CN101686946A

CN101686946A - micellar nanoparticles of chemical substances

Info

Publication number: CN101686946A
Application number: CN200780039046A
Authority: CN
Inventors: J·P·莫斯科维泽
Original assignee: Solvay Pharmaceuticals GmbH
Current assignee: Abbott Products GmbH; Abbott Healthcare Products BV
Priority date: 2006-10-20
Filing date: 2007-10-19
Publication date: 2010-03-31
Also published as: AR063330A1; SA07280548B1; BRPI0719826A2; BRPI0719826A8; UA97496C2; CN104188926A; TWI392507B; MX2009004124A; HK1199829A1; TW200824711A

Abstract

The present invention relates to a thermostable solid composition containing nanosized micelles, the micelles containing a poorly soluble chemical substance, such as a biologically active substance, dissolved in an auxiliary material, and the micelles being embedded in a water soluble carrier. The invention further relates to a process for preparing a thermostable solid composition and to a process for preparing pharmaceutical dosage forms comprising the same.

Description

The micellar nanoparticles of chemical substance

Background of invention

The most of novel drugs molecule that reveals in the works from drug discovery demonstrates the dissolubility of the difference aqueous medium, and perhaps they are dissolved in aqueous medium hardly.Therefore with can parenteral or Orally administered mode to prepare these active substances be very challenging.Rate of dissolution and intestinal permeability are the crucial determiners about bioavailability, particularly for the medicine of dosage forms for oral administration (according to Noyes-Whitney (people such as Jinno, Effect of particlesize reduction on dissolution and oral absorption of a poorlywater-soluble drug, cilostazol, in beagle dogs, J.of ControlledRelease 111 (1-2), 56-64,2006) law of Ti Chuing, low solubility is general relevant with low rate of dissolution).According to Biopharmaceutics Classification System (G.L.Amidon, H.Lennernas, V.P.Shah, with J.R.Crison.Atheoretical basis for a biopharmaceutics drug classification:the correlation of in vitro drug product dissolution and in vivobioavailability.Pharm.Res.12:413-420 (1995)), insoluble drug belongs to BCS II class or BCS IV class.BCS IV class means medicine and shows poor dissolubility and low permeability simultaneously, and the bioavailability of BCV II class medicine is subjected to dissolution rate usually, the restriction of (dissolution rate), (Formulation of poorly water-solubledrugs for oral administration:Physicochemical andphysiological issues and the lipid formulation classificationsystem, Colin W.Pouton, European Journal of PharmaceuticalSciences 2006 29, 278-87).This means, and the bioavailability of BCS II class medicine can be by improving its rate of dissolution and/or saturation solubility c _sAnd obtain increasing.

Used dissolubility and the dissolution rate of various preparation strategies to improve insoluble drug.

The formation of the inclusion complex of active substance and cyclodextrin can improve the dissolubility (using cyclodextrin to make the WO9932107 of THC solubilising referring to for example disclosing) of medicine.Cyclodextrin is the cyclic oligomeric thing of glucose or glucosan derivative, and it can form reversible, non-covalent association so that described medicament solubilization with insoluble drug.

For example emulsion, micro emulsion, self-emulsifying drug delivery systems (SEDDS) or self-emulsifying microemulsion drug delivery system (SMEDDS) are suitable for dissolving in the active substance of lipid and oil based on the system of lipid.In these lipid formulations, active substance is dissolved in oil or the lipid, and it forms emulsion or form the emulsion system behind dilute with water.

Keep at active substance under the situation of solid form, a kind of method that has been applied to improving the solubility behavior of insoluble drug is to reduce particle size solid amorphous or crystalline active substance has the particle size of minimizing with generation solid amorphous or crystalline material.The particle size minimizing causes surface area to increase.Because bigger surface area, drug particles has the rate of dissolution of improvement.

Generally speaking, in the production of the material of particle size, from top to bottom (top-down) and there are differences between (bottom-up) technology from bottom to top with minimizing.Technology relates to energy input so that bulky grain is resolved into granule from top to bottom.Depend on employed technology, can obtain the material through grind of average particle size particle size in micrometer range (for example jet grinding, hammer grinds) or nanometer range (for example wet bulb grinds and high pressure homogenizationization).For the latter, and the micronized parent material of recommendation use (US 5,145, and 684; US 5,858, and 410).The exemplary shortcomings of these technology is that they need huge energy to decompose parent material.

Technology is used for producing the medicament nano crystal via precipitation process from bottom to top.This technology is described as " via humida paratum " in old pharmacopeia.Active substance is dissolved in the solvent, this solvent is added to non-solvent or anti-solvent (anti-solvent) (it can be miscible with described solvent), be precipitated out with the form of active substance with amorphous or crystalline nano-particle, crystalline nano-particle is also referred to as the medicament nano crystal.Described granule is generally stablized by surfactant or polymer stabilizer.This principle is applied to produce so-called " hydrosol " (US5,389,382).Some modification (US patent application 20050139144) of this precipitation principle has been described recently.Yet, be difficult to make sedimentary crystal to be fixed in the nanoscale scope.The nanoparticle structure tends to growth usually to form microgranule or crystallite.A kind of method that addresses this problem is dry immediately prepared suspension liquid, for example by lyophilizing (Sucker, H., Hydrosole-eine Alternative f ü r die parenterale Anwendung vonschwer

Wirkstoffen, in:M ü ller, R.H., Hildebrand, G.E., (Hrsg.), and Pharmazeutische Technologie:Moderne Arzneiformen, 2.Auflage, 1998, WVG, Stuttgart).

More relate to supercritical fluid or the spraying-cryodesiccated particle size minimizing method of recent development have obtained describing (Jiahui Hu in about the document of producing the solid drugs nano-particle, Keith P.Johnston, with Robert O.Williams III, NanoparticleEngineering Processes for Enhancing the Dissolution Rates ofPoorly Water Soluble Drugs, DRUG DEVELOPMENT AND INDUSTRIALPHARMACY, the 30th volume, No.3, the 233-245 page or leaf, 2004).

All particle size minimizing technology have a common shortcoming; Usually medicine need be dissolved with by intestinal absorption.For some extremely insoluble medicine, the minimizing of particle size may be not enough to improve solubility behavior and increase bioavailability.

The another kind of method of improving the solubility behavior of slightly solubility active substance is that described material is mixed in amorphous system such as the solid dispersion.Term " solid dispersion " has defined the solid-state system (relative with liquid or gas system) that comprises at least 2 kinds of components, and wherein a kind of component is on a rough average to be dispersed in another or various ingredients everywhere.At chemistry and physically all the time evenly or homogeneity or also can be called solid solution (for example, WO97/044014) by the single-phase solid dispersion that constitutes that defines in as thermodynamics.Solid matrix can be crystalline or unbodied.Medicine can molecular dispersion or is existed with the form of amorphous granular (bunch (clusters)) and crystalline particles (solid dispersion).The example of this type of solid dispersion is US 5,281, the bioactive peptide preparation of describing among tebufelone preparation of describing in 420 and the WO2005/053727.

Solid dispersion can make in all sorts of ways and be prepared, fusion method, hot melt extrusion molding, solvent evaporated method or supercritical fluid method (D.J.van Drooge " Combining theIncompatible " for example, Rijksuniversiteit Groningen, PhD-Thesis 2006).Solid dispersion or solid solution can comprise surfactant or other excipient dissolve or stable medicine to strengthen.Several technology that are used for producing solid dispersion are discussed at U.S. Patent application 20050266088A1.This application also discloses the method for producing the sugared glass of lipophilic compound, and wherein lipophilic compound is dissolved in the preferred C of cosolvent ₁-C ₆In the alcohol.Preferred solvent has high vapour pressure and high-melting-point.Yet, use high vapour pressure, the inflammable cosolvent of suggestion to cause difficulty, particularly when using spray drying as dry technology to large-scale production.In order to protect whole system to avoid blast, the oxygen content in the dry air must reduce.In addition, lipophilic compound stable inadequately and trend in aqueous cosolvent system is precipitated out.For this reason, the suggestion rapid processing is to avoid occurring " muddiness ".

When active substance is hydrophobic rather than lipophilic, when promptly being insoluble to lipid and oil, cosolvent or cosolvent-surfactant mixture can be used to make the active substance solubilising.In order to give different solubilising system classification, C.Pouton has proposed lipid formulations categorizing system (LFCS).The later versions of this scheme is distinguished 4 kinds of different preparation types (Formulation of poorlywater-soluble drugs for oral administration:Physicochemicaland physiological issues and the lipid formulationclassification system, Colin W.Pouton, European Journal ofPharmaceutical Sciences 2006 29, 278-87).LFCS IV type has been described the no oil formulation based on surfactant-cosolvent mixtures.Usually, these surfactant-cosolvent mixtures are filled in the hard gelatin capsule of Perle or sealing.When oral using, medicine discharges in capsule shells dissolving back.Because medicine has been dissolved in the carrier, so it can be by fast Absorption (Liquid-Filled and Seal Hard Gelatine CapsuleTechnologies, Ewart T.Cole, in:Modified-Release Drug DeliveryTechnology, eds.M.J.Rathbon, J.Hadgraft, M.S.Roberts, Marcel Dekker, Basel, 2003).

In order to produce conventional solid dosage forms from the slightly solubility liquid drug, by people such as Spireas (people such as Spireas, Powdered solution technology:principles andmechanisms, Pharm.Res.9 No.10,1351-1358,1992) production of " powdery solution (powdered solutions) " has been proposed." powdery solution " is produced by liquid drug or drug solution are mixed with selected carrier.The product that obtains by this technology is the physical mixture or the admixture of drug/surfactant solution and selected carrier.The example of this class preparation is open in WO2005/041929, WO2006/113631 and WO2006/135480.Yet the common shortcoming of resulting powder is that its mobile poor, its poor heat resistance and/or its compressibility are poor.

The purpose of this invention is to provide about chemical compound particularly biologically active cpds further and the preparation that improves, material that described preparation can be obtained commercially by use and standard method and equipment prepare.Under the situation of biologically active cpds, further target of the present invention provides the preparation with good bioavailability.

Summary of the invention

The present invention relates to have the heat resistant type compositions of the solubility behavior of improvement, described compositions comprises nanoscale micelle (nanosized micelle), and wherein said micelle comprises insoluble chemical compound.In one embodiment, pharmaceutical composition of the present invention comprises the nanoscale micelle, wherein said micelle comprises and contains slightly solubility chemical substance (medicine for example, insoluble drug) surfactant or surfactant-cosolvent mixtures, wherein said micelle are embedded in water-solubility carrier for example in the water-soluble base of pharmaceutically acceptable carrier.

Another aspect of the present invention relates to preparation of drug combination, and it comprises that preparation comprises the micellar aqueous solution of insoluble chemical compound, auxiliary material (auxiliary material) or mixtures of auxiliary materials and water-soluble base; And make described micellar solution drying so that these micelles are embedded in the water-soluble base of carrier, thereby obtain the heat resistant type compositions.The micelle that comprises insoluble chemical compound by use one or more surfactants and randomly one or more cosolvents (co-solvent) produce.

The accompanying drawing summary

Fig. 1 is used to prepare for example diagram of the conventional method of pharmaceutical composition of compositions according to of the present invention.

Fig. 2 is such figure, and it illustrates is giving the male plasma concentration of using the chemical compound 1 of 4 kinds of different preparations (comprising according to preparation of the present invention) back acquisition than lattice sleuth (beagle dog).

Detailed Description Of The Invention

Aspect first, the present invention relates to comprise the heat resistant type solid composite of nanoscale micella, wherein said micella comprises the slightly solubility chemical substance that is dissolved in the auxiliary material, and wherein said micella is embedded in the water-solubility carrier.

On the other hand, the present invention relates to comprise the heat resistant type solid composite medicament of nanoscale micella, wherein said micella comprises the slightly solubility bioactivator that is dissolved in the auxiliary material, and wherein said micella is embedded in the matrix of water miscible pharmaceutically acceptable carrier.

Within the scope of the invention, term " heat resistant type " means, and preparation is still free-pouring stable powder when heating surpasses the fusing point of main auxiliary material.This means, and preparation is still physically stable when heating surpasses 5 ℃, 10 ℃, 20 ℃, 30 ℃, 40 ℃ of the fusing points of main auxiliary material or 50 ℃.

For example, vitamin E TPGS (d-alpha-tocopherol cetomacrogol 1000 succinate) has 36 ℃ fusing point (reference: Eastman, Material Safety Data Sheet of VitE TPGS NF Grade).Those skilled in the art will suppose, if vitamin E TPGS is the main component of preparation, so this preparation will show at least according to the experience partial melting when being exposed to temperature far above 36 ℃ as 80 ℃.Yet if vitamin E TPGS is used as the auxiliary material among the present invention, the micelle of vitamin E TPGS formation micelle and vitamin E TPGS (and active substance) is embedded in fusing point above in 36 ℃ the water-soluble base material so.Therefore, resulting powder will can not show powder morphology and mobile significant change.Even when being exposed to the temperature of 5 ℃, 10 ℃, 20 ℃, 30 ℃, 40 ℃ of fusing points surpassing main auxiliary material vitamin E TPGS or 50 ℃, it is still stable free-pouring powder.

Within the scope of the invention, term " biological active agents ", " pharmaceutically active substances ", " medicine ", " reactive compound ", " active component " are used in reference to interchangeably, induce the chemical substance or the chemical compound of pharmacological effect when being administered to the human or animal.

Within the scope of the invention, term " insoluble chemical compound " refers to 37 ℃ of chemical compounds that have less than the dissolubility of 33g/L in water.In particular for pharmaceutically active compound, the term insoluble chemical compound (for example is used to describe in vivo the site, stomach, intestinal, subcutaneous) condition located particularly has the chemical compound less than the dissolubility of 33g/L under the pH, in described body in the site chemical compound expection become can be by health utilization (particularly compound dissolution be to be absorbed by health).Therefore, for example the dissolved under one's belt insoluble chemical compound of expectation has the dissolubility that is lower than 33g/l in gastric juice (the about 1-3 of pH), and treats that dissolved insoluble chemical compound has the dissolubility that is lower than 33g/l in intestinal juice (usually up to about pH7.4) in intestinal.(with reference to US 0050266088, Frijlink).The present invention is particularly useful for the chemical compound of indissoluble more, for example has the chemical compound of the dissolubility that is lower than 10g/L, 4g/L, 1g/L, 100mg/L, 40mg/L, 10mg/L, 4mg/L, 1mg/L, 0.4mg/L or 0.1mg/L in gastro-intestinal Fluid.

The insoluble chemical compound that can process according to the present invention can be liquid, semisolid, solid amorphous, liquid is crystalline or solid is crystalline.

Treat preferably forms of pharmacologically active agents of the insoluble chemical compound processed according to the present invention, and can be selected from analgesic, anti-arrhythmic, anti-asthmatic, antibiotic, vermifuge, antiinflammatory, antiviral agent, anticoagulant, antidepressants, antidiabetic drug, antuepileptic, anti-erectile dysfunction agent, antifungal, antigout drug, antihypertensive, antimalarial, antimigraine, antimuscarinic drug, antineoplastic agent, appetrol, antiparkinsonian drug, antiprotozoal, antithyroid drug, cough medicine, antianxiety drug, receptor blocking agent, hypnotic, immunosuppressant, neuroleptic, cannabinoid receptor agonists and antagonist, heart inotropic agent (cardicinotropic agent), cell adhension inhibitors, corticosteroid, the cytokine receptor active regulator, diuretic, gastrointestinal drug, histamine H-receptor antagonist, keratolytic agent, lipid regulating agent, muscle relaxant, Nitrates and other antianginal agent, on-steroidal anti-asthmatic, opium kind analgesics, tranquilizer, gonadal hormone and beta stimulant.

Some examples of insoluble chemical compound are slightly solubility cannabinoid agonists, inverse agonists and antagonist.Some examples of these chemical compounds are WO01/70700; WO02/076949; WO03/026647; WO03/026648; WO03/027076; WO2005/074920; WO2005/080345; disclosed chemical compound among WO2005/118553 and the WO2006/087355; (the 4S)-3-that for example describes among the WO03/026648 (4-chlorphenyl)-4; 5-dihydro-N-methyl-4-phenyl-N '-(piperidino-sulfonyl)-1H-pyrazoles-1-carbonamidine; and (the 4S)-3-that describes among the WO02/076949 (4-chlorphenyl)-N-[(4-chlorphenyl) sulfonyl]-4; 5-dihydro-N '-methyl-4-phenyl-1H-pyrazoles-1-carbonamidine (being also referred to as ibipinabant or SLV319) and (4S)-3-(4-chlorphenyl)-4,5-dihydro-N-methyl-4-phenyl-N '-[[4-(trifluoromethyl) phenyl] sulfonyl]-1H-pyrazoles-1-carbonamidine.

Insoluble chemical compound in the present composition preferably has and is lower than 10, more preferably less than 5, be more preferably and be lower than 2.5 log P, and can with the 0.05%w/w-of composition total weight at least the amount of 50%w/w exist, preferably the amount with 0.05%-10% or 0.05%-5% or 0.05%-1% exists.

Within the scope of the invention, term " auxiliary material " is to make it possible to form micellar material when it contacts with water, or when micelle forms, its stability had the material of positive influences, for example a mixture of surfactant, cosolvent or surfactant and cosolvent.

Within the scope of the invention, term " micelle " means the associated complex (reference that surpasses the surfactant molecule of Krafft (Krafft) point and critical micell concentration in aqueous solution

Online Dictionary).According to IUPAC, surfactant forms association colloid usually in solution.That is to say that their trends form the aggregation of colloid size, described aggregation and molecule or ion (forming described aggregation by described molecule or ion) exist with balancing each other.This type of aggregation is called micelle.

Krafft point means such temperature (more accurately, the narrow temperature scope), and promptly the dissolubility of surfactant in water sharply rises on this temperature.At this temperature place, the dissolubility of surfactant becomes and equals critical micelle concentration.It can be measured the abrupt change of the curve chart slope of t or 1/T by the logarithm of location dissolubility.Have less relatively surfactant concentration ranges, it has separated the lower limit and the upper limit, is lower than describedly almost to detect down less than micelle in limited time and be higher than nearly all extra surfactant molecule formation micelle of prescribing a time limit on described.If at the concentration mapping, many character of surfactant solution seem to change with different rates above and below this scope the time so.By extrapolate this type of character on this scope and under track intersect until them, can obtain to be called critical micell concentration (critical micelle concentration) value (IUPAC Compendium of Chemical Terminology, Goldbook).

Micelle in compositions according to the present invention has the average-size less than 1000nm, preferably less than 500nm, or less than 200nm, or less than 100nm.

Within the scope of the invention, term " average-size " be meant by dynamic light scattering determination effective average diameter (for example, light correlation spectrometry (PCS), laser diffraction (LD), low-angle laser light scattering (LALLS), middle equal angles laser light scattering (MALLS), light transmission method (lightobscuration methods) (for example Ku Leerte (Coulter) method), rheology or microscopic method (optics or electronics) are in scope mentioned above)." less than effective average particle size particle size of about x nm " means, and when by above-mentioned commercial measurement, at least 90% granule has the weight average particle size less than about x nm.

At least 10% surfactant or at least 30% or at least 50% can be comprised according to compositions of the present invention, and surfactant can be comprised up to 99.95%.Randomly, compositions also comprises one or more cosolvents and/or one or more cosurfactants (co-surfactant).

For pharmaceutical composition, operable surfactant and optional cosurfactant be at M.M.Rieger, " Surfactants ", Pharmaceutical Dosage Forms, Marcel Dekker Inc., (1993) the 8th chapters are listed in the 285-359 page or leaf.Preferred surfactants is the HLB value greater than 8 surfactant.Most preferred surfactant (for example is selected from Myrj 45

), the polyoxyethylene sorbitan aliphatic ester (for example ), castor oil derivatives (for example

), vitamin E TPGS, nonionic polyox-yethylene-polyoxypropylene block copolymer (for example ), the water-soluble long-chain organophosphorus ester (for example

), inulin lauryl carbamate (Inutec for example

).

For pharmaceutical composition, the optional preferably pharmaceutically acceptable non-volatile cosolvent of cosolvent of use, this is the material that has less than the vapour pressure of 0.50mm Hg in 25 ℃.Described pharmaceutical composition is only relevant with the solubilising mixture of the IV type of lipid formulations categorizing system (LFCS), described LFCS IV type is defined as the no oil formulation based on surfactant and cosolvent by Pouton (referring to paragraph [0012]), and thereby in the present invention oil by being got rid of outside cosolvent especially.Also got rid of LFCS I type preparation (non-distribution; Need digestion), LFCS II type preparation (SEDDS that does not have water-soluble component), LFCS IIIA type preparation (SEDDS/SMEDDS), LFCS IIIB type preparation (SMEDDS) with water-soluble component and low oil content with water-soluble component.

The example of non-volatile cosolvent includes but not limited to that aklylene glycol is Polyethylene Glycol (PEG), propylene glycol, diethylene glycol monoethyl ether, glyceryl triacetate, benzyl alcohol for example; Polyhydric alcohol is mannitol, Sorbitol and xylitol for example; Polyoxyethylene; Linear polyhydric alcohol is ethylene glycol, 1 for example, 6-hexanediol, neopentyl glycol and methoxy poly (ethylene glycol); And composition thereof.

What can be used as non-volatile cosolvent among the present invention especially is PEG (it is polymers of ethylene oxide), and it generally defers to formula (HOCH ₂CH ₂) _nOH, wherein n is a number of unit, this number still defines the number of the mean molecule quantity (m.w.) of this polymer.

Useful in the present invention PEG type can be classified by its states of matter, that is, described material is to exist with solid or liquid form under indoor temperature and pressure.Within the scope of the invention, " liquid PEG " refers to that PEG has such molecular weight (m.w.), thereby makes that this material is liquid under indoor temperature and pressure.For example, has PEG less than 800 daltonian average m.w..Useful especially is PEG 400 (the about 380-420 dalton of m.w.), PEG 600 (the about 570-630 dalton of m.w.) and composition thereof.(Danbury Conn.) is obtained commercially PEGs, under CARBOWAX SENTRY product line from Dow Chemical.

Within the scope of the invention, " solid PEG " refers to that PEG has such molecular weight (m.w.), thereby makes that this material is solid-state under indoor temperature and pressure.For example, average m.w. is 900-20, and 000 daltonian PEG is solid PEG.Useful especially solid PEGs is that m.w. is 3,350 dalton (about 3685 dalton of the about 3015-of m.w.) to those of 8,000 dalton (m.w. about 7,000-9,000 dalton).That can be used as solid PEG especially is PEG 3350, PEG 4000 (m.w. about 3,600-4,400 dalton), PEG 8000 and composition thereof.

When substituting liquid PEG (for example PEG 400) with solid PEG (for example PEG 4000), resulting medicine-surfactant-cosolvent mixtures must be heated to 80 ℃.Be surprised to find, release behavior does not change much when substituting PEG 400 with PEG 4000, although the block that is produced by the lyophilization of PEG 4000 products is harder during than use PEG 400.

When existing, preparation comprises 0.01%w/w-99.95%w/w, preferred 10.0%w/w-90.0%w/w, the most preferably cosolvent of the amount of 20.0%w/w-70.0%w/w.

Water-solubility carrier (being also referred to as substrate) can be water-soluble any polymeric material.If a at least host material can be dissolved in 10-30 part water, host material can be considered as water soluble (according to the definition of 24, the 2254 pages of USP) so.

For pharmaceutical composition, water-solubility carrier should be pharmaceutically acceptable.The example of spendable pharmaceutically acceptable carrier is selected from the present invention:

-alkylcellulose, for example methylcellulose;

-hydroxy alkyl cellulose, for example hydroxy methocel, hydroxyethyl-cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose;

-hydroxyalkyl alkylcellulose, for example hydroxyethylmethyl-cellulose and hydroxypropyl emthylcellulose;

-carboxyl alkyl cellulose, for example carboxymethyl cellulose;

The alkali metal salt of-carboxyl alkyl cellulose, for example sodium carboxymethyl cellulose;

-carboxyalkyl alkylcellulose, for example carboxymethylethylcellulose;

-carboxyl alkyl cellulose ester;

-starch;

-pectin, for example carboxymethyl amylopectin sodium;

-chitin derivatives, for example chitosan;

-polysaccharide, for example alginic acid, its alkali metal and ammonium salt;

-chondrus ocellatus Holmes polysaccharide, galactomannan, Tragacanth, agar, arabic gum, guar gum and xanthan gum;

-polyacrylic acid and salt thereof;

-polymethylacrylic acid and salt thereof, methacrylate copolymer;

-polyvinyl alcohol;

-polyvinylpyrrolidone, the copolymer of polyvinylpyrrolidone and vinyl acetate;

-polyalkylene oxide, for example poly(ethylene oxide) and poly(propylene oxide), and the copolymer of oxirane and expoxy propane.

Pharmaceutically acceptable and the polymer of not enumerating that have as mentioned a suitable physicochemical property of definition is suitable in the present invention the carrier as pharmaceutical composition equally.

Spendable in the present invention preferred water-soluble polymer comprises hydroxypropyl emthylcellulose and HPMC.HPMC comprises enough hydroxypropyls and methoxyl group so that its water soluble.Methoxyl group replacement degree generally is water miscible for the HPMC that about 0.8-about 2.5 and hydroxypropyl mole are substituted by about 0.05-about 3.0.Methoxyl group replacement degree refers to the average number of the methyl ether groups that exists in each dehydrated glucose unit of cellulosic molecule.The hydroxypropyl mole replaces the molar average number refer to the expoxy propane of each dehydrated glucose unit reaction of cellulosic molecule.Hypromellose (Hypromellose) is the title that the U.S. of hydroxypropyl emthylcellulose adopts.

Can comprise one or more other additives according to compositions of the present invention.Under the situation of pharmaceutical composition, these additives should be pharmaceutically acceptable additives, for example flavoring agent, coloring agent, binding agent, filler, filler-binding agent, lubricant, disintegrate auxiliary agent and/or other pharmaceutically acceptable additives.

Preparation of compositions according to the present invention relates to the micellar aqueous solution for preparing insoluble chemical compound, subsequently for drying steps these micelles are embedded in carrier for example in the water-soluble base of pharmaceutically acceptable carrier.The micelle that comprises insoluble chemical compound produces by using one or more surfactants.In case of necessity, can also comprise one or more cosolvents.

In another aspect of this invention, the micellar solution that comprises insoluble chemical compound prepares by insoluble chemical compound is dissolved in one or more surfactants.To mean insoluble chemical compound be dispersive with unimolecule basically in dissolving, that is, at least 95%, preferably at least 98%, more preferably at least 99%, it is dispersive with unimolecule being more preferably at least 99.5% and most preferably at least 99.9% insoluble chemical compound.In case of necessity, can add one or more cosolvents.In one aspect of the invention, can apply energy and reach molecular dispersion completely so that can or mix described component by heating, fusion.When described component has formed the molecular dispersion system, they and water are mixed together to form micellar solution.Water can comprise for example dissolved substrate of pharmaceutically acceptable carrier of carrier, or afterwards the water-soluble base of carrier is dissolved in the micellar solution.With this mixture drying to obtain pressed powder.Powder can use like this, or mixes mutually and further processing with other excipient.

In another aspect of this invention, compositions according to the present invention promotes the absorption of insoluble drug by the micellar solution that forms medicine when the applying said compositions.

A further aspect of the present invention is, described compositions for example pressed powder can easily be processed to preparation, even use known and the inconsistent excipient of hard gelatin capsule (PEG 400, glycerol, polyoxyethylene (35) Oleum Ricini (Cremophor for example for example

), propylene glycol, diethylene glycol monoethyl ether (Transcutol for example

), sorbitan monoleate (Span for example

)) also can be processed into powder to be used for the capsule filling.

Lyophilization is not the production method that is used for large-scale production usually, and generally only is applied to for example protein of the unsettled medicine of extreme.Spray drying is more convenient and be more suitable in large-scale production.Therefore, spray drying is tested as the drying means according to micellar solution of the present invention, and finds to be very suitable for producing.Because do not use inflammable cosolvent,, the production of spray-dried powders need not special protection so can carrying out on standard device at blast with high vapour pressure.In addition, described micellar solution is stable in a few hours, and in some cases even a few days, medicine can not precipitate.The dissolving test shows, can obtain approximately identical rate of dissolution, and is irrelevant with the drying means that uses.

Use laser diffraction grain size analysis in case the test drying steps to the influence of micelle particle size, and shown, before spray drying with in the particle size behind spray-dired powder redispersion under the same order of magnitude.Can reach a conclusion from this result, dry run does not change resulting micellar size.

The inventive method is not limited to surfactant-cosolvent mixtures.In case can obtain the micellar aqueous solution of insoluble chemical compound in the presence of dissolved pharmaceutically acceptable carrier, resulting micellar solution just can be processed according to the present invention.

Can further be processed into any solid dosage forms to be used for any route of administration according to pharmaceutical composition of the present invention.Interested especially dosage form is granule, the compacting that is used for oral delivery (discharging immediately) tablet, sublingual lozenge or buccal tablet and is filled with powder or particulate hard gelatin capsule or wafer (sachets).

Tablet is the solid dosage forms that is used for the drug administration compositions of common type.Yet, up to the present be difficult to produce tablet by the liquid or the semi-solid preparation of the insoluble drug that comprises solubilising (i.e. dissolving) form.A kind of mode that has been used to produce this type of tablet is that liquid medicine or drug solution are adsorbed onto selected carrier (people such as Spireas, Powdered solutiontechnology:principles and mechanisms, Pharm.Res.9 No.10,1351-1358,1992).Yet the common shortcoming of resulting powder is that it is mobile and compressibility is poor.An object of the present invention is to provide this way to solve the problem.Powder produced according to the invention, particularly the powder of producing by spray drying demonstrates very good flowability.Dry powder can be mixed with pharmaceutical excipient with drying regime.Resulting mixture of powders can directly be filled in the capsule, also is fine yet be pressed into tablet.The tablet that obtains has demonstrated drug release very fast, and rate of release is with respect to the rate of release of the capsule preparations of the powder of similar composition.Particularly (for example work as granular pyrogenic silica

During 300) as the filler among the present invention, obtain disintegration of tablet and therefore excellent drug release very fast.

Tablet produced according to the invention has demonstrated those much better drug releases of producing than by standard method (for example melt extrusion or liquid filling capsule).

When tablet formulation more produced according to the invention is composed with the release characteristics of the preparation for preparing by melt extrusion, seem to be very difficult to make the agglomerate that solidifies that obtains by melt extrusion to powder; Therefore can only obtain inhomogenous tablet, and after 20 minutes, have only 60% drug release, when using, discharge by comparison above 80% according to preparation of the present invention.

The production of liquid filling capsule (liquid-filled capsule) is the prior art that another kind is used to provide the dosage form that can be used for the drug administration compositions.When medicine-surfactant-cosolvent (PEG 4000) mixture that will fusing is filled in the hard gelatin capsule, solidifies and submits to when being used for drug release studies, seem that the medicine-surfactant-cosolvent mixtures and the capsule shells that melt are compatible.Yet these capsules equally also demonstrate drug release relatively slowly.After 20 minutes, have only 52% medicine to be released.Therefore, the drug release from preparation according to the present invention (it has the release above 80%) is better than the drug release from conventional filled capsules known in the art.

Although lyophilization is not used in large-scale production usually, it also can be used to produce the powder that can be pressed into tablet according to the present invention.When obtaining limited amount medicine (for example development phase in) in early days and need be according to tablet of the present invention the time, can using lyophilization.Find that cryodesiccated powder can successfully be pressed into tablet, even need not to add any other excipient.These " were not prepared " tablet and demonstrated about 62% drug release likely after 20 minutes, and this certainly is improved by adding standard tabletting excipient.

The invention still further relates to the method that is used to prepare the present composition.

Aspect first, the present invention relates to prepare the method for aforesaid solid composite medicament, it comprises the following steps:

A) the slightly solubility active substance is dissolved in auxiliary material or the mixtures of auxiliary materials;

B) randomly in the solution that in a), obtains, add one or more other auxiliary material;

C) will a) or b) in the solution that obtains mix with water with formation nanoscale micelle;

D) substrate being formed material (matrix forming material) is dissolved at c) in the mixture that obtains; With

E) make at d) in the mixture drying that obtains, thereby obtain solid composite medicament, wherein said micelle is embedded in described substrate and forms in the material.

One further aspect, the present invention relates to prepare the method for aforesaid solid composite medicament, it comprises the following steps:

C) substrate is formed material dissolves in water;

D) will a) or b) in the solution that obtains with at c) in the solution of acquisition mix with formation nanoscale micelle; With

B) solution that will obtain in a) is dissolved in the water to form the nanoscale micelle;

C) randomly at b) in add one or more other auxiliary material in the solution that obtains;

D) substrate is formed material dissolves at b) or c) in the solution that obtains; With

On the other hand, the present invention relates to prepare the method for aforesaid solid composite medicament, it comprises the following steps:

A) auxiliary material or mixtures of auxiliary materials are dissolved in the water to form the nanoscale micelle;

B) the slightly solubility active substance is dissolved in the solution that obtains in a), wherein the solution that is obtained comprises the micelle that contains described slightly solubility active substance;

Aspect another one, the present invention relates to prepare the method for aforesaid solid composite medicament, it comprises the following steps:

A) auxiliary material or mixtures of auxiliary materials are dissolved in the water;

B) the slightly solubility active substance is dissolved in the solution that in a), obtains;

C) at b) in add one or more other auxiliary material in the solution that obtains, comprise the micellar solution that contains described slightly solubility active substance thereby form;

D) substrate is formed material dissolves at c) in obtain comprise in the micellar solution that contains described slightly solubility active substance; With

When using said method, can in step a), step b), step c) or step d), form micelle.For example, when employed auxiliary material or mixtures of auxiliary materials in step a) contain surfactant and surfactant is contacted with water, can in step a), form micelle.Under the sort of situation, described micelle does not comprise the slightly solubility active substance yet and the slightly solubility active substance is included in the micelle in step b).Alternatively, when surfactant is contacted with water, can in step b), form micelle.As the third alternative, when at step a) or b) in when not forming micelle yet, in step c), form micelle.In this case, in step c), add surfactant and/or surfactant is contacted with water first.As the 4th kind of alternative, when surfactant is contacted with water, in step d), form micelle.

A) merge slightly solubility active substance, auxiliary material or mixtures of auxiliary materials, randomly one or more other auxiliary material, substrate form material and water, to form the nanoscale micelle; With

B) make at A) in the mixture drying that obtains, thereby obtain solid composite medicament, wherein said micelle is embedded in described substrate and forms in the material.

Above-mentioned drying steps can be undertaken by lyophilization, spray drying or cryospray drying.Most preferred drying means is a spray drying.

The powder that forms by one of application said method is free-pouring, and when surpassing the fusion temperature of main auxiliary material, heating keeps stable and free-flow, even form the amount of material when very low when substrate, for example be lower than 50% even be lower than 30% even be lower than 20% or even be lower than 10%.In this powder, micelle keeps as existence in the initial micellar aqueous solution, but they are embedded in the solid matrix now, thereby stabilized.Form initial micellar aqueous solution (referring to Fig. 1) after being dissolved in the water once more.

Dried product can further be processed into granule, compressed tablets, sublingual lozenge or buccal tablet, and perhaps dry compositions can be filled in capsule or the wafer by means of conventional method and device with form of powder or particulate form.

Advantage of the present invention is the heat resistant type solid composite that can obtain the slightly solubility reactive compound, and it has very high bioavailability.Comprise the preparation of insoluble chemical compound (chemical compound 1 (SLV330)) bioavailability research (male than lattice sleuth in).Find, compare with the relative bioavailability of the compositions that comprises micronized (micronized) reactive compound, compositions according to the present invention male be about 6 times (referring to following Fig. 2) than the relative bioavailability in the lattice sleuth.

Develop out although the present invention is based on the active substance that can use in medical domain, this principle nano-scale particle therein has in the other technologies field of advantage and uses, and therefore purposes of the present invention is not limited to medical domain.

The following example only wishes further to illustrate in more detail the present invention, and therefore these embodiment mentioned herein are not considered as having limited by any way scope of the present invention.

Embodiment

Embodiment 1. materials and method.

Material:Polyethylene Glycol (for example PEG 400 and PEG 4000), polyoxyethylene sorbitan monoleate (Polysorbat for example

), Polyethylene Glycol-15 hydroxy stearic acid ester (for example

HS 15), anhydrous citric acid, mannitol, carboxylic propyl methocel (HPMC for example

), d-alpha-tocopherol cetomacrogol 1000 (vitamin E TPGS), sodium lauryl sulphate (SDS), polyvinylpyrrolidone (PVP-CL), stearyl alcohol fumaric acid sodium (for example

), microcrystalline Cellulose (MCC) and granular pyrogenic silica (Aeropearl for example

) obtain from commercial source.

Chemical compound 1:(4S)-and 3-(4-chlorphenyl)-4, be prepared described in 5-dihydro-N-methyl-4-phenyl-N '-(piperidino-sulfonyl)-1H-pyrazoles-1-carbonamidine such as the WO03/026648.

Chemical compound 2:(4S)-and 3-(4-chlorphenyl)-N-[(4-chlorphenyl) sulfonyl]-4, be prepared described in 5-dihydro-N '-methyl-4-phenyl-1H-pyrazoles-1-carbonamidine such as the WO02/076949.

Chemical compound 3:(4S)-and 3-(4-chlorphenyl)-4, be prepared described in 5-dihydro-N-methyl-4-phenyl-N '-[[4-(trifluoromethyl) phenyl] sulfonyl]-1H-pyrazoles-1-carbonamidine such as the WO02/076949.

Method

Plasma sample is analyzed according to following operating process.(20 μ L 250ng/mL) add in the plasma sample (20 μ L) that thaws with internal standard.Use methanol (210 μ L) that sample is implemented protein precipitation then.With sample mix, centrifugal (5 minutes, 3400rpm, room temperature), and the resulting supernatant of 50 μ L transferred in the 96 hole flat boards.(0.2%, 150 μ L) adds in each hole with formic acid.Extract mixture is merged centrifugal (5 minutes, 3400rpm, 4 ℃ of demarcation), submit to subsequently be used for Waters Acquity UPLC that Applied Biosystems API 4000 is connected on carry out the LC-MS/MS analysis.The mass spectrograph operator scheme is TurboIonSpray+, and analytical column is Waters Acquity BEH phenyl 1.7um, 100mm * 2.1mm (id).The concentration of the chemical compound 1 in calibration criterion and the QC sample adopts quadratic regression, determines as weighting with the inverse (1/x) of concentration.Use AppliedBiosystems/MDS Sciex Analyst ^TMSoftware 1.4.1 collects and process data.The preparation of embodiment 2. chemical compounds 1 preparations (FD PEG 400).

The 50mg insoluble drug chemical compound 1 of in the glass injection bottle, weighing.In this bottle, add then and comprise 66.34% (w/w) PEG 400,16.58% (w/w) Polysorbat 80,16.58% (w/w)

950mg surfactant-the cosolvent mixtures of HS 15 and 0.5% anhydrous citric acid (w/w).After medicine dissolves fully, in bottle, add 4ml Osmitrol (10%w/w), and inclusions is fully mixed.In ensuing 5 seconds, bottle is put into liquid nitrogen bath with the quick freezing mixture.At last, refrigerated mixture is in lyophilizing 48 hours under-80 ℃ and 0.050mbar in the laboratory freeze dryer (Christ Alpha 2-4, Salm and Kipp, The Netherlands).Obtain loose block.

The preparation of embodiment 3. chemical compounds 1 preparations (FD PEG 4000).

The 50mg insoluble drug (chemical compound 1) of in the glass injection bottle, weighing.In this bottle, add then and comprise 66.34% (w/w) PEG 4000,16.58% (w/w) Polysorbat80,16.58% (w/w)

950mg surfactant-the cosolvent mixtures of HS 15 and 0.5% anhydrous citric acid (w/w).This mixture storage is stored in 80 ℃ the baking oven and dissolves fully until medicine.In bottle, add (80 ℃) Osmitrols (10%w/w) of 4ml heating then, and inclusions is fully mixed until any solid contents dissolving.In ensuing 5 seconds, bottle is put into liquid nitrogen bath with the quick freezing mixture.At last, refrigerated mixture is in lyophilizing 48 hours under-80 ℃ and 0.050mbar in the laboratory freeze dryer (Christ Alpha 2-4, Salm and Kipp, The Netherlands).Acquisition can be with the spatula block of pulverize easily.

The preparation of embodiment 4. chemical compounds 1 preparations (SD PEG 4000).

The 13.7g insoluble drug (chemical compound 1) of in glass flask, weighing.In this flask, add then and comprise 66.34% (w/w) PEG 4000,16.58% (w/w) Polysorbat80,16.58% (w/w) 260g surfactant-the cosolvent mixtures of HS 15 and 0.5% anhydrous citric acid (w/w).This mixture storage is stored in 80 ℃ the baking oven and dissolves fully until medicine.Solution and 250ml hydroxypropyl emthylcellulose aqueous solution (HPMC Grad E5,0.016%w/w) mixing with this fusing of 1g.Then, (B ü chi Switzerland) comes the resulting solution of spray drying to use Mini SprayDryer B ü chi 191.Air-flow is 600l/ hour, and inlet temperature is 150 ℃, and aspirator sets 80% for, and the feed flow velocity is about 90 ℃ for about 5.5g/ minute and outlet temperature under these conditions.Obtain free flowable powder.

The preparation of embodiment 5. chemical compounds 1 preparations (SD TPGS).

The 1.0g insoluble drug (chemical compound 1) of in flask, weighing.(80 ℃) the vitamin E TPGS that in this flask, adds the 20.0g heating that comprises 0.5% (w/w) anhydrous citric acid then.This mixture storage is stored in 80 ℃ the baking oven and dissolves fully until medicine.Solution and 25ml hydroxypropyl emthylcellulose aqueous solution (HPMC Grad E5,0.16%w/w) mixing with this fusing of 1g.Then, (B ü chi Switzerland) comes the resulting solution of spray drying to use Mini Spray Dryer B ü chi 191.Air-flow is 600l/ hour, and inlet temperature is 150 ℃, and aspirator sets 80% for, and the feed flow velocity is about 5.5g/ minute, and outlet temperature under these conditions is about 90 ℃.Obtain free flowable powder.This embodiment shows, the invention is not restricted to surfactant-cosolvent mixtures.In case in the presence of dissolved pharmaceutically acceptable carrier, obtained the micellar aqueous solution of insoluble chemical compound, just resulting micellar solution processed according to the present invention.

The particle size of embodiment 6. chemical compounds 1 preparation (SD PEG 4000 is before with afterwards).

Use is equipped with the laser-diffractometer Coulter LS 13 320 of Coulter Aqueous Liquid Module, and (CA is USA) before carrying out spray drying and measure the micellar particle size of medicine afterwards for Beckman Coulter, Fullerton.For fluid true refractive index is set at 1.33 (water).For sample, true refractive index is set at 1.46 and empty refractive index is set at 0.01.The 50mg insoluble drug (chemical compound 1) of in the glass injection bottle, weighing.In this bottle, add then and comprise 66.67% (w/w) PEG 4000,16.67% (w/w) Polysorbat 80 and 16.67% (w/w)

(80 ℃) surfactant-cosolvent mixtures of the 950mg heating of HS 15.This mixture storage is stored in 80 ℃ the baking oven and dissolves fully until medicine.Solution and 250ml hydroxypropyl emthylcellulose aqueous solution (HPMC Grad E5,0.016%w/w) mixing with this fusing of 1g.The particle size of resulting micellar solution is a volume weighting diameter d 95% by determination of laser diffraction, and it is 345nm.1.4g is dissolved in the 250ml water according to the powder that contains medicine (comprising 50mg chemical compound 1) that embodiment 3 produces.The particle size of resulting micellar solution is a volume weighting diameter d 95% by determination of laser diffraction, and it is 254nm.

The tabletting of the FD powder of embodiment 7. chemical compounds 1.

By use experimental hydraulic press and apply 100 the crust compressed pressure 40 seconds, will become the two sides tablet of diameter 12.5mm by the powder compaction that embodiment 3 obtains.

The tabletting of the SD powder of embodiment 8. chemical compounds 1.

Powder that 325mg is produced according to embodiment 4 and the granular hydrophilic pyrogenic silica of 325mg ( 300/30, Degussa AG, Germany) and the 125mg polyvinylpyrrolidone (

CL, BASF Germany) mixes.Then, by use experimental hydraulic press and apply 40 the crust compressed pressure 2 seconds, described mixture is pressed into the two sides tablet of diameter 12.5mm.

The release characteristics spectrum of PEG 400 capsules (FD) of embodiment 9. chemical compounds 1.

To be filled in the hard gelatin capsule according to the powder that embodiment 2 produces.Medicament contg in capsule is 25mg.Dissolve test according to USP II.In 37.5 ℃, container is filled the 0.1M HCl that 900mL comprises the 0.5%w/v sodium lauryl sulphate.Stirring paddle speed is set at 50rpm during first 90 minutes, after this in other 30 minutes stirring paddle speed be increased to 150rpm.Filter the 10mL sample that after 0,5,10,20,30,45,60,90 and 120 minute, obtains by 0.22 μ m filter.All experiments are carried out in triplicate, and the meansigma methods ± covariance of these 3 times experiments is drawn as time function.Medicament contg in the sample uses HPLC to measure.About 95% medicine is released after 20 minutes.

The release characteristics spectrum of PEG 4000 capsules (FD) of embodiment 10. chemical compounds 1.

To be filled in the hard gelatin capsule by the powder that embodiment 3 obtains.Medicament contg in capsule is 25mg.Dissolve test according to USP II.In 37.5 ℃, container is filled the 0.1M HCl that 900mL comprises the 0.5%w/v sodium lauryl sulphate.Stirring paddle speed is set at 50rpm during first 90 minutes, after this in other 30 minutes stirring paddle speed be increased to 150rpm.Filter the 10mL sample that after 0,5,10,20,30,45,60,90 and 120 minute, obtains by 0.22 μ m filter.All experiments are carried out in triplicate, and the meansigma methods ± covariance of these 3 times experiments is drawn as time function.Medicament contg in the sample uses HPLC to measure.About 85% medicine is released after 20 minutes.

The release characteristics spectrum of PEG 4000 capsules (SD) of embodiment 11. chemical compounds 1.

650mg is filled in the hard gelatin capsule according to the powder that embodiment 4 produces.Medicament contg in capsule is 25mg.Dissolve test according to USP II.In 37.5 ℃, container is filled the 0.1M HCl that 900mL comprises the 0.5%w/v sodium lauryl sulphate.Stirring paddle speed is set at 50rpm during first 90 minutes, after this in other 30 minutes stirring paddle speed be increased to 150rpm.Filter the 10mL sample that after 0,5,10,20,30,45,60,90 and 120 minute, obtains by 0.22 μ m filter.All experiments are carried out in triplicate, and the meansigma methods ± covariance of these 3 times experiments is drawn as time function.Medicament contg in the sample uses HPLC to measure.About 85% medicine is released after 20 minutes.

The release characteristics spectrum of PEG 4000 tablets (SD) of embodiment 12. chemical compounds 1.

Drug release from the tablet of producing according to embodiment 8 is tested.The medicament contg of each tablet is 25mg.Dissolve test according to USP II.In 37.5 ℃, container is filled the 0.1M HCl that 900mL comprises the 0.5%w/v sodium lauryl sulphate.Stirring paddle speed is set at 50rpm during first 90 minutes, after this in other 30 minutes stirring paddle speed be increased to 150rpm.Filter the 10mL sample that after 0,5,10,20,30,45,60,90 and 120 minute, obtains by 0.22 μ m filter.All experiments are carried out in triplicate, and the meansigma methods ± covariance of these 3 times experiments is drawn as time function.Medicament contg in the sample uses HPLC to measure.About 82% medicine is released after 20 minutes.

Embodiment 13. does not carry out PEG 4000 tablets of spray-dired chemical compound 1.

In the present embodiment, prepared comparative formulations, so that those of the release characteristics of preparation more produced according to the invention spectrum and standard method (for example melt extrusion) have been produced other preparations.Therefore, the 150mg insoluble drug (chemical compound 1) of in the glass injection bottle, weighing.In this bottle, add then and comprise 66.67% (w/w) PEG 4000,16.67% (w/w) Polysorbat 80 and 16.67% (w/w)

(80 ℃) surfactant-cosolvent mixtures of the 2850mg heating of HS 15.This mixture storage is stored in 80 ℃ the baking oven and dissolves fully until medicine.Be poured on resulting solution on the glass plate and be cooled to 25 ℃ to solidify.With spatula solid mass is crushed to the irregular particle of the about 2mm-5mm of diameter then.Compress pressure 2 seconds by what use experimental hydraulic press and apply 40 crust, suppress the two sides tablet of 3 diameter 12.5mm, its solid mass (comprising the 12.5mg medicine) by 325mg crushing, the granular hydrophilic pyrogenic silica of 325mg (

300/30, DegussaAG, Germany) and the 125mg polyvinylpyrrolidone (

CL, BASF Germany) forms.

Embodiment 14. does not carry out the dissolving of spray-dired PEG 4000 chemical compounds 1 tablet.

Drug release from the tablet of producing according to embodiment 13 is tested.The medicament contg of each tablet is 12.5mg.Dissolve test according to USP II.In 37.5 ℃, container is filled the 0.1M HCl that 900mL comprises the 0.5%w/v sodium lauryl sulphate.Stirring paddle speed is set at 50rpm during first 90 minutes, after this in other 30 minutes stirring paddle speed be increased to 150rpm.Filter the 10mL sample that after 0,5,10,20,30,45,60,90 and 120 minute, obtains by 0.22 μ m filter.All experiments are carried out in triplicate, and the meansigma methods ± covariance of these 3 times experiments is drawn as time function.Medicament contg in the sample uses HPLC to measure.About 60% medicine is released after 20 minutes.

Embodiment 15. is based on the liquid filling capsule of the chemical compound 1 of PEG 4000.

In the present embodiment, prepared comparative formulations, so that those of the release characteristics of preparation more produced according to the invention spectrum and standard method (for example liquid filling capsule) have been produced other samples.Therefore, the 150mg insoluble drug (chemical compound 1) of in the glass injection bottle, weighing.In this bottle, add then and comprise 66.67% (w/w) PEG 4000,16.67% (w/w) Polysorbat 80 and 16.67% (w/w)

(80 ℃) surfactant-cosolvent mixtures of the 2850mg heating of HS 15.This mixture storage is stored in 80 ℃ the baking oven and dissolves fully until medicine.With resulting solution be filled into hard gelatin capsule (Licaps size 0, Capsugel, Belgium) in and be cooled to 25 ℃ to solidify.Pack into the agglomerate (comprising 25mg chemical compound 1) of 500mg fusing of each capsule.

Embodiment 16. is based on the capsular dissolving of liquid filling of the chemical compound 1 of PEG 4000.

Drug release from the capsule of producing according to embodiment 15 is tested.The medicament contg of each tablet is 25mg.Dissolve test according to USP II.In 37.5 ℃, container is filled the 0.1M HCl that 900mL comprises the 0.5%w/v sodium lauryl sulphate.Stirring paddle speed is set at 50rpm during first 90 minutes, after this in other 30 minutes stirring paddle speed be increased to 150rpm.Filter the 10mL sample that after 0,5,10,20,30,45,60,90 and 120 minute, obtains by 0.22 μ m filter.All experiments are carried out in triplicate, and the meansigma methods ± covariance of these 3 times experiments is drawn as time function.Medicament contg in the sample uses HPLC to measure.About 52% medicine is released after 20 minutes.

The preparation of embodiment 17. chemical compounds, 2 preparations (SD).

The 250mg insoluble drug chemical compound 2 of in glass flask, weighing.In this flask, add the 9.75g surfactant-cosolvent mixtures that comprises 66.34% (w/w) PEG 4000,16.58% (w/w) Polysorbat 80,16.58% (w/w) vitamin E TPGS and 0.5% anhydrous citric acid (w/w) then.This mixture storage is stored in 80 ℃ the baking oven and dissolves fully until medicine.Solution and 100ml hydroxypropyl emthylcellulose aqueous solution (HPMC Grad E5,0.016%w/w) mixing with this fusing of 1g.Then, (B ü chi Switzerland) comes the resulting solution of spray drying to use Mini Spray DryerB ü chi 191.Air-flow is 600l/ hour, and inlet temperature is 150 ℃, and aspirator sets 80% for, and the feed flow velocity is about 5.5g/ minute, and outlet temperature under these conditions is about 90 ℃.It is processed until whole medicine-surfactants-cosolvent mixtures to repeat this process.Obtain free flowable powder.

The tabletting of the SD powder of embodiment 18. chemical compounds 2.

Powder that 650mg is produced according to embodiment 17 and the granular hydrophilic pyrogenic silica of 450mg (

300/30, Degussa AG, Germany) and the 200mg polyvinylpyrrolidone (

The release characteristics spectrum of PEG 4000 capsules (SD) of embodiment 19. chemical compounds 2.

Drug release from the tablet of producing according to embodiment 18 is tested.The medicament contg of each tablet is 12.5mg.Dissolve test according to USP II.In 37.5 ℃, container is filled the 0.1M HCl that 900mL comprises the 0.5%w/v sodium lauryl sulphate.Stirring paddle speed is set at 50rpm during first 90 minutes, after this in other 30 minutes stirring paddle speed be increased to 150rpm.Filter the 10mL sample that after 0,5,10,20,30,45,60,90 and 120 minute, obtains by 0.22 μ m filter.All experiments are carried out in triplicate, and the meansigma methods ± covariance of these 3 times experiments is drawn as time function.Medicament contg in the sample uses HPLC to measure.About 92% medicine is released after 20 minutes.

The preparation of embodiment 20. chemical compounds 3 preparations (SD TPGS).

The 0.2g insoluble drug (chemical compound 3) of in flask, weighing.(80 ℃) the vitamin E TPGS that in this flask, adds the 1.8g heating that comprises 0.5% (w/w) anhydrous citric acid then.This mixture storage is stored in 80 ℃ the baking oven and dissolves fully until medicine.Solution and 100ml hydroxypropyl emthylcellulose aqueous solution (HPMC Grad E5,0.6%w/w) mixing with this fusing of 2g.Then, (B ü chi Switzerland) comes the resulting solution of spray drying to use Mini Spray Dryer B ü chi 191.Air-flow is 600l/ hour, and inlet temperature is 120 ℃, and aspirator sets 80% for, and the feed flow velocity is about 5.5g/ minute, and outlet temperature under these conditions is about 80 ℃.Obtain free flowable powder.This embodiment shows, the invention is not restricted to surfactant-cosolvent mixtures.In case in the presence of dissolved pharmaceutically acceptable water-solubility carrier, obtained the micellar aqueous solution of insoluble chemical compound, just resulting micellar solution processed according to the present invention.

The expansion experiment of embodiment 21. chemical compounds 1 preparations (SD TPGS).

The 100.0g insoluble drug (chemical compound 1) of in flask, weighing.(80 ℃) the vitamin E TPGS that in this flask, adds the 1900.0g heating that comprises 0.5% (w/w) anhydrous citric acid then.This mixture storage is stored in 80 ℃ the baking oven and stirs and dissolve fully until medicine.Solution (2000.0g) and 18.0L hydroxypropyl emthylcellulose aqueous solution (HPMC Grad E5,3.33%w/w) mixing with this fusing of 2kg.Use spray dryer Niro Atomizer Mobile Minor (Niro Inc.) to come the resulting micellar solution of spray drying then.Inlet temperature is 250 ℃, and the feed flow velocity is about 50g/ minute, and outlet temperature under these conditions is about 80 ℃.Obtain free flowable powder.This embodiment shows, is extended to more that large equipment also is fine, and resulting powder have with the identical character of the powder of small test chamber large-scale production.

Embodiment 22. measures the temperature stability of the powder that obtains among the embodiment 21 (SD TPGS).

The product (large-scale production chemical compound 1 SD TPGS) of embodiment 21 is placed 80 ℃ baking oven, and kept for 4 weeks in 80 ℃.Do not observe great change about powder morphology.Even after 80 ℃ of 4 weeks of storage, still keep free flowable powder.On the contrary, the physical mixture with same composition has just melted after storing 1 hour fully in 80 ℃ in identical baking oven.

4 kinds of different preparations of embodiment 23. chemical compounds 1 male than the comparison bioavailability data in the lattice sleuth.

Adopt the comparison bioavailability research of cross-over design, to test according to the bioavailability that comprises through the micellar final dosage form of embedding of the present invention with respect to other preparation types.Give 4 male 50mg chemical compounds 1 that are formulated in several dosage forms of as shown in following table 1, forming of using than lattice sleuth.

The composition of the preparation that table 1. is studied

In all cases, used 50mg chemical compound 1,2 dosage forms are used in this expression in some cases simultaneously.The average plasma levels of measuring according to method described in the embodiment 1 after Orally administered is described among Fig. 2.By the data of these measurement results acquisitions as providing in the table 2.

Table 2. male than lattice sleuth in the result of comparison bioavailability research of chemical compound 1

Preparation type	??C _MaximumRatio	Relative bioavailability
Preparation type	??C _MaximumRatio	Relative bioavailability	Micellar solution	??18	??7.6
Tablet (micronized)	??1	??1	Micellar solution	??18	??7.6
Tablet (micronized)	??1	??1	The liquid filling capsule	??8	??3.5
The micelle tablet of embedding	??10	??5.7	The liquid filling capsule	??8	??3.5

As above shown, compare with the relative bioavailability of the tablet that comprises micronized reactive compound, according to compositions of the present invention, for example comprise the tablet of micelle (containing reactive compound) through embedding, male be about 6 times than the relative bioavailability in the lattice sleuth.

Claims

1. comprise the micellar heat resistant type solid composite of nanoscale, wherein said micelle comprises the slightly solubility chemical substance that is dissolved in the auxiliary material, and wherein said micelle is embedded in the water-solubility carrier.

2. comprise the micellar heat resistant type solid composite medicament of nanoscale, wherein said micelle comprises the slightly solubility active substance that is dissolved in the auxiliary material, and wherein said micelle is embedded in the substrate of water miscible pharmaceutically acceptable carrier.

3. according to the compositions of claim 1 or 2, wherein said micelle has the effective average particle size particle size less than about 1000nm.

4. according to the compositions of claim 3, wherein said micelle has the effective average particle size particle size less than about 500nm.

5. according to the compositions of claim 1-4, wherein said auxiliary material comprise the surfactant of 10%w/w at least, and randomly one or more cosolvents and/or one or more cosurfactants.

6. according to the compositions of claim 1-5, wherein said auxiliary material (for example are selected from Myrj 45

), the polyoxyethylene sorbitan aliphatic ester (for example ), castor oil derivatives (for example ), vitamin E TPGS, nonionic polyox-yethylene-polyoxypropylene block copolymer (for example

), the water-soluble long-chain organophosphorus ester (for example

), inulin lauryl carbamate (Inutec for example

).

7. according to the compositions of claim 5 or 6, wherein said cosolvent is selected from aklylene glycol for example PEG, propylene glycol; Polyhydric alcohol is mannitol, Sorbitol and xylitol for example; Polyoxyethylene; Linear polyhydric alcohol is ethylene glycol, 1 for example, 6-hexanediol, neopentyl glycol and methoxy poly (ethylene glycol); And composition thereof.

8. according to the compositions of claim 7, wherein said cosolvent is that molecular weight is equal to or less than 800 daltonian Polyethylene Glycol (PEG).

9. compositions according to Claim 8, wherein said cosolvent is selected from PEG 200, PEG400 and PEG 800.

10. according to the compositions of claim 7, wherein said cosolvent is that molecular weight is 950-20,000 daltonian Polyethylene Glycol (PEG).

11. according to the compositions of claim 10, wherein said cosolvent is selected from PEG 2000, PEG 3350, PEG 4000 and PEG 8000.

12. according to the compositions of claim 2-11, acceptable carrier is selected from the wherein said water solublity pharmacy:

-alkylcellulose, for example methylcellulose;

-carboxyl alkyl cellulose, for example carboxymethyl cellulose;

-carboxyalkyl alkylcellulose, for example carboxymethylethylcellulose;

-carboxyl alkyl cellulose ester;

-starch;

-pectin, for example carboxymethyl amylopectin sodium;

-chitin derivatives, for example chitosan;

-polysaccharide, for example alginic acid, its alkali metal and ammonium salt;

-polyacrylic acid and salt thereof;

-polymethylacrylic acid and salt thereof, methacrylate copolymer;

-polyvinyl alcohol;

-polyvinylpyrrolidone, the copolymer of polyvinylpyrrolidone and vinyl acetate;

13. according to the compositions of claim 1-12, the form of wherein said compositions is powder, granule, compressed tablets, sublingual lozenge, buccal tablet, filled capsules or fills wafer.

14. according to the compositions of claim 1-13, wherein said slightly solubility active substance is selected from cannabinoid agonists, cannabinoid inverse agonists and cannabinoid antagonist.

15. according to the compositions of claim 14, wherein said slightly solubility active substance is (4S)-3-(4-chlorphenyl)-4,5-dihydro-N-methyl-4-phenyl-N '-(piperidino-sulfonyl)-1H-pyrazoles-1-carbonamidine.

16. according to the compositions of claim 14, wherein said slightly solubility active substance is (4S)-3-(4-chlorphenyl)-N-[(4-chlorphenyl) sulfonyl]-4,5-dihydro-N '-methyl-4-phenyl-1H-pyrazoles-1-carbonamidine.

17. according to the compositions of claim 14, wherein said slightly solubility active substance is (4S)-3-(4-chlorphenyl)-4,5-dihydro-N-methyl-4-phenyl-N '-[[4-(trifluoromethyl)-phenyl] sulfonyl]-1H-pyrazoles-1-carbonamidine.

18. preparation is according to the method for the solid composite medicament of claim 2-17, it comprises the following steps:

D) substrate is formed material dissolves at c) in the mixture that obtains; With

19. preparation is according to the method for the solid composite medicament of claim 2-17, it comprises the following steps:

C) substrate is formed material dissolves in water;

20. preparation is according to the method for the solid composite medicament of claim 2-17, it comprises the following steps:

21. preparation is according to the method for the solid composite medicament of claim 2-17, it comprises the following steps:

22. preparation is according to the method for the solid composite medicament of claim 2-17, it comprises the following steps:

23. according to the method for claim 18-22, wherein said drying steps makes up by lyophilization, spray drying, cryospray drying, vacuum drying or its and carries out.

24. according to the method for claim 18-23, it further comprises described solid composite medicament is processed into granule, compressed tablets, sublingual lozenge or buccal tablet.

25. according to the method for claim 18-23, it further comprises described solid composite medicament is packed in capsule or the wafer.