ES2350001T3 - COMPOSITION AND DOSAGE FORM INCLUDING A SOLID OR SEMI-SOLID MATRIX. - Google Patents

Abstract

A composition comprising a solid or semi-solid matrix, which has at least one active ingredient uniformly dispersed therein, the matrix comprising at least one pharmaceutically acceptable agent that forms a matrix selected from pharmaceutically acceptable polymers having a glass transition temperature Tg between 50 ° and 180 ° C; and 1,3-bis (pyrrolidon-1-yl) -butane, wherein the matrix contains less than 6% by weight of water or any compound that is liquid at room temperature and has a higher volatility than water, and where The solubility of the active ingredient in water at 25 ° C is less than 1g / 100ml.

Description

The present invention relates to a composition comprising a solid or semi-solid matrix, which has at least one active ingredient dispersed uniformly therein, a pharmaceutical dosage form comprising the matrix, as well as a process for its preparation.

A measure of the potential utility of an oral dosage form of a pharmaceutical agent is the bioavailability observed after oral administration of said dosage form. Several factors can affect the bioavailability of a drug when administered orally. These factors include aqueous solubility, absorption of the drug through the gastrointestinal tract, dosing force and first-pass effect. Aqueous solubility is one of the most important factors of these. Unfortunately, many active ingredients are generally characterized by poor aqueous solubility.

For a variety of reasons, such as patient compliance and taste masking, a solid dosage form is usually preferred over a liquid dosage form. In many cases, however, solid dosage forms of a drug provide a lower bioavailability than oral solutions of the drug.

There have been attempts to improve the bioavailability provided by solid dosage forms, by forming dispersions of solids or solids solutions of the drug. Solids solutions are preferred physical systems because the components in it easily form liquid solutions when they come in contact with a liquid medium such as gastric juice. This increase in the predisposition for dissolution can be attributed at least in part to the fact that the energy required to dissolve the components from a solid solution is less than that necessary to dissolve the components from a crystalline or microcrystalline solid phase. .

A continuous process for producing solid pharmaceutical forms, including solid solution products, has been known for some time and demands the conversion of a molten material from a polymeric mixture, which contains the active ingredients and is released from the solvents in the drug form. necessary by injection or extrusion molding and subsequent molding (see, for example, EP-A-240 904, EP-A-240 906 and EP-A-337 256). Satisfactory results were obtained in this process when the active ingredient has a low melting point and / or a high solubility in the molten polymer mixture. The active ingredients having a low melting point are liquefied upon contact with the molten polymer mixture, and the molten active ingredient can be easily dispersed in the molten polymer mixture. Alternatively, the active ingredients that have a high solubility in the molten polymer mixture dissolve easily in the molten polymer mixture.

Problems occur when the active ingredient has a high melting point and / or limited solubility in the molten polymer mixture. Proper dispersion of the active ingredient may require high temperatures, a relatively long mixing time and / or high shear, in order to achieve a sufficient mixture of the active ingredient with the molten polymer mixture. This can lead to local overheating and damage to the product, especially when an ingredient, temperature sensitive shear and active ingredient, is being used.

WO 98/10752 discloses a process for producing solid dosage forms in which a polymeric mixture, optionally an active ingredient, and additives are mixed and extruded. The reference suggests the dissolution of temperature-sensitive active ingredients in a solvent and the introduction of the solvent solution into the extruder. The process requires that the solvent be removed from the molten material by evaporation in the extruder.

WO 98/15291 relates to the use of 1,3-bis (pyrrolidon-1-yl) -butane and other 1,3-bis (lactamyl) -propanes as a solvent in pharmaceutical and cosmetic agents.

Breitenbach, J. et al. in Pharmaceutical Research, Vol. 16, No. 7, 1999 p. 1109-1113 compares the state of ibuprofen in 1,3-bis (pyrrolidon-1-yl) -butane with a polymer matrix of polyvinylpyrrolidone.

DE 196 41 436 discloses hydrogen peroxide complexes and 1,3-bis (N-lactamyl) propanes.

There is a continuing need for the development of solid oral dosage forms that have appropriate bioavailability and oral stability and that adapt to active ingredients that have a high melting point and / or limited solubility in molten polymer blends.

It is known that 1,3-bis (lactamyl) -butanes have a high dissolution capacity for many active ingredients. It has now been discovered, very surprisingly, that considerable amounts of 1,3-bis (lactamyl) -butanes can be incorporated into the matrix of a solid dosage form without compromising the mechanical and storage properties of said dosage form. Thus, the invention allows the incorporation of active ingredients in a liquid dissolved state in a solid or semi-solid matrix and exempts the requirement to remove the solvent.

The invention provides a composition comprising a solid or semi-solid matrix having at least one active ingredient uniformly dispersed therein, the matrix comprising at least one pharmaceutically acceptable agent that forms a matrix selected from pharmaceutically acceptable polymers having a temperature of glass transition Tg between 50 ° and 180 ° C; and 1,3-bis (pyrrolidon-1-yl) -butane, wherein the matrix contains less than 6% by weight of water or any compound that is liquid at room temperature and has a higher volatility than water, and where The solubility of the active ingredient in water at 25 ° C is less than 1g / 100 ml.

The composition according to the invention comprises a solid or semi-solid matrix having at least one active ingredient dispersed uniformly therein. The term "semi-solid matrix" is intended to mean a non-fluid system that can be deformed when acting on it by force. A "solid matrix" usually fragile and breaks into pieces when a deforming force is applied.

The invention also provides a dosage form, preferably a solid dosage form, comprising (or consisting of) the above composition.

To handle it more easily, a semi-solid matrix may need an outer shell that completely envelops the semi-solid matrix, such as an empty coating or capsule, for example an empty soft or hard gelatin capsule.

On the other hand, a solid matrix can be molded into a desired shape and used as a dosage form as such. Alternatively, the solid matrix can be ground and compressed into a tablet. Alternatively, the solid matrix can be ground and the ground product can be filled in a capsule.

One or more active ingredients are dispersed uniformly throughout the matrix. This encompasses systems that have small particles, usually less than 1 µm in diameter, of the active ingredient in the matrix phase. These systems do not contain significant amounts of active ingredients in their crystalline or microcrystalline state, as evidenced by thermal analysis (DSC) or X-ray diffraction analysis (WAXS). Generally, at least 98% by weight of the total amount of active ingredients is present in an amorphous state.

When said dispersion of the components is such that the system is chemically and physically uniform or homogeneous through or consists of a phase (as defined in thermodynamics), said dispersion is called a "solid solution". Solid solutions of active ingredients are the preferred physical systems.

The 1,3-bis (pyrrolidon-1-yl) -butane compound acts as a non-volatile solvent for the active ingredient and, optionally, other ingredients. Preferably, the matrix is essentially free of non-volatile solvents (solvents having a lower volatility than water) different from the compound. Usually, the matrix contains less than 6%, preferably less than 3%, and more preferably less than 2% by weight of a non-volatile solvent other than the compound.

The matrix does not contain significant amounts of volatile solvents. The term "volatile solvent" is intended to cover water and any compound that is liquid at room temperature and has a higher volatility of water. The matrix contains less than 6%, preferably less than 3%, and more preferably less than 2% by weight of a volatile solvent.

In relation to the total weight of the active ingredient (s) and other components that constitute the matrix, the preferred compositions of the invention comprise a matrix comprising:

about 1 to 30% by weight (preferably 5 to 25% by weight) of 1,3-bis (pyrrolidon-1-yl) butane,

about 50 to 98% by weight (preferably 60 to 90% by weight) of the matrix forming agent (or any combination of said matrix forming agents),

about 1 to 49% by weight (preferably 1 to 30% by weight) of an active ingredient or a combination of active ingredients, from 0 to 25% by weight (preferably 1 to 15% by weight) of additives.

The preparation of 1,3-bis (pyrrolidon-1-yl) -butane is described in detail in WO 98/15291.

The matrix forming agent is capable of fixing or gelling from a liquefied state, for example from a melted or dissolved state, to form a continuous matrix. When a solid matrix is desired, the agent that forms a matrix is selected to form a continuous matrix of sufficient mechanical stability. Mixtures of agents that form a matrix can, of course, be used. The matrix forming agent is a pharmaceutically acceptable polymer or a mixture of pharmaceutically acceptable polymers. Usually, pharmaceutically acceptable polymers are water soluble or at least water dispersible.

The pharmaceutically acceptable polymer employed in the invention has a Tg between 50 ° and 180 ° C. "Tg" means glass transition temperature. The methods for determining the Tg values of organic polymers are described in "Introduction to Physical Polymer Science", 2nd Edition by

L.H. Sperling, published by John Wiley & Sons, Inc., 1992. The Tg value can be calculated as the heavy sum of the Tg values of the homopolymers derived from each of the individual monomers i, which carries the polymer, i.e. Tg = E Wi Xi, where W is the percentage by weight of the monomer i in the organic polymer and X is the Tg value of the homopolymer derived from monomer i. Tg values for homopolymers are indicated in "Polymer Handbook", 2nd Edition by J. Brandrup and E.H. Immergut, Editors, published by John Wiley & Sons, Inc., 1975.

Pharmaceutically acceptable polymers having a Tg as defined above allow the preparation of solids dispersions that are mechanically stable and, within ordinary temperature ranges, sufficiently stable temperature such that said solids dispersions can be used as dosage forms without another process or it can be compacted to tablets with only a small amount of compression aids.

The pharmaceutically acceptable polymer comprised in the composition is a polymer that preferably has an apparent viscosity, when dissolved at 20 ° C in a 2% aqueous solution (weight / volume) of 1 to 50,000 mPa.s more preferably 1 to 10,000 mPa.s, and more preferably 5 to 100 mPa.s. For example, preferred pharmaceutically acceptable polymers can be selected from the group comprising:

homopolymers of N-vinyl lactams, especially polyvinylpyrrolidone (PVP),

copolymers of an N-vinyl lactam and one or more copolymerizable comonomers therewith, the comonomers that are selected from nitrogen-containing monomers and oxygen-containing monomers; especially a copolymer of N-vinyl pyrrolidone and a vinyl carboxylate, the preferred examples being a copolymer of N-vinyl pyrrolidone and vinyl acetate or a copolymer of N-vinyl pyrrolidone and vinyl propionate;

cellulose esters and cellulose ethers, in particular methylcellulose and ethylcellulose, hydroxyalkylcelluloses, in particular hydroxypropylcellulose, hydroxyalkylalkylcelluloses, in particular hydroxypropylmethylcellulose, cellulose phthalates or succinates, in particular cellulose phthalate acetate or hydroxypropylcellulose succinate hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate;

grafted polyvinyl alcohol-polyethylene glycol copolymers (available as Kollicoat® IR from BASF AG, Ludwigshafen, Germany);

high molecular weight polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide;

polyacrylates and polymethacrylates such as methacrylic acid / ethyl acrylate copolymers, methacrylic acid / methyl methacrylate copolymers, butyl methacrylate / 2-dimethylaminoethyl methacrylate copolymers, poly (hydroxyalkyl acrylates) and poly (hydroxyalkyl methacrylates);

polyacrylamides; vinyl acetate polymers such as copolymers of vinyl acetate and crotonic acid, partially hydrolyzed vinyl polyacetate (also referred to as partially saponified "polyvinyl alcohol");

polyvinyl alcohol;

poly (hydroxy acids) such as poly (lactic acid), poly (glycolic acid), poly (3-hydroxybutyrate) and poly (3-hydroxybutyrate-co-3-hydroxyvalerate);

or mixtures of one or more of these.

Among these, homopolymers or copolymers of N-vinyl pyrrolidone, in particular a copolymer of N-vinyl pyrrolidone and vinyl acetate, are preferred. A particularly preferred polymer is a 60% by weight copolymer of the N-vinyl pyrrolidone copolymer and 40% by weight of the vinyl acetate copolymer.

Hydroxypropylcellulose is another example of a particularly preferred polymer.

The active ingredients used to carry the present invention are biologically active agents and include those that exert a local physiological effect, as well as those that exert a systemic effect, after oral administration. The invention is useful for water insoluble or poorly water soluble (or "lipophilic") compounds. The compounds are considered insoluble in water or poorly soluble in water when their solubility in water at 25 ° C is less than 1 g / 100 ml.

Solids dispersion products are usually prepared by a process known as extrusion of molten material. In order to obtain a homogeneous distribution and a sufficient degree of dispersion of the active ingredient, an active ingredient containing the molten material is stored in the hot barrel of a molten material extruder, for a sufficient residence time. As the manufacturer of the compositions, according to the invention uses a solution of the pre-formed active ingredient, the residence time of the active ingredient in the extruder can be significantly reduced. In this way, the invention is particularly adapted for the formulation of active ingredients that are susceptible to thermal decomposition.

The invention greatly reduces the need to handle powders of the active ingredient, which are prone to powder formation. Exposure of dusts can constitute significant health hazards for the personnel of a manufacturing plant, in particular where high potent ingredients are affected. American Industrial Hygiene Association Journal 57: 3342 (1996) allocates assets in categories (PB-ECL) development-based exposure control limits, based on the extent to which exposure impacts human health. The range of PB-ECL categories from PB-ECL 1 (low severity of acute effects; non-chronic effects) to PB-ECL 5 (high severity of acute effects; acute chronic effects). The invention is particularly useful for active ingredients that fall into the PB-ECL 3, 4, or 5 categories, and especially those that fall into the PB-ECL 4 or 5 categories.

Examples of appropriate active substances include, but are not limited to:

analgesic and anti-inflammatory drugs such as NSAIDs, fentanyl, indomethacin, ibuprofen, ketoprofen, nabumetone, paracetamol, piroxicam, meloxicam, tramadol, and COX-2 inhibitors such as celecoxib and rofecoxib;

anti-arrhythmic drugs such as procainamide, quinidine and verapamil;

antibacterial and antiprotozoal agents such as amoxicillin, ampicillin, benzathine penicillin, benzylpenicillin, cefaclor, cefadroxil, cefprozil, cefuroxime axetil, cephalexin, chloramphenicol, chloroquine, ciprofloxacin, clarithromycin, clavulanic acid, clindamycin, doxixiclina, erythromycin, flucloxacillin sodium, halofantrine, isoniazid, kanamycin sulfate, lincomycin, mefloquine, minocycline, naphcillin sodium, nalidixic acid, neomycin, nortloxacin, ofloxacin, oxacillin, phenoxymethyl-penicillin potassium, pyrimethamine-sulfadoxime and streptomycin;

anti-coagulants such as warfarin;

Antidepressants such as amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dotiepine, doxepine, fluoxetine, reboxetine, amineptin, selegiline, gepirone, imipramine, lithium carbonate, mianserin, milnacipran, nortriptyline [paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3- paroxetine 3-paroxetine 3 4-dihydrobenzofuro [3,2-c] pyridin-2 (1H) -yl] ethyl] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one;

anti-diabetic drugs such as glibenclamide and metformin;

anti-epileptic drugs such as carbamazepine, clonazepam, ethosuximide, gabapentin, lamotrigine, levetiracetam, phenobarbitone, phenytoin, primidone, thiagabine, topiramate, valpromide and vigabatrin;

antifungal agents such as amphotericin, clotrimazole, econazole, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole nitrate, nystatin, terbinafine and voriconazole;

antihistamines such as astemizole, cinnarizine, cyproheptadine, decarboethoxyloratadine, fexofenadine, flunarizine, levocabastine, loratadine, norastemizole, oxatomide, promethazine and terfenadine;

anti-hypertensive drugs such as captopril, enalapril, ketanserin, lisinopril, minoxidil, prazosin, ramipril, reserpine, terazosin and telmisartan;

anti-muscarinic agents such as atropine sulfate and hyoscine;

6 antineoplastic and antimetabolite agents such as platinum compounds, such as cisplatin and carboplatin; taxanes such as paclitaxel and docetaxel; tecans such as camptothecin, irinotecan and topotecan; vinca alkaloids such as vinblastine, vindecin, vincristine and vinorelbine; nucleoside derivatives and folic acid antagonists such as 5-fluorouracil, capecitabine, gemcitabine, mercaptopurine, thioguanine, cladribine and methotrexate; alkylating agents such as nitrogen mustards, for example cyclophosphamide, chlorambucil, chlormetin, ifosfamide, melphalan, or nitrosoureas, for example carmustine, lomustine, or other alkylating agents, for example busulfan, dacarbazine, procarbazine, thiotepa; antibiotics such as daunorubicins, doxorubicins, idarubicins, epirubicins, bleomycins, dactinomycins and mitomycins; HER 2 antibody such as trastuzumab; podophyllotoxin derivatives such as etoposide and teniposide; famesyl transferase inhibitors; anthraquinone derivatives such as mitoxantron; anti-migraine drugs such as alniditan, naratriptan and sumatriptan; anti-Parkinson's drugs such as bromocriptine mesylate, levodopa and selegiline; antipsychotic, hypnotic and sedation agents such as alprazolam, buspirone, chlordiazepoxide, chlorpromazine, clozapine, diazepam, flupentixol, flufenazine, flurazepam, 9-hydroxyrisperidone, lorazepam, mazapertin, olanzapine, pyrosemothromamine, oxazimone, prazophone, prothromamothol, prothromamotholone, oxazimone, prazophone, primate , sertindole, sulpiride, temazepam, thiothixen, triazolam, trifluperidol, ziprasidone and zolpidem; cerebrovascular anti-accident agents such as lubeluzole, lubeluzole oxide, riluzole, aptiganel, eliprodil and remacemide; antitussives such as dextrometorfan and levodropropizine; antivirals such as acyclovir, ganciclovir, loviride, tivirapine, zidovudine, lamivudine, zidovudine / lamivudine, didanosine, zalcitabine, stavudine, abacavir, lopinavir, amprenavir, nevirapine, efavirenz, delavironavir, indirvirinevirvirvirinevirvirinevirvirvirvirine beta-adrenoceptor blocking agents, such as atenolol, carvedilol, metoprolol, nebivolol and propanolol; inotropic cardiac agents such as amrinone, digitoxin, digoxin and milrinone; corticosteroids such as beclomethasone dipropionate, betamethasone, budesonide, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone; disinfectants such as chlorhexidine; diuretics such as acetazolamide, furosemide, hydrochlorothiazide and isosorbide; enzymes; Essential oils such as anethole, aniseed oil, caraway, cardamom, cassia oil, cineole, cinnamon oil, clove oil, coriander oil, mint mint oil, dill oil, eucalyptus oil, eugenol, ginger, oil of lemon, mustard oil, orange flower oil, nutmeg oil, orange oil, peppermint, sage, spearmint, terpineol and thymus; Gastro-intestinal agents such as cimetidine, cisapride, cleboprida, diphenoxylate, domperidone, famotidine, lansoprazole, loperamide, loperamide oxide, mesalazine, metoclopramide, mosapride, nizatidine, norcisapride, olsalazine, omeprazoleprraprolpraprolidol, pantoprazoleprolprazoleprolprrazidraprolprazoleprolprrazidraprolprazoleprolprazoleprolprrazidrazol and sulfasalazine; hemostats such as aminocaproic acid;

7 lipid regulating agents such as atorvastatin, fenofibrate, fenofibric acid, lovastatin, pravastatin, probucol and simvastatin; local anesthetics such as benzocaine and lignocaine; opioid analgesics such as buprenorphine, codeine, dextromoramide, dihydrocodeine, hydrocodone, oxycodone and morphine; Parasympathomimetic and anti-dementia drugs such as AIT-082, eptastigmine, galantamine, metrifonate, milameline, neostigmine, physostigmine, tacrine, donepezil, rivastigmine, sabcomelin, talsaclidine, xanomelin, memantine and lazabemide; peptides and proteins such as antibodies, becaplermin, cyclosporine, tacrolimus, erythropoietin, immunoglobulins and insulin; sex hormones such as estrogens: conjugated estrogens, ethinylestradiol, mestranol, oestradiol, oestriol, oestrone; progestogens; chlormadinone acetate, cyproterone acetate, 17deacetyl norgestimate, desogestrel, dienogest, didrogesterone, ethinodiol diacetate, signodene, 3-keto desogestrel, levonorgestrel, linestrenol, medroxy-progesterone acetate, megestrol, norethindroneone, norethrettoneone noretate , noretinodrel, norgestimate, norgestrel, norgestrienone, progesterone and quingestanol acetate; stimulating agents such as sildenafil; vasodilators such as amlodipine, buflomedil, amyl nitrite, diltiazem, dipyridamole, glyceryl trinitrate, isosorbide dinitrate, lidoflazine, molsidomine, nicardipine, nifedipine, oxpentifillin and pentaerythritol tetranitrate; their N-oxides, their pharmaceutically acceptable acid or base addition salts and their stereochemically isomeric forms. Pharmaceutically acceptable acid addition salts comprise the forms of the acid addition salt, which can be conveniently obtained by treating the base form of the active ingredient with appropriate organic and inorganic acids. The active ingredients that contain an acid proton can be converted into their non-toxic metal amine or addition salt forms, by treatment with appropriate organic and inorganic bases. The term "addition salt" also comprises the hydrate and solvent addition forms that the active ingredients are capable of forming. Examples of such forms are, for example, hydrates, alcoholates and the like. The N-oxide forms of the active ingredients comprise those active ingredients in which one or more nitrogen atoms oxidize to the so-called N-oxide. The term "stereochemically isomeric forms" defines all possible stereoisomeric forms that the active ingredients may possess. In particular, stereogenic centers may have the R-or S-configuration and the active ingredients containing one or more double bonds may have the E-or Z-configuration. The invention is particularly adapted for the manufacture of dosage forms that incorporate the active ingredients that have relatively high melting points, for example active ingredients that have a melting point of 170 ° C or more. Typical examples of these include meloxicam and telmisartan. The matrix of the dosage form may comprise one or more additives selected from surfactants, flow regulators, disintegrants, thickeners and pharmaceutically acceptable lubricants.

The term "pharmaceutically acceptable surfactant" as used herein refers to a pharmaceutically acceptable non-ionic surfactant. The incorporation of surface active agents is especially preferred for matrices containing poorly soluble active ingredients. The surfactant can perform an instant emulsification of the active ingredient released from the dosage form and prevents precipitation of the active ingredient in the aqueous fluids of the gastrointestinal tract.

Preferred surface active agents are selected from:

polyoxyethylene alkyl ethers, for example polyoxyethylene (3) lauryl ether, polyoxyethylene (5) cetyl ether, polyoxyethylene (2) stearyl ether, polyoxyethylene (5) stearyl ether; polyoxyethylene alkylaryl ethers, for example polyoxyethylene (2) nonylphenyl ether, polyoxyethylene (3) nonylphenyl ether, polyoxyethylene (4) nonylphenyl ether or polyoxyethylene (3) octylphenyl ether;

polyethylene glycol fatty acid esters, for example PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate or PEG-300 dioleate;

mono esters of alkylene glycol fatty acids, for example propylene glycol monolaurate (Lauroglycol®);

sucrose fatty acid esters, for example sucrose monostearate, sucrose distearate, sucrose monolaurate or sucrose dilaurate;

sorbitan mono fatty acid esters such as sorbitan mono laurate (Span® 20), sorbitan monooleate, sorbitan monopalmitate (Span® 40), or sorbitan stearate,

polyoxyethylene castor oil derivatives, for example polyoxyethylene glycerol tryricinoleate

or polyoxyl 35 castor oil (Cremophor® EL; BASF Corp.) or polyoxyethylene glycerol oxystearate such as polyethylene glycol hydrogenated castor oil 40 (Cremophor® RH 40) or hydrogenated castor oil 60 polyethylene glycol (Cremophor® RH 60); or

block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene or polyoxyethylene poly-propylene glycol block copolymers such as Poloxamer® 124, Poloxamer® 188, Poloxamer® 237, Poloxamer® 388, or Poloxamer® 407 (BASF Wyandotte Corp. ); or

polyoxyethylene (20) sorbitan mono fatty acid esters, for example polyoxyethylene (20) sorbitan monooleate (Tween® 80), polyoxyethylene (20) sorbitan monostearate (Tween® 60), polyoxyethylene (20) sorbitan monopalmitate (Tween® 40), polyoxyethylene (20) sorbitan monolaurate (Tween® 20), or mixtures of one or more of these.

The dosage forms of the invention may contain at least one conventional additive such as flow regulators, lubricants, thickening agents (fillers) and disintegrants.

Several methods can be used to manufacture the solid dosage forms according to the invention. These methods usually involve the formation of a solution of an active ingredient in a sufficient amount of 1,3-bis (pyrrolidon-1-yl) -butane to obtain a solution of the active ingredient. In preferred embodiments, a pre-formed solution of the active ingredient (which may contain part or all of the optional ingredients) is combined with the matrix forming agent and the mixture is heated to obtain a molten material. Alternatively, the active ingredient solution is formed in situ by combining the active ingredient in a solid state, for example crystalline state, a sufficient amount of 1,3-bis (pyrrolidon-1-yl) butane, the agent that forms a matrix and any of the optional ingredients and heating of the mixture obtained in this way to obtain a homogeneous fusion. It is believed that during the mixing and heating operations the active ingredient is dissolved in 1,3-bis (pyrrolidon-1-yl) -butane; in this way the presence of 1,3-bis (pyrrolidon-1-yl) -butane collaborates in the homogeneous distribution of the active ingredient in the matrix provided by the matrix forming agent.

In order to prepare a pre-formed solution of the active ingredient, the active ingredient is contacted with 1,3-bis (pyrrolidon-1-yl) -butane, usually with stirring. If desired, the solution can be heated to accelerate the dissolution or to improve the solubility of the active ingredient. Conveniently, the temperature is in the range between about 20 ° C to about 150 ° C, preferably about 20 ° C to about 100 ° C; higher temperatures are usually not advisable. Generally, the content of the active ingredient in the solution is below the value at which the solution is saturated. However, the active ingredient solution can also be saturated or even supersaturated, i. e., the active ingredient solution may contain the suspended or undissolved active ingredient.

The dosage forms according to the invention are preferably obtained by a method comprising:

a) dissolving the active ingredient in a sufficient amount of 1,3-bis (pyrrolidon-1-yl) -butane to obtain a solution of the active ingredient;

b) providing a powder composition comprising the matrix forming agent;

c) mixing the solution of the active ingredient in the powder composition to obtain a uniform granulate;

d) heating the uniform granulate at an elevated temperature to obtain a molten material; Y

e) allow the molten material to solidify, to obtain a solid dispersion product.

Alternatively, the dosage forms according to the invention were obtained by a method comprising:

a) heating the matrix forming agent at an elevated temperature to obtain a molten material of a matrix forming agent,

b) dissolve the active ingredient in a sufficient amount of 1,3-bis (pyrrolidon-1-yl) -butane to obtain a solution of the active ingredient,

c) adding the solution of the active ingredient to the molten material of the matrix forming agent, and

d) allow the molten material to solidify, to obtain a solid dispersion product.

Obviously, two or more active ingredients can be incorporated by mixing a first active ingredient (or a combination of the first active ingredient) in the composition of the agent that forms a sprayable matrix, heating, and adding a solution of a second active ingredient (or a combination of the second active ingredient) with the molten material.

"Fusion" means a transition in a liquid or gummy state, in which it is possible for a component that is embedded homogeneously in the other. Fusion usually involves heating above the softening point of the matrix forming agent such as a pharmaceutically acceptable polymer. The preparation of the molten material can take place in a variety of ways.

Usually, the melting temperature is in the range of 70 to 250 ° C, preferably 80 to 180 ° C, more preferably 100 to 140 ° C.

The active ingredients are used as a solution in an appropriate amount of 1,3bis (pyrrolidon-1-yl) -butane. This solution is mixed with and in the matrix forming agent either before or after the fusion of said matrix forming agent. Usually, the molten material is homogenized in order to disperse the active ingredient solution efficiently.

Various additives may be included in the molten material, for example flow regulators such as colloidal silica; lubricants, fillers, disintegrants, plasticizers, stabilizers such as antioxidants, light stabilizers, radical sequestrants or stabilizers against microbial attack.

The fusion and / or mixing takes place in an apparatus commonly used for this purpose. Particularly suitable are extruders or kneaders. Appropriate extruders include single screw extruders, geared screw extruders or more multi-screw extruders, preferably twin screw extruders, which can be co-rotating or countercurrent and optionally equipped with forming discs. It will be appreciated that the working temperatures will also be determined by the extruder class or the configuration class within the extruder that is used. Some of the energy needed to melt, mix and dissolve the components in the extruder can be provided by heating elements. However, friction and shearing of the material in the extruder can also provide the mixture with a substantial amount of energy and help the formation of a homogeneous fusion of the components.

Fusion ranges from pasty to viscous. Before allowing the molten material to solidify, the molten material can be molded in virtually any desired shape. The molding of the extrudate is conveniently carried out by a calender with two rollers against current with mutual pairing depressions on its surface. A wide range of tablet forms can be achieved using rollers with different forms of depression. Alternatively, the extrudate is cut into pieces, either before (hot cutting) or after solidification (cold cutting).

In a preferred embodiment, the molten material is extruded through a groove matrix to obtain a film. The film thus obtained is optionally stretched, axial or biaxial. The film can be cut to the desired size.

Optionally, the resulting solid dispersion product is milled or macerated to granules. The granules can then be compacted. Compaction means a process whereby a mass of dust comprising the granules is condensed under high pressure in order to obtain a compact with low porosity, for example a tablet. Compression of the dust mass is usually done in a compression press, more specifically in a steel die between two movement punches.

Preferably, at least one additive selected from flow regulators, disintegrants, thickening agents (fillers) and lubricants, is used in the compaction of the granules. The disintegrants promote rapid disintegration of the compact in the stomach and preserve the granules that are released separately from each other. Appropriate disintegrants are crosslinked polymers such as crosslinked polyvinyl pyrrolidone and crosslinked sodium carboxymethyl cellulose. Appropriate thickening agents (also referred to as "fillers") are selected from lactose, calcium hydrogen phosphate, microcrystalline cellulose (Avicel®), silicates, in particular silicon dioxide, talcum, potato or corn starch, and isomalt.

Appropriate flow regulators are selected from highly dispersed silica (Aerosil®), and animal or vegetable fats or waxes.

Preferably a lubricant is used in the compaction of the granules. Appropriate lubricants are selected from polyethylene glycol (for example, having an Mw between 1000 and 6000), magnesium and calcium stearates, sodium stearyl fumarate, and the like.

11 Several other additives can be used, for example dyes such as azo dyes, organic or inorganic pigments such as iron oxides or titanium dioxide, or dyes of natural origin; stabilizers such as antioxidants, light stabilizers, radical sequestrants and stabilizers against microbial attack. The dosage forms according to the invention can be provided as dosage forms consisting of several layers, for example multilayer or laminated tablets. They can be open or closed. "closed dosage forms" are those in which one layer is completely surrounded by at least one other layer. Multilayer forms have the advantage that two active ingredients that are incompatible with others can be processed and that the release characteristics of the active ingredient (s) can be controlled. For example, it is possible to provide an initial dose including an active ingredient in one of the outer layers, and a maintenance dose including the active ingredient in the inner layer (s). The types of multilayer tablets can be produced by compressing two or more layers of granules. Alternatively, multilayer dosage forms can be produced by a process known as "coextrusion." In essence, the process comprises preparing at least two different molten material compositions as explained above, and passing these molten compositions into a coupling co-extrusion die. The shape of the coextrusion die depends on the shape of the necessary drug. For example, dies with a flat die opening, called a slot die, and dies with an annular groove are appropriate. In order to facilitate the taking of said dosage form by a mammal, it is advantageous to give the dosage form an appropriate form. Large tablets that can be swallowed comfortably, therefore, are preferably elongated rather than round. A coating on the tablet also contributes to the ease with which it can be ingested. A coating also improves taste and provides an elegant appearance. If desired, the coating may be an enteric cover. The coating usually includes a material that forms a polymeric film such as hydroxypropyl methylcellulose, hydroxypropylcellulose, and acrylate or methacrylate copolymers. In addition to a polymer that forms a film, the coating can also comprise a plasticizer, for example polyethylene glycol, a surface active agent, for example a Tween® type, and optionally a pigment, for example titanium dioxide or iron oxides. The coating may also comprise talc as an anti-adhesive. The coating usually represents at least about 5% by weight of the dosage form. The following examples will serve to better illustrate the invention without limiting it. In examples 1 to 8, a dye (Sudan Red III) was used as a model compound in order to visualize the distribution of the compound in the solid dispersion product. It will be appreciated that biologically active ingredients can be processed in an essentially similar manner. Example 1 Sudan Red III was dissolved in 1,3-bis (pyrrolidon-1-yl) -butane at a concentration of 0.5% by weight. 5 parts by weight of the resulting deep red solution were mixed with 95 parts by weight of Kollidon VA 64 (N-vinyl pyrrolidone / vinyl acetate 60:40 copolymer). The mixture was granulated in a high-scale laboratory scale mixer. The granulate obtained in this way was fed into a co-rotating twin screw extruder and extruded at a temperature of 130 ° C. The extrudate solidified into a homogeneous, brittle, non-sticky light red mass. The glass transition temperature of the extrudate as determined by DSC was 86 ° C. Example 2

12 Example 1 was repeated, except that 10 parts by weight of Sudan Red solution and 90 parts by weight of Kollidon VA 64 were used. Again, a homogeneous, brittle, non-sticky light red mass was obtained. The glass transition temperature of the extrudate as determined by DSC was 76 ° C Example 3 Example 1 was repeated, except that 15 parts by weight of the Sudan Red solution and 85 parts by weight of Kollidon VA 64 were used. Again, a homogeneous, brittle, non-sticky light red mass was obtained. The glass transition temperature of the extrudate as determined by DSC was 58 ° C. Example 4 Example 1 was repeated, except that 20 parts by weight of a Sudan Red solution and 80 parts by weight of Kollidon VA 64 were used. Again, a homogeneous, brittle, non-sticky light red mass was obtained. The glass transition temperature of the extrudate as determined by DSC was 49 ° C. Example 5 Example 1 was repeated, except that 30 parts by weight of Sudan Red solution and 70 parts by weight of Kollidon VA 64 were used. The extrusion of the molten material was carried out at a temperature of 110 ° C. A homogeneous, brittle, slightly sticky light red mass was obtained. The glass transition temperature of the extrudate as determined by DSC was 24 ° C. Example 6 Sudan Red III was dissolved in 1,3-bis (pyrrolidon-1-yl) -butane at a concentration of 0.5% by weight. 20 parts by weight of the resulting deep red solution were mixed with 80 parts by weight of Kollidon 25 (N-vinyl pyrrolidone homopolymer). The mixture was granulated in a high-scale laboratory scale mixer. The granulate obtained in this way was fed into a co-rotating twin screw extruder and extruded at a temperature of 110 ° C. The extrudate solidified into a homogeneous, brittle, non-sticky light red mass. The glass transition temperature of the extrudate as determined by DSC was 74 ° C. Example 7 Sudan Red III was dissolved in 1,3-bis (pyrrolidon-1-yl) -butane at a concentration of 0.5% by weight. 10 parts by weight of the resulting deep red solution were mixed with 90 parts by weight of Klucel EF (hydroxypropyl cellulose). The mixture was granulated in a laboratory scale high-shear mixer. The granulate obtained in this way was fed into a co-rotating twin screw extruder and extruded at a temperature of 110 ° C. The extrudate solidified into a homogeneous, elastic, non-sticky light red mass. The glass transition temperature of the extrudate as determined by DSC was 1 ° C. Example 8 Example 7 was repeated, except that 20 parts by weight of Sudan Red solution and 80 parts by weight of Klucel EF were used. The extrusion of the molten material was carried out at a temperature of 100 ° C. A homogeneous, elastic, slightly sticky light red mass was obtained. The glass transition temperature of the extrudate as determined by DSC was -10 ° C. Example 9 Tramadol hydrochloride (2.5 g) was dissolved in 1,3-bis (pyrrolidon-1-yl) -butane (7.5 g) with gentle heating. 5 g of the resulting solution were mixed with 25 g of Kollidon VA 64 in a laboratory mill (IKA blade mill) to obtain a homogeneous granulate. The composition

of the granulate was: 4.2% by weight of tramadol hydrochloride, 12.5% by weight of 1,3-bis (pyrrolidon-1-yl) -butane, and 83.3% by weight of Kollidon VA 64.

The granulate was fed into a laboratory twin screw extruder and extruded at a temperature of 120 ° C. Crystalline tramadol hydrochloride could not be detected in the clear solidified extrudate by DSC, indicating that tramadol hydrochloride was present exclusively in a non-crystalline state.

Example 10

Example 9 was repeated, however, tramadol hydrochloride, 1,3-bis (pyrrolidon-1-yl) butane, and Kollidon VA 64 were mixed and granulated as such, i. and. without dissolving the active ingredient in 1,3-bis (pyrrolidon-1-yl) -butane in advance. Crystalline tramadol hydrochloride could not be detected in the clear solidified extrudate by DSC, indicating that tramadol hydrochloride was present exclusively in a non-crystalline state.

Example 11 (Comparison)

A homogeneous spray mixture of 4.2% by weight of tramadol hydrochloride, and 95.8% by weight of Kollidon VA 64, was fed into the twin screw extruder as used in Examples 9 and 10. At 120 ° C , extrusion falls due to extremely high torque. Could not prepare molten material.

Example 12 (Comparison)

A homogeneous spray mixture of 4.2% by weight of tramadol hydrochloride, and 95.8% by weight of Kollidon VA 64 was fed into the twin screw extruder as used in Examples 9 and 10. The extrusion was carried out. out at 125 ° C. A cloudy molten material was obtained (as opposed to the clear molten material obtained in examples 9 and 10). The turbidity of the molten material indicates that the molten material still contains undissolved particles or aggregates.

Example 13 (Comparison)

A homogeneous spray mixture of 4.2% by weight of tramadol hydrochloride and 95.8% by weight of Kollidon VA 64 was fed into the twin screw extruder as used in Examples 9 and 10. Extrusion was carried out. at 140 ° C. A cloudy molten material was obtained. The turbidity of the molten material indicates that the molten material still contains undissolved particles or aggregates.

REFERENCES CITED IN THE DESCRIPTION

5 This list of references cited by the applicant is only for the convenience of the reader. It is not part of the European patent document. Even though great care has been taken in collecting references, errors or omissions cannot be excluded and the EPO disclaims all responsibility in this regard.

Patent documents cited in description 10 • EP 240904 A [0005]

•

EP 240906 A [0005]

•

EP 337256 A [0005]

•

WO 9810752 A [0007]

•

WO 9815291 A [0008] [0023]

15 • DE 19641436 [0010] Non-patent literature cited in the description

•

Breitenbach, J. et al. Pharmaceutical Research, 1999, vol. 16 (7), 1109-1113 [0009]

•

Introduction to Physical Polymer Science. John Wiley & Sons, Inc, 1992 [0025]

• Polymer Handbook. John Wiley & Sons, Inc, 1975 [0025] 20 • American Industrial Hygiene Association Journal, 1996, vol. 57, 3342 [0032]

Claims (14)

 Claims

one.

A composition comprising a solid or semi-solid matrix, which has at least one active ingredient uniformly dispersed therein, the matrix comprising at least one pharmaceutically acceptable agent that forms a matrix selected from pharmaceutically acceptable polymers having a glass transition temperature Tg between 50 ° and 180 ° C; Y

1,3-bis (pyrrolidon-1-yl) -butane, wherein the matrix contains less than 6% by weight of water or any compound that is liquid at room temperature and has a higher volatility than water, and where the solubility of the active ingredient in water at 25 ° C is less than 1g / 100ml.

2.

The composition of claim 1, wherein the matrix comprises, in relation to the weight of the matrix, about 1 to 30% by weight of 1,3-bis (pyrrolidon-1-yl) -butane and about 50 to 98 % by weight of one or more matrix forming agents, and about 1 to 49% by weight of an active ingredient or a combination of active ingredients.

3.

The composition of claim 1 or 2, wherein the active ingredient is dispersed in the matrix in a state of a solid solution.

Four.

The composition of any one of claims 1 to 3, wherein the pharmaceutically acceptable polymer is selected from the group consisting of homopolymers of N-vinyl lactams,

copolymers of an N-vinyl lactam and one or more comonomers selected from monomers containing nitrogen and oxygen-containing monomers, cellulose esters and cellulose ethers, high molecular weight polyalkylene oxides, polyacrylates and polymethacrylates, oligo-and polysaccharides, poly (hydroxy acids), or mixtures thereof. 5. The composition of claim 4, wherein the pharmaceutically acceptable polymer is selected from polyvinylpyrrolidone, a copolymer of N-vinyl pyrrolidone and a vinyl carboxylate, a hydroxyalkylcellulose, to hydroxyalkylalkylcellulose, poly (lactic acid), poly (glycolic acid), poly (3-hydroxybutyrate), poly (3-hydroxyvalerate), poly (3-hydroxybutyrate-co-3-hydroxyvalerate), or mixtures thereof.

6.

The composition of claim 5, wherein the pharmaceutically acceptable polymer is selected from a copolymer of N-vinyl pyrrolidone and vinyl acetate and hydroxypropyl cellulose.

7.

The composition of any of the preceding claims, wherein the active ingredient is selected from meloxicam and telmisartan.

8.

The composition of any of the preceding claims, wherein the matrix additionally comprises at least one additive selected from the group consisting of surface active agents, flow regulators, disintegrants, thickening agents, lubricants, effervescent agents, colorants, flavorings.

9.

A dosage form comprising, or consisting of, the composition of any of the preceding claims.

10. A method of preparing a composition of claim 1 comprising: 15 a) dissolving the active ingredient in a sufficient amount of 1,3-bis (pyrrolidon-1-yl) -butane to obtain a solution of the active ingredient; b) providing a powder composition comprising the matrix forming agent; c) mixing the solution of the active ingredient in the powder composition to obtain a uniform granulate; d) heating the uniform granulate at an elevated temperature to obtain a molten material; and e) allow the molten material to solidify to obtain a solid dispersion product.

eleven.

A method of preparing a composition of claim 1, comprising: a) heating the matrix forming agent at an elevated temperature to obtain a molten material of the matrix forming agent; b) dissolve the active ingredient in a sufficient amount of 1,3-bis (pyrrolidon-1-yl) -butane to obtain a solution of the active ingredient; c) adding the solution of the active ingredient to the molten material of the agent that forms a

matrix; and d) allow the molten material to solidify, to obtain a solid dispersion product.

12.

The method of claim 10 or 11, further comprising milling said solid dispersion product.

13.

The method of claim 12, further comprising compression of said solid dispersion product in a tablet.

14.

The method of claim 13, further comprising the application of a coating film to the tablet.