JP5439182B2 - Chemical micelle nanoparticles - Google Patents

Description

Most new drug molecules emerging from drug discovery schemes show low solubility in aqueous media or are practically insoluble in aqueous media. It is therefore very challenging to formulate these active substances in such a way that they can be administered parenterally or orally. Dissolution rate and intestinal permeability are important determinants, especially for the bioavailability of orally administered drugs [Noyes-Whitney's law (Jinno et al., The low water solubility drug in beagle dogs, cilostazol) Due to the effect of particle size reduction on dissolution and oral absorption, 1), low solubility generally correlates with low dissolution rates. Biopharmaceutical classification system [G. L. Amidon, H .; Lennernas, V.M. P. Shah and J.H. R. Crison. Theoretical basis for drug classification in biopharmaceutics: correlation between in vitro formulation dissolution and in vivo bioavailability. According to Non-Patent Document 2], low-solubility drugs belong to either BCS class II or BCS class IV. BCS class IV means that the drug simultaneously exhibits low solubility and low permeability, whereas the bioavailability of a BCS class II drug is typically limited to dissolution rate ( Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological problems and lipid formulation classification system, Non-Patent Document 3). This means that the bioavailability of BCS class II drugs can be increased by improving their dissolution rate and / or saturation solubility C _s .

  Various formulation methods have been applied to improve the solubility and dissolution rate of low solubility drugs.

  Formation of inclusion complexes of active substances with cyclodextrins can improve the solubility of the drug (see, for example, US Pat. No. 6,077,086 which discloses the use of cyclodextrins for THC solubilization). . Cyclodextrins are cyclic oligomers of dextrose or dextrose derivatives that can form reversible non-covalent bonds with low-solubility drugs to solubilize them.

  Lipid-based systems such as emulsions, microemulsions, self-emulsifying delivery systems (SEDDS) or self-microemulsifier delivery systems (SMEDDS) are suitable for active substances that are soluble in lipids and oils. In these lipid formulations, the active substance is dissolved in an oil or lipid that forms an emulsion or forms an emulsion system when diluted with water.

  In situations where the active substance is retained in solid form, one approach that has been applied to improve the dissolving action of low solubility drugs is to reduce the particle size of the solid amorphous or crystalline active substance. To form solid amorphous or crystalline material with reduced particle size. Reduced particle size results in increased surface area. Due to the larger surface area, the drug particles have an improved dissolution rate.

  In general, in the production of materials with reduced particle size, a distinction is made between top-down and bottom-up processes. The top-down method involves energy input to break large particles into small particles. Depending on the method used, the average particle size of the material to be crushed can be obtained in micrometer dimensions (eg jet mill method, hammer mill method) or nanometer dimensions (eg wet ball milling and high pressure homogenizing method). . For the latter, the use of finely pulverized starting materials is recommended (see Patent Documents 2 and 3). A typical drawback of these methods is that they require enormous amounts of energy to destroy the starting material.

  The bottom-up method is used to form drug nanocrystals by precipitation. This method is described as “via humida paratum” in the old pharmacopoeia. The active substance is dissolved in a solvent, the solvent is added to a non-solvent or anti-solvent (which is miscible with the solvent), and the active substance is precipitated in the form of amorphous or crystalline nanoparticles, the latter also being Also called drug nanocrystals. The particles are generally stabilized by a surfactant or polymer stabilizer. This principle was applied to produce so-called “hydrosols” (see Patent Document 4). In recent years, several improvements of this precipitation principle have been described (see Patent Document 5). However, it is very difficult to fix precipitated crystals in nano-sized dimensions. Nanoparticulate structures usually have a tendency to grow and form microparticles or microcrystals. One way to solve this problem is to immediately dry the prepared suspension, for example by freeze-drying (Non-patent Document 4) (see Non-Patent Document 4).

  More recently developed particle size reduction methods involving supercritical fluids or spray lyophilization are described in the literature for the production of solid drug nanoparticles (see Non-Patent Document 5).

  All particle size reduction methods have one common drawback: that is, usually the drug needs to be dissolved in order to be absorbed from the intestine. For some very low solubility drugs, particle size reduction may not be sufficient to improve solubility and increase bioavailability.

  Another way to improve the solubility of low solubility active substances is to incorporate the substance in an amorphous system such as a solid dispersion. The term “solid dispersion” refers to a solid state system (relative to a liquid or gas system) comprising at least two components in which one component is more or less uniformly dispersed in one or more other components. Defined. A solid dispersion consisting of one phase which is chemically or physically uniform or homogeneous or defined by thermodynamics as a whole can also be called a solid solution (see, for example, Patent Document 6). The solid matrix may be crystalline or amorphous. The drug may be dispersed as molecules or may exist as amorphous particles (clusters) as well as crystalline particles (solid dispersions). Examples of such solid dispersions are the tebuferon formulations described in US Pat. No. 6,057,089 and the biologically active peptide formulations described in US Pat.

The solid dispersion can be prepared using various methods, for example, fusion method, hot melt extrusion method, solvent evaporation method or supercritical fluid method (see Non-Patent Document 6). The solid dispersion or solid solution can comprise a surfactant or other excipient to increase solubility or stabilize the drug. Several methods for the production of solid dispersions are discussed in US Pat. The application document also lipophilic compound cosolvent, preferably discloses a process for producing glass (sugar Glass) sugar lipophilic compound is dissolved in C ₁ -C ₆ alcohol. Preferred solvents have a high vapor pressure and a high melting point. However, the use of the proposed high vapor pressure flammable co-solvents can cause problems in large scale production, especially when spray drying is applied as a drying method. In order to protect the complete system from explosions, the oxygen content in the dry air must be reduced. Furthermore, lipophilic compounds are not sufficiently stabilized in aqueous cosolvent systems and tend to precipitate. Therefore, rapid processing is proposed to avoid the occurrence of “clouding”.

  When the active substance is hydrophobic but not lipophilic, ie not soluble in lipids and oils, a cosolvent or cosolvent-surfactant mixture can be used to stabilize the active substance. To classify the different solubilization systems, C.I. Pouton introduced the Lipid Formulation Classification System (LFCS). Recent versions of this scheme distinguish between four different formulation types (7). LFCS Type IV describes an oil-free formulation of a surfactant-cosolvent mixture base. Usually, 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. Since the drug is already dissolved in the carrier, it can be absorbed rapidly (see Non-Patent Document 8).

  In order to produce a conventional solid dosage form from a low-solubility liquid, the production of “powdered solution” was proposed by Spires et al. (See Non-Patent Document 9). A “powdered solution” was prepared by mixing a liquid drug or drug solution with a selected carrier. The product obtained by this method is a physical mixture or blend of drug / surfactant solution and selected carrier.

  Examples of these types of formulations are disclosed in US Pat. However, typical disadvantages of the resulting powder are its low flowability, its low thermal stability and / or its low compressibility.

  It is an object of the present invention to provide further and improved formulations for commercially available materials and compounds that can be prepared using standard methods and equipment, particularly biologically active compounds. is there. A further object of the invention in the case of biologically active compounds is to provide formulations with good bioavailability.

International Publication No. 9932107 Pamphlet US Pat. No. 5,145,684 US Pat. No. 5,858,410 US Pat. No. 5,389,382 US Patent Application No. 20050139144 International Publication No. 97/044404 Pamphlet US Pat. No. 5,281,420 International Publication No. 2005/053727 Pamphlet US Patent Application No. 20050266088A1 International Publication No. 2005/041929 Pamphlet International Publication No. 2006/113631 Pamphlet International Publication No. 2006/135480 Pamphlet

J. et al. of Controlled Release 111 (1-2), 56-64, 2006 Pharm. Res. 12: 413-420 (1995) Collin W. Pouton, European Journal of Pharmaceutical Sciences 2006, 29, 278-87 Sucker, H.M. , Hydrosole-eine Alternative fuse die parenteral Ann von von Schwer Wasserloesrichen Wirksoffen, Mueller, R .; H. Hildebrand, G .; E. , (Hrsg.), Pharmazeutice Technology: Moderne Arzneiformen, 2. Auflag, 1998, WVG, Stuttgart Jiahui Hu, Keith P .; Johnston and Robert O. Williams III, a nanoparticle engineering method for increasing the dissolution rate of low water-soluble drugs, DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, Vol. 30, no. 3, pp. 233-245, 2004 D. J. et al. van Drouge “Process of combining incompatible substances”, Rijksuniversite Groningen, PhD-Thesis 2006 Formulation of poorly water soluble drugs for oral administration: physicochemical and physiological issues and lipid formulation classification system, Colin W. Pouton, European Journal of Pharmaceutical Sciences 2006, 29, 278-87 Liquid-filled and sealed hard gelatin capsule method, Ewart T .; Cole, a modified release drug delivery method, eds. M.M. J. et al. Rathbon, J.M. Hadgraft, M .; S. Roberts, Marcel Dekker, Basel, 2003 Spireas et al. , Powdered Solution Method: Principle and Mechanism, Pharm. Res. 9 No. 10, 1351-1358, 1992

  The present invention relates to a thermally stable composition with improved solubility, comprising nano-sized micelles, wherein the micelles comprise a low solubility compound. In one embodiment, the pharmaceutical composition of the invention comprises a surfactant or surfactant-cosolvent mixture, the micelles of which comprise a low solubility chemical such as a low solubility drug, The micelles comprise nano-sized micelles embedded in a water-soluble matrix of a water-soluble carrier such as a pharmaceutically acceptable carrier.

  Another embodiment of the present invention is to prepare an aqueous micellar solution comprising a low solubility compound, an auxiliary substance or mixture of auxiliary substances and a water soluble matrix, and drying the micelle solution to make these micelles water soluble in the carrier. It relates to the preparation of a pharmaceutical composition comprising the step of embedding in a sex matrix to obtain a heat stable composition. Micelles containing low solubility compounds are made using one or more surfactants and optionally one or more co-solvents.

FIG. 1 is a diagram of the general process for preparing a composition, eg, a pharmaceutical composition, in accordance with the present invention. FIG. 4 is a graph representing the plasma concentration of Compound 1 obtained after administration of four different formulations, including formulations according to the present invention, to male Beagle dogs.

DETAILED DESCRIPTION OF THE INVENTION In a first embodiment, the present invention comprises a low solubility chemical wherein the micelle is dissolved in an auxiliary material, and the micelle is embedded in a water soluble carrier. The present invention relates to a heat-stable solid composition comprising nano-sized micelles.

  In another embodiment, the present invention comprises a low-solubility biologically active material wherein the micelle is dissolved in an auxiliary material, and the micelle is a water-soluble pharmaceutically acceptable carrier matrix. The invention relates to a thermostable solid pharmaceutical composition comprising nano-sized micelles embedded therein.

The term thermal stability within the framework of the present invention means that the formulation remains a free-flowing stable powder when heated above the melting point of the main auxiliary material. This means that the formulation remains physically stable when heated to 5 ° C, 10 ° C, 20 ° C, 30 ° C, 40 ° C or 50 ° C above the melting point of the main auxiliary material.

  For example, vitamin E TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate) has a melting point of 36 ° C. (see: Eastman, Material Safety Data Sheet of Vit E TPGS NF Grade (Vitamin E TPGS NF Grade Material Safety) Data sheet)). Those skilled in the art will know that if vitamin E TPGS is the main component of the formulation, the formulation will exhibit at least partial melting experience when exposed to temperatures well above 36 ° C, eg 80 ° C. I will presume. However, when Vitamin E TPGS is used as an auxiliary substance in the present invention, Vitamin E TPGS forms micelles, and Vitamin E TPGS (and active substance) micelles have a melting point above 36 ° C. Embedded in. Thus, the powder produced will not show a major change in powder morphology and fluidity. It is a stable, free-acting powder even when exposed to temperatures above 5 ° C, 10 ° C, 20 ° C, 30 ° C, 40 ° C or 50 ° C above the melting point of the main auxiliary vitamin E TPGS Remains.

  The terms biologically active substance, pharmaceutically active substance, drug, active compound, active ingredient within the framework of the present invention are chemical substances that induce a pharmacological effect when administered to humans or animals Or used interchangeably to represent a compound.

  The term low solubility compound within the framework of the present invention means a compound having a water solubility at 37 ° C. of less than 33 g / L. In particular, for pharmaceutically active compounds, the term low solubility compound is intended to make the compound available to the body in vivo (especially the compound is dissolved so that it is absorbed by the body). Are used to describe compounds having a solubility of less than 33 g / L at conditions, such as in the stomach, intestine, subcutaneous, especially at pH. Thus, for example, a low solubility compound intended to dissolve in the stomach has a solubility of less than 33 g / l in gastric juice (pH of about 1 to 3) and is poorly soluble in the intestine The compound has a solubility of less than 33 g / l in intestinal fluid (typically up to about pH 7.4) (see US Pat. No. 5,006,660,88, Frijlink). The present invention is particularly less than 10 g / L, 4 g / L, 1 g / L, 100 mg / L, 40 mg / L, 10 mg / L, 4 mg / L, 1 mg / L, 0.4 mg / L or less than 0.1 mg / L. Useful for even less soluble compounds, such as compounds having gastrointestinal solubility.

  Low solubility compounds that can be processed according to the present invention may be liquid, semi-solid, solid, amorphous, liquid crystalline or solid crystalline.

  The low solubility compounds that can be treated according to the present invention are preferably pharmaceutically effective substances and are analgesic, antiarrhythmic, antiasthmatic, antibiotic, anti-helmintics, Anti-inflammatory, antiviral, anticoagulant, antidepressant, antidiabetic, antiepileptic, erectile dysfunction, antifungal, anti-ventilant, antihypertensive, antimalarial, antimigraine, Antimuscarinic agent, anti-neoplastic agent, anti-obesity agent, anti-parkinsonian agent, antiprotozoal agent, anti-thyroid hormone agent, antitussive agent, anxiolytic agent, beta blocker, hypnotic agent, immunosuppressant, nerve stabilizer, cannabinoid Receptor agonists and antagonists, myocardial contractors, cell adhesion inhibitors, corticosteroids, cytokine receptor activity modulators, diuretics, gastrointestinal drugs, histamine H-receptors Can be selected from antagonists, keratolytic agents, lipid regulators, muscle relaxants, nitrates and other anti-anginal agents, non-steroidal anti-asthma agents, opioid analgesics, sedatives, sex hormones and stimulants it can.

  Some examples of low solubility compounds are low solubility cannabinoid agonists, inverse agonists and antagonists. Some examples of these compounds are (4S) -3- (4-chlorophenyl) -4,5-dihydro-N-methyl-4-phenyl-N described in WO 03/026648. '-(1-piperidinyl-sulfonyl) -1H-pyrazole-1-carboxyimidamide and (4S) -3- (4-chlorophenyl) -N-[(4 described in WO 02/076949. -Chlorophenyl) sulfonyl] -4,5-dihydro-N'-methyl-4-phenyl-1H-pyrazole-1-carboxyimidamide (also known as ibipinabant or SLV319) and (4S) -3- (4-chlorophenyl) ) -4,5-dihydro-N-methyl-4-phenyl-N ′-[[4- (trifluoromethyl) fe L] sulfonyl] -1H-pyrazole-1-carboxyimidamide, such as International Publication Nos. 01/70700, 02/076949, 03/026647, 03/026648, 03/027076. , 2005/074920, 2005/080345, 2005/118553, and 2006/087355 pamphlets.

  The low solubility compounds in the compositions of the present invention preferably have a log P of less than 10, more preferably less than 5, and even more preferably less than 2.5, and 0.05 of the total weight of the composition In an amount of wt / wt% to at least 50 wt / wt%, preferably between 0.05 and 10 wt / wt%, or between 0.05 and 5 wt / wt%, or 0.05 It can be present in an amount between ˜1 wt / wt%.

  The term auxiliary substance within the framework of the present invention is a substance that allows the formation of micelles on contact with water, such as a surfactant, a co-solvent or a mixture of a surfactant and a co-solvent, or those formed. It is a substance that has an effective effect on the stability of micelles.

  The term micelle within the framework of the present invention refers to the association of surfactant molecules above the Kraft point and critical micellization concentration in aqueous solution (see Roempp Online Dictionary). According to IUPAC, surfactants in solution often form associated colloids. That is, they tend to form colloidal dimensional aggregates that exist in equilibrium with the molecules or ions formed therefrom. Such agglomerates are called micelles. Kraft point means the temperature above which the solubility of the surfactant in water suddenly increases (more precisely, the narrow temperature range). At this temperature, the surfactant solubility is equal to the critical micelle concentration. It can be determined by finding a sudden change in the slope of the logarithm of solubility versus t or 1 / T. There is a relatively narrow range of surfactant concentrations that divides the limit below which virtually no micelles are detected from the limit above which virtually all additional surfactant molecules form micelles. To do. Many properties of the surfactant solution appear to change at different rates above and below this range when plotted against concentration. By extrapolating the loci of such properties above and below this range until they intersect, a value known as the critical micelle concentration (critical micelle concentration) can be obtained (IUPAC summary of chemical terms) Goldbook).

  The micelles in the composition according to the invention have an average particle size of less than 1000 nm, preferably less than 500 nm, or less than 200 nm or less than 100 nm.

The term average particle size within the framework of the present invention refers to dynamic light scattering methods (eg, light correlation spectroscopy (PCS), laser diffraction (LD), low angle laser light scattering (LALLS), medium angle laser light scattering. Represents the effective average particle size determined by the method (MALLS), light obstruction (eg, Coulter method), rheology, or microscope (optical or electronic) within the ranges indicated above. By "effective average particle size of less than about xnm" is meant that at least 90% of the particles have a weight average particle size of less than about xnm, as measured by the method described above.

  The composition according to the invention comprises at least 10%, or at least 30%, or at least 50% surfactant and may comprise up to 99.95% surfactant. Optionally, the composition also includes one or more co-solvents and / or one or more co-surfactants.

Surfactants that can be used for the pharmaceutical composition and optionally used co-surfactants are described in Pharmaceutical Dosage Forms (Pharmaceutical Dosage Form), Marcel Dekker Inc. (1993), p. 285-359. M.M. Listed in Rieger, “Surfactants”, Chapter 8. Preferred surfactants are those having an HLB value greater than 8. The most preferred surfactants are polyoxyethylene stearates (e.g., Solutol ^(R)), polyoxyethylene sorbitan fatty acid esters (e.g., Tween ^(R)), polyoxyethylene castor oil derivatives (e.g., Chremophor ^(R)) , vitamin E TPGS, non-ionic polyoxyethylene - polyoxypropylene block copolymers (e.g., Poloxamer ^(R)), water-soluble long-chain organic phosphate esters (e.g., Arlatone ^(R)), inulin lauryl carbamate (e.g., Inutec SP1 ^(R) ).

  The optionally used co-solvent used for the pharmaceutical composition is preferably a pharmaceutically acceptable non-volatile co-solvent of substances having a vapor pressure of less than 0.50 mmHg at 25 ° C. It is. The pharmaceutical composition is a lipid formulation classification system (LFCS) defined by Pouton (see paragraph [0012]) as an oil-free formulation based on surfactants and co-solvents. It relates only to type IV solubilized mixtures and is therefore explicitly excluded as a co-solvent in the present invention. In addition, LFCS Type I formulation (non-dispersible; requires digestion), LFCS Type II formulation (SEDDS without water soluble components), LFCS Type IIIA formulation (SEDDS / with water soluble components) SMEDDS), LFCS Type IIIB formulations (SMEDDS with water soluble components and low oil content) are excluded.

  Examples of non-volatile cosolvents include, but are not limited to, polyethylene glycol (PEG), propylene glycol, diethylene glycol monoethyl ether, glyceryl triacetate, benzyl alcohol, polyhydric alcohols such as alkylene glycols such as mannitol, sorbitol and xylitol; Polyoxyethylene; linear polyols such as ethylene glycol, 1,6-hexanediol, neopentyl glycol and methoxypolyethylene glycol; and mixtures thereof.

Particularly useful as a non-volatile co-solvent in the present invention is generally the formula (HOCH ₂ CH ₂ ) _{n, where n} is the number of units that are also numbers defining the average molecular weight (mw) of the polymer. PEG, a polymer of ethylene oxide according to OH.

  The types of PEG useful in the present invention can be classified according to their state of matter, ie whether the material exists in solid or liquid form at room temperature and pressure. “Liquid PEG” within the framework of the present invention means a PEG having a molecular weight (mw) such that the substance is in a liquid state at room temperature and pressure. For example, average m. w. PEG with a liquid PEG. Particularly useful are PEG 400 (about 380-420 Dalton MW), PEG 600 (about 570-630 Dalton MW) and mixtures thereof. PEG is commercially available from Dow Chemical (Danbury, Conn.) Under the product CARBOWA SENTRY line.

  “Solid PEG” within the framework of the present invention refers to a PEG having a molecular weight such that the substance is in a solid state at room temperature and pressure. For example, average m.d. in the range between 900 and 20,000 daltons. w. PEG having a solid PEG. Particularly useful solid PEGs have a m.p. of between 3,350 daltons (mw of about 3015 to about 3585 daltons) and 8,000 daltons (mw of about 7,0009,000 daltons). w. It is what has. Particularly useful as solid PEG are PEG 3350, PEG 4000 (3,600-4,400 MW), PEG 8000 and mixtures thereof.

  When liquid PEG (eg, PEG 400) is replaced with solid PEG (eg, PEG 4000), the resulting drug-surfactant-cosolvent mixture must be heated to 80 ° C. Surprisingly, it has been discovered that the cake produced from lyophilization of the PEG 4000 product is harder than when PEG 400 is used, but the release is not significantly altered when PEG 400 is replaced by PEG 4000.

  When present, 0.01 wt / wt% to 99.95 wt / wt%, preferably 10.0 wt / wt% to 90.0 wt / wt%, and most preferably 20.0 wt% A cosolvent in an amount of from / wt% to 70.0 wt / wt%.

  The water-soluble carrier (also described as a matrix) can be any polymeric material that is soluble in water. A matrix material can be considered soluble in water if at least part of the matrix material can be dissolved in 10-30 parts of water (definition according to USP 24, 2254).

A water-soluble carrier for a pharmaceutical composition must be pharmaceutically acceptable. Examples of pharmaceutically acceptable carriers useful in the present invention are selected from:
An alkyl cellulose (eg methyl cellulose),
-Hydroxyalkylcelluloses (e.g. hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose), -hydroxyalkylalkylcelluloses (e.g. hydroxyethylmethylcellulose and hydroxypropyl-methylcellulose),
-Carboxyalkylcellulose (eg carboxymethylcellulose),
An alkali metal salt of carboxyalkyl cellulose (eg sodium carboxymethyl cellulose),
A carboxyalkyl alkyl cellulose (eg carboxymethyl ethyl cellulose),
-Carboxyalkyl cellulose esters,
-Starch,
-Pectin (eg sodium carboxymethyl amylopectin,
A chitin derivative (eg chitosan),
Polysaccharides (eg alginic acid, its alkali metal and ammonium salts),
-Carrageenan, galactomannan, tragacanth, agar, gum arabic, guar gum and xanthan gum,
-Polyacrylic acids and their salts,
-Polymethacrylic acid and their salts, methacrylate copolymers,
-Polyvinyl alcohol,
-Polyvinylpyrrolidone, a copolymer of polyvinylpyrrolidone with vinyl acetate,
Polyalkylene oxides (eg polyethylene oxide and polypropylene oxide) and copolymers of ethylene oxide and propylene oxide.

  Non-enumerated polymers with suitable physicochemical properties as defined above that are pharmaceutically acceptable are likewise suitable as carriers in the present invention for pharmaceutical compositions.

  Preferred water soluble polymers useful in the present invention include hydroxypropyl methylcellulose and HPMC. HPMC contains sufficient hydroxypropyl and methoxy groups to make it water soluble. HPMC having a methoxy degree of substitution of about 0.8 to about 2.5 and a hydroxypropyl molar degree of substitution of about 0.05 to about 3.0 are generally water soluble. The degree of methoxy substitution represents the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. Hydroxy-propyl molar substitution represents the average number of moles of propylene oxide reacted with each anhydroglucose unit of the cellulose molecule. Hypromellose is the US adopted name for hydroxypropyl methylcellulose (Adopted Name).

  The composition according to the invention may contain one or more other additives. These additives in the case of pharmaceutical compositions include pharmaceutically acceptable additions such as fragrances, colorants, binders, fillers, filler-binders, lubricants, disintegration aids. And / or other pharmaceutically acceptable additives.

  The preparation of the composition according to the invention involves the preparation of an aqueous micelle solution of a low solubility compound, followed by drying and encapsulating these micelles in a water soluble matrix of a carrier, such as a pharmaceutically acceptable carrier. It involves a process of filling. Micelles containing low solubility compounds are produced by using one or more surfactants. If desired, one or more co-solvents can also be included.

  In another embodiment of the invention, a micelle solution comprising a low solubility compound is prepared by dissolving the low solubility compound in one or more surfactants. Dissolution is achieved by dispersing the low solubility compound substantially as a single molecule, ie at least 95%, preferably at least 98%, more preferably at least 99%, even more preferably 99.5% and most preferably 99.99. It means that 9% of low solubility compound is dispersed as a single molecule. If necessary, one or more co-solvents can be added. In one embodiment of the invention, energy can be applied to allow complete molecular dispersion by heating, blending or mixing the components. When the components form a molecular dispersion, they are mixed with the aqueous phase to form a micellar solution. The aqueous phase contains a dissolution matrix of the carrier, such as a pharmaceutically acceptable carrier, or later dissolves the aqueous matrix of the carrier in the micelle solution. This mixture is dried to obtain a solid powder. The powder may be used as is or mixed with other excipients for further processing.

  In another aspect of the invention, the composition according to the invention facilitates the absorption of a low solubility drug by forming a micelle solution of the drug when the composition is administered.

A further aspect of the invention, the composition, for example, a solid powder can be easily processed to the formulation, hard gelatin capsules [e.g. PEG 400, glycerol, polyoxyl 35 castor oil (e.g. Cremophor EL ^(R)), Capsules using excipients known to be incompatible with propylene glycol, diethylene glycol monoethyl ether (eg, Transcutol P ^(R) ), sorbitan monooleate (eg, Span 80 ^(R) )) It can be processed into powder for filling.

  Lyophilization is typically not a manufacturing process used for large-scale production, and is usually applied only to very unstable drugs such as proteins. Spray drying is more convenient and more suitable for large scale production. Accordingly, spray drying was tested as a drying method for micelle solutions according to the invention and found to be very suitable for its production. Since no flammable co-solvent with high vapor pressure is used, the production of spray-dried powders can be carried out on standard equipment without any special protection against explosions. Furthermore, the micelle solution is stable for several hours, sometimes even days, without drug precipitation. Solubility tests have shown that almost the same dissolution rate can be obtained regardless of the drying method used.

  To test the effect of drying process on micelle particle size, particle size analysis using laser diffraction was performed and the particle size before spray drying and after redispersion from spray dried powder was of the same dimension It has been shown. From this result it can be concluded that the drying process does not change the particle size of the micelles produced.

  The method of the present invention is not limited to surfactant-cosolvent mixtures. If an aqueous micelle solution of a low solubility compound can be obtained in the presence of a dissolved pharmaceutically acceptable carrier, the resulting micelle solution can be processed according to the present invention.

  The pharmaceutical composition according to the invention can be further processed into any solid dosage form for any route of administration. Particularly interesting dosage forms are granules, compressed (immediate release) tablets for oral delivery, sublingual or buccal tablets and powders or hard gelatin capsules or sachets filled with granules.

Tablets are a common type of solid dosage form used to administer pharmaceutical compositions. To date, however, it is difficult to tablet from a liquid or semi-solid formulation containing a low solubility drug in solubilized (ie, dissolved) form. One method that has been used to tablet such tablets is the adsorption of a liquid drug or drug solution onto a selected carrier (Spires et al., Powder Solution Method: Principles and Mechanisms, Pharm). Res.9 No. 10, 1351-1358, 1992). However, the typical drawbacks of the resulting powder are its low flowability and compressibility. It is an object of the present invention to provide a solution to this problem. The powders produced according to the invention, especially those produced by spray drying, exhibit very good flow properties. The dry powder can be mixed with pharmaceutical excipients in the dry state. The resulting powder mixture can be filled directly into capsules but can even be tableted. The resulting tablets showed a very rapid drug release, with a release rate comparable to that of powder capsule formulations with similar ingredients. In the present invention, when using a granulated fumed silica as filler (e.g. AEROPERL (R) ^300), in particular, to obtain a very rapid disintegration and thus good drug release tablet.

  Tablets tableted according to the present invention showed much better drug release than tablets tableted by standard methods (eg melt extrusion or liquid-filled capsules).

  Comparing the release profile of a tablet formulation made according to the present invention with a formulation prepared by melt extrusion, it seems very difficult to pulverize the solidified mass obtained by melt extrusion, Thus, only very uneven tablets could be obtained, and only 60% of the drug was released after 20 minutes compared to more than 80% when the formulation according to the invention is used. It was.

  The manufacture of liquid-filled capsules is another state of the art for providing a dosage form that can be used to administer a pharmaceutical composition.

  When the melted drug-surfactant-cosolvent (PEG 4000) mixture is filled into a hard gelatin capsule, solidified and submitted to a drug release study, the melted drug-surfactant-cosolvent mixture is compatible with the capsule shell. It seemed to be sex. However, these capsules also showed relatively slow drug release. Only 20% of the drug was released after 20 minutes. Thus, drug release from formulations according to the present invention having a release of greater than 80% is superior to drug release from conventional liquid-filled capsules known in the art.

  Although lyophilization is not typically used for large scale production, it can also be used according to the present invention for the production of powders that can be compressed into tablets. Lyophilization can be used only when a limited amount of drug is available (eg, during the initial development phase) and when a tablet according to the invention is desired. It has been found that the lyophilized powder can be effectively compressed without adding any further excipients. These “non-formulated” tablets showed a promising drug release of about 62% after 20 minutes, which can be reliably increased by adding standard tableting excipients.

  The invention also relates to a method for preparing the composition of the invention.

In a first aspect, the present invention relates to a method for preparing said solid pharmaceutical composition comprising the following steps:
a) dissolving a low-solubility active substance in an auxiliary substance or mixture of auxiliary substances;
b) optionally adding one or more further auxiliary substances to the solution obtained in a)
c) mixing the solution obtained in a) or b) with water to form nano-sized micelles;
d) Dissolving the matrix-forming substance in the mixture obtained in c), and e) drying the mixture obtained in d) so that the micelles are embedded in the matrix-forming substance. Get things.

In a further aspect, the present invention relates to a method for preparing said solid pharmaceutical composition comprising the following steps:
a) dissolving a low-solubility active substance in an auxiliary substance or mixture of auxiliary substances;
b) optionally adding one or more further auxiliary substances to the solution obtained in a)
c) dissolving the matrix-forming substance in water;
d) The solution obtained in c) and the solution obtained in a) or b) are mixed to form nano-sized micelles, and e) the mixture obtained in d) is dried so that the micelles are matrix-forming substances. A solid pharmaceutical composition is obtained which is embedded therein.

In a further aspect, the present invention relates to a method for preparing said solid pharmaceutical composition comprising the following steps:
a) dissolving a low-solubility active substance in an auxiliary substance or mixture of auxiliary substances;
b) dissolving the solution obtained in a) in water to form nano-sized micelles;
c) optionally adding one or more further auxiliary substances to the solution obtained in b)
d) Dissolving the matrix-forming substance in the solution obtained in b) or c), and e) drying the mixture obtained in d) so that the micelles are embedded in the matrix-forming substance. To obtain a biological composition.

In another embodiment, the invention relates to a method for preparing said solid pharmaceutical composition comprising the following steps:
a) dissolving an auxiliary substance or mixture of auxiliary substances in water to form nano-sized micelles;
b) dissolving the low solubility active substance in the solution obtained in a), wherein the resulting solution contains micelles comprising the low solubility active substance;
c) optionally adding one or more further auxiliary substances to the solution obtained in b)
d) Dissolving the matrix-forming substance in the solution obtained in b) or c), and e) drying the mixture obtained in d) so that the micelles are embedded in the matrix-forming substance. To obtain a biological composition.

In yet another embodiment, the present invention relates to a method for preparing said solid pharmaceutical composition comprising the following steps:
a) dissolving an auxiliary substance or mixture of auxiliary substances in water;
b) dissolving the low-solubility active substance in the solution obtained in a),
c) One or more additional auxiliary substances are added to the solution obtained in b) to form a solution containing micelles comprising a low solubility active substance, and d) the low substance obtained in c) Dissolve the matrix-forming substance in a solution containing micelles comprising a soluble active substance, and dry the mixture obtained in e) d) so that the micelle is embedded in the matrix-forming substance. To obtain a pharmaceutical composition of

  When the above method is applied, micelles can be formed in any one of step a), step b), step c) or step d). For example, when the auxiliary substance or mixture of auxiliary substances used in step a) contains a surfactant, and the surfactant is contacted with water in step a), micelles form in step a). Can do. In that case, the micelles do not yet contain a low-solubility active substance, which is contained in the micelle in step b). Alternatively, when the surfactant is contacted with water in step b), micelles can be formed in step b). As a third alternative, when micelles are not yet formed in step a) or b), they are formed in step c). In this case, the surfactant is added for the first time in step c) and / or the surfactant is contacted with water in step c). As a fourth alternative, when the surfactant is first contacted with water in step d), micelles are formed in step d).

In yet another embodiment, the present invention relates to a method for preparing said solid pharmaceutical composition comprising the following steps:
A) a low-soluble active substance, an auxiliary substance or a mixture of auxiliary substances, optionally one or more further auxiliary substances, a matrix-forming substance and water to form nano-sized micelles, and B) in A) The resulting mixture is dried to obtain a solid pharmaceutical composition whose micelles are embedded in a matrix-forming material.

  The drying step can be carried out by freeze drying, spray drying or freeze spray drying. The most preferred drying method is spray drying.

  Powders formed by applying one of the above methods are very low in the amount of matrix-forming material, such as less than 50%, even less than 30%, even less than 20%, or even less than 10%. Even when heated above the melting point of the main auxiliary substance, it is free-flowing, stable and free-flowing. In the powder, the micelles remain in the original aqueous micellar solution, but are now embedded in the solid matrix and thereby stabilized. When dissolved in water, an initial aqueous micelle solution is formed again (see FIG. 1).

  After drying, the product is further processed into granules, compressed tablets, sublingual or buccal tablets, or with the help of conventional methods and equipment, the dried composition is filled into capsules or sachets in powder or granule form. Can do.

  It is an advantage of the present invention that a heat stable solid composition of low solubility active compound with very high bioavailability can be obtained. A bioavailability study (male beagle) of a formulation comprising the low solubility compound, Compound 1 (SLV330) was performed. It has been observed that the relative bioavailability of the composition according to the invention in male beagle dogs is about 6 times higher compared to the relative bioavailability of the composition comprising the micronized active compound. (See Table 2 below).

  Although the present invention has been developed on the basis of active substances that can be used in the field of medicine, its principles can be used in other technical fields where nano-sized particles have advantages, so the present invention is It is not restricted to its use for the field.

  The following examples are only intended to illustrate the invention in more detail and more specifically, and therefore these examples provided herein are considered to limit the scope of the invention in any way. must not.

Materials and methods
Materials: polyethylene glycol (e.g., PEG 400 and PEG 4000), polyoxyethylene sorbitan monooleate (e.g. Polysorbat 80 ^(R)), macrogol -15 hydroxystearate (e.g. Solutol ^(R) HS15), citric acid anhydrous, mannitol, Hydroxypropyl methylcellulose (eg HPMC E5 ^(R) ), d-alpha-tocopheryl polyethylene glycol 1000 (vitamin E
TPGS), sodium dodecyl sulfate (SDS), polyvinylpolypyrrolidone (PVP-CL), sodium stearyl fumarate (e.g. Pruv ^(R)), microcrystalline cellulose (MCC) and granulated fumed silica (e.g. Aeropearl 300 ^{(R )} ) Was obtained from commercial sources.
Compound 1: (4S) -3- (4-chlorophenyl) -4,5-dihydro-N-methyl-4-phenyl-N ′-(1-piperidinyl-sulfonyl) -1H-pyrazole-1-carboxyimidamide is Prepared as described in WO 03/026648.
Compound 2: (4S) -3- (4-Chlorophenyl) -N-[(4-chlorophenyl) sulfonyl] -4,5-dihydro-N′-methyl-4-phenyl-1H-pyrazole-1-carboxyimidamide Was prepared as described in WO 02/076949.
Compound 3: (4S) -3- (4-chlorophenyl) -4,5-dihydro-N-methyl-4-phenyl-N ′-[[4- (trifluoromethyl) phenyl] sulfonyl] -1H-pyrazole- 1-Carboxymidamide was prepared as described in WO 02/076949.

Method:
Plasma samples were analyzed according to the following method. An internal standard (20 μL, 250 ng / mL) was added to the thawed plasma sample (20 μL). The sample was then subjected to protein precipitation using methanol (210 μL). Samples were mixed, centrifuged (5 minutes, 3400 rpm, room temperature) and 50 μL of the resulting supernatant was transferred to a 96-well plate. Formic acid (0.2%, 150 μL) was added to each well. The extracts were mixed, centrifuged (5 min, 3400 rpm, nominally 4 ° C.) and then subjected to LC-MS / MS analysis on a Waters Acquity UPLC connected to an Applied Biosystems API 4000. The operation mode of the mass spectrometer was Turbo IonSpray positive, and the analytical column was Waters Acquity BEH phenyl 1.7 um, 100 mm × 2.1 mm (inner diameter). The concentration of Compound 1 in the calibration standards and QC samples was determined using quadratic regression with the inverse of the concentration (1 / x) as the weighting. Data was collected and processed using Applied Biosystems / MDS Sciex Analyst ^™ software 1.4.1.

Preparation of Compound 1 Formulation (FD PEG400) 50 mg of low solubility drug Compound 1 was weighed into a glass injection vial. Then, this vial 66.34% PEG400,16.58% (wt / wt) Polysorbat80,16.58% (wt / wt) (wt / wt) Solutol of ^(R) HS15 and 0.5% ( 950 mg of surfactant-cosolvent mixture containing (w / w) anhydrous citric acid was added. After complete dissolution of the drug, 4 ml of mannitol aqueous solution (10 wt / wt%) was added to the vial and the contents were mixed well. Within the next 5 seconds, the vial was placed in a liquid nitrogen bath to quickly freeze the mixture. Finally, the frozen mixture was lyophilized in a laboratory freeze dryer (Christ Alpha 2-4, Salm and Kipp, The Netherlands) for 48 hours at −80 ° C. and 0.050 mbar. I got a fluffy cake.

Preparation of Compound 1 Formulation (FD PEG 4000) 50 mg of low solubility drug (Compound 1) was weighed into a glass injection vial. Then, this vial 66.34% PEG4000,16.58% (wt / wt) Polysorbat80,16.85% (wt / wt) (wt / wt) Solutol of ^(R) HS15 and 0.5% ( 950 mg of surfactant-cosolvent mixture containing (w / w) anhydrous citric acid was added. This mixture was stored in an 80 ° C. oven until the drug was completely dissolved. Thereafter, 4 ml of heated (80 ° C.) aqueous mannitol (10 wt / wt%) was added to the vial and the contents were mixed well until all solid contents were dissolved. Within the next 5 seconds, the vial was placed in a liquid nitrogen bath to quickly freeze the mixture. Finally, the frozen mixture was lyophilized in a laboratory freeze dryer (Christ Alpha 2-4, Salm and Kipp, The Netherlands) for 48 hours at −80 ° C. and 0.050 mbar. A cake was obtained that could be easily powdered with a spatula.

Preparation of Compound 1 Formulation (SD PEG 4000) 13.7 g of low solubility drug (Compound 1) was weighed into a glass flask. Thereafter, to the flask 66.34% PEG4000,16.58% (wt / wt) Polysorbat80,16.85% (wt / wt) (wt / wt) Solutol of ^(R) HS15 and 0.5% ( 260 g surfactant-cosolvent mixture containing (wt / wt) citric anhydride was added. This mixture was stored in an 80 ° C. oven until the drug was completely dissolved. 1 g of this molten solution was mixed with 250 ml of an aqueous solution of hydroxypropylmethylcellulose (HPMC grade E5, 0.016 wt / wt%). The resulting solution was then spray dried using Mini Spray Dryer Büchi 191 (Buechi, Switzerland). The air flow is 600 l / hour, the inlet temperature is 150 ° C., the aspirator is set to 80%, the feed flow rate is about 5.5 g / min, and the outlet temperature under these conditions is about 90 ° C. Met. A free-flowing powder was obtained.

Preparation of Compound 1 Formulation (SD TPGS) 1.0 g of low solubility drug (Compound 1) was weighed into a flask. Then, 20.0 g of heated (80 ° C.) vitamin E TPGS containing 0.5% (w / w) anhydrous citric acid was added to the flask. This mixture was stored in an 80 ° C. oven until the drug was completely dissolved. 1 g of this molten solution was mixed with 25 ml of an aqueous solution of hydroxypropylmethylcellulose (HPMC grade E5, 0.16% w / w). The resulting solution was then spray dried using Mini Spray Dryer Büchi 191 (Buechi, Switzerland). The air flow is 600 l / hour, the inlet temperature is 150 ° C., the aspirator is set to 80%, the feed flow rate is about 5.5 g / min, and the outlet temperature under these conditions is about 90 ° C. Met. A free-flowing powder was obtained. This example shows that the present invention is not limited to surfactant-cosolvent mixtures. After an aqueous micelle solution of a low solubility compound was obtained in the presence of a dissolved pharmaceutically acceptable carrier, the resulting micelle solution was processed according to the present invention.

Before and after spray drying using a laser diffractometer Coulter LS 13 320 (Beckman Coulter, Fullerton, Calif., USA) equipped with a Coulter Aqueous Liquid Module before and after the compound 1 formulation (SD PEG 4000) The particle size of drug micelles was measured. The true refractive index of the fluid was set to 1.33 (water). The true refractive index for the sample was set to 1.46 and the imaginary refractive index was set to 0.01. 50 mg of low solubility drug (Compound 1) was weighed into a glass injection vial. Thereafter, containing Solutol ^(R) HS15 of 66.67% in the vial Polysorbat80 and 16.67% of PEG4000,16.67 percent (wt / wt) (wt / wt) (wt / wt), of 950mg A heated (80 ° C.) surfactant-cosolvent mixture was added. This mixture was stored in an 80 ° C. oven until the drug was completely dissolved. 1 g of this molten solution was mixed with 250 ml of an aqueous solution of hydroxypropylmethylcellulose (HPMC grade E5, 0.016 wt / wt%). The particle size of the resulting micelle solution, measured by laser diffraction as volume weighted diameter d95% (as volume weighted diameter d 95%), was 345 nm. 1.4 g of the powder prepared according to Example 3 (containing 50 mg of compound 1) was dissolved in 250 mL of water. The particle size of the resulting micellar solution, determined by laser diffraction as a volume weighted diameter d 95%, was 254 nm.

Tableting of FD powder of compound 1 Double-sided tablet with a particle size of 12.5 mm from the powder produced from Example 3 by using an experimental hydraulic press and a compression pressure of 100 bars applied for 40 seconds. Tableted.

Tableting Example 325mg powder of 325mg of which was prepared according to 4 granulated hydrophilic fumed silica SD powder Compound ^{1 (AEROPERL (R) 300/} 30, Degussa AG, Germany) and 125mg polyvinylpyrrolidone ( Kollidon ^(R) CL, mixed BASF, Germany) and. The mixture was then compressed into double-sided tablets with a particle size of 12.5 mm by using an experimental hydraulic press and a compression pressure of 40 bars applied for 2 seconds.

Release profile of PEG 400 (FD) of Compound 1 The powder produced according to Example 2 was filled into hard gelatin capsules. The drug content in one capsule was 25 mg. Dissolution tests were performed according to USPII. At 37.5 ° C., 900 mL of 0.1 M HCl containing 0.5 wt / vol% sodium dodecyl sulfate was charged to the container. The paddle speed was set to 50 rpm for the first 90 minutes and then the paddle speed was increased to 150 rpm for another 30 minutes. Ten mL samples were taken after 0, 5, 10, 20, 30, 45, 60, 90 and 120 minutes and filtered through a 0.22 μm filter. All experiments were performed in triplicate and the mean ± covariance of these three experiments was plotted as a function of time. The drug content in the sample was measured by HPLC. After 20 minutes, about 95% of the drug was released.

Release Profile of Compound 1 PEG 4000 Capsule (FD) The powder produced from Example 3 was filled into hard gelatin capsules. The drug content in one capsule was 25 mg. Dissolution tests were performed according to USPII. At 37.5 ° C., 900 mL of 0.1 M HCl containing 0.5 wt / vol% sodium dodecyl sulfate was charged to the container. The paddle speed was set to 50 rpm for the first 90 minutes and then the paddle speed was increased to 150 rpm for another 30 minutes. Ten mL samples were taken after 0, 5, 10, 20, 30, 45, 60, 90 and 120 minutes and filtered through a 0.22 μm filter. All experiments were performed in triplicate and the mean ± covariance of these three experiments was plotted as a function of time. The drug content in the sample was measured by HPLC. After 20 minutes, about 85% of the drug was released.

Release Profile of Compound 1 PEG 4000 Capsules (SD) 650 mg of powder prepared from Example 4 was filled into hard gelatin capsules. The drug content in one capsule was 25 mg. Dissolution tests were performed according to USPII. At 37.5 ° C., 900 mL of 0.1 M HCl containing 0.5 wt / vol% sodium dodecyl sulfate was charged to the container. The paddle speed was set to 50 rpm for the first 90 minutes and then the paddle speed was increased to 150 rpm for another 30 minutes. Ten mL samples were taken after 0, 5, 10, 20, 30, 45, 60, 90 and 120 minutes and filtered through a 0.22 μm filter. All experiments were performed in triplicate and the mean ± covariance of these three experiments was plotted as a function of time. The drug content in the sample was measured by HPLC. After 20 minutes, about 85% of the drug was released.

Release profile of PEG 4000 tablets (SD) of Compound 1 Drug release from tablets tableted according to Example 8 was tested. The drug content in one tablet was 25 mg. Dissolution tests were performed according to USPII. At 37.5 ° C., 900 mL of 0.1 M HCl containing 0.5 wt / vol% sodium dodecyl sulfate was charged to the container. The paddle speed was set to 50 rpm for the first 90 minutes and then the paddle speed was increased to 150 rpm for another 30 minutes. Ten mL samples were taken after 0, 5, 10, 20, 30, 45, 60, 90 and 120 minutes and filtered through a 0.22 μm filter. All experiments were performed in triplicate and the mean ± covariance of these three experiments was plotted as a function of time. The drug content in the sample was measured by HPLC. After 20 minutes, about 82% of the drug was released.

PEG 4000 tablets of Compound 1 not spray dried In this example, a comparison to compare the release profile of a formulation made in accordance with the present invention with that of other formulations made by standard methods (eg, melt extrusion) A formulation was prepared. Therefore, 150 mg of low solubility drug (Compound 1) was weighed into a glass injection vial. Thereafter, containing Solutol ^(R) HS15 of 66.67% in the vial Polysorbat80 and 16.67% of PEG4000,16.67 percent (wt / wt) (wt / wt) (wt / wt), of 2850mg A heated (80 ° C.) surfactant-cosolvent mixture was added. This mixture was stored in an 80 ° C. oven 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 was then ground with a spatula into irregular particles having a particle size of about 2 mm to 5 mm. By using an experimental hydraulic press and a compression pressure of 40 bars applied for 2 seconds, 325 mg ground solid mass (containing 12.5 mg drug), 325 mg granulated hydrophilic fumed silica (AEROPERL® 300 ⁾ / 30, Degussa AG, consisting of Germany) and 125mg polyvinyl pyrrolidone ^{(Kollidon (R) CL, BASF} , Germany) were tableted three sided tablet having a particle size of 12.5 mm.

Dissolution of one tablet of PEG 4000 compound without spray drying Drug release from tablets prepared according to Example 13 was tested. The drug content per tablet was 12.5 mg. Dissolution tests were performed according to USPII. At 37.5 ° C., 900 mL of 0.1 M HCl containing 0.5 wt / vol% sodium dodecyl sulfate was charged to the container. The paddle speed was set to 50 rpm for the first 90 minutes and then the paddle speed was increased to 150 rpm for another 30 minutes. Ten mL samples were taken after 0, 5, 10, 20, 30, 45, 60, 90 and 120 minutes and filtered through a 0.22 μm filter. All experiments were performed in triplicate and the mean ± covariance of these three experiments was plotted as a function of time. The drug content in the sample was measured by HPLC. After 20 minutes, about 60% of the drug was released.

PEG 4000-based Compound 1 Liquid Filled Capsule In this example, to compare the release profile of a formulation made in accordance with the present invention with that of other samples made by standard methods (eg, liquid filled capsules). Comparative formulations were prepared. Therefore, 150 mg of low solubility drug (Compound 1) was weighed into a glass injection vial. Thereafter, containing Solutol ^(R) HS15 of 66.67% in the vial Polysorbat80 and 16.67% of PEG4000,16.67 percent (wt / wt) (wt / wt) (wt / wt), of 2850mg A heated (80 ° C.) surfactant-cosolvent mixture was added. This mixture was stored in an 80 ° C. oven until the drug was completely dissolved. The resulting solution was filled into hard gelatin capsules (Licaps, size 0, Capsugel, Belgium) and cooled to 25 ° C. for solidification. Each capsule was filled with 500 mg of molten mass (containing 25 mg of Compound 1).

Dissolution of PEG 4000 Base Liquid Filled Compound 1 Capsules Drug release from capsules prepared according to Example 15 was tested. The drug content per tablet was 25 mg. Dissolution tests were performed according to USPII. At 37.5 ° C., 900 mL of 0.1 M HCl containing 0.5 wt / vol% sodium dodecyl sulfate was charged to the container. The paddle speed was set to 50 rpm for the first 90 minutes and then the paddle speed was increased to 150 rpm for another 30 minutes. Ten mL samples were taken after 0, 5, 10, 20, 30, 45, 60, 90 and 120 minutes and filtered through a 0.22 μm filter. All experiments were performed in triplicate and the mean ± covariance of these three experiments was plotted as a function of time. The drug content in the sample was measured by HPLC. After 20 minutes, about 52% of the drug was released.

Preparation of Compound 2 Formulation (SD) 250 mg of poorly soluble drug compound 2 was weighed into a glass flask. The flask was then charged with 66.34% (w / w) PEG 4000, 16.58% (w / w) Polysorb 80, 16.58% (w / w) vitamin E TPGS and 0.5% (w / w). 9.75 g of surfactant-cosolvent mixture containing (by weight) of anhydrous citric acid was added. This mixture was stored in an 80 ° C. oven until the drug was completely dissolved. 1 g of the molten solution was mixed with 100 ml of an aqueous hydroxypropylmethylcellulose solution (HPMC grade E5, 0.016 wt / wt%). The resulting solution was then spray dried using Mini Spray Dryer Büchi 191 (Buechi, Switzerland). The air flow is 600 l / hour, the inlet temperature is 150 ° C., the aspirator is set to 80%, the feed flow rate is about 5.5 g / min, and the outlet temperature under these conditions is about 90 ° C. Met. This process was repeated until the complete drug-surfactant-cosolvent mixture was processed. A free flowing powder was obtained.

Tableting embodiment the powder formulation has been 650mg of 450mg according 17 granulated hydrophilic fumed silica SD powder Compound ^{2 (AEROPERL (R) 300/} 30, Degussa AG, Germany) and 200mg polyvinylpyrrolidone ( Kollidon ^(R) CL, mixed BASF, Germany) and. The mixture was then compressed into double sided tablets with 12.5 mm particle size by using an experimental hydraulic press and a compression pressure of 40 bars applied for 2 seconds.

Release profile of PEG 4000 capsules (SD) of Compound 2 Drug release from tablets tableted according to Example 18 was tested. The drug content per tablet was 12.5 mg. Dissolution tests were performed according to USPII. At 37.5 ° C., 900 mL of 0.1 M HCl containing 0.5 wt / vol% sodium dodecyl sulfate was charged to the container. The paddle speed was set to 50 rpm for the first 90 minutes and then the paddle speed was increased to 150 rpm for another 30 minutes. Ten mL samples were taken after 0, 5, 10, 20, 30, 45, 60, 90 and 120 minutes and filtered through a 0.22 μm filter. All experiments were performed in triplicate and the mean ± covariance of these three experiments was plotted as a function of time. The drug content in the sample was measured by HPLC. After 20 minutes, about 92% of the drug was released.

Preparation of Compound 3 Formulation (SD TPGS) 0.2 g of low solubility drug (Compound 3) was weighed into a flask. The flask was then charged with 1.8 g of heated (80 ° C.) Vitamin E TPGS containing 0.5% (w / w) anhydrous citric acid. This mixture was stored in an 80 ° C. oven until the drug was completely dissolved. 2 g of this molten solution was mixed with 100 ml of an aqueous hydroxypropylmethylcellulose solution (HPMC grade E5, 0.6 wt / wt%). The resulting solution was then spray dried using Mini Spray Dryer Büchi 191 (Buechi, Switzerland). The air flow is 600 l / hour, the inlet temperature is 120 ° C., the aspirator is set to 80%, the feed flow rate is about 5.5 g / min, and the outlet temperature under these conditions is about 80 ° C. Met. A free-flowing powder was obtained. This example shows that the present invention is not limited to surfactant-cosolvent mixtures. Once an aqueous micelle solution of a low solubility compound was obtained in the presence of a dissolved pharmaceutically acceptable aqueous carrier, the resulting micelle solution was treated according to the present invention.

Scale-up experiment of Compound 1 formulation (SD TPGS) 100.0 g of low solubility drug (Compound 1) was weighed into a flask. The flask was then charged with 1900.0 g of heated (80 ° C.) vitamin E TPGS containing 0.5% (w / w) anhydrous citric acid. This mixture was stored in an 80 ° C. oven until the drug was completely dissolved. 2 kg (2000.0 g) of this molten solution was mixed with 18.0 L of an aqueous hydroxypropylmethylcellulose solution (HPMC grade E5, 3.33 wt / wt%). The resulting solution was then spray dried using a spray dryer, Niro Atomizer Mobile Minor (Niro Inc.). The inlet temperature was 250 ° C., the feed flow rate was about 50 g / min, and the outlet temperature under these conditions was about 80 ° C. A free-flowing powder was obtained. This example shows that scaling to larger equipment is also possible, resulting in a powder with similar properties as a powder produced on a small laboratory scale.

Measurement of temperature stability of powder (SD TPGS) obtained in Example 21 The product of Example 21 (mass-produced compound 1, SD TPGS) was placed in an oven at 80 ° C. and stored at 80 ° C. for 4 weeks. No major changes in powder morphology were observed. Even after 4 weeks of storage at 80 ° C., free-flowing powder still remained. In contrast, a physical mixture with a similar composition was already completely melted after 1 hour storage at 80 ° C. in the same oven.

Comparative Bioavailability Data for Four Different Formulations of Compound 1 in Male Beagle Dogs Test the bioavailability of the final dosage form containing embedded micelles according to the invention for other formulation types In order to do this, we conducted a cross-planned bioavailability comparison study. Four male Beagle dogs were administered 50 mg of Compound 1 formulated in several dosage forms containing ingredients as shown in Table 1 below.

