Composition and dosage form containing solid or semisolid matrix

FIELD: medicine, pharmaceutics.

SUBSTANCE: composition for medical use contains a solid or semisolid matrix, at least one active ingredient uniformly dispersed therein. The matrix contains at least one pharmaceutically acceptable matrix-forming agent and compound 1,3-bis(lactamyl)butane, especially 1,3-bis(pyrrolidone-1-yl)butane. The active component has water-solubility less than 1 g/100 ml at 25°C. The active ingredient is preferentially dispersed in a matrix as a solid solution. The matrix-forming agent is chosen from a group of alcohol sugars, alcohol sugar derivatives, pharmaceutically acceptable polymers and their mixtures. The composition is used for preparing the pharmaceutical dosage forms for oral administration of the active ingredients.

EFFECT: composition provides higher bioavailability of poorly water-soluble active ingredient due to its presence in the composition in a non-crystalline state.

19 cl, 13 ex

The present invention relates to compositions containing solid or semi-solid matrix having at least one active ingredient uniformly dispersed therein to contain a matrix of the pharmaceutical form and the method of their preparation.

Measure the potential suitability of the oral dosage form of the pharmaceutical agent is its bioavailability observed after oral administration of the mentioned dosage forms. The bioavailability of the drugs in his oral intake can be influenced by various factors. These factors include solubility, drug absorption in the gastrointestinal tract, drug efficacy and the primary effect. One of the most important of these factors is the solubility. Unfortunately, many active ingredients are typically characterized by poor solubility.

For many reasons, such as the regimen of the patient and the sense of taste, solid dosage form is generally preferred over liquid dosage form. However, in most cases, solid oral dosage forms of medicines offer a lower bioavailability than the oral solution of the drug.

Attempts were made to improve biological dost is pnasty, provide solid dosage forms through the production of solid dispersions and solid solutions of the drug. Preferred physical systems are solid solutions, as their components are easily form a liquid solution in contact with a liquid medium, such as gastric juice. This increased willingness to dissolution may be attributed, at least partially, to the fact that the energy required for dissolution of the components of the solid solution, is less than the energy required for dissolution of the components of the crystalline or microcrystalline solid phase.

Since some time already known continuous method of producing solid pharmaceutical forms, including products in the form of solid solution, including the transformation of the melt polymer binder containing the active ingredients and does not contain solvents, the desired dosage form injection molding or extrusion and subsequent giving her forms (see, for example, European patents EP-A-240904, EP-A-240906 and EP-A-337256). Satisfactory results in this way we obtain in the case when the active ingredient has a low melting temperature and/or high solubility in molten polymeric binder. Active ingredients having a low melting point szhizhajut the ri contact with the melt polymer binder, and liquid active ingredient can be easily dispersed in the melt of a polymeric binder. Alternatively, the active ingredients having a high solubility in molten polymeric binder that is easily dissolved in the melt of a polymeric binder.

Problems occur when the active ingredient has a high melting point and/or of limited solubility in molten polymeric binder. Adequate dispersion of the active ingredient may require high temperatures, a relatively long mixing and/or high shear forces to achieve sufficient mixing the active ingredient with a molten polymeric binder. This can lead to local overheating and damage to the product, especially when used active ingredient sensitive to shear effects, and temperature.

In the international patent application WO 98/10752 describes a method for solid dosage forms in which the mixed polymer binder, if necessary, the active ingredient and additives and ekstragiruyut. The proposal dissolution temperature-sensitive active ingredients in the solvent and the introduction of the solution with the solvent in an extruder. This method requires removal of the solvent from the melt by evaporation in ek is tradere.

International patent application WO 98/15291 refers to the use of 1,3-bis(pyrrolidone-1-yl)butane and other 1,3-bis(lactamin)propanol as a solvent in pharmaceutical and cosmetic agents.

There is a continuous need for the development of oral solid dosage forms with appropriate oral bioavailability and stability and adapted to the active ingredients having a high melting point and/or of limited solubility in molten polymeric binder.

It is known that 1,3-bis(lactamin)butane have a high ability to dissolve many of the active ingredients. Now quite unexpectedly been discovered that a significant amount of 1,3-bis(lactamin)butane can be entered in a matrix of solid dosage forms, without compromising the mechanical properties and the ability to store the mentioned dosage forms. Thus, the invention allows to enter the active ingredients dissolved in a liquid state into a solid or semi-solid matrix and distributed by removing the solvent.

According to the invention features a composition comprising a solid or semi-solid matrix having at least one uniformly distributed in the active ingredient, the matrix contains at least one pharmaceutically acceptable arr is based on the matrix agent and the compound of formula (I):

where n is an integer from 3 to 5.

The composition according to the invention comprises a solid or semi-solid matrix having at least one active ingredient uniformly distributed in it. The term "semi-solid matrix implies a stagnant system, which can lose its shape under the force of the impact.

"Solid matrix" is usually brittle and breaks into pieces deforming under the impact.

According to the invention it is also proposed dosage form, preferably a solid dosage form containing the above-mentioned composition (or consisting of).

To facilitate manipulation of the semi-solid matrix may require the outer shell, fully covering the semi-solid matrix, such as coating or capsule shell, such as soft or hard gelatin capsule shell.

On the other hand, the solid matrix can be given the desired shape, and it can be used as a dosage form as such. Alternatively, the solid matrix can be milled and compressed into tablet form. As another alternative, the solid matrix can be subjected to grinding (grinding), and the milled product may be enclosed in the capsule.

One or more active ingredients renominalisation in the matrix. This includes systems having small particles of the active ingredient, typically less than 1 micron in diameter, distributed in a matrix phase. These systems do not contain any significant quantities of the active ingredients in their crystalline or microcrystalline state, as shown by thermal analysis (differential scanning calorimetry, DSC) or x-ray diffraction analysis (WAXS). Usually, at least 98 wt.% of the total amount of active ingredient present in the amorphous state.

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

The compound of formula (I) acts as a non-volatile solvent for the active ingredient and possibly other ingredients. Preferably, the matrix, essentially, does not contain non-volatile solvents (solvents with lower volatility than water)that are different from the compounds of formula (I). Usually the matrix contains less than 6 wt.%, preferably, less than 3 wt.% and, most preferably, less than 2 wt.% non-volatile solvent, other than the connection Faure the uly (I).

The matrix does not contain significant amounts of volatile solvents. The term "volatile solvent" means water and any substance that is liquid at room temperature and has a higher volatility than water. Usually the matrix contains less than 6 wt.%, preferably, less than 3 wt.% and, most preferably, less than 2 wt.% volatile solvent.

With regard to the total mass content of active (active) ingredient (ingredient) and other components that make up the matrix, the preferred compositions according to the invention contain a matrix, consisting of:

from about 1 to 30 wt.% (preferably, from 5 to 25 wt.%) the compounds of formula (I),

from about 50 to 98 wt.% (preferably, from 60 to 90 wt.%) forming a matrix agent (or combination of such forms the matrix agents),

from about 1 to 49 wt.% (preferably, from about 1 to 30 wt.%) the active ingredient or combination of active ingredients,

from 0 to 25 wt.% (preferably, 1 to 15 wt.%) additives.

Obtaining compounds of formula (I) is described in detail in international patent application WO 98/15291, the contents of which are incorporated herein by reference.

Especially preferred are the following compounds:

1,3-bis(1-pyrrolidinyl)butane,

1,3-bis(1-piperidyl)butane,

1,3-bis(1-caprolactone)butane,

1-(1-caprolactone)-3-(1-piperidyl)butane,

-(1 caprolactone)-1-(1-piperidyl)butane,

1-(1-caprolactone)-3-(1-pyrrolidinyl)butane,

3-(1-caprolactone)-1-(1-pyrrolidinyl)butane,

1-(1-piperidinyl)-3-(1-pyrrolidinyl)butane,

3-(1-piperidinyl)-1-(1-pyrrolidinyl)butane.

Preferably, the compound of formula (I) is 1,3-bis(1-pyrrolidone-1-yl)butane.

Forming a matrix agent may be any agent capable of seize or to gelatinize from the liquid state, i.e. from molten or dissolved state, with the formation of a continuous matrix. If it is desirable solid matrix, forming a matrix agent is chosen so as to form a continuous matrix with a sufficient mechanical stability. Of course, can be used in the mixture forming the matrix agents.

Suitable forming the matrix agents are selected from sugar alcohols, such as mannitol, sorbitol, xylene;

derivatives, sugar alcohols such as isomalt, hydrogenated condensed palatinose (as described in German patent DE-A 10262005);

the maltodextrins.

Preferably, forming the matrix agent is a pharmaceutically acceptable polymer or a mixture of pharmaceutically acceptable polymers. Typically, pharmaceutically acceptable polymers are water-soluble or at least photodisplaytype.

Typically, pharmaceutically acceptable polymer used is output according to the invention, has a glass transition temperature T_gat least +40°C, preferably at least about +50°C., most preferably from about 50°C. to 180°C.

Methods for the determination of glass transition temperature T_gorganic polymers are described in "Introduction to Physical Polymer Science", 2-nd Edition by L.H. Sperling published by John Wiley &Suns, Inc., 1992. The value of T_gcan be calculated from a weighted sum of the Tg values of the homopolymers derived from each of the individual monomers i, forming the polymer, i.e. T_g=ΣW_iX_iwhere W represents the weight percentage of the monomer in the organic polymer, and X is a value of T_ghomopolymer derived from monomer i. The values of glass transition temperature T_gthe homopolymers are listed in Polymer Handbook", 2nd Edition by J. Brandrup and E. H. Immergut, Editors, published by John Wiley &Suns, Inc., 1975.

Pharmaceutically acceptable polymers having a Tg, as defined above, allow to obtain a solid dispersion, mechanically stable and sufficiently stable under normal temperatures, resulting in the named solid dispersion can be used as dosage forms without additional processing or may be compressed into tablets using only a small number of auxiliary tabletiruemyh funds.

Included in the composition pharmaceutically acceptable the second polymer is a polymer which has an apparent viscosity, when dissolved in an aqueous solution at a temperature of 20°C and a concentration of 2% (wt./about.) from 1 to 50000 MPa·s, more preferably from 1 to 10000 MPa·s and most preferably from 5 to 100 MPa·S. Preferred pharmaceutically acceptable polymers may be selected, for example, from the group including:

the homopolymers of N-vinylation, especially polyvinylpyrrolidone (PVP);

copolymers of N-vinylation and one or more comonomers capable of copolymerisate with them, and the comonomers are selected from among nitrogen-containing monomers and oxygen-containing monomers, in particular a copolymer of N-vinylpyrrolidone and vinylcarbazole, preferred examples of which are a copolymer of N-vinylpyrrolidone and vinyl acetate or a copolymer of N-vinylpyrrolidone and finalproject;

esters and ethers of cellulose, in particular methylcellulose and ethylcellulose; hydroxyethylcellulose, especially hydroxypropylcellulose; hydroxyethylmethylcellulose, especially hypromellose; phthalates or succinate cellulose, especially acatitla cellulose phthalate of hydroxypropylmethylcellulose, succinate of hydroxypropylmethylcellulose or atsetobutirattselljuloznye;

graft copolymers of polyvinyl alcohol and polyethylene glycol (supplied under the Naim is a Finance Kollicoat®) IR from BASF AG, Ludwigshafen, Germany);

high polyalkylene, such as polyethylene oxide and polypropyleneoxide, and copolymers of ethylene oxide and propylene oxide;

the polyacrylates and polymethacrylates such as methacrylic acid and ethyl acrylate, copolymers of methacrylic acid and methylmethacrylate, copolymers of butyl methacrylate and 2-dimethylamino-ethyl methacrylate, polyhydroxyalkanoate and polyhydroxyethylmethacrylate;

polyacrylamides;

polymers of vinyl acetate, such as copolymers of vinyl acetate and cretonne easy acid, partially hydrolyzed polyvinyl acetate (also known as partially stylenny "polyvinyl alcohol");

polyvinyl alcohol;

PHAs, such as polylactic acid, polyglycolic acid, poly(3-hydroxybutyrate) and copolymers of poly(3-hydroxy-butyrate-3-hydroxyvalerate) or mixtures of one or more of them.

Preferred among these are the homopolymers or copolymers of N-vinylpyrrolidone, especially a copolymer of N-vinylpyrrolidone and vinyl acetate. Particularly preferred polymer is a copolymer of 60 wt.% copolymer of N-vinylpyrrolidone and 40 wt.% copolymer of vinyl acetate.

Another example of a particularly preferred polymer is hydroxypropylcellulose.

Used in the implementation of the present invention the active ing eventy are biologically active agents and include biologically active agents, providing local physiological effects, as well as those who have systemic exposure after oral administration. The invention is particularly suitable for water-insoluble or poorly water-soluble (or "lipophilic") connections. The compounds are water-insoluble or poorly water-soluble, if their solubility in water at 25°C. is less than 1 g/100 ml

The product is solid dispersions usually get method, known as extrusion from the melt. To achieve a homogeneous distribution and a sufficient degree of dispersion of the active ingredient in the melt containing the active ingredient, soak in the heated tank extruder for extruding the melt in sufficient time. So as to obtain the composition according to the invention using a pre-formed solution of the active ingredient, while staying active ingredient in the extruder can be reduced significantly. Thus, the invention is particularly adapted to the formation of active ingredients which are sensitive to thermal decomposition.

The invention significantly reduces the need for processing powders of the active ingredients, is prone to dust. Dust can pose significant harm to the health of the personnel of the production site the activities, especially when it comes to highly active ingredients. In the journal American Industrial Hygiene Association Journal 57: 3342 (1996) active substances are divided into categories of hazard impacts on human health (PB-ECL, performance-based exposure control Limit based on the extent to which the impact is harmful to human health. PB-ECL category range from PB-ECL-1 (low degree of acute complications, absence of chronic complications) to PB-ECL-5 (high acute complications chronic complications). The invention is particularly useful for active ingredients related to PB-ECL category 3, 4 or 5, and in particular to PB-ECL category 4 or 5.

Examples of suitable active substances, is not limited to these examples, are:

analgesics and anti-inflammatory drugs such as NSAID, fentanyl, indomethacin, ibuprofen, Ketoprofen, nabumetone, paracetamol, piroxicam, meloxicam, tramadol and MOR-2 inhibitors, such as celecoxib and rofecoxib;

antiarrhythmic drugs, such as procainamide, quinidine and verapamil;

antibacterial and Antiprotozoal agents, such as amoxicillin, ampicillin, benzatinpenicilline penicillin, cefaclor, cephalo-Smoking, cefprozil, cefuroxime aksetil, cephalexin, chloramphenicol, chloroquine, ciprofloxacin, clarithromycin, clavulanic acid, to indamycin, doxycycline, erythromycin, sodium, Flucloxacillin, halofantrine, isoniazid, kanamycin sulfate, lincomycin, mefloquin, minocycline, nafcillin sodium salt, Kalinicheva acid, neomycin, norfloxacin, ofloxacin, oxacillin, phenoxymethyl-penicillin potassium salt, pyrimethamine-sulfadoxine and streptomycin;

anticoagulants, such as warfarin;

antidepressants, such as amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dothiepin, doxepin, fluoxetine, reboxetine, amineptine, selegiline, Garion, imipramine, lithium carbonate, mianserin, milnacipran, nortriptyline, paroxetine, sertraline and 3-[2-[3,4-dihydrobenzofuran[3,2-C]pyridine-2-(1H)-yl]ethyl]-2-methyl-4H-pyrido-[1,2-a]pyrimidine-4-one;

antidiabetic drugs such as glibenclamide and Metformin;

protevoepilepticeski medicinal substances, such as carbamazepine, clonazepam, ethosuximide, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, primidone, tiagabine, topiramate, valproic and vigabatrin;

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

antihistamines, such as astemizole, Cinnarizine, cyproheptadin, descarboethoxyloratadine, Fexofenadine, lunaris is h, levocabastine, loratadine, erastamisel, oxatomide, promethazine and terfenadine;

antihypertensive drugs, such as captopril, enalapril, ketanserin, lisinopril, Minoxidil, prazosin, ramipril, reserpine, terazosin and telmisartan;

antimuskarinovoe act occurs agents, such as atropine sulfate and hyoscine;

antitumor and antimetabolites agents such as platinum compounds such as cisplatin and carboplatin; taxanes such as paclitaxel and docetaxel; tekani, such as camptothecin, irinotecan and topotecan; vinca alkaloids such as vinblastine, vindesin, vincristine and vinorelbine; derivatives nuleotide and folic acid antagonists such as 5-fluorouracil inside the body, capecitabine, gemcitabine, mercaptopurine, tioguanin, cladribine and methotrexate; alkylating agents such as nitrogen mustards (nitrogen mustards, such as cyclophosphamide, chlorambucil, Hermelin, ifosfamide, melphalan or nitrosoanatabine, for example, carmustin, lomustin or other alkylating agents such as busulfan, dacarbazine, procarbazine, thiotepa; antibiotics such as daunorubicin, doxorubicin, idarubitsin, epirubicin, bleomycin, dactinomycin and mitomycin; HER-2 antibodies, such as trastuzumab; derivatives podofillotoksina, such as etoposide and teniposide; inhibitors transfer gamezilla; derivatives of anthraquinone, such as mitacs intron;

caused medicinal substances, such as alniditan, naratriptan and sumatriptan;

medicinal agents against Parkinson's disease, such as parlodel mesilate, levodopa and selegiline;

protivomicrobnye, hypnotic and sedative agents, such as alprazolam, buspirone, chlordiazepoxide, chlorpromazine, clozapine, diazepam, flupentixol, fluphenazine, flurazepam, 9-hydroxy-risperidone, lorazepam, motaparthy, olanzapine, oxazepam, pimozide, pipamperone, piracetam, promazine, risperidone, selfotel, seroquel, sertindole, sulpiride, temazepam, thiothixene, triazolam, trifluperidol, ziprasidone and zolpidem;

anti-stroke, such as lubeluzole, lubeluzole oxide, riluzole, aptiganel, eliprodil and remacemide;

antitussive agents, such as dextromethorphan and levodropropizine;

antiviral agents such as acyclovir, ganciclovir, lowered, teveren, zidovudine, lamivudine, zidovudine/lamivudine, didanosine, zalcitabine, stavudine, abacavir, lopinavir, APV, nevirapine, efavirenz, delavirdine, indinavir, nelfinavir, ritonavir, saquinavir, adefovir and hydroxyurea;

the β-adrenergic blockers, such as atenolol, carvedilol, metoprolol, nebivolol and propanolol;

cardiac inotropic agents, such as amrinone, digitoxin, digoxin, milrinone;

corticos erode, such as beclomethasone, dipropionate, betamethasone, budesonide, dexamethason, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone;

disinfecting agents, such as chlorhexidine;

diuretics such as acetazolamide, furosemide, hydrochlorothiazide and isosorbide;

enzymes;

essential oils, such as anethole, anise oil, caraway, cardamom, butter Alexandria leaf (Cassia oil), cineole, cinnamon oil, clove oil, coriander oil, demetalization oil, mint oil, dill oil, eucalyptus oil, eugenol, ginger, lemon oil, mustard oil, neroli oil (oil of wild orange colors), oil of nutmeg, orange oil, peppermint oil, sage, spearmint leaf, terpineol and thyme oil;

gastrointestinal agents such as cimetidine, cisapride, clebopride, Diphenoxylate, domperidone, famotidine, lanzoprazol, loperamide, loperamide oxide, mesalazin, metoclopramide, mosapride, nizatidine, norcisapride, olsalazine, omeprazole, pantoprazole, perprazole, prucalopride, raberprazole, ranitidine, ridogrel and sulfasalazin;

hemostatic, such as aminocaproic acid;

lipitorhoodia (gipolipidemicheskie) agents, such as atorvastatin, fenofibrate, fenofibrinova acid, lovastatin, pravastatin, probucol and simvastatin;

localanesthetic means, such as benzocaine, lignocaine;

bioanalytica, such as buprenorphine, codeine, dextromoramide, Dihydrocodeine, hydrocodone, oxycodone and morphine;

parasympathomimetic and protivogelmintnye medicinal substances, such as AT-082, eptastigmine, galantamine, metrifonate, milameline, neostigmine, physostigmine, taken, donepezil, rivastigmine, sabcomeline, talsaclidine, xanomeline, memantine and lazabemide;

peptides and proteins, such as antibodies, becaplermin, cyclosporine, tacrolimus, erythropoetin, immunoglobulins and insulin;

sex hormones, such as estrogens: conjugated estrogens, ethinyl estradiol, mestranol, estradiol, estriol, estrone; POCs; chlormadinone acetate, cyproterone acetate, 17-diacetyl-norgestimate, desogestrel, dienoguest, dydrogesterone, ethynodiol diacetate, gestodene, 3-ketodesogestrel, levonorgestrel, lynestrenol, medroxy-progesterone acetate, megestrol, norethindrone, norethindrone acetate, norethisterone, norethisterone acetate, norethynodrel, norgestimate, norgestrel, norgestrienone, progesterone and quingestanol acetate;

stimulating agents, such as sildenafil;

vasodilatory, such as amlodipine, buflomedil, amyl nitrate, diltiazem, dipyridamole, glyceryl trinitrate, the isosorbide dinitrate treatment, lidoflazine, molsidomin, nicardipine, nifedipine, oxpentifylline and pentaerythritol tetranitro is t;

their N-oxides, their pharmaceutically acceptable acidic and basic additive salts and their stereochemical isomeric form.

Pharmaceutically acceptable acid additive salts include such forms, which can be obtained in the usual manner by processing the basic form of the active ingredient corresponding organic or inorganic acid.

Active ingredients containing acidic protons may be converted into the form of their nontoxic additive metal or amine salt by treatment with appropriate organic or inorganic bases.

The term "additive salt" also includes the additive form of the hydrates and solvents, which are capable of forming active ingredients. Examples of such forms are, for example, hydrates, alcoholate, and the like.

The N-oxide forms of the active ingredients include active ingredients, in which one or more atoms of nitrogen oxidized to the so-called N-oxide.

The term "stereochemical isomeric form" refers to all the possible stereoisomeric forms which can have the active ingredients.

In particular, stereogenic centers may have the R - or S-configuration, and active ingredients containing one or more double bonds, can have the E - or Z-configuration.

The invention especially as optiwave to receive dosage forms, including active ingredients, having a relatively high melting point, for example the melting point of 170°C and above. Typical examples of them include meloxicam and telmisartan.

The matrix of the dosage form may contain one or more additives selected from pharmaceutically acceptable surfactants, regulators fluidity, disintegrators, fillers and lubricants.

Used herein, the term "pharmaceutically acceptable surfactant" refers to pharmaceutically acceptable non-ionic surfactant. Introduction surfactants are particularly preferred for matrices containing poorly water-soluble active ingredients. Surfactant may contribute to the instantaneous emulsification of the active ingredient released from the dosage form, and to prevent precipitation of the active ingredient in an aqueous liquid medium of the gastrointestinal tract.

Preferred surfactants are selected from:

polyoxyethyleneglycol ethers, for example polyoxyethyleneglycol ether (3), polyoxyethyleneglycol ether (5), polyoxyethyleneglycol simple ether (2), polyoxyethyleneglycol simple ether (5), polyoxyethyleneglycol ethers, e.g. polyoxyethyleneglycol simple ether (2), polyoxyethyleneglycol simple ether (3), polyoxyethyleneglycol simple ether (4) or polyoxyethyleneglycol simple ether (3);

a complex of polyethylene glycol ethers of fatty acids, such as PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate or PEG-300 dioleate;

complex alkalophilic of monoamino fatty acids, for example of propilenglikolmonostearata (Lauroglycol®);

esters of sucrose and fatty acids such as sucrose monostearate, distearate sucrose, monolaurate sucrose or dilaurate sucrose;

sorbitolovy complex monoamino fatty acids, such as sorbitanoleat (Span® 200), servicemanual, servicemanagement (Span® 40) or servicestart;

derivatives polyoxyethylene castor oil, such as polyoxyethylenesorbitan or polysilicone castor oil 35 (Cremophor® EL, BASF Corp.) or polyoxyethylenesorbitan, such as peg-40 hydrogenated castor oil (Cremophor® RH 40) or polyethyleneglycol 60 hydrogenated castor oil (Cremophor® RH 60) or block copolymers of ethylene oxide and propylene oxide, known as polyoxyethylenesorbitan block copolymers or policyactioninpolicyrule-glycol, such as Poloxamer® 124, Poloxamer® 188, Poloxamer® 237, Potoxamr® 388 or Poloxamer® 407 (BASF Wyandotte Corp.) or

complex monetary fatty acids, and polyoxyethylene(20)sorbitane, such as monooleate polyoxyethylene(20)sorbitan (Tween® 80), monostearate polyoxyethylene(20)sorbitan (Tween® 60), monopalmitate polyoxyethylene(20)sorbitan (Tween@ 40), monolaurate polyoxyethylene(20)sorbitan (Tween® 20), or mixtures of one or more of them.

Dosage forms according to the invention may contain at least one conventional additive, such as fluidity regulators, lubricants, fillers and disintegrators.

For solid dosage forms according to the invention can be used in various ways. These methods generally involve the formation of a solution of active ingredient in a sufficient amount of the compounds of formula (I) to obtain a solution of the active ingredient. In a preferred embodiment of the invention a pre-formed solution of the active ingredient (which may contain some or all of the possible ingredients) connect with an agent forming a matrix, and the mixture is heated to obtain a melt. Alternatively, a solution of the active ingredient is formed in situ by the combination of active ingredient in the solid state, for example in the crystalline state, a sufficient amount of the compounds of formula (I), agent, forming a matrix, and any possible ingredients and heating the resulting mixture to the floor is placed a homogeneous melt. It is assumed that in the process of mixing and heating the active ingredient enters the dissolved state in the compound of formula (I). Thus, the presence of the compounds of formula (I) promotes a homogeneous distribution of the active ingredient in the matrix in the presence of forming a matrix agent.

The compounds of formula (I) are liquid at room temperature or become liquid after weak heating. With the aim of obtaining a pre-formed solution of the active ingredient the active ingredient is brought into contact with the liquid compound of formula (I), typically with stirring. If necessary, the solution can be heated to accelerate the dissolution or increase the solubility of the active ingredient. Usually the temperature is in the range from about 20 to about 150°C., preferably from about 20 to about 100°C. a higher temperature is generally not recommended. The concentration of active ingredient in solution usually does not reach the value at which the solution becomes saturated. However, the solution of the active ingredient may also be saturated or even supersaturated, i.e. the solution of the active ingredient may contain suspended or dissolved active ingredient.

Dosage forms according to the invention, preferably, the receiving method including:

a) the solution is the active ingredient in a sufficient amount of the compounds of formula (I) to obtain a solution of the active ingredient;

b) preparation of a powder composition containing forming a matrix agent;

c) the adulteration of the solution of active ingredient in the powdered composition to obtain a homogeneous granulate;

d) heating the homogeneous granulate to elevated temperature to obtain a melt and

e) curing the melt to obtain a solid product dispersion.

Alternatively, the dosage form according to the invention produced by the method including:

a) heating forming a matrix agent to an elevated temperature to obtain a melt forming a matrix agent;

b) dissolving the active ingredient in a sufficient amount of the compounds of formula (I) to obtain a solution of the active ingredient;

c) adding a solution of the active ingredient to melt forming a matrix agent and

d) curing the melt to obtain a solid product dispersion.

It is obvious that two or more active ingredients may be introduced by the adulteration of the first active ingredient (or the first combination of the active ingredient in powdered composition forming a matrix agent, by heating and the addition of a solution of the second active ingredient (or second combination of the active ingredient) to melt.

"Fusion" means the transition in liquid or kauchukopodobnoe state, in the cat the rum is possible homogeneous introduction of one component to another. Fusion usually requires heating above the softening temperature forming a matrix agent, such as a pharmaceutically acceptable polymer. Receiving a melt can occur in different ways.

Typically, the melting temperature is in the range from 70 to 250°C., preferably from 80 to 180°C. and, most preferably, from 100 to 140°C.

Active ingredients used in the form of a solution in an appropriate amount of compounds of formula (I). This solution is mixed with forming a matrix agent, or admixed thereto either before melting, or after melting forming a matrix agent. Typically, the melt is homogenized for effective dispersion solution of the active ingredient.

In the melt can be introduced various additives such as a fluidity regulators, such as colloidal silicon dioxide; lubricants, fillers, disintegrators, plasticizers, stabilizers such as antioxidants, light stabilizers, absorbers radicals or stabilizers against microbial infections.

The melting and/or mixing is carried out in a usually employed for this purpose hardware. Particularly suitable extruders and mixers. Suitable extruders include single screw extruders, coupled screw extruders or even mnogochasovye extruders, preferably twin-screw extruders, BP is saudies in the same or in opposite directions and do not necessarily equipped with a mixing disks. Be aware that the operating temperature will also be determined by the type of extruder, or view configuration used inside the extruder. Part of the energy required for melting, mixing or dissolving the components in the extruder may be provided with heating elements. However, friction and shear effects of the material in the extruder may also provide a mixture of sufficient energy and to promote the formation of a homogeneous melt of the components.

The melt ranges from pasty to viscous. Before solidification of the melt can be attached to virtually any desired shape. Giving the extrudate forms usually carry a calender with two counter-rotating rolls having a match indentations on their surface. A wide selection of tablet forms can be achieved by the use of rolls with different shape of the recesses. Alternatively, the extrudate is cut into pieces or before hardening (hot cutting), or after hardening (cold cutting).

In a preferred embodiment, the melt ekstragiruyut from the crack tip to obtain a film. Received the film with optional melt axially or biaxially. The film may be cut to the desired size.

Optionally the product obtained solid dispersion of rasmalai the Ute or pound to obtain a granulate. Then the granules can be compressed. Spressovyvanie means a process in which powdered mass, containing granules, compressed under high pressure to obtain a pressed powder with low porosity, for example, in the form of tablets. Compression of the powder mass is usually carried out in a tablet press, more specifically, in the steel stamp between two moving presses.

Preferably, when xpressmoney granules are used, at least one additive, selected from among regulators fluidity, disintegrators, fillers and lubricants. Disintegrator promote rapid disintegration of the compacted product in the stomach and support the released granules separate from each other state. Suitable disintegrators are transverse cross-linked polymers, such as crosslinked polyvinylpyrrolidone and cross-linked sodium carboxymethylate. Suitable fillers are selected from among lactose, acid calcium phosphate, microcrystalline cellulose (Avicel®), silicates, especially silicon dioxide, talc, potato or corn starch and isomalt.

Suitable regulators fluidity choose from highly disperse silicon dioxide (Aerosil®), and animal or vegetable fats or waxes.

The lubricant is preferably used in the compaction of the granules. Suitable lubricants are selected from the of poliatilenglikola (for example, having a mass-average molecular mass M_wfrom 1000 to 6000), stearates of magnesium and calcium, sodium fumarate, and the like.

Can also be used in a variety of other additives, such as dyes, such as azo dyes, organic and inorganic pigments such as iron oxides or titanium dioxide, or natural dyes; stabilizers, such as antioxidants, light stabilizers, absorbers radicals and stabilizers against microbial damage.

Dosage forms of the present invention can be produced in the form of a dosage form consisting of several layers. For example, laminated or multilayer tablets. They can be open or closed forms. "Closed medicinal forms" are such dosage forms, in which one layer is completely surrounded by at least one other layer. Multilayer forms have the advantage that the method can be used two active ingredients that are incompatible with each other, and the ability of the active ingredient (ingredients) to release from the mold can be controlled. For example, it is possible to obtain an initial dosage forms incorporating the active ingredient in one of the outer layers and the supporting dosage forms incorporating the active ingredient in the inner construction of the th layer (layers). Multilayer tablets can be obtained by pressing two or more layers of granules. Alternatively, the multilayer pharmaceutical form can be obtained by the process known as "co-extrusion". Essentially, the method includes preparing at least two different compositions of melts, as explained above, and the transmission of these molten compositions through a common mouthpiece for co-extrusion. The shape of the mouthpiece for co-extrusion depends on the desired dosage form. For example, suitable mouthpieces flat gap, called slotted mouthpieces, mouthpieces with a circular hole.

To facilitate receipt of such dosage forms mammals, it is advisable to give a dosage form appropriate form. Therefore, large tablets, which can be easily swallowed, preferably have an elongated shape, not round.

Film coating of tablets additionally contributes to its more easily swallowed. Film coating also improves the taste and gives a pleasant appearance. If necessary, the film coating can be interoperation. Film coating typically includes a film-forming polymeric material, such as hypromellose, hydroxypropylcellulose and acrylic or methacrylic copolymers in Addition to the film-forming polymer film coating can optionally contain a plasticizer, for example, a polyethylene glycol; a surfactant, such as Tween®, and optional pigment, for example titanium dioxide or iron oxides. Film coating may also contain as antiadhesive talc. Film coating is usually less than about 5 wt.% from a medicinal dose.

The following examples serve to further illustrate the invention without limiting it. In Examples 1 to 8 used dye (Sudan Red III) as model compounds to visualize the distribution of the compounds in the product solid dispersion. Obviously, biologically active ingredients can be processed essentially in a similar manner.

Example 1.

The dye Sudan Red III was dissolved in 1,3-bis(pyrrolidone-1-yl)butane concentration of 0.5 wt.%. 5 parts by weight of the obtained dark red solution was mixed with 95 parts by weight of copolymer Kollidon VA 64 (copolymer of N-vinyl-pyrrolidone and vinyl acetate 60:40). The mixture was granulated in a laboratory high-speed mixer. Resulting granulate is fed into the extruder together with two rotating augers and extrudible at a temperature of 130°C. the Extrudate was subjected to solidification with the formation of a homogeneous transparent red fragile, non-sticky mass. The glass transition temperature of the extrudate, determined by the method of differential scanning calorimetry (DSC), was avna 86°C.

Example 2.

Repeating Example 1 except that used 10 parts by weight solution of the dye Sudan Red and 90 parts by weight of copolymer Kollidon VA 64. Got a homogeneous transparent red fragile non-sticky mass. The glass transition temperature of the extrudate, determined by the DSC method, amounted to 76°C.

Example 3.

Repeating Example 1 except that used 15 parts by weight solution of the dye Sudan Red and 85 parts by weight of copolymer Kollidon VA 64. Got a homogeneous transparent red fragile non-sticky mass. The glass transition temperature of the extrudate, determined by the DSC method, was equal to 58°C.

Example 4.

Repeating Example 1 except that used 20 parts by weight solution of the dye Sudan Red and 80 parts by weight of copolymer Kollidon VA 64. Got a homogeneous transparent red fragile non-sticky mass. The glass transition temperature of the extrudate, determined by the DSC method, amounted to 49°C.

Example 5.

Repeating Example 1 except that used 30 parts by weight solution of the dye Sudan Red and 70 parts by weight of copolymer Kollidon VA 64. The melt extrusion was carried out at a temperature of 110°C. the Obtained homogeneous transparent red fragile weakly sticky mass. The glass transition temperature of the extrudate, determined by the DSC method, was equal to 24°C.

Example 6.

The dye Sudan Red III was dissolved in 1,3-bis(pyrrolidone-1-yl)butane concentration of 0.5 wt.%. 20 parts by weight of poluchennogo the dark red solution was mixed with 80 parts by weight of copolymer Kollidon VA 25 (a homopolymer of N-vinyl-pyrrolidone). The mixture was granulated in a laboratory high-speed mixer. Resulting granulate is fed into the extruder together with two rotating augers and extrudible at a temperature of 110°C. the Extrudate was subjected to solidification with the formation of a homogeneous transparent red fragile, non-sticky mass. The glass transition temperature of the extrudate, determined by the DSC method was equal to 74°C.

Example 7.

The dye Sudan Red III was dissolved in 1,3-bis(pyrrolidone-1-yl)butane concentration of 0.5 wt.%. 10 parts by weight of the obtained dark red solution was mixed with 90 parts by weight of copolymer Klucel EF (hydroxypropylcellulose). The mixture was granulated in a laboratory high-speed mixer. Resulting granulate is fed into the extruder together with two rotating augers and extrudible at a temperature of 110°C. the Extrudate was subjected to solidification with the formation of a homogeneous transparent red fragile, non-sticky mass. The glass transition temperature of the extrudate, determined by the DSC method, was equal to 1°C.

Example 8.

Repeating Example 7, except that used 20 parts by weight solution of the dye Sudan Red and 80 parts by weight of copolymer Klucel EF. The melt extrusion was carried out at a temperature of 100°C. the Obtained homogeneous transparent red elastic, slightly sticky mass. The glass transition temperature is extrudate, determined by the DSC method, was equal to -10°C.

Example 9.

Tramadol hydrochloride (2.5 g) was dissolved in 1,3-bis(pyrrolidone-1-yl)-butane (7.5 g) in low heat. 5 g of the obtained solution was mixed with 25 g of a copolymer Kollidon VA 64 in a laboratory mill (IKA paddle mill to obtain a homogeneous granulate. The composition of the granulate: 4.2 wt.% tramadol hydrochloride, 12.5 wt.% 1,3-bis-(pyrrolidone-1-yl)butane and 83.3 wt.% Kollidon VA64.

The granulate was served in a laboratory twin-screw extruder and was extrudible at a temperature of 120°C. In a transparent solidified extrudate by the DSC method was unable to detect crystalline tramadol hydrochloride, indicating that the tramadol hydrochloride was present exclusively in non-crystalline condition.

Example 10.

Repeating Example 9, but tramadol hydrochloride, 1,3-bis(pyrrolidone-1-yl)-butane and a copolymer of Kollidon VA 64 were mixed and granulated as such, i.e. without dissolution of the active ingredient 1,3-bis(pyrrolidone-1-yl)butane. In transparent solidified extrudate by the DSC method was unable to detect crystalline tramadol hydrochloride, indicating that tramadol hydrochloride is present exclusively in non-crystalline condition.

Example 11 (comparative).

A homogeneous powder mixture of 4.2 wt.% tramadol hydrochloride and 95.8 wt.% copolymer Kollidon VA 64 was filed in vuksanovic extruder such as used in Examples 9 and 10. At 120°C. to carry out the extrusion failed due to extremely high torque. The melt was impossible to get.

Example 12 (comparative).

A homogeneous powder mixture of 4.2 wt.% tramadol hydrochloride and 95.8 wt.% copolymer Kollidon VA 64 was filed in the co-rotating twin screw extruder as used in Examples 9 and 10. The extrusion was carried out at 125°C. the Obtained turbid melt (as opposed to transparent melt obtained in Examples 9 and 10). The turbidity of the melt was observed that the melt still contained undissolved particles or aggregates.

Example 13 (comparative).

A homogeneous powder mixture of 4.2 wt.% tramadol hydrochloride and 95.8 wt.% copolymer Kollidon VA 64 was filed in the co-rotating twin screw extruder as used in Examples 9 and 10. The extrusion was carried out at 140°C. the Obtained turbid melt. The turbidity of the melt was observed that the melt still contained undissolved particles or aggregates.

1. Composition for medical purposes, containing solid or semi-solid matrix having at least one uniformly dispersed therein an active ingredient having a solubility in water at 25°C. of less than 1 g/100 ml, and the matrix contains at least one pharmaceutically acceptable forming a matrix agent, selected from the group on the expectation sugar alcohols, derivatives, sugar alcohols, pharmaceutically acceptable polymers, and mixtures thereof, and the compound of formula (I)

where n is an integer from 3 to 5,
moreover, the matrix contains the calculation of the mass matrix, from about 1 to 30 wt.% the compounds of formula (I) and from about 50 to 98 wt.% one or more forming a matrix agent and from about 1 to 49 wt.% the active ingredient or combination of active ingredients.

Campsite according to claim 1, in which the active ingredient dispersed in the matrix in a state of solid solution.

3. The composition according to claim 1, in which the compound of the formula (I) is 1,3-bis(pyrrolidone-1-yl)butane.

4. The composition according to claim 1, in which the pharmaceutically acceptable form the matrix agent is a pharmaceutically acceptable polymer or a mixture of pharmaceutically acceptable polymers.

5. The composition according to claim 4, in which the pharmaceutically acceptable polymer has a glass transition temperature of at least about 40°C.

6. The composition according to claim 4, in which the pharmaceutically acceptable polymer is selected from the group consisting of homopolymers of N-vinylacetate, copolymers of N-vinylacetate and one or more comonomers selected from nitrogen-containing monomers and oxygen-containing monomers; cellulose ethers and ethers of cellulose; macromolecular polyalkyleneglycol, polyacrylates and polim is acrylato; oligo - and polysaccharides; poly(hydroxy acids), and mixtures thereof.

7. The composition according to claim 6, in which the pharmaceutically acceptable polymer is selected from polyvinylpyrrolidone, a copolymer of N-vinyl-pyrrolidone and vinylcarbazole; hydroxyethylcellulose, hydroxyethylmethylcellulose; polylactic acid, polyglycolic acid, poly(3-hydroxybutyrate), poly(3-hydroxyvalerate), mixed poly(3-hydroxybutyrate-3-hydroxyvalerate) and mixtures thereof.

8. The composition according to claim 7, in which the pharmaceutically acceptable polymer is selected from a copolymer of N-vinylpyrrolidone with vinyl acetate and hydroxypropylcellulose.

9. The composition according to any one of claims 1 to 8, in which the active ingredient is selected from the meloxicam and telmisartan.

10. The composition according to any one of claims 1 to 8, in which the matrix contains additionally at least one additive selected from the group consisting of surfactants, regulators fluidity, disintegrators, fillers, lubricants, violently effervescent emit gas agents, coloring agents, flavoring substances.

11. Dosage form for oral administration of active ingredients containing or consisting of the composition according to any one of claims 1 to 10.

12. A method of obtaining a composition according to claim 1, including
a) dissolving the active ingredient in a sufficient amount of the compounds of formula (I) to obtain rest the RA of the active ingredient;
b) preparation of a powder composition containing forming a matrix agent;
c) the adulteration of the solution of active ingredient in the powdered composition to obtain a homogeneous granulate;
d) heating the homogeneous granules at an elevated temperature to obtain a melt and
e) curing the melt to obtain a solid product dispersion.

13. The method according to item 12, including additional grinding named product of the solid dispersion.

14. The method according to item 13, including additional pressing this product a solid dispersion tablets.

15. The method according to 14, including additional drawing on the tablet film coating.

16. A method of obtaining a composition according to claim 1, including
a) heating forming a matrix agent to an elevated temperature to obtain a melt forming a matrix agent;
b) dissolving the active ingredient in a sufficient amount of the compounds of formula (I) to obtain a solution of the active ingredient;
c) adding a solution of the active ingredient to melt forming a matrix agent and
d) curing the melt to obtain a solid product dispersion.

17. The method according to item 16, including additional grinding named product of the solid dispersion.

18. The method according to 17, including additional pressing named product is the solid dispersion tablets.

19. The method according to p, including additional drawing on the tablet film coating.