TW200824711A - Embedded micellar nanoparticles - Google Patents

Abstract

The present invention is related to a thermostable solid composition comprising nanosized micelles of a poorly soluble chemical substance, such as a biologically active substance, dissolved in an auxiliary material, said micelles being embedded in a water soluble carrier. The invention is further related to a process for preparing said solid composition and to pharmaceutical dosage forms prepared from this composition.

Description

200824711 IX. Description of the invention: [Technical field of invention of genus] The invention is an embedded micro-nanoparticle. [Prior Art 3 5 Background of the Invention Most of the new drug molecules revealed from the drug discovery program show poor solubility in aqueous media, or they are even almost insoluble in aqueous media. It is therefore very challenging to formulate these active substances in a manner which can be administered parenterally or orally. Dissolution rate (according to 10 Noyes_Whitney (Jimio et al., Effect of particle size reduction on dissolution and oral absorption of a poorly water-soluble drug, cilostazol, in beagle dogs, J. of Controlled Release 111 (1-2), 56-64 , 2006) The proposed law, low solubility is generally associated with low dissolution rates) and intestinal permeability is a key decision about bioavailability of the I5 factor', especially for orally administered drugs. According to Biopharmaceutics Classification Systein (GL Amidon 5 H. Lennernas 5 VP Shah, and J. R. Crison. A theoretical basis for a biopharmaceutics drug classification e. the correlation of in vitro drug product dissolution and in vivo bioavailability. 20 Pharm· Res· 12 ·· 413 - 420 (1995)), poorly soluble drugs belong to BCS class II or BCS class IV. BCS class IV means that the drug shows both poor solubility and low permeability, while the bioavailability of BCV class II drugs is usually limited by the dissolution rate (Formulation of poorly water-soluble drugs for oral administration 'Physicochemical 5 200824711 and physiological issues and the lipid formulation classification system 5 Colin W. Pouton 5 European Journal of

Pharmaceutical Sciences 2006,, 278-87) ° This means that the bioavailability of the bcS class II drug can be increased by improving its dissolution rate and/or saturation 5 solubility cs. Various formulation strategies have been applied to improve the solubility and dissolution rate of poorly soluble drugs. The formation of the inclusion complex of the active substance and the cyclodextrin can improve the solubility of the drug (for example, 10 wo9932107 which uses cyclodextrin to solubilize THC is disclosed). Cyclodextrins are cyclic aggregates of glucose or glucose derivatives that form reversible, non-covalent associations with poorly soluble drugs to solubilize the drug. Lipid-based systems such as emulsions, microemulsions, self-emulsifying drug delivery systems (SEDDS) or self-microemulsifying drug delivery systems (SMEDDS) are suitable for active substances that are soluble in lipids and oils. These lipid preparations contain oils or lipids in which the active substance is dissolved, and they are present in the form of an emulsion or they are diluted with water to form an emulsion system. In the case where the active material remains in a solid form, the first method is to reduce the particle size of the solid amorphous or crystalline active material to produce a solid amorphous or crystalline material having a particle size reduced by 2 Å. A reduction in particle size results in an increase in surface area. The drug particles have an improved dissolution rate due to the larger surface area. In general, in the production of materials with reduced particle size, there is a difference between top-down (t〇P-d〇wn) and bottom-up (bott〇m) technologies. Top-down techniques involving energy rounding to break up large particles into small particles depending on the technique being fabricated, can achieve average particle size in the micron range (eg jet milling, hammer milling) or nano range (eg wet ball milling) And the substance to be ground in the high pressure homogenization). For the latter, it is recommended to use a micronized starting material (US 5,145,684; US 5,858,410). A typical disadvantage of these techniques is that they require enormous energy to break down the starting material. The technique of bottom-up technology for producing drug nanocrystals via a precipitation process is described in the old pharmacopoeia as "via pamtum." Dissolving the active substance in a solvent, adding the solvent to a non-solvent or anti-solvent 10 (which is miscible with the solvent), and the active substance in the form of amorphous or crystalline nanoparticles The form precipitates, and the crystalline nanoparticle is also called a drug nanocrystal. The particles are generally stabilized by surfactants or polymeric stabilizers. This principle applies to the production of so-called, hydrosols (us 5, 389, 382). Some modifications of this precipitation principle have recently been described (us patent application 1550139144). However, it is difficult to immobilize precipitated crystals at the nanometer level. In the range, nanoparticulate structures generally tend to grow to form microparticles or crystallites. One way to solve this problem is to immediately dry the prepared suspension 'for example by beam drying (Sucker, H., Hydrosole-eine Altemative fiir die parenterale Anwendung) Von schwer wasserloslichen 20 Wirkstoffen, in · Mtiller, R. H., Hildebrand, GE, (Hrsg.), Pharmazeutische Technologie : Moderne Arzneiformen, 2. Auflage, 1998, WVG, Stuttgart). More recently developed involving supercritical fluids Or spray-freeze-dried particle size reduction method in the literature on the production of solid drug nanoparticles 7 200824711 to description (Jiahui Hu, Keith R Johnston, and Robert O. Williams III ^ Nanoparticle Engineering Processes for Enhancing the Dissolution Rates Of Poorly Water Soluble Drugs ^ DRUG DEVELOPMENT AND INDUSTRI AL PHARMACY, Vol. 30, No. 3, pp. 233-245, 2004). All particle size reduction techniques have a common disadvantage; usually the drug needs to be dissolved to be absorbed by the intestine. For some very difficult to dissolve Drug, particle size reduction may not be sufficient to improve dissolution behavior and increase bioavailability.10 Another way to improve the dissolution behavior of poorly soluble actives is to incorporate the materials into an amorphous system such as a solid dispersion. A solid dispersion" defines a solid state system (as opposed to a liquid or gas system) comprising at least two components, wherein one component is substantially evenly dispersed throughout the other component or components. A solid dispersion which is chemically and physically uniform or homogeneous or consists of a single phase as defined in Thermodynamics 15 may also be referred to as a solid solution (W097/044014). The solid substrate can be crystalline or amorphous. The drug may be present in molecular dispersion or in the form of amorphous particles (clusters) as well as crystalline particles (solid dispersion). Examples of such solid dispersions are the tert-butylidone formulations described in U.S. Patent 5,281,420 and the bioactive peptide formulations described in WO 2005/053727. The solid dispersion can be prepared by various methods such as melting, hot melt extrusion, solvent evaporation or supercritical fluid (D.j. van

Drooge "Combining the Incompatible", Rijksimiversiteit

Gnmingen, PhD-Thesis 2006). Solid dispersions or solid solutions may contain 8 200824711 containing surfactants or other excipients to enhance dissolution or stabilization of the drug. Several techniques for producing solid dispersions are discussed in U.S. Patent Application No. 20050266088 A1. This application also discloses a process for producing a sugar glass of a lipophilic compound in which a lipophilic compound is dissolved in a cosolvent, preferably a CrC6 5 alcohol. Preferred solvents have a high vapor pressure and a high melting point. However, the use of the recommended high vapor pressure, flammable cosolvent may cause difficulties for large-scale production, especially when “application of hemospheres as a drying technique. In order to protect the entire system from explosion, the oxygen content in the dry air must be reduced. In addition, lipophilic compounds are not sufficiently stable and tend to precipitate in aqueous cosolvent systems. For this reason, rapid processing is recommended to avoid "turbidity." When the active substance is hydrophobic rather than lipophilic, it is insoluble. In the case of lipids and oils, a cosolvent or cosolvent-surfactant mixture can be used to solubilize the active substance. In order to classify different solubilizing systems, c. Pouton has proposed the Lipid Formulation System (LFCS). The recent version distinguishes four types of formulation: p 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 LFCS Type IV describes surfactant based - An oil-free formulation of 20 solvent mixtures. Typically, these surfactant-cosolvent mixtures are filled into soft gelatin capsules or sealed hard gelatin capsules. When administered orally, the drug is released after dissolution of the capsule shell. The reason in the carrier 'so it can be absorbed quickly (LiqUid-Filled and Seal

Hard Gelatine Capsule Technologies, Ewart Τ· Cole, in : 9 200824711

Modified-Release Drug Delivery Technology ^ eds. MJ Rathbon, J. Hadgmft, M. S. Roberts, Marcel Dekker, Basel, 2003) In order to produce conventional solid dosage forms from liquid poorly soluble drugs, by Spireas 5 et al. (Spireas et al. , Powdered solution technology: principles and mechanisms, Pharm. Res. 9 No. 10, 1351-1358, 1992) The production of "powdered solutions" is proposed. "Powdered solution" is produced by mixing a liquid drug or drug solution with a selected carrier. The product obtained by this technique is a physical mixture or blend of the drug/surfactant solution and the selected carrier. Examples of such formulations are disclosed in WO 2005/041929, WO 2006/113631 and WO 2006/135480. However, the usual disadvantages of the obtained powder are its poor fluidity, poor heat resistance and poor compressibility. It is an object of the present invention to provide further and improved formulations for compounds, particularly biologically active compounds, which can be prepared by using commercially available materials as well as standard methods and equipment. In the case of biologically active compounds, a further goal is to provide formulations with good bioavailability. [Brightness 3 20 SUMMARY OF THE INVENTION The present invention relates to resistance,, i, and b of poorly soluble compounds having improved dissolution behavior. The novel pharmaceutical composition of the present invention comprises a surfactant chelating surfactant-cosolvent mixture comprising a poorly soluble chemical such as a drug, a poorly soluble drug, which is embedded by drying its aqueous micelle solution 10 200824711 A water soluble carrier such as a pharmaceutically acceptable carrier is in a water soluble matrix. In another aspect, the present invention relates to a micellar water/liquid mixture for preparing a poorly soluble compound, followed by a drying step to embed these micelles in a water-soluble shell of a carrier to obtain a heat-resistant composition. The 朦 t containing the poorly soluble compound is produced by using one or more kinds of surfactants and optionally one or more kinds of cosolvents. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a general 10 method in accordance with the present invention in the case of pharmaceutical use. The 囷β gave out the plasma concentration of Compound 1 obtained after administration of four different preparations (including the preparation according to the present invention) to a male beagle dog. C. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS In the first aspect, the present invention relates to a heat-resistant solid composition comprising a nano-sized micelle of a poorly soluble chemical substance of the auxiliary material towel. The micelles are embedded in a water-soluble carrier. In another aspect, the present invention relates to a heat-resistant solid pharmaceutical composition, wherein each of the micelles of the poorly soluble biologically active substance in the auxiliary material is encapsulated in a water-soluble pharmaceutically acceptable substance. Accepted in the matrix of the carrier. Within the scope of the present invention, the term, the term "fever type" means that the formulation is still a free flowing stable powder when heated above (4). This 11 200824711 means that when heated above the melting point of the main auxiliary material 5 . , ι〇. 2〇. 3〇. At 40° or 50°, the formulation is still physically stable. For example, vitamin E TPGS (d_a • tocopherol polyethylene glycol 1 〇〇〇 amber

The acid ester) has a melting point of 36 ° C (reference: Eastman, Material Safety Data 5 Sheet of Vit E TPGS NF Grade). Those skilled in the art will assume that if the vitamin ETPGS is the major component of the formulation, such formulation will exhibit at least partial melting when exposed to temperatures well above 36 °C, such as 80 °C. However, if vitamin ETPGS is used as an auxiliary material according to the present invention, this means that the vitamin E TPGS (and active substance) micelles are embedded in the melting point over ^. In the water-soluble matrix material of 匸 10, the resulting powder will not show a significant change in powder morphology and fluidity. Even after exposure to the melting point of the main auxiliary material TPGS 5 . , 10. 20. 3〇. 4〇. Or 5〇. At the temperature, it is still a stable free-flowing powder. Within the scope of the present invention, the terms, biologically active substance, "pharmaceutical substance", "active compound", "active ingredient", are used interchangeably when applied to humans or animals. A chemical substance or chemical compound that induces a pharmacological effect. Within the scope of the present invention, the term "insoluble compound," means a compound having a solubility of less than 33 g/L in water. Particularly for pharmaceutical deuterated substances, the term poorly soluble compounds are used to describe conditions at sites in the body (eg, 'stomach, intestine, subcutaneous), particularly having a degree of resolution of less than 33 g/L at 11 . A compound at which the compound is expected to become available to the body (especially the compound dissolves to be absorbed by the body). Thus, for example, it is desirable that the poorly soluble compound dissolved in the stomach has a solubility in the gastric fluid (pH about i~3) of 12 200824711 at 33 g/l, while the poorly soluble compound to be dissolved in the intestine is in the intestinal fluid (usually up to about Solubility below 33 § 8 in pH 7.4). (Refer to US 005Θ266_ ‘ Frijlink). The invention is particularly useful for more sparingly soluble compounds 'e.g., having less than 1 〇, 4 §, 1 _, 1 〇〇 5 mg/L, 40 mg/L, 10 mg/L, 4 mg in gastrointestinal fluids /L, 1 mg/L, 0.4 mg/L or 0.1 mg/L solubility of the compound. The poorly soluble compound to be processed in accordance with the present invention may be liquid, semi-solid, solid amorphous, liquid crystalline or solid crystalline. The poorly soluble compound to be processed according to the present invention is preferably a pharmaceutical active agent, and may be selected from the group consisting of analgesics, antiarrhythmic drugs, antiasthmatics, antibiotics, anthelmintics, anti-inflammatory agents, antiviral agents, and antibiotics. Coagulant, antidepressant, antidiabetic, antiepileptic, anti-erectile dysfunction, antifungal, anti-gout, antihypertensive, antispasmodic, antimigraine, antimuscarinic, antibiotic Oncology drugs, diet pills, anti-shock palsy drugs, anti-protozoal drugs, 15 anti-thyroid drugs, antitussives, anti-anxiety agents,/5-blockers, hypnotics, immunosuppressants, neuroleptics, cannabinoids Receptor agonists and antagonists, cardie inotropic agents, cell-associated inhibitors, corticosteroids, cytokine receptor activity modulators, diuretics, gastrointestinal drugs, histamine receptor antagonists, Cuticular layer separating agents, lipid regulators, muscle relaxant 20 relaxants, nitrates and other anti-angina drugs, non-steroidal antiasthmatics, opioid analgesics, sedatives, sex hormones and stimulants. Preferred classes of poorly soluble compounds are poorly soluble cannabinoid agonists, inverse agonists and antagonists. Examples of such compounds are W001/70700, WO02/076949, WO03/026647, WO03/026648, 13 200824711

Compounds disclosed in W003/027076, WO2005/074920, WO 2005/080345, WO 2005/118553 and WO2006/087355, such as (4S)-3-(4-chlorophenyl)-4 described in WO 03/026648 ,5-dihydro-N-methyl-4-phenyl·Ν'-(1-i °定基-基醯基)-1Η-吼嗤-1-甲脒, and w〇5 02/076949 (4S)-3-(4-chlorophenyl)-N-[(4-chlorophenyl)sulfonyl]-4,5·dihydro-Nf-methyl-4-phenyl-1H-σ嗤-1-甲脒 (also known as ipipinabant or SLV319) and (4S)-3-(4-chlorophenyl)-4,5-dihydromethyl-4-phenyl-[[4_(three Fluoromethyl)phenyl]sulfonyl]-iH-n is smaller than indole. The poorly soluble compound in the composition of the invention preferably has a log P of less than 1 Torr, more preferably less than 5, more preferably less than 2.5, and may range from 0.05% w/w to at least 50% by weight based on the total weight of the composition. The amount of /w is present, preferably 〇.〇5〇/0 - 10°/. Or 0.05% - 5% or 0.05% - 1% of the amount. Within the scope of the present invention, the term "auxiliary material" is a material which, when contacted with water, enables the formation of micelles, or a material which positively affects its stability when the micelles have been formed, such as surfactants a cosolvent or a mixture of a surfactant and a cosolvent. Within the scope of the present invention, the term ''micelle," means a surfactant that exceeds the Krafft point and the critical micellization concentration in an aqueous solution. Molecular associations (see Riimpp 〇nline Dicti〇nary). According to IUPAC, surface 20 active agents are usually associated colloids in solution, ie they tend to form colloid-sized aggregates, molecules or ions (The aggregate formed by the molecules or ions) is present in equilibrium. Such aggregates are called micelles. The Clough feature means such a temperature (more precisely, a narrow temperature range), ie at that temperature The solubility of the upper surfactant in water rises sharply. At 14 200824711, the solubility of the surfactant becomes equal to the critical micelle concentration. It passes the solubility of the solution. The steepness of the slope of the plot of the logarithm versus t*1/T is optimally determined. There is a relatively small range of surfactant concentrations that separate the lower and upper limits, and near the lower limit, almost no micelles are detected. ,

At and above the upper limit, almost all of the additional surfactant molecules form micelles. If plotted against concentration, many of the properties of the surfactant solution appear to change at different rates when they are below and below this range. By extrapolating the trajectories of such properties above and below this range until they intersect, a value called the critical micellization concentration (critical micelle concentration) can be obtained (IUPAC 10 Compendium of Chemical Terminology, Goldbook). The micelles in the composition according to the invention have an average size of less than 1 〇〇〇 nm 'preferably less than 500 nm, or less than 200 legs, or less than 100 nm 〇 within the scope of the invention, the average size means through dynamics Effective average diameter measured by light scattering method 15 (for example, light correlation spectroscopy (PCS), laser diffraction (LD), small angle laser scattering (LALLS), medium angle laser scattering (MALLS), light obscuration methods (for example, the Coulter method), rheology, or microscopy (optical or electronic), within the ranges described above). An effective average particle size of less than about x nm means that at least 90% of the particles have a weight average particle size of less than about X nm when measured by the above technique. The composition according to the invention may comprise at least 10% of a surfactant or at least 30%, or at least 50%, and may comprise up to 99.95% of a surfactant. Optionally, the composition further comprises one or more co-solvents and/or 15 200824711 one or more co-surfactants. For pharmaceutical compositions, surfactants and optional co-surfactants that can be used are in Μ·Μ· Rieger, "Surfactants", Pharmaceutical

Dosage Forms, Marcel Dekker Inc" (1993) Chapter 8, pages 285-359, page 5. Preferred surfactants are surfactants having an HLB value greater than 8. The most preferred surfactants are selected from the group consisting of polyoxyethylenes. Stearates (eg Solutol®), ethoxylated sorbitan fatty acid vinegar (eg Tween®), polyoxyethylene castor oil derivatives (eg Chremophor®), vitamin E TPGS, nonionic polyoxyethylene-poly Oxypropylene block copolymers (eg 10 P〇l〇xamer®), water-soluble long-chain organophosphates (10) such as Arlat〇ne@), inulin lauryl carbamate (eg Inutec SP1®). Preferably, the optional co-solvent used is a pharmaceutically acceptable non-volatile co-solvent which is a material having a vapor pressure of less than 0.50 mm Hg at 25 ° C. The pharmaceutical composition is only classified with the lipid formulation classification. Related to a solubilized mixture of type 1V (LFCS), which is defined by Ponton (see paragraph [〇〇12]) as an oil-free formulation based on a surfactant and a co-solvent, and thus in the present invention Specially excluded from the cosolvent. LFCS I was also excluded. Formulation (non-dispersive; need to digest), LFCS π type preparation (SEDDS without water-soluble components), LFCS ΙΙΙΑ type preparation (SEDDS/SMEDDS with 20 water-soluble components), LFCS ΙΙΙΒ type preparation (with water-soluble preparation) Sex components and low oil content of SMEDDS. Examples of non-volatile cosolvents include, but are not limited to, alkylene glycols such as polyethylene glycol (PEG), propylene glycol, diethylene glycol monoethyl ether, triacetin vinegar , phenyl sterol; polyhydric alcohols such as mannitol, sorbitol, and xylitol; poly 16 200824711 oxyethylene; linear polyols such as ethylene glycol, it hexane diol, neopentyl diol, and decyloxypolyethylene glycol, and Mixture. Particularly useful as a non-volatile co-solvent is PEG, which is a polymer of ethylene oxide, which generally follows the formula (HOCf^CHAOH, where the number of units is 5 mesh, this number also defines the polymer Average molecular weight (ΠΜν.) The type of PEG useful in the present invention can be classified by its state of matter, that is, whether the substance exists in a solid or liquid form at room temperature and pressure. Within the scope of the present invention, Liquid PEG" refers to PEG There is such a molecular weight (mw·) that the substance is liquid at room temperature and pressure. 10 For example, 'PEG with an average mw of less than 800 Daltons. Particularly useful 疋 PEG 400 (mw·about 380-420 Dalton), PEG 600 (mw about 570-630 Daltons) and mixtures thereof. PEGs from d〇w

Chemical (Danbury, Corni) is commercially available under the CARBOWAX SENTRY product line. 15 Within the scope of the present invention, "solid PEG" means that PEG has such a molecular weight (m.w.) that the material is solid at room temperature and pressure. For example, a PEG having an average m.w. of 900 to 20,000 Daltons is a solid PEG. Particularly useful solid PEGs are those having an m.w. of 3,350 Daltons (m.w. from about 3015 to about 3,685 Daltons) to 8,000 Daltons (m.w. about 7,000 to 9,000 Daltons). Particularly useful as solid PEG is PEG 3350, PEG 400001 about 3,600-4,400 Daltons), ? £0 8000 and its mixture. When a solid PEG (e.g., PEG 4000) is used in place of a liquid PEG (e.g., PEG 400), the resulting drug-surfactant-cosolvent mixture must be heated to 80 °C. It has been surprisingly found that the release of PEG 400 when PEG 400 is substituted 17 200824711 does not change much, although the lumps produced by lyophilization of the peg 4000 product are more rigid than when PEG 400 is used. When present, the formulation comprises 〇.1% w/w to 99.95% w/w, preferably 10.0% W/W-90.0% W/W, most preferably 2 〇.〇%w/w_7〇〇%w/w The amount of 5 cosolvent.

The water soluble carrier (also referred to as the matrix) can be any polymeric material that is soluble in water. If at least a portion of the matrix material can be dissolved in 1Q to 3g of water, then the matrix material can be considered to be soluble in water (according to usp 24, page 2254, 10 for pharmaceutical compositions, the water-soluble contact should be pharmaceutically acceptable) The pharmaceutically acceptable carrier should preferably be selected from the group consisting of: another alkyl cellulose, such as methyl cellulose; hydroxyethyl fibers - burnt cellulose, such as (tetra) cellulose, hydroxypropyl cellulose, and Hydroxybutyl cellulose;

Monohydroxyalkylalkylcellulose, such as hydroxyethylmethyl mercaptocellulose; & cellulose and C-reposted cellulose, such as cellulose; carboxyalkyl cellulose alkali metal _ - carboxyalkyl silk fiber f, _ cellulose sodium 20 I (tetra) 竣 methyl ethyl cellulose · a ketone cellulose ester; " ' a starch; - pectin, such as around the methyl branch condensate; - chitin derivatives, such as chitosan; a polysaccharide such as alginic acid, compound base metal and ammonium salt 18 200824711 - carrageenan, galactomannan, tragacanth, kines, gum arabic, melon And xanthan gum; a polyacrylic acid and its salts; a poly-mercaptoacrylic acid and its salt, a methacrylate copolymer, 5 a polyvinyl alcohol; - a polyethylene halpyrone, a polyvinylpyrrolidone a copolymer of ethyl acetate vinegar; a polyepoxy burn, such as polyethylene oxide and polypropylene oxide, and a copolymer of ethylene oxide and propylene oxide. 10 pharmaceutically acceptable and having the definition as defined above An unlisted polymer of suitable physical and chemical properties is also suitable as a drug group in the present invention. The carrier of the material. 15 20 The preferred water-soluble polymer is propyl mercapto cellulose or HpMC. The HPMC contains sufficient hydroxypropyl and methoxy groups to make it soluble in water. The degree of methoxy substitution is HPMC which is from about G.8 to about 2.5 and which is substituted by propyl moles from about 0.05 to about 3.0 is generally water soluble. The degree of foxy substitution refers to the presence of the (iv) group of the persaccharide unit of the cellulose molecule. The average number. (4) The base molar substitution refers to the average number of moles of propylene oxide that has been reacted with each of the anhydroglucose units of the cellulose molecule. The propofol cellulose ellose is a US adopting propylmethylcellulose. The composition according to the invention may comprise one or more other additives. In the case of pharmaceutical compositions, these additives should be pharmaceutically acceptable additives, such as flavoring agents, coloring agents, filling, filling, filling Agent old mixture, lubrication #1, disintegration aid and/or other additives pharmaceutically acceptable as 19 200824711 5 L· • The preparation of the composition according to the invention involves preparing an aqueous micelle solution of a poorly soluble compound, The drying step is followed by embedding the micelles in a water-soluble matrix of a carrier such as a pharmaceutically acceptable carrier. The micelles comprising the poorly soluble compound are produced by using one or more surfactants, and may also be included if necessary. One or more cosolvents. In another aspect of the invention, a micellar solution of a poorly soluble compound is produced by dissolving it in one or more surfactants. Dissolution means that the poorly soluble compound is substantially monodisperse dispersed. That is, at least 95%, preferably at least 98%, more preferably at least 99%, even more preferably at least 99.5%, and most preferably at least 99.9% of the poorly soluble compound is dispersed in a single molecule. If necessary, one or more may be added. A variety of cosolvents. Energy can be applied to enable complete molecular dispersion by heating, blending or mixing the components. When the components have formed a molecular dispersion system, they are mixed with the aqueous phase to form a micellar solution. The aqueous phase may comprise a carrier such as a dissolved matrix of a pharmaceutically acceptable carrier, or the water soluble matrix of the carrier may later be dissolved in the micellar solution. This mixture was dried to obtain a solid powder. The powder can be used as such or mixed with other excipients and further processed. In another aspect of the invention, the composition according to the invention promotes absorption of a poorly soluble drug because it forms a drugic micellar solution when administered. A further aspect of the invention is that it facilitates the production of formulations, even those known to be incompatible with hard gelatin capsules (e.g., PEG 400, glycerin, polyoxyethylene (35) castor oil (e.g., Cremophor EL8) ), propylene glycol, diethylene glycol monoethyl scale (eg Transcutol P®), sorbitan monooleate 20 200824711 (eg Span 808)) can also be processed into powders for capsule filling. Freeze-drying is clearly not a preferred production method for large-scale production, and is usually applied only to extremely unstable drugs such as proteins. Spray dry grass is more convenient and more suitable for mass production. Therefore, spray drying was tested as a drying method of the micelle solution according to 5 invention, and it was found to be very suitable for production. Since flammable cosolvents with high vapor pressure are not used, the production of spray dried powders can be carried out on standard equipment without special protection against explosion. Furthermore, the micelle solution is stable within a few hours and in some cases even a few days, the drug does not precipitate. The dissolution test has been performed to obtain approximately the same dissolution rate regardless of the drying used. Particle size analysis using chirp diffraction was performed to test the effect of the drying step on the size of the micelle particles, and it was shown that the particle size after spray drying and after redispersion from the spray dried powder was of the same order of magnitude. From this result, it can be concluded that the drying process does not change the size of the obtained micelles. The process of the invention is not limited to surfactant-cosolvent mixtures. The micelle solution obtained by obtaining a poorly soluble compound bundle in the presence of a dissolved pharmaceutically acceptable carrier can be processed according to the present invention. The pharmaceutical composition according to the present invention can be further processed into any solid J1L® for any route of use. The dosage forms of particular interest are granules, for delivery, delivery of tablets, sublingual tablets or buccal tablets, and hard gelatin capsules or capsules filled with powder or granules ^ 21 200824711 The agent is clearly the most preferred solid dosage form in the pharmaceutical industry. However, it has heretofore been difficult to produce tablets from liquid or semi-solid preparations containing solubilized (i.e., dissolved) forms of poorly soluble drugs. One way is to absorb the liquid drug or drug solution onto the selected carrier (Spireas et al., powdered solution 5 technology: principles and mechanisms > Pharm. Res. 9 No. 10, 1351-1358, 1992). However, the usual disadvantage of the obtained powder is its poor fluidity and compressibility. A particular object of the invention is to provide a solution to this problem. The powder produced according to the present invention, particularly the powder produced by spray drying, shows very good fluidity. The dry powder can be mixed with the pharmaceutical excipients in a dry state. The resulting powder mixture can be filled directly into the capsule, however compression into tablets is also possible. The tablets obtained have shown very rapid drug release with a release rate relative to the release rate of capsule formulations of similarly composed powders. Especially when granular igneous cerium oxide (for example AEROPERL® 300) is used as a filler, a very fast 15 speed tablet disintegration and thus good drug release are obtained. Tablets produced in accordance with the present invention have been shown to release much better than those produced by standard methods such as solution extrusion or liquid filled capsules. When it is more difficult to make the solidified mass obtained by melt extrusion into a powder when the release profile of the tablet preparation produced according to the present invention and the preparation prepared by the melt extrusion is turned into a powder; A non-uniform tablet was obtained and only 60% of the drug was released after 20 minutes, compared to more than 80% when using the formulation according to the invention. The production of liquid filled capsules is another prior art. When the melted 22 200824711 drug·surfactant-cosolvent (PEG 4000) mixture was filled into hard gelatin capsules, coagulated and submitted for drug release studies, it appeared that the molten drug-surfactant-cosolvent mixture was The capsule shell is compatible. However, these capsules also showed relatively slow drug release. After 2 minutes, only 5 52% of the drug was released. It can therefore be stated that the technique according to the invention can be considered to be superior to the techniques known in the prior art. Although freeze drying is not preferred for mass production use, it can also be used in accordance with the present invention to produce a powder that can be compressed into tablets. This method may be desirable when only a limited amount of drug can be obtained (e.g., in an early development stage) and a tablet according to this H) invention is required. It appears that the cold-rolled dry powder can be successfully compressed into tablets without even adding any additional excipients. These, unformulated "tablets showed approximately 62% promising drug release after 2 minutes, which of course could be improved by the addition of standard tableting excipients. 15 Shuming also relates to the preparation of this A method of the invention. In a first aspect, the invention relates to a method of preparing a solid pharmaceutical composition as described above, comprising the steps of: • transferring said debris to said auxiliary material or said auxiliary material 20 b) optionally adding one or more additional auxiliary materials; 现 bringing the obtained solution into contact with water to form a nano-sized micelle;) dissolving the base material into the crucible In the obtained mixture; e) drying the mixture. In a further aspect, the present invention relates to the preparation of a solid 23 200824711 pharmaceutical composition as described above, comprising the steps of τ: the auxiliary material a) The active substance is dissolved in the mixture of the auxiliary materials; 4 b) optionally adding one or more additional auxiliary materials C) dissolving the matrix forming material in water; mixing the solution d) will be in a) or b) The solution obtained is obtained in a crucible to form a nano-sized micelle; e) drying the mixture. 10 In an aspect of the invention, the invention relates to a method of injuring a pharmaceutical composition, which comprises The following steps: "solid a" will dissolve the active substance in the material or the auxiliary material in the water; b) of the T is optionally added with one or more additional auxiliary materials; The shaped stock is dissolved in the solution d) obtained in a) - to dry the mixture. In another aspect, the invention relates to a method of preparing a solid pharmaceutical composition as described above, which comprises the steps of: a) Said active substance is dissolved in an aqueous solution of said auxiliary material or a mixture of said auxiliary material; b) optionally adding one or more additional auxiliary materials; c) dissolving said matrix forming material in the obtained solution ·, d) drying the mixture. The above drying step can be carried out by cold drying, mist drying or cold image spraying 24 200824711. The most preferred drying method is spray drying. The powder formed by applying one of the above methods is free-flowing and remains stable and free flowing when heated above the melting temperature of the primary auxiliary material, even when the amount of matrix-forming material is very low, such as below 50 〇/〇, 5 is even less than 30%, even less than 20% or even less than 10%. In the powder, the micelles remain as in the original aqueous micelle solution, but they are now embedded in the solid matrix and thus stabilized. The initial aqueous micelle solution is formed again after dissolving in water (see Figure 1). The dried product may be further processed into a granule, a compressed tablet or a buccal tablet, or the dried composition may be filled into a capsule or capsule in the form of a powder in the form of a powder by means of conventional methods and equipment. An advantage of the present invention is that a heat resistant solid composition of a poorly soluble active compound can be obtained which has a very high bioavailability. When applied to the human character 1 (SLV_, it appears that the relative bioavailability of the composition according to the invention in canine studies is approximately compared to the composition comprising the micronized active 2 15 compound. 6 times. Although the invention has been developed on the basis of active substances which can be used in the medical field, the principle can be used in other technical fields in which nano-sized particles have advantages, and thus the use of the invention is not limited to the medical field: The present invention is only intended to be a more detailed example of the invention, and thus these examples are not to be construed as limiting the embodiment of the invention in any way. Materials and methods. PEG4 (10) and PEG side), polygas B 25 200824711 sorbitan monooleic acid vinegar (such as p〇lyS〇rbat 80®), polyethylene glycol-15 hydroxy stearate (such as Solutol® HS 15), Anhydrous citric acid, mannitol, Weipropyl decyl cellulose (eg HPMC E5®), d-α-tocopherol polyethylene glycol 1000 (vitamin ETPGS), sodium dodecyl sulfate (SDS), polyvinylpyrrole 5 Alkanone (PVp-CL), sodium stearyl fumarate (eg pruv®), microcrystalline cellulose (]\/1 €; (1;) and granular igneous sulphur dioxide (eg into the 61 « 叩 6 anal 1 300 pass) obtained from commercial sources. (4S)-3-(4-chlorophenyl)-4,5-dihydro-indole-methyl-4-phenyl-N'-(l-monopyridyl-sulfonyl)_1Η-σ-pyrazole Small armor is prepared as described in 10 of w〇〇3/〇26648. Compound 2: (48)-3-(4-chlorophenyl)-N-[(4-chlorophenyl)sulfonyl]_4 , 5_ Dihydrogen is prepared as described in the -methyl-p-phenyl-1H-indazole-1-carboxamide as described in WO 02/076949. Compound 3: (4S)-3-(4-Azyl) _4,5-Dihydro-N-methyl-4-phenyl 15 _N-[[4-(difluoromethyl)phenyl]indenyl]]HH1-methyl vein as described in w〇02/076949 The preparation was performed. The method was analyzed according to the following procedure: The internal standard (2 〇 from L '250 ng/mL) was added to the thawed plasma sample (2〇#L). Then 20 was used for sterol (210 # L) Perform protein precipitation on the sample. Mix the sample, centrifuge (5 minutes, 3400 rpm, room temperature), and transfer the resulting supernatant to a 96-well plate. Formic acid (〇·2%) , 15〇#L) is added to each well. Will extract The mixture was mixed and centrifuged (5 min, 3400 rpm, calibrated 4. 〇, then submitted for LC-MS/MS analysis on 26 200824711 5 • Waters Acquity UPLC connected to Applied Bi〇systems API 4000. The mass spectrometer operating mode is Turbo lonSpray + and the analytical column is Waters Acquity BEH phenyl 1·7 um ′ 100 mm x 2·1 mm (id). The calibration standard and the concentration of Compound 1 in the QC sample were determined by quadratic regression using the reciprocal of the concentration (1/x) as a weight. Data was collected and processed using Applied Biosystems/MDS Sciex AnalystTM software 1.4.1. Example 2. Preparation of Compound 1 Formulation (FD PEG 400). 50 mg of the poorly soluble drug compound 1 was weighed in a glass injection bottle. Then add 66.34% (w/w) PEG 400, 10 16.58% (w/w) Polysorbat 80, 16.58% (w/w) Solutol® HS 15 and 0.5% anhydrous citric acid (w/w) to the bottle. 950 mg surfactant-cosolvent mixture. After the drug was completely dissolved, 4 ml of an aqueous mannitol solution (10% w/w) was added to the bottle, and the contents were thoroughly mixed. In the next 5 seconds, the bottle was placed in a liquid nitrogen bath to quickly freeze the mixture. Finally, the frozen mixture 15 • was lyophilized in a laboratory cold; East Dryer (Christ Alpha 2-4, Salm and Kipp, The Netherlands) at -80 ° C and 0.050 mbar for 48 hours. A loose mass is obtained. 20 Example 3 Preparation of Compound 1 Formulation (FD PEG 4000). 50 mg of the poorly soluble drug (Compound 1) was weighed in a glass vial. Then add 66.34% (w/w) PEG 4000, 16.58% (w/w) P〇lysorbat 80, 16.58% (w/w) Solutol® HS 15 and 0.5% anhydrous citric acid (w/w) to this bottle. a 950 mg surfactant-cosolvent mixture. The mixture was stored in an oven at 80 ° C until the drug was completely dissolved. Then 4 ml of heated (80 °C) aqueous mannitol solution 27 200824711 (10% w/w) was added to the bottle and the contents were thoroughly mixed until any solid content dissolved. The bottle was placed in a liquid nitrogen bath for the next 5 seconds to rapidly freeze the mixture. Finally, the frozen mixture is in a laboratory freeze dryer (Christ

Alpha 2-4, Salm and Kipp, The Netherlands) was lyophilized for 48 hours at -8 ° C and 5 0.050 mbar. A block which can be easily ground into a powder with a spatula is obtained. Example 4 Preparation of Compound 1 Formulation (SDPEG 4000). 13.7 g of a poorly soluble drug (Compound 1) was weighed in a glass flask. Then, 66.34% (w/w) PEG 4000, 10 16.58% (w/w) Polysorbat 80, 16.58% (w/w) Solutol® HS 15 and 0.5% anhydrous citric acid (w/) were added to the flask. w) 260 g surfactant-cosolvent mixture. The mixture was stored in an oven at 80 ° C until the drug was completely dissolved. This molten solution of lg was mixed with 250 ml of an aqueous solution of propylmethylcellulose (HPMC Grad E5, 0.016% w/w). The resulting solution was then spray dried using a Mini Spray Dryer 15 Btichi 191 (Btichi, Switzerland). The gas flow was 600 1 / hour, the inlet temperature was 150 ° C, the aspirator was set to 80%, the feed flow rate was about 5.5 g / min, and the outlet temperature under these conditions was about 9 ° C. A free flowing powder is obtained. Example 5 Preparation of Compound 1 Formulation (SDTPGS). 2〇 Weigh 1·〇 g poorly soluble drug (Compound 1) in a flask. Then 20.0 g of heated (8 ° C) vitamin E TPGS containing 0.5% (w/w) anhydrous citric acid was added to the flask. The mixture was stored in an oven at 8 ° C until the drug was completely dissolved. 1 g of this molten solution was mixed with 25 ml of an aqueous solution of hydroxypropylmethylcellulose (HPMC Grad E5, 0.16o/〇w/w). Then, use Mini 28 200824711

Spray Dryer Btichi 191 (Biichi, Switzerland) was spray dried to obtain the resulting solution. The gas flow was 600 V hours, the inlet temperature was 15 (rc, the suction cry was set to 80%, the feed flow rate was about 5·5 g/min, and the outlet temperature under these conditions was about 90 C. A free-flowing powder was obtained. This embodiment shows that the present invention is not limited to a surfactant-cosolvent mixture. Once an aqueous micelle solution of a poorly soluble compound can be obtained in the presence of a dissolved pharmaceutically acceptable carrier, the resulting micellar solution can be The invention was processed. Example 6 - Particle size of the formulation of Compound 1 (before and after 3 〇 40 〇〇 40 。) 10 Using a laser diffractometer equipped with a Coulter Aqueous Liquid Module Coulter LS 13 320 (Beckman Coulter, Fullerton) , CA, USA) Determine the particle size of the drug micelle before and after spray drying. Set the true refractive index to 1.33 (water) for the fluid. For the sample, the true refractive index is not set to 1.46 ' and the virtual refraction will be The rate was set to 〇·〇1. 5 〇mg of poorly soluble drug (Compound 1) was weighed in a glass vial 15. Then 66.67% (w/w) PEG 4000, 16.67% (w/w) was added to the bottle. )Polyso Rbat 80 and 16.67% (w/w) 950 mg of heated (80 ° C) surfactant-cosolvent mixture of Solutol® HS 15. Store the mixture in an oven at 80 ° C until the drug is completely dissolved. This molten solution was mixed with 250 ml of aqueous hydroxypropylmethyl 20 cellulose (HPMC Grad E5, 0.016% w/w). The particle size of the obtained micelle solution was determined by laser diffraction to be a volume-weighted diameter d 95%. It is 345 nm. 1.4 g of the drug-containing powder (containing 50 mg of Compound 1) produced according to Example 3 was dissolved in 250 ml of water. The particle size of the obtained micelle solution was 29 200824711, which was determined by laser diffraction to be a volume-weighted diameter. d 95%, which is 254 nm. Example 7·Pressing of powder of Compound 1. The powder obtained in Example 3 was pressed into a press by using an experimental hydraulic press and applying a pressing pressure of 10 Torr for 40 seconds. Standard two-sided tablets with a diameter of 12.5 5 mm. Example 8 · Tableting of SD powder of Compound 1. 325 mg of powder produced according to Example 4 and 325 mg of granular hydrophilic emulsified dream (AEROPERL® 300/ 30, Degussa AG, Germany) and 125 Mg polyvinylpyrrolidone (Kollidon® CL, BASF, Germany) 10 was mixed and compressed into a two-sided tablet having a diameter of 12.5 mm by using an experimental hydraulic press and applying a compression pressure of 4 bar for 2 seconds. Example 9· Release profile of PEG 400 capsule (FD) of Compound 1. The powder produced according to Example 2 was filled into a hard gelatin capsule. The drug content in a capsule is 25 mg. The dissolution test was performed according to USP II. At 15 37.5 ° C, the vessel was filled with 900 mL of 0.1 N HCl containing 0.5% w/v sodium dodecyl sulfate. The paddle speed was set to 50 rpm during the first 90 minutes, after which the paddle speed was increased to 150 rpm in another 30 minutes. The 10 mL sample taken at 0, 5, 1 〇, 20, 30, 45, 60, 90 and 120 minutes was filtered through a 0.22 // m screening program. All experiments were performed in triplicate into 20 rows, and the mean ± covariance of the three experiments was plotted as a function of time. The drug content in the sample was determined using HPLC. Approximately 95% of the drug was released after 20 minutes. Example 10 - Release profile of PEG 4000 capsule (fD) of Compound 1. 30 200824711 The powder obtained in Example 3 was filled into a hard gelatin capsule. The table in a capsule contains 25 mg. The dissolution test was performed according to USP II. At 37.5 C, the trough is filled with 900 mL of o.in HC1 containing 0.5% w/v sodium lauryl sulfate. The paddle speed was set at .5 rpm during the first 90 minutes, after which the paddle speed was increased to 150 rpm in another 3 minutes. The 10 mL sample taken after 〇, 5, 10, 2 〇, 3 〇, 45, 60, 90 and 120 minutes was filtered through a 0.22 // m screening program. All experiments were performed in triplicate and the mean soil covariance of the three experiments was plotted as a function of time. The drug content in the sample was determined using HPLC. Approximately 85% of the drug was released after 20 minutes. Example 11. Release profile of Compound 1 PEG 4000 capsules (SD). 650 mg of the powder produced according to Example 4 was filled into hard gelatin capsules. The drug content in a capsule is 25 mg. The dissolution 15 test was performed according to USP II. At 37.5 ° C, the vessel was filled with 900 mL of 0.1 mL NHC1 containing 0.5% w/v sodium dodecyl sulfate. The paddle speed was set to 50 rpm during the first 90 minutes, after which the paddle speed was increased to ι 5 rpm for another 30 minutes. The 10 mL sample taken after 〇, 5, 10, 20, 30, 45, 60, 90 and 120 minutes was filtered through a 〇·22 screening program. All experiments were performed in triplicate and the mean ± covariance of the three experiments was plotted as a function of time. The drug content in the sample was determined using HPLC. Approximately 85% of the drug was released after 20 minutes. Example 12· Release profile of PEG 4000 tablets (SD) of Compound 1. 31 200824711 A drug release from a tablet produced according to Example 8 was tested. Each tablet has a drug content of 25 mg. Dissolution testing was performed according to USP Π. At 37.5 ° C, the vessel was filled with 900 mL of 〇·1 NHC1 containing 5.5 % w/v sodium dodecyl sulfate. The paddle speed was set to 50 5 rpm during the first 9 minutes, after which the paddle speed was increased to 150 rpm in another 30 minutes. The 10 mL sample taken after 〇, 5, 1 〇, 2 〇, 3 〇, 45, 6 〇, 90, and 120 minutes was filtered through a 〇·22 screening program. All experiments were performed in triplicate and the mean ± covariance of the three experiments was plotted as a function of time. The drug content in the sample was determined using HPLC. Approximately 85% of the 10 drugs were released after 20 minutes. Example 13 - pEG 4000 tablets of Compound 1 without spray drying. In order to compare the release profile of the formulations produced according to the invention with those of standard methods (e.g. melt extrusion), other formulations were produced. Therefore, 150 mg of the poorly soluble drug (Compound 1) was weighed in a glass bottle. Then, 2850 mg of heated (80 ° C) surface active containing 66.67% (w/w) PEG 4000, 16.67% (w/w) Polysorbat 80 and 16.67% (w/w) Solutol® HS 15 was added to the bottle. Agent and cosolvent mixture. The mixture was stored in an oven at 80 ° C until the drug was completely dissolved. The resulting solution was poured onto a glass plate and cooled to 25 ° C for solidification. The solid mass is then crushed by a spatula into irregular particles having a diameter of about 2 mm to 5 mm. Three tablets of 12.5 mm diameter were pressed by using an experimental hydraulic press and applying a compression pressure of 40 bar for 2 seconds, consisting of 325 mg of crushed solid mass (containing 12.5 mg of drug), 325 mg of granular hydrophilic Pyrochlore dioxide (AER 〇 pERL8 32 200824711 300/30, Degussa AG, Germany) and 125 mg of polyethylene hydrazine 11 each ketone (Kollidon® CL, BASF, Germany). Example 14. Dissolution of a PEG 4000 compound 1 tablet without spray drying. 5 The drug release from the tablets produced according to Example 13 was tested. The drug content per tablet is 12.5 mg. The dissolution test was performed according to USP II. At 37.5 ° C, the vessel was filled with 900 mL of 0.1 mL NHC1 containing 0.5% w/v sodium dodecyl sulfate. The paddle speed was set to 50 rpm during the first 90 minutes, after which the paddle speed was increased to 150 10 rpm over the other 30 minutes. The 10 mL samples taken after 0, 5, 10, 20, 30, 45, 60, 90 and 120 minutes were filtered through a 0.22 /zm screening procedure. All experiments were performed in triplicate and the mean ± covariance of the three experiments was plotted as a function of time. The drug content in the sample was determined using HPLC. About 60% of the drug was released after 20 minutes. 15 Example 15 - Liquid filled capsule of Compound 1 based on PEG 4000. In order to compare the release profile of the formulations produced according to the invention with those of standard methods (e.g. liquid filled capsules), other samples were produced. Therefore, 150 mg of the poorly soluble drug (Compound 1) was weighed in a glass injection bottle. Then, 2850 mg of heated (80 ° C) containing 66.67 ° / 〇 (w / w) PEG 4000, 20 16.67% (w / w) Polysorbat 80 and 16.67% (w / w) Solutol ® HS 15 was added to the bottle. Surfactant-cosolvent mixture. The mixture was stored in an oven at 80 ° C until the drug was completely dissolved. The resulting solution was filled in a hard gelatin capsule (Licaps size 0, Capsugel, Belgium) and cooled to 25 ° C for solidification. Each capsule was filled with 500 mg of molten pellets 33 200824711 (containing 25 mg of Compound 1). Example 16. Dissolution of a liquid filled capsule of Compound 1 based on PEG 4000. A test was conducted on the release of the drug from the capsule produced according to Example 15. Each tablet has a drug content of 25 mg. The dissolution test was carried out according to USPII. At 37.5 ° C, the vessel was filled with 900 mL of 0.1 NHC1 containing 0.5% w/v sodium lauryl sulfate. The paddle speed was set to 50 rpm during the first 90 minutes, after which the paddle speed was increased to 150 rpm in another 30 minutes. A 10 mL sample taken at 0, 5, 10, 20, 30, 45, 60, 10 9 and 120 minutes was filtered from the m screening program by 0.22. All experiments were performed in triplicate and the mean ± covariance of the three experiments was plotted as a function of time. The drug content in the sample was determined using HPLC. Approximately 52% of the drug was released after 20 minutes. Example 17. Preparation of Compound 2 Formulation (SD). 15 Weigh 250 mg of the poorly soluble drug compound 2 in a glass flask. Then, 66.34% (w/w) PEG 4000, 16.58% (w/w) Polysorbat 80, 16.58% (w/w) vitamin e TPGS and 〇·5% anhydrous citric acid (w/w) were added to the flask. 9.75 g of surfactant-cosolvent mixture. The mixture was stored in an oven at 80 ° C until the drug was completely dissolved. 20 This molten solution of lg was mixed with 1 〇〇 ml of an aqueous solution of propylmethylcellulose (HPMC Grad E5, 0.016% w/w). Then, use Mini Spray

Dryer Biichi 191 (Btichi, Switzerland) to spray dry the resulting solution. The gas flow was 600 1 / hour, the inlet temperature was 150 ° C, the aspirator was set to 80%, the feed flow rate was about 5.5 g / min, and the outlet temperature 34 200824711 under these conditions was about 90 ° C. This process is repeated until all of the drug-surfactant-cosolvent mixture is processed. A free flowing powder is obtained. Example 18·Pressing of SD powder of Compound 2. 650 mg of the powder produced according to Example 17 was mixed with 450 mg of granular hydrophilic 5 smoldering sulphur dioxide (AEROPERL® 300/30, Degussa AG, Germany) and 200 mg of polyvinylpyrrolidone (Kollidon® CL, BASF, Germany) And a two-sided tablet having a diameter of 12.5 mm was pressed by using an experimental hydraulic press and applying a compression pressure of 40 bar for 2 seconds. Example 19· Release Characteristics of PEG 4000 Capsules (SD) of Compound 2 10 Spectrum. The drug release from the tablets produced according to Example 18 was tested. The drug content per tablet is 12.5 mg. The dissolution test was performed according to USP II. At 37.5 ° C, the vessel was filled with 900 mL of 0.1 NHC1 containing 0.5% w/v sodium lauryl sulfate. The paddle speed was set to 15 50 rPm during the first 90 minutes, after which the paddle speed was increased to 150 rpm for another 30 minutes. The 1 〇 mL sample taken after 〇, 5, 10, 20, 30, 45, 60, 90 and 120 minutes was filtered by the 〇·22 screening program. All experiments were performed in triplicate and the mean ± covariance of the three experiments was plotted as a function of time. The drug content in the sample was determined using HPLC. Approximately 20 92% of the drug was released after 20 minutes. Example 20. Preparation of Compound 3 Formulation (SDTPGS). The 〇·2 g poorly soluble drug (Compound 3) was weighed in a flask. Then, 1.8 g of heated (8 〇 ° C), biotic E TPGS containing 〇.5% (w/w) anhydrous citric acid was added to the flask. The mixture was stored in an oven at 80 ° C until the drug 35 200824711 was completely dissolved. 2 g of this molten solution was mixed with a solution of 1 guanidine hydroxypropyl decylcellulose (HPMC Grad E5, 0.6% w/w). Then, the resulting solution was spray dried using a Ni spray Dryer Biidii 191 (Biidii, Switzerland). The gas flow was 600 1 / hour, the inlet temperature was 12 (Tc, the aspirator 5 was set to 80%, the feed flow rate was about 5.5 g/min, and the outlet temperature under these conditions was about 80 ° C. Obtaining free flow Powder. This example shows that the invention is not limited to surfactant-cosolvent mixtures. Once the micelle aqueous solution of the poorly soluble compound can be obtained in the presence of a dissolved pharmaceutically acceptable water-soluble carrier, the resulting micellar solution is It can be processed according to the present invention. Example 21: Enlargement experiment of Compound 1 formulation (SDTPGS). 100.0 g of poorly soluble drug (compound oxime) was weighed in a flask, and then 5%. w/w) 1900.0 g of heated citric acid (80 ° C) Vitamin E TPGS. Store the mixture in an oven at 8 ° C and stir until the drug is completely dissolved. 2 kg of this molten solution (2000.0 g) mixed with 18.0 L of propylmethylcellulose aqueous solution (HPMC Grad E5, 3.33% w/w), then sprayed with a spray dryer 〇At〇mizer M〇bile Minor (Nii:o Inc.) Dry the obtained micelle solution. Inlet temperature 250 C, the feed flow rate was about 5 〇g/min, and the outlet temperature under these conditions was 20 ° C. A free-flowing powder was obtained. This example shows that it is also possible to expand to larger equipment, and The obtained powder had the same properties as the powder produced on a small laboratory scale.Example 22·Measure the temperature stability of the powder obtained in Example 21 (SD TPGS). 36 200824711 The product of Example 21 (large Scale production of Compound 1 SD TPGS) was placed in an oven at 80 C and maintained at 80 ° C for 4 weeks. No significant changes in the morphology of the powder were observed. Even at 80 it remained free flowing powder after 4 weeks of storage. In contrast, the physical mixture having the same composition was completely melted after storage in the same oven for 5 hours at 80 ° C. Example 23. Comparison of four different formulations of Compound 1 in male beagle dogs Bioavailability data. A comparative bioavailability study was conducted using cross-over design to test the final 10 dosage forms of the encapsulated micelles according to the present invention relative to other formulation types. Utilization. Four male beagle dogs were administered 50 mg of Compound 1 formulated in several dosage forms as shown in Table 1. Table 1. Composition of the studied formulations Micellar solution Micronized tablets Liquid filled capsules Embeded micelle tablets (mg) (%) (mg) (%) (mg) (%) (mg) (%) Compound 1 50 5 25 8.33 25 5 25 1.72 SDS 0.5 0.17 PVP-CL 30 10 400 27.59 HPMC E5® 2.5 0.83 150 10.34 Vitamin ETPGS 945.25 94.53 472.63 94.53 472.63 32.6 Citric acid 4.75 0.48 2.37 0.47 2.37 0.16 Pruv® 1.5 0.5 MCC 240.5 80.17 Aeropearl 300® 400 27.59 Total 100 100 300 100 500 100 1450 100

15 In all cases, 50 mg of Compound 1 was administered, which means that in some cases two dosage forms were administered simultaneously. The mean plasma levels after oral administration measured according to the method described in Example 1 are depicted in Figure 2. From these measurements 37 200824711 results obtained the data as given in Table 2. Table 2. Comparison of Compounds 1 in Male Beagle Dogs Results of Bioavailability Study Formulation Type C Maximum Ratio Relative Bioavailability Micellar Solution 18 7.6 Tablets (Micronized) 1 1 Liquid Filled Capsules 8 3.5 Embedded Micellar Tablets 10 5.7 5 [Simple Description of the Drawings] Figure 1 shows the general method according to the invention in the case of pharmaceutical use. Fig. 2 shows the plasma 10 concentration of Compound 1 obtained after administration of four different preparations (including the preparation according to the present invention) to a male beagle dog. [Main component symbol description] (none)

38

Claims (1)

200824711 X. Patent application scope: 1. A heat-resistant solid composition comprising nano-sized micelles, wherein the bundle 3 contains/dissolves poorly soluble chemicals in the auxiliary material, and 4 of them are embedded in the micelle In a water soluble carrier. /, 5 10 15 20 2 - a nano-powder phase heat-resistant solid pharmaceutical composition, wherein the household micelle comprises a poorly soluble active substance dissolved in an auxiliary material, and wherein the micelle is embedded in a water-soluble pharmaceutically acceptable substance Accepted carrier hair, quality. The composition of claim 4, wherein the micelle has an effective average particle size of less than about 1000 nm. 4. The composition of claim 3, wherein the micelles have an effective average particle size of about 500 nm. 5. The composition of claim 1 or 2, wherein the auxiliary material comprises at least 10% w/w of a surfactant, and optionally a genus of co-solvent and/or one or more auxiliary Surfactant. 6. The composition of claim 1 or 2, wherein the supplemental material is selected from the group consisting of polyoxyethylene stearate (e.g., Soiutol®) 'polyoxyethylene sulphate, a glycan fatty acid S (e.g., Tween) ®), polyoxyethylene f sesame oil derivatives (eg Chremophor®), vitamin E TPGS, nonionic polyoxyethylene-polyoxypropylene block copolymers (eg Poloxamer®), water soluble ^ _ organophosphates (eg Arlatone 8), inulin lauryl carbamate (eg Inutec SP18). 7. The composition of claim 5, wherein the auxiliary material is selected from the group consisting of polyoxyethylene stearate (e.g., Solutol®), polyoxyethylene sorbitan poly 39 200824711, sugar fatty acid ester (e.g., Tween®). Polyoxyethylene castor oil derivatives (eg Chremophor®), vitamin E TPGS, nonionic polyoxyethylene polyoxypropylene block copolymers (eg Poloxamer®), water soluble long chain organophosphates (eg Arlatone®) ), inulin lauryl carbamate (Example 5 such as Inutec SP1®). 8. The composition of claim 5, wherein the co-solvent is selected from the group consisting of pyridyls such as PEG, propylene glycol; polydextrose such as mannitol, sorbitol, and xylitol; polyoxyethylene; linear polyol For example, ethylene glycol, 1,6-hexanediol, neopentyl glycol, and methoxypolyethylene glycol; and mixtures thereof. The composition of claim 8, wherein the co-solvent is polyethylene glycol (PEG) having a molecular weight of 800 Daltons or less. 10. The composition of claim 9, wherein the co-solvent is selected from the group consisting of PEG 200, PEG 400, and PEG 800. 11. The composition of claim 8, wherein the co-solvent is polyethylene glycol (PEG) in an amount of from 950 to 20,000 Daltons. 12. The composition of claim n, wherein the co-solvent is selected from the group consisting of PEG 2000, PEG 3350, PEG 4000, and PEG 8000. 13. The composition of claim 2, wherein the water-soluble pharmaceutically acceptable carrier is selected from the group consisting of 20-alkyl celluloses, such as mercapto cellulose; monohydroxyalkyl celluloses, such as hydroxyl groups. Cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose; a calcined cellulose, such as ethyl methyl cellulose and hydroxypropyl methyl cellulose; 40 200824711 a carboxyalkyl cellulose, such as carboxymethyl cellulose; an alkali metal salt of a carboxyalkyl cellulose, such as sodium carboxymethyl cellulose; a carboxyalkyl alkyl cellulose, such as carboxymethyl ethyl cellulose ; a carboxyalkyl cellulose ester; a temple powder; a pectin, such as the Wei 曱 支 殿 殿 ;; _ chitin derivative, such as chitosan; a polysaccharide, such as alginic acid, its metal and ammonium salts; a carrageenan, galactomannan, tragacanth, agar, gum arabic, guar gum and xanthan gum; - polyacrylic acid and its salts ; a polymethacrylic acid and its salts, methacrylate copolymer; - polyethylene glycol; 15 - polyvinylpyrrolidone, a copolymer of polyvinylpyrrolidone and vinyl acetate; - polyepoxy burning, such as polyepoxy Ethylene and polyglycol, and copolymers of ethylene oxide and propylene oxide. 14. The composition of claim 1 or 2, wherein the composition 20 is in the form of a powder, a granule, a compressed tablet, a sublingual tablet, a buccal tablet, a filled capsule or a filled capsule. 15. The composition of claim 2, wherein the poorly soluble active substance is selected from the group consisting of a cannabinoid agonist, a cannabinoid inverse agonist, and a cannabinoid antagonist. 0 41 200824711 16. As claimed in claim 15 a composition wherein the poorly soluble active substance is (4S)-3-(4-chlorophenyl)-4,5-dihydro-N-methyl-4-phenylacridinyl-sulfonyl)-1? -pyrazole-1-carboxamidine. 17. The composition of claim 15 wherein the poorly soluble active 5 material is (4S)-3 -(4-chlorophenyl)-N-[(4.chlorophenyl)sulfonyl]- 4,5-Dihydro-indole*-methyl 4-phenyl_1H-pyrazole-1-indole. 18. The composition of claim 15 wherein the poorly soluble active substance is (4S)-3-(4-chlorophenyl)-4,5-dihydro-N-methyl-4-benzene -N4[4_(Trifluoromethyl)-phenyl]sulfonyl]-1H-indazole-1-indole. 10 19. A method of preparing a solid pharmaceutical composition according to claim 2, comprising the steps of: a) dissolving the poorly soluble active substance in a mixture of auxiliary materials or auxiliary materials; b) optionally Adding one or more auxiliary materials other than 15 to the solution obtained in a); c) mixing the solution obtained in a) or b) with water to form a nano-sized micelle; d) dissolving the matrix-forming material In the mixture obtained in c); and 20 e) drying the mixture obtained in d) to obtain a solid pharmaceutical composition, wherein the micelles are embedded in the matrix forming material. 20. A method of preparing a solid pharmaceutical composition according to claim 2, which comprises the steps of: a) dissolving a poorly soluble active substance in a mixture of an auxiliary material or auxiliary material 42; b) optionally Adding one or more additional auxiliary materials to the solution obtained in a); c) dissolving the matrix forming material in water; 5 d) mixing the solution obtained in a) or b) with the solution obtained in c) To form a nano-sized micelle; and e) to dry the mixture obtained in d) to obtain a solid pharmaceutical composition, wherein the micelle is embedded in the matrix-forming material. 21. A method of preparing a solid pharmaceutical composition according to claim 2, comprising the steps of: a) dissolving a poorly soluble active substance in a mixture of auxiliary materials or auxiliary materials; b) The solution obtained in a) is dissolved in water to form a nano-sized micelle; 15 c) optionally adding one or more additional auxiliary materials to the solution obtained in b); d) dissolving the matrix-forming material in b) or a solution obtained in c); and e) drying the mixture obtained in d) to obtain a solid drug 20 composition, wherein the micelle is embedded in the matrix forming material. 2 2. A method of preparing a solid pharmaceutical composition according to claim 2, comprising the steps of: a) dissolving a mixture of an auxiliary material or an auxiliary material in water to form a nano-sized micelle; 43 200824711 b Dissolving a poorly soluble active substance in a solution obtained in a), wherein the solution obtained comprises a binder containing the poorly soluble active substance; C) optionally adding one or a solution obtained in b) a plurality of additional auxiliary materials; d) dissolving the matrix forming material in the solution obtained in the illusion; and e) drying the mixture obtained in d) to obtain a solid pharmaceutical composition, wherein the gel A beam is embedded in the matrix forming material. A method of preparing a solid pharmaceutical composition according to claim 2, which comprises the steps of: a) dissolving a mixture of an auxiliary material or an auxiliary material in water; b) dissolving the poorly soluble active substance in a) In the solution obtained; i5 C) adding one or more additional auxiliary materials to the solution obtained in b) to form a solution comprising micelles containing the poorly soluble active substance; d) dissolving the matrix forming material In the solution obtained in c), which comprises a micelle containing the insoluble active substance; and 2, the mixture obtained in d) is dried to obtain a solid pharmaceutical composition, which is embedded in the matrix. Formed in the material. 24. The method of claim 19-23, wherein the drying step is carried out by cold green drying, machine cooling, east reading, vacuum drying or a combination thereof. 25. The method of claim 24, further comprising processing the solid pharmaceutical composition into a granule, a compressed tablet, a sublingual tablet or a buccal tablet. 26. The method of claim 24, further comprising filling the solid pharmaceutical composition into a capsule or elixir.