KR101434334B1 - Micellar nanoparticles of chemical substances - Google Patents

Abstract

The present invention relates to a thermally stable solid composition containing an insoluble chemical dissolved in an auxiliary material, for example, a nanoscale micelle containing a biologically active substance and entrapped in a water-soluble carrier. The present invention also relates to a process for the preparation of a thermally stable solid composition and to a process for the preparation of a pharmaceutical dosage form comprising the same.

Thermally stable solid composition, micelle

Description

Micellar nanoparticles of chemical substances < RTI ID = 0.0 >

Most new drug molecules generated from the drug discovery program are poorly soluble in the aqueous medium or substantially insoluble in the aqueous medium. It is therefore very attractive to formulate these active substances in a manner that can be administered parenterally or orally. The dissolution rate and intestinal permeability are important determinants of bioavailability, especially for oral administered drugs (low solubility generally relates to low dissolution rate, the law of by-Noyes-Whitney) (Jinno et al , J. of Controlled Release 111 (1-2), 56-64, 2006)). In addition, the effect of particle size reduction on dissolution and absorption of a poorly water-soluble drug, cilostazol, in beagle dogs, J. of Controlled Release 111 (1-2), 56-64, 2006). 12: Biological pharmacological classification system (see GL Amidon, H. Lennernas, VP Shah, and JR Crison, A: Theoretical basis for a biopharmaceutical drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. 413-420 (1995)), drugs that are poorly soluble belong to BCS class II or BCS class IV. BCS class IV means that the drug exhibits both poor solubility and low permeability while the bioavailability of the BCS class II drug is usually limited by dissolution rate (see Formulation of poorly water-soluble drugs for oral administration: Physicochemical and physiological Issues and the lipid formulation classification system, Colin W. Pouton, European Journal of Pharmaceutical Sciences 2006, 29, 278-87). This means that bioavailability of BCS Class II drugs can be increased by improving their dissolution rate and / or saturation solubility c _s .

Various formulation strategies were applied to improve the solubility and dissolution rate of poorly soluble drugs.

Formation of an inclusion complex with the cyclodextrin of the active substance may improve the solubility of the drug (see WO 9932107, which describes the use of cyclodextrins for the solubilization of THC). Cyclodextrins are cyclic oligomers of dextrose or dextrose derivatives, which can form reversible non-covalent bonds with insoluble 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) Suitable for materials. In these lipid formulations, the active substance is dissolved in oils or lipids that form an emulsion or form an emulsion system upon dilution with water.

One approach that has been applied to improve the dissolution behavior of poorly soluble drugs in the situation where the active substance remains in solid form is to use a solid amorphous or crystalline active material to produce a solid amorphous or crystalline material with reduced particle size Particle size reduction. As the particle size decreases, the surface area increases. Due to the larger surface area, the drug particles have an improved dissolution rate.

Generally, in the generation of material with reduced particle size, top-down and bottom-up techniques are distinguished. The top-down technique involves injecting energy to break large particles into small particles. Depending on the technique used, the average particle size of the material to be milled may be obtained in the micrometer range (e.g. jet-milling, hammer milling) or in the nm range (e.g. wet-ball milling and high pressure homogenisation). In the latter case, the use of an atomized starting material is recommended (US Pat. No. 5,145,684; US Pat. No. 5,858,410). A common drawback of these techniques is that they require enormous amounts of energy to break up the starting material.

Bottom-up techniques are used to create drug nanocrystals through precipitation. This technique is described as "via humida paratum" in the Old Testament. The active substance is dissolved in a solvent and the solvent is added to the non-solvent or anti-solvent (which is miscible with the solvent), the active substance precipitates in the form of amorphous or crystalline nanoparticles, and the latter may also be referred to as drug nanocrystals. The particles are generally stabilized by surfactants or polymeric stabilizers. This principle has been applied to generate so-called "Hydrosols " (US Pat. No. 5,389,382). Some variations of this precipitation principle have recently been described (see U.S. Patent Application No. 20050139144). However, it is very difficult to adjust the precipitated crystals to the nanoscale range. Nanoparticle structures generally tend to grow to form microparticles or microcrystals. One approach to solving this problem is to immediately dry the resulting suspension by, for example, lyphilization (see Sucker, H., Hydrosole-eine Alternative fungus parenterale Anwendung von schwer wasserloslichen Wirkstoffen, in: Muller, RH, Hildebrand, GE, (Hrsg.), Pharmazeutische Technologie: Moderne Arzneiformen, 2. Auflage, 1998, WVG, Stuttgart).

More recently developed particle size reduction methods, including supercritical fluid or spray-lyophilization, have been described in the literature for the preparation of solid drug nanoparticles (Jiahui Hu, Keith P. Johnston, and Robert O Williams III, Nanoparticle Engineering Processes for Enhancing the Dissolution Rates of Poorly Water Soluble Drugs, DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, Vol.30, No. 3, pp. 233-245, 2004).

All particle size reduction techniques typically have one common drawback that the drug needs to be dissolved to be absorbed from the digestive tract. For some drugs that are very poorly tolerated, the reduction in particle size may not be sufficient to improve dissolution behavior and increase bioavailability.

Another approach to improve the dissolution behavior of poorly soluble active materials is to introduce the above materials into an amorphous system such as a solid dispersion. "Solid dispersion" defines a solid state system (as opposed to a liquid or gas phase system) comprising two or more components, wherein one component is more or less uniformly dispersed throughout the remaining components or components. Solid dispersions consisting of one phase chemically and physically homogeneous, homogeneous, or thermodynamically defined throughout, may also be named as solid solutions (e.g., International Publication WO 97/044014). The solid matrix can be crystalline or amorphous. The drug may be dispersed as a molecule or as crystalline particles (solid dispersion) as well as amorphous particles (clusters). Examples of such solid dispersions are the tebufelone formulations described in U.S. Patent No. 5,281,420 and the bioactive peptide formulations described in WO 2005/053727.

Solid dispersions can be prepared using a variety of methods, such as fusion methods, hot-melt extrusion, volumetric evaporation or supercritical fluid methods (see DJ van Drooge "Combining the Incompatible ", Rijksuniversiteit Groningen, PhD- Thesis 2006). The solid dispersion or solid solution may contain a surfactant or other excipient for enhancing dissolution or stabilizing the drug. A number of techniques for the preparation of solid dispersions are discussed in U. S. Patent Application No. 20050266088A1. This application also describes a method of producing sugary glass of a lipophilic compound, wherein the lipophilic compound is dissolved in a co-solvent, preferably a 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 cosolvent can cause difficulties in large scale production, especially when spray drying is applied as a drying technique. To protect the complete system from explosion, the oxygen content in the dry air must be reduced. In addition, lipophilic compounds are not sufficiently stable in aqueous co-solvent systems and tend to precipitate. For that reason, rapid processing is proposed to prevent the occurrence of "clouding ".

If the active substance is not lipophilic but hydrophobic, i. E. Insoluble in lipids and oils, the cosolvent or co-surfactant mixture can be used to solubilise the active substance. To classify different solubilization systems, Mr. C. Pouton introduced a lipid formulation classification system (LFCS). A recent version of this system distinguishes between four different formulation types (see Formulation of poorly water-soluble drugs for oral administration: Physicochemical and physiological issues and the lipid formulation classification system, Colin W. Pouton, European Journal of Pharmaceutical Sciences 2006, 29, 278-87). LFCS Type IV describes an oil component formulation based on a surfactant-co-solvent mixture. Typically, these surfactant-co-solvent 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. Because the drug is already dissolved in the carrier, it can be rapidly absorbed (see Liquid-Filled and Seal Hard Gelatine Capsule Technologies, Ewart T. Cole, in: Modified-Release Drug Delivery Technology, eds. Hadgraft, MS Roberts, Marcel Dekker, Basel, 2003).

In order to produce a conventional solid dosage form from a poorly soluble liquid drug, a method of producing a "powder solution" has been proposed (Spireas et al., Powdered solution technology: principles and mechanisms, Pharm. Res. -1358, 1992). A "powder solution" is produced by mixing a liquid drug or drug solution with a selected carrier. The product obtained by the technique is a physical mixture or blend of the drug / surfactant solution and the selected carrier.

Examples of this type of formulation are described in International Patent Publications WO 2005/041929, WO 2006/113631 and WO 2006/135480. However, a common drawback of the resulting powders is its poor fluidity, its poor thermal stability and / or its poor compressibility.

It is an object of the present invention to provide further improved formulations of compounds, particularly biologically active compounds, which can be prepared using commercially available materials and standard methods and equipment. In the case of biologically active compounds, a further object of the present invention is to provide formulations with better bioavailability.

[Summary of the Invention]

The present invention relates to a thermostable composition comprising nanosized micelles and having improved dissolution behavior, wherein the micelles comprise a poorly soluble compound. In one embodiment, the pharmaceutical composition of the present invention comprises nanosized micelles, wherein the micelles comprise a poorly soluble chemical, for example, a surfactant or surfactant-cosolvent mixture containing a poorly soluble drug, Is incorporated into a water-soluble carrier, e. G., A water-soluble matrix of a pharmaceutically acceptable carrier.

A further aspect of the invention is to prepare a micellar aqueous solution comprising a poorly soluble compound, an auxiliary material or a mixture of auxiliary materials and a water soluble matrix, and drying the micellar solution to bond these micelles to a water soluble matrix of the carrier to obtain a thermally stable composition To a method for preparing a pharmaceutical composition comprising the same. Micelles containing poorly soluble compounds are prepared using one or more surfactants and optionally one or more co-solvents.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a diagram of a method of making a composition according to the present invention, for example, a pharmaceutical composition in general.

Figure 2 is a graph illustrating the plasma concentration of Compound 1 obtained after administration of four different formulations, including formulations in accordance with the present invention, to male Beagle dogs.

In a first aspect, the present invention relates to a heat stable solid composition comprising nanosized micelles, wherein said micelles comprise an insoluble chemical dissolved in an auxiliary material and are encapsulated in a water soluble carrier.

In a further aspect, the invention is directed to a thermostable solid pharmaceutical composition comprising nanosized micelles, wherein the micelle comprises an insoluble biologically active material dissolved in an adjuvant, wherein the water soluble, pharmaceutically acceptable < RTI ID = Lt; / RTI > matrix of the carrier.

In the context of the present invention, "thermal stability" means that the formulation is present as a stable, free-flowing powder when heated above the melting point of the major auxiliary material. This means that the formulation is physically stable when heated to 5 ° C, 10 ° C, 20 ° C, 30 ° C, 40 ° C or 50 ° C or more of 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). One of skill in the art can assume that if the vitamin E TPGS is the major component of the formulation, the formulation will exhibit at least partial melting upon exposure to temperatures much higher than 36 占 폚 (e.g., 80 占 폚). However, when vitamin E TPGS is used as an adjuvant in the present invention, vitamin E TPGS forms micelles, and micelles (and active substances) of vitamin E TPGS are incorporated into water soluble matrix materials having a melting point of 36 ° C or higher. Thus, the powder produced does not exhibit major changes in powder morphology and fluidity. The powder is present as a stable free flowing powder even when exposed to a temperature higher than the melting point of vitamin E TPGS, which is the main auxiliary material, at 5 ° C, 10 ° C, 20 ° C, 30 ° C, 40 ° C or above 50 ° C.

In the context of the present invention, a biologically active substance, a pharmaceutically active substance, a drug, an active compound, an active ingredient may be administered interchangeably to mean a chemical or chemical compound which, when administered to a human or animal, Is used.

In the context of the present invention, "poorly soluble compound" means a compound having a solubility in water of less than 33 g / l at 37 < 0 > C. Especially in the case of pharmaceutically active compounds, the poorly soluble compounds can be used in situ (e.g. gastric, intestinal, subcutaneous) under conditions, especially under pH, in which the compound becomes available to the body (in particular, Lt; RTI ID = 0.0 > 33g / l. ≪ / RTI > Thus, for example, a poorly soluble compound to be dissolved at the top has a solubility of 33 g / L or less in gastric juice (pH of about 1 to 3), and a poorly soluble compound dissolved in intestine is a serous (usually pH of about 7.4 or less) (See U.S. Patent No. 050266088, Frijlink). The present invention is based on the surprising discovery that solubility in far less soluble compounds, for example in gastrointestinal fluids, of 10 g / l, 4 g / l, 1 g / l, 100 mg / l, 40 mg / l, 10 mg / , 1 mg / l, 0.4 mg / l or 0.1 mg / l or less.

The poorly soluble compounds that can be processed according to the present invention can be liquid, semi-solid, solid amorphous, liquid crystalline or solid crystalline.

The refractory compound to be processed according to the present invention is preferably a pharmaceutically active agent and is preferably selected from the group consisting of an analgesic agent, an antiarrhythmic agent, an anti-asthmatic agent, an antibiotic, an insect repellent, an antipyretic, an antibacterial agent, an anticoagulant, an antidepressant, Antihistamines, antihypertensive agents, antihypertensive agents, anti-malarial agents, anti-migraine agents, antimuscarinics, anti-neoplastic agents, anti-obesity agents, antiparkinsonian agents, anti-thyroid agents, anti-thyroid agents, , Neuroleptic agents, cannabinoid receptor agonists and antagonists, cardiac contraction stimulators, cell adhesion inhibitors, corticosteroids, cytokine receptor activity modulators, diuretics, gastrointestinal drugs, histamine H-receptor antagonists, keratolytics, lipid modifiers, muscