lorcainide, and mixtures thereof 1) CARDIAC STIMULANTS, ORGANIC NITRATES Mononitrate or Isosorbide Dinitrate, Nitroglycerol, Pentaerythrityl Tetranitrate, Molsidomine, and mixtures thereof m) ANTIHYPERTENSIVES; ANTAGONISTS OF ALPHA ADRENORECEPTORS Doxazosin, Urapidil, Nipradilol, Indoramine, Prazosin, Labetalol, Amosulalol, Terazosin, Monatepilo, and mixtures thereof n) DIURETICS Triamterene, Canrenoate, Spironolactone, Furosemide, Torasemide, Cycletanin, Pyrentanide, Chlorotiazide, Chlorthalidone, Hydroflumethiazide, Bendroflumetazide, Methyclothiazide, Politiazide, Clopamide, Quinetazone, Bumetanide, Indapamide, Xipamide, Cyclopentiazide, Canrenone, Docarpamine, Hydrochlorothiazide, Metolazone, Azosemide, Anaritide, Ularitide, Ecadotril, Candoxatrile, Amiloride, Ethacrynic Acid, Conivaptan, Telmisartan, Mebutizide, and mixtures thereof or ) PERIPHERAL VAS0DILATORS Dihydroergocristine, Piracetam, Nicergoline, Vinburnine, Cadralazine, Flunarizine, Metergoline, Hydralazine, Fasudil, Nicorandil, Linsidomine, Sildenafil, Cinnarizine, Heptaminol, Almitrine, Raubasin, Pentoxifylline, Trimetazidine, Buflomedil, Alprostadil, Brovincamine, Cinepazet, Dilazep, Lidoflazine , Molsidomina, Nicorandil, Nifedipino, Trapidil, Viskenit, and mixtures thereof p) VASOPROTECTORES Diosmin, Hidrosmina, Hesperidina, Troxerutina, and mixtures thereof q) ANTIHYPERTENSIVES - BETA BLOCKERS SELECTIVE AGENTS Atenolol, Esmolol, Carteolol, Metoprolol, Bisoprolol, Carvedilol, Nebivolol, Propranolol, Tertatolol, Betaxolol, Cetamolol, Nipradil l, Tilisolol, Mepindolol, Nadolol, Oxprenolol, Acebutolol, Sotalol, Timolol, Labetalol, Penbutolol, Celiprolol, Amosulalol, Alprenolol, Chloranolol, Bopindolol, Soquinolol, Arotinolol, Pindolol, Talinolol, Esatenolol, Indenolol, Befunolol, Bevantolol, Bucomololo, Bunitrolol, Butofilolol, Carazolol, Lervonoprolol, Nifenalol, Rescimetol, Bunazosin, Doxazosin, Guanabenzo, Guanadrel, Guanfacine, Guanoxabenz, Indoramine, Rilmenidin, Lofexidin, Naftopidil, Prazosin, and mixtures thereof. r) SELECTIVE CALCIUM CHANNEL BLOCKERS WITH MAINLY VASCULAR EFFECTS Amlodipine, Nisoldipine, Nicardipine, Nitrendipine, Felodipine, Anipamil, Zonisamide, Benidipine, Darodipine, Tiapamil, Tetrandrino, Lercanidipine, Gallopamil, Bepridil, Diproteverin, Isradipine, Franidipine, Nivaldipine, Levetiracetam, Nimodipine, Verapamil, Aranidipine, Fasudil, Dotarizine, Lacidipine, Lomerizine, Cilnidipine, Nifedipine, Diltiazem, Palonidipine, Monatepilo, Fantofarone, Semotiadil, Efenidipine, Manidipine, Barnidipine, Elgodipine, Pranidipine, Furaldipine, Cycladelate, and mixtures thereof, s) AGENTS THAT ACT IN THE RENIÑA-ANGIOTENSIN SYSTEM; ACE INHIBITORS Enalapril, Ramipril, Quinapril, Captopril, Perindopril, Fosinopril, Trandolapril, Cilazapril, Lisinopril, Spirapril, Moexipril, Delapril, Alacepril, Enalaprilat, Benazepril, Fentiapril, Zofenopril, Fosinoprilat, Utibapril, Temocapril, Ceranapril, Zofenoprilat, Imidapril, and mixtures of them, t) ANGIOTENSIN II ANTAGONISTS Candesartan, Losartan, Eprosartan, Irbesartan, Valsartan, Tasosartan, Telmisartan, Olmesartan, and mixtures thereof. u) REDUCTORS OF CHOLESTEROL AND TRIGLYCERIDES Atorvastatin, Lovastatin, Eptastatin, Simvastatin, Fluvastatin, Dalvastatin, Itavastatin, Rosuvastatin, Pravastatin, Probucol, Policosanol, Ciprofibrate, Fenofibrate, Benzafibrate, Cloribrate, Filicol, Gemfibrozil, Benfluorex, Cholestyramine, Phytosterols, Acipimox, Binifibrate, Clinofibrate, Colestilan, Diethylaminoethyl dextran, colestrol, Etiroxate, Etofibrate, Gugulipid, Meglutol, Melinamide, Niceritrol, Omacor, Pirifibrate, Sorbinicato, Sulodexide, Sultosilic acid, and mixtures thereof. v) ESTROGENS; FEMALE CONTRACEPTIVES Estradiol, Ethinylestradiol, Norethisterone, and mixtures thereof. w) ACTIVE PRINCIPLES USED IN BENIGN PROSTATE HYPERTROPHY Pigeum Extract, Alfuzosin, Dutasteride, Finisteride, Oxendolone, Tamsulosin, and mixtures thereof. x) HOMEOSTASIS OF CALCIUM; ANTIPARATHROID HORMONES Calcitonin, Elcatonin, and mixtures thereof. y) ANTINEOPLASTIC AGENTS Ameticina, Atrimustina, Diaziquona, Espiromustina, Melphalan, Elmustine, Estramustine, Ranimustine, Dibromomulcitol, Tauromustine, Temozolomide, Carboplatin, Photemustine, Arañóse, Perfosfamide, Eptaplatin, Busulfan, Iphoria, Ifosfamide, Chlorambucil, Altretamine, Cisplatin, Lomustine, Improsulphan, Mytobronitol, Mitolactol, Nedaplatin, Oxaliplatin, Prednimustine, Temozolomide, Treosuflane, Trofosfamide, Cyclophosphamide, Methotrexate, Butocin, Capecitabine, Carmofur, Cladribine, Cytarabine, Doxifluridine, Enocythabin, Fludarabine, Gemcitabine, Pentostatin, Raltitrexed, Tegafur, Etoposide, Pirarubicin, Aminogluteimide, Anastrozole, Bicalutamide, Clodronate, Epitiostanol, Exemestane, Fadrozole, Flutamide, Formestane, Fulvestrant, Letrozole, Mepitiostane, Nilutamide, Tamoxifen, Toremifene, Trilostane, Krestin, Lentinan, Picibanil, Procodazole, Sizofirán, Ukrain, Virulizin, Alitretinoin, Amsacrine, Bexarotene, Docetaxel, I inotecan, Miltefosine, Mitoxantrone, Nitracrine, Bortezomib, Paclitaxel, Porfimer , Razoxane, Sobuzoxane, Teniposide, Topotecan, Vindesine, Vinorelbine, Geftinib, Imatinib; Bleomycin, Megestrol, Lenograstim, and mixtures thereof, ANTI-INFLAMMATORY AND ANTIREUMATIC PRODUCTS Aceclofenac, Diclofenac, Ketorolac, Meloxicam, Naproxen, Piketoprofen, Acemetacin, Alclofenac, Amfenac, Ampiroxicam, Azapropazone, Bufexamaco, Butibufen, Carprofen, Chondroitin, Cinmetacin, Clidanaco, Dexketoprofen, Difenpyramide, Droxicam, Emorfazone, Acenic Acid, Epirizol, Etersalate, Fenbufen, Fentiazac, Feprazone, Flunoxaprofen, Flurbiprofen, Guaimesal, Ibuproxam, Indomethacin, Ketoprofen, Lonazolac, Mabuprofen, Nabumetone, Nimesulide, Oxametacin, Parsalmide, Perisoxal, Piroxicam, Pranoprofen , Proglumethacin, Proquazone, Proticinic acid, Sulindac, Talniflumate, Tolfenamic acid, Tolmethine, Zaltoprofen, Benzydamine, Etofenamate, Felbinaco, Fepradinol, Idocrilamide, Loteprednol, Vessiflex, Glucosaline, Celecoxib, Hyaluronic Acid, Meclofenamate, Piproxene, Tenoxicam, Valdecoxib, Etoricoxib, Rofecoxib, and mixtures thereof, aa) BISPHOSPHONATES Risedronate, Tiludronate, Clodronate, Pamidronate, Etidronate , Alendronate, Zoledronate, Cimadronate, Neridronate, Olpadronate, Minodronate, Ibandronate, and mixtures thereof. bb) ANALGESICOS Acetylsalicylic acid, Acetaminophen, Codeine, Dihydrocodeine, Dexibuprofen, Alminoprofen, Carbasalate, Desflurane, Diflunisal, Enflurane, Etomidate, Floctafenin, Fosfosal, Isoflurane, Isonixin, Ketorolac, Lornoxicam, Clonixinate, Midazolam, Mofezolac, Naproxen, Nefopam, Propofol , Rimazolium, Rofecoxib, Ropivacaine, Sevoflurane, Parecoxib, Propacetamol, Zaltoprofen, Acemetacin, Sulindaco, Indomethacin, Mefenamic acid, Ketoprofen, Diclofenac, Piroxicam, Flupirtine, Mofezolac, Ibuprofen, Fenoprofen, Flurbiprofen, Amtolmentin, Fepradinol, Celecoxib, Valdecoxib, Etoricoxib, Fluproquazone, Nefopam, Astaxanthin, and mixtures thereof. ce) ANTIMIGRAIN PREPARATIONS Almotriptan, Propofol, Gabapentin, Zonisamide, Lisinopril, Valproate, Pirprofen, Indoramine, Lidocaine, Metoprolol, Ergotamine, Cyproheptadine, Propranolol, Pizotifen, Flunarizine, Nadolol, Metergoline, Ketoprofen, Metysergide, Buclizine, Timolol, Tiaspirone, Topira ato , Somatostatin, Etiracetam, Cinarizine, Dihydroergotamine, Matricaria, Dronabinol, Dotarizine, Lomerizine, Ibuprofen, Sumatriptan, Naratriptan, Donepezil, Zolmatriptan, Naproxen, Rizatriptan, Montelukast, Frovatriptan, Botulinum Toxin, Alniditan, Avitriptan, Eletriptan, Metoclopramide, Targinine, Aminophylline, Tolfenamic acid, Isometeptene, and mixtures thereof. dd) ANTIEPYLEPTICS Phenobarbital, Clonazepam, Felbamate, Fosfentoin, Gabapentin, Lamotrigine, Levetiracetam, Oxcarbazepine, Tiagabine, Topiramate, Valproate, Vigabatrin, Zonisamide, Milacemide, Denzimol, Bretazenil, Eterobarb, Diazepam, Chlormetiazole, Clonazepam, Clobazam, Mephobarbital, Mephenytoin, Primidone , Acetazolamide, Valpromide, Ralitoline, Fengabine, Licarbazepine, Lorazepam, Antiepilepsirin, Rufinamide, Zaleplon, Abecamil, Losigamone, Selfotel, Midafotel, Remacemide, Carbamazepine, Ethosuximide, Methoximide, Retigabine, Valnoctamide, and mixtures thereof, ee) ANTIPSYCHOTICS Haloperidol, Sulpiride, Blonanserin, Spiperone, Rimcazol, Isofloxitepin, Remoxipride, Emonapride, Bretanezil, Zuclopenthixol, Veralipride, Bromperidol, Droperidol, Trifluoperazine, Bromazepam, Le opromazine, Fluopromazine, Perfenazine, Thioridazine, Chlorprothixene, Flufenazine, Periciazine, Thiotomyne, Flupentixol, Benperidol, Fluspirilene , Pimozide, Clozapine, Pipotiazine, Loxapine, Tiapride, Zotepine, Sultopride, Lithium Carbonate, Asenapine, Tiaspirone, Ritanserin, Tandospirone, Amperozide, Clospipramine, Nalmefene, Prochlorperazine, Amisulpride, Levosulpiride, Risperidone, Promazine, Perospiron, Aripiprazole, Chlorpromazine, Carpipramine, Iloperidone, Remoxepride, Carbamazepine, Olanzapine, Quetiapine, Ziprasidone, Valproate, Azaperone, Ciamemazine, Tiperone, Bifeprunox, and mixtures thereof. ff) ANXIOLYTICS Diazepam, Clorazepate, Pyridoxine, Sulpiride, Lorazepam, Phenobarbital, Meprobamate, Buspirone, Suriclone, Citalopram, Brotizolam, Adinazolam, Etizolam, Bretazenil, Medicar, Enciprazine, Loflazepate, Propranolol, Chlordiazepoxide, Hydroxyzine, Trifluoperazine, Oxazepam, Medazepam, Clonazepam , Oxprenolol, Bromazepam, Clobazam, Nordazepam, Ketazolam, Halazepam, Alprozolam, Flufenazine, Chlorimipramine, Venlafaxine, Ritanserin, Ipsapirone, Tandospirone, Buspirone, Pazinaclone, Flesinoxane, Fluoxetine, Selfotel,, Zatosetron, Pagoclone, Carpipramine, Sunepitron, Sertraline, Paroxetine, Cyclobenzaprine, Ciamemazine, Valnoctamide, Clotiazepam, and mixtures thereof. gg) ANTIDEPRESSANTS Citalopram, Venlafaxine, Atomoxetine, Clopradone, Binedaline, Sertraline, Femoxetine, Oxaprotiline, Viqualine, Clovoxamine, Milacemide, Brofaromine, Cyanoprine, Moclobemide, Midalcipran, Adinazolam, Nefazodone, Azamianserin, Reboxetine, Tianeptine, Toloxatone, Fluvoxamine, A Itriptyline, Imipramine, Trifluoperazine, Phenelzine, Flufenazine, Flupentixol, Isocarboxazide, Tranylcypromine, Trimipramine, Desipra ina, Opipramol, Nortriptyline, Protriptyline, Doxepin, Lithium Carbonate, Chlorimipramine, Dosulepin, Trazodone, Butriptyline, Viloxazine, Maprotiline, Amoxapine, Lofepramine, Bupropion, Ritanserin, Doconexento, Paroxetine, Ipsapirone, Fengabine, Tandospirone, Setiptiline, Amphebutamine, Lazabemide, Flesinoxane, Adrafinil, Ademethionine, Modafinil, Litoxetine, Fluoxetine, Ceronapril, Cericlamin, Beloxepine, Sunepitron, Agomelatine, Aprepitant, Amineptine, Nomifensine, Chromium Picolinate, and mixtures thereof. hh) ALCOHOL DEPENDENCY TREATMENT Acamprosate, Vigabatrin, Diazepam, Disulfiram, Ritanserin, Naltrexone, Nalmefene, Carbamazepine, Hydroxybutyrate, Nitrefazole, Metadoxin, and mixtures thereof. ii) Nasal decongestants Pseudoephedrine, Fluticasone, Indanazoline, Tinazoline, Ipratropium, and mixtures thereof. jj) ACTIVE PRINCIPLES FOR ASTHMA AND OBSTRUCTIVE DISEASES OF THE RESPIRATORY ROUTE Salmeterol, Fenoterol, Ipratropium, Fluticasone, Beclomethasone, Flutropium, Talniflumate, Terbutaline, Oxitropium, Rolipram, Seratrodast, Pranlukast, Formoterol, Albuterol, Salbutamol, Midestein, Tiotropium, Sibenadet , Roflumilast, Aminophylline, budesonide, Almitrine, Glycopyrrolate, Bambuterol, mabuterol, Procaterol, tulobuterol, Rimiterol, reproterol, Pirbuterol, daltroban, ramatroban, tomelukast, Ibudilast, pobilukast, Zafirlukast, Montelukast, Methylprednisolone, Dexamethasone, Triamcinolone, Tipredane, Mometasone, Loteprednol , Flunisolide, Hydrocortisone, and mixtures thereof, kk) EXPECTORANTS OR ANTITUSIGANS Carbocysteine, Citiolone, Dropropizine, Cloperastin, Ozagrel, Nesosteine, Levodropropizine, Cystinexin, Dextromethorphan, Guaimesal, Nepinalone, Fudosteine, Quinidine, Hydrocodone, Noscapine, Chlorpheniramine, and Blends thereof . 11) ANTIHISTAMINES FOR SYSTEMATIC USE Terfenadine, Ebastine, Dexchlorpheniramine, Azelastine, Acrivastine, Emedastine, Loratadine, Picumast, Diphenhydramine, Promethazine, Fenclozine, Levocabastine, Desloratadine, Cinnarizine, Setastine, Tagorizine, Mizolastine, Cetirizine, Taziphilin, Epinastine, Olopatadine, Bepotastine, Rupatadine, Norastemizole, Triprolidine, Fexofenadine, Ketotifen, Azatadine, Clemastine, Brompheniramine, and mixtures thereof, mm) BUCCAL ANTISEPTICS Chlorhexidine, Chloramine T, Benzalkonium Chloride, and mixtures thereof. nn) OTHERS Sulfamethoxazole, Centella Asiatica, Calcium Folinate, Palmidrol, Tiomucase, Glucomannan, Leucocyanidol, Bacterial Lysate, Espagul, and mixtures thereof.

It is preferred that the active substances that may be present in the compositions of the present invention are selected from the group of non-lipophilic active substances. Preferred pharmaceutically active substances are antacid compounds. Preferred antacids for use in the invention are usually calcium, magnesium, aluminum or bismuth carbonate or hydroxy carbonate salts and combinations thereof, and are generally very insoluble in water. Other antacids such as sodium bicarbonate, calcium bicarbonate and other carbonates, silicates and phosphates are included in this invention. Preferred antacids are aluminum and magnesium antacids, such as, for example, aluminum hydroxide and magnesium hydroxide and crystalline aluminum and magnesium hydroxy carbonates such as hydrotalcite, magaldrate and almagate are also preferred. The almagate is particularly preferred. Mixtures of the antacid compounds can be used if desired. When antacids are used as pharmaceutically active substances, they are present in amounts of between 5 and 50% by weight of the composition, preferably between 10 and 45% by weight of the composition and still more preferably between 20 and 50% by weight of the composition. 35% by weight of the composition. The compositions of the present invention preferably comprise water, more preferably at least 1% by weight of water and do not comprise edible gums. The present invention also relates to a process for producing individually dosed non-compressed administration forms comprising the steps of: (a) forming a composition comprising at least one pharmaceutically active substance dispersed or dissolved in a matrix material comprising a mixture of gelatin, at least one stabilizing agent and at least one alcohol soluble in water and / or water as a solvent, which is plastic at an elevated temperature and maintaining said composition above 37 ° C in a heating tank, (b) transferring the composition , when flowing to a heated dosing apparatus, (c) discharging the composition onto a preformed substrate, through a controlled mechanism so that a constant amount of the fluid formulation material is dosed onto the substrate, (d) cooling the composition, in which the stabilizing agent (s) present in the composition is selected from the group formed by esters of glycerin and fatty acids and products originated by the reaction of alcoholysis / esterification of such esters with polyethylene glycols and has a melting point in the range of 42 ° C to 63 ° C and (e) optionally sealing the substrate containing the composition.

An optional embodiment of the present invention is that a separating agent that reduces adhesion is placed on the inner surface of a cavity or a blister, prior to step (c) of the aforementioned process. Examples of such separating agents that reduce adhesion are lecithin, talc, starch, petrolatum and fats that are fluid at 25 ° C. It is a preferred embodiment of the present invention that the cavities or blister of the individually dosed administration forms are made from a material selected from PVC (polyvinyl chloride), PVDC (polyvinylidene chloride), PP (polypropylene), Aclar or laminates such as OPA-Aluminum-PVC (oriented polyamide-aluminum-polyvinyl chloride). PVC is particularly preferred. The manufacturing processes described and claimed in European Patent Application No. 0 250 578, which are explicitly incorporated by reference, are modified by the addition of the stabilizing agent to the composition to be processed and constitute in this modified form particular preferred embodiments. of the process of the present invention. In another aspect, the present invention relates to the use of at least one stabilizing agent selected from the group consisting of (i) esters of glycerin and fatty acids and (ii) products originated by the reaction of alcoholysis / esterification of such esters with polyethylene glycols and that have a melting point in the range of 42 ° C to 63 ° C to facilitate the extraction of the blisters or cavities in which they have been packed, of compositions comprising pharmaceutically active substances dispersed or dissolved in a matrix material comprising a mixture of gelatin and at least one alcohol soluble in water and / or water as solvent, said plastic composition being at elevated temperature. As used herein, the term "high temperature plastic composition" is used to designate a composition that can be molded at temperatures between 45 ° C and 120 ° C and which retains its molded shape after cooling to 20 ° C. C. As used herein, the term "melting point" is used to designate the temperature at which the last visible particle of a small column of substance introduced into a capillary is melted as described in FIG. the European Pharmacopoeia 2.2.14. A suitable apparatus for this determination is the "Melting Point Apparatus B-5 0" available from Büchi Labortechnik AG. As used herein, the term "non-compressed form of administration" is used to refer to any form that has not been manufactured using conventional compression tablet preparation methods such as compression of granular or powdered compositions. in an eccentric or rotary press. As used herein, the term "edible gum" is used to refer to polysaccharide gums comprising, inter alia, gum arabic, gum tragacanth, gum agar, xanthan gum, alginates. As used herein, the term "water-soluble alcohol" is used to designate a pharmaceutically acceptable liquid monohydric or polyhydric alcohol which can be mixed with water to form a uniform solution in an amount of at least 10 volumes of alcohol for 100 volumes of water. Examples of such alcohols are ethanol, n-propanol iso-propanol, glycerol, propylene glycol, 1,3-butylene glycol, polyethylene glycols with a molecular weight of between 100 and 600 Dalton. BLISTER EXTRACTION TEST The compositions to be tested are manufactured in accordance with the procedure described in example 1 and are metered into the cylindrical cavities of circular cross section with a diameter of 25 mm of a blister pack made of PVC. The blister is heat sealed with an aluminum foil. The blisters are stored in a climatic chamber at 40 ° C and 75% relative humidity for 10 weeks. After this period they are left at 25 ° C and 60% relative humidity for 24 hours. For each product to be tested, 5 samples of each formulation are supplied to a group of 5 experts and the experts are asked to extract the composition of the blister in which they are packaged by deforming the plastic cavity by pressing with the thumb on the wall of the container. plastic of the cavity until the composition is expelled from the cavity through the aluminum foil. After having expelled the composition, the rest of the aluminum seal sheet is removed and the plastic cavity is visually inspected. Experts are asked to give the sample the "Failure" rating if residuals exceeding 0.5 mm can be seen in any dimension in the empty cavity. Otherwise, the "Pass" valuation must be assigned. EXAMPLES Example 1 2060.8 g of an 85% solution of glycerin in water are heated in an Erweka SG3W reactor to 65-75 ° C. They are added slowly and continuously for approximately 4 minutes, until the complete solubilization takes place, 288 g of 240 ° Bloom pig skin gelatin. The mixture is stirred for an additional 10 minutes. 48 g of lecithin are incorporated and the mixture is stirred for 10 minutes. Subsequently, 800 g of almagate are added slowly and continuously for about 15 minutes and the mixture is stirred for another 20 minutes at 75-80 ° C. 3.2 g of flavoring are incorporated successively and the solution is stirred for 5 minutes. 4 g of the molten composition are metered into cylindrical cavities of circular cross section having a diameter of 25 mm of a blister pack made of PVC. The blister is heat sealed with an aluminum foil. The composition of each individual cavity is as follows: Examples 2 to 7 Compositions 2 to 7 were made following the procedure described in the modified Example 1 in which 1900.8 g of glycerin solution were used and 160 g of a stabilizing agent was added after the complete solubilization had taken place. of gelatine and before the addition of lecithin. After the gelatin was solubilized, the mixture was stirred for 20 minutes, the reactor temperature was raised to 75-80 ° C and 160 g of stabilizing agent was added slowly and continuously for about 5 minutes. The following compositions were made following this procedure: To evaluate the contribution of the stabilizing agent, the compositions of Examples 1 to 7 were subjected to the "blister extraction test" described above with the following results: It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (22)

2. Having described the invention as above, the claim contained in the following claims is claimed as property: 1. Individually dosed uncompressed administration forms comprising a composition of at least one pharmaceutically active substance dissolved or dispersed in a matrix material comprising a mixture of at least 0.2% by weight of gelatin, at least one stabilizing agent and at least one alcohol soluble in water and / or water as solvent, said plastic composition being at elevated temperature, characterized by: a. the stabilizing agent is selected from the group consisting of (i) glycerin esters and fatty acids and (ii) products originating from the alcoholysis / esterification reaction of said esters of glycerin and fatty acids with polyethylene glycols, and b. the stabilizing agent has a melting point in the range of 42 ° C to 63 ° C, c. the water is present in an amount of not more than 46% by weight of the composition. 2. Dosage forms individually dosed uncompressed, according to claim 1, characterized in that the stabilizer is present in an amount greater than 1% by weight of the formulation.
3. 3. Administration forms individually dosed uncompressed, according to any of the preceding claims, characterized in that they are packaged in blisters or cavities preformed from sheets.
4. 4. Individually dosed non-compressed administration forms according to any of the preceding claims, characterized in that they comprise more than 18% by weight of at least one pharmaceutically active substance
5. 5. Administration forms individually dosed uncompressed, in accordance with 6. Any of the preceding claims, characterized in that they comprise an antacid
6. 6. Individually dosed uncompressed administration forms, according to any of the preceding claims, characterized in that they comprise at least 10% by weight of the composition of at least one alcohol soluble in water and / or water as a solvent
7. 7. Individually dosed uncompressed administration forms according to claim 6, characterized in that they comprise more than 46% by weight of at least one water-soluble alcohol.
8. 8. Dosage forms individually dosed uncompressed, according to any of the preceding claims, characterized in that they comprise water, preferably in an amount exceeding 1% by weight of the total composition.
9. 9. Dosage forms individually dosed uncompressed, according to any of the preceding claims, characterized in that the composition does not comprise edible gums.
10. 10. Process for producing individually dosed non-compressed administration forms characterized in that it comprises the following steps: • forming a composition comprising at least one pharmaceutically active substance dispersed or dissolved in a matrix material comprising a mixture of at least 0.2% by weight of gelatin, at least one stabilizing agent and at least one alcohol soluble in water and / or water as a solvent, which is plastic at an elevated temperature and maintaining said composition above 37 ° C in a heating tank; • transferring the composition, when fluid, to a heated dosing apparatus; • discharging the composition on a preformed substrate, through a controlled mechanism so that a constant amount of the fluid formulation material is dosed on the substrate; • cool the composition; • optionally sealing the substrate containing the composition; wherein the water is present in an amount of not more than 46% by weight of the composition and the at least one stabilizing agent is selected from the group consisting of (i) glycerin esters and fatty acids and (ii) products caused by the reaction of alcoholysis / esterification of said esters with polyethylene glycols, and has a melting point in the range of 42 ° C to 63 ° C.
11. 11. Method according to claim 10, characterized in that the stabilizer is present in an amount greater than 1% by weight of the formulation.
12. 12. Process, according to any of claims 10 or 11, characterized in that the composition comprises more than 18% by weight of a pharmaceutically active substance.
13. 13. Process, according to any of claims 10 to 12, characterized in that the pharmaceutically active substances comprise an antacid. Process, according to any of claims 10 to 13, characterized in that the composition comprises water, preferably in an amount exceeding 1% by weight of the total composition. 15. Process according to any of claims 10 to 14, characterized in that the composition comprises at least 10% by weight of the water composition and / or a water-soluble alcohol as a solvent. 16. Process according to any of claims 10 to 15, characterized in that the composition comprises more than 46% by weight of at least one water-soluble alcohol. 17. Process, according to any of claims 10 to 16, characterized in that the composition does not comprise edible gums. 18. Process according to any of claims 10 to 17, characterized in that the cavity or blister comprises a material selected from the group consisting of PVC, PVDC, PP, Aclar or laminates such as OPA-Aluminum-PVC. 19. Individually dosed uncompressed administration forms characterized in that they can be obtained by the method according to claims 10 to 18. 20. Use of at least one stabilizing agent selected from the group consisting of (i) glycerin esters and fatty acids and (ii) products originated by the reaction of alcoholysis / esterification of said esters with polyethylene glycols, which have a melting point in the range of 42 to 63 ° C to facilitate the extraction of the blisters or cavities, in which they have been packaged, of compositions comprising at least one pharmaceutically active substance dispersed or dissolved in a matrix material comprising a mixture of gelatin and at least one alcohol soluble in water and / or water as solvent, said plastic composition being at elevated temperature. 21. Use according to claim 20, wherein the stabilizing agents are used in an amount greater than 1% by weight of the composition. 22. Use according to claim 20, wherein the stabilizing agents are used in an amount greater than 1% by weight of the composition.