  In all examples, 50 mg of Compound 1 was administered, which means that optionally two dosage forms were administered simultaneously. Mean plasma levels after oral administration measured according to the method described in Example 1 are shown in FIG. The data given in Table 2 were obtained from these measurements.

  As mentioned above, the relative bioavailability of a composition according to the invention, for example a tablet comprising an embedded micelle containing an active compound, in male beagle dogs is that of a tablet containing a micronized active compound. About 6 times higher compared to relative bioavailability.

Claims (26)

Of a water-soluble pharmaceutically acceptable carrier comprising a micelle comprising a low solubility chemical dissolved in a mixture of one or more surfactants and optionally one or more co-solvents A thermally stable solid pharmaceutical composition comprising nano-sized micelles, wherein the micelles are embedded in a matrix,
Water-soluble carrier
-Alkyl cellulose,
-Hydroxyalkyl cellulose,
-Hydroxyalkyl-alkylcellulose,
-Carboxyalkyl cellulose,
-An alkali metal salt of carboxyalkyl cellulose;
-Carboxyalkyl alkyl cellulose,
-Carboxyalkyl cellulose esters,
-Starch,
-Pectin,
-Chitin derivatives,
-Polysaccharides,
-Carrageenan, galactomannan, tragacanth, agar, gum arabic, guar gum and xanthan gum,
-Polyacrylic acids and their salts,
-Polymethacrylic acid and their salts, methacrylate copolymers,
-Polyvinyl alcohol,
-Polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate,-polyalkylene oxide,
The above composition selected from the group consisting of:   Water-soluble carrier is methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxyethyl-methyl cellulose, hydroxypropyl-methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl ethyl cellulose, carboxymethyl amylopectin, chitosan, alginic acid The composition of claim 1, selected from the group consisting of: alkali metal and ammonium salts of alginic acid, polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide.   The composition of claim 1 or 2, wherein the micelle has an effective average particle size of less than about 1000 nm.   4. The composition of claim 3, wherein the micelle has an effective average particle size of less than about 500 nm.   A mixture of one or more surfactants and optionally one or more co-solvents is at least 10% w / w surfactant and optionally one or more co-solvents and / or one or more. A composition according to any one of claims 1 to 4, comprising a co-surfactant.   A mixture of one or more surfactants is polyoxyethylene stearate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, vitamin E TPGS, nonionic polyoxyethylene-polyoxypropylene block copolymer; The composition according to any one of claims 1 to 5, which is selected from the group consisting of a water-soluble long-chain organic phosphate ester and inulin lauryl carbamate. The mixture of one or more surfactants is selected from the group consisting of Solutol ^(R) ), Tween ^(R) , Chremophor ^(R) , Poloxamer ^(R) , Arlatone ^(R) , Inutec SP1 ^(R) The composition according to claim 6.   The composition according to any of claims 1 to 7, wherein the co-solvent is selected from the group consisting of alkylene glycol; polyhydric alcohol; polyoxyethylene; linear polyol and mixtures thereof.   9. The cosolvent is selected from the group consisting of PEG, propylene glycol, mannitol, sorbitol and xylitol, ethylene glycol, 1,6-hexanediol, neopentyl glycol and methoxypolyethylene glycol and mixtures thereof. Composition.   The composition of claim 9, wherein the co-solvent is polyethylene glycol (PEG) having a molecular weight of 800 Daltons or less.   The composition of claim 10, wherein the co-solvent is selected from the group consisting of PEG200, PEG400 and PEG800.   The composition of claim 9, wherein the co-solvent is polyethylene glycol (PEG) having a molecular weight in the range of 950 to 20,000 daltons.   13. The composition of claim 12, wherein the co-solvent is selected from the group consisting of PEG2000, PEG3350, PEG4000 and PEG8000.   The composition according to any one of claims 1 to 13, further processed into granules, compressed tablets, sublingual tablets, buccal tablets, filled capsules or filled sachets.   The composition according to any one of claims 1 to 14, wherein the low-solubility active substance is selected from the group consisting of a cannabinoid agonist, a cannabinoid inverse agonist and a cannabinoid antagonist.   The low solubility active substance is (4S) -3- (4-chlorophenyl) -4,5-dihydro-N-methyl-4-phenyl-N ′-(1-piperidinyl-sulfonyl) -1H-pyrazole-1-carboxy 16. A composition according to claim 15, which is imidamide.   The low solubility active substance is (4S) -3- (4-chlorophenyl) -N-[(4-chlorophenyl) sulfonyl] -4,5-dihydro-N′-methyl-4-phenyl-1H-pyrazole-1- 16. A composition according to claim 15, which is carboxyimidamide.   The low solubility active substance is (4S) -3- (4-chlorophenyl) -4,5-dihydro-N-methyl-4-phenyl-N ′-[[4- (trifluoromethyl) phenyl] sulfonyl] -1H 16. The composition of claim 15, which is -pyrazole-1-carboxyimidamide. The following steps:
a) dissolving a low-solubility active substance in a mixture of one or more surfactants and optionally one or more co-solvents;
b) optionally adding one or more further surfactants or auxiliary substances to the solution obtained in a)
c) mixing the solution obtained in a) or b) with water to form nano-sized micelles;
d) Dissolving the matrix-forming substance in the mixture obtained in c), and e) drying the mixture obtained in d) so that the micelles are embedded in the matrix-forming substance. Obtaining a product,
A method for preparing a solid pharmaceutical composition according to any of claims 1-18. The following steps:
a) dissolving a low-solubility active substance in a mixture of one or more surfactants and optionally one or more co-solvents;
b) optionally adding one or more further surfactants or auxiliary substances to the solution obtained in a)
c) dissolving the matrix-forming substance in water;
d) The solution obtained in c) and the solution obtained in a) or b) are mixed to form nano-sized micelles, and e) the mixture obtained in d) is dried so that the micelles are matrix-forming substances. Obtaining a solid pharmaceutical composition embedded therein,
A method for preparing a solid pharmaceutical composition according to any of claims 1-18. The following steps:
a) dissolving the low solubility active in either one or more surfactants and optionally a mixture of one or more co-solvents;
b) dissolving the solution obtained in a) in water to form nano-sized micelles;
c) optionally adding one or more further surfactants or auxiliary substances to the solution obtained in b),
d) Dissolving the matrix-forming substance in the solution obtained in b) or c), and e) drying the mixture obtained in d) so that the micelles are embedded in the matrix-forming substance. Obtaining a biological composition;
A method for preparing a solid pharmaceutical composition according to any of claims 1-18. The following steps:
a) dissolving a mixture of one or more surfactants and optionally one or more co-solvents in water to form nano-sized micelles;
b) dissolving the low solubility active substance in the solution obtained in a), wherein the resulting solution contains micelles comprising the low solubility active substance;
c) optionally adding one or more further surfactants or auxiliary substances to the solution obtained in b) and d) dissolving the matrix-forming substance in the solution obtained in b) or c), And e) drying the mixture obtained in d) to obtain a solid pharmaceutical composition in which the micelles are embedded in a matrix-forming substance,
A method for preparing a solid pharmaceutical composition according to any of claims 1-18. The following steps:
a) dissolving a mixture of one or more surfactants and optionally one or more co-solvents in water;
b) dissolving the low-solubility active substance in the solution obtained in a),
c) One or more additional surfactants or auxiliary substances are added to the solution obtained in b) to form a solution containing micelles comprising a low solubility active substance, and d) c) The matrix-forming substance is dissolved in a solution containing micelles comprising the low-solubility active substance obtained in step e) and the mixture obtained in e) d) is dried so that the micelles are embedded in the matrix-forming substance. Obtaining a solid pharmaceutical composition, wherein
A method for preparing a solid pharmaceutical composition according to any of claims 1-18. The method according to any one of claims 19 to 23, wherein the drying step is carried out by freeze drying, spray drying, freeze spray drying, vacuum drying or a combination thereof. The method according to any one of claims 19 to 24, further comprising the step of processing the solid pharmaceutical composition into granules, compressed tablets, sublingual tablets or buccal tablets. 25. A method according to any one of claims 19 to 24, further comprising the step of filling the solid pharmaceutical composition into capsules or sachets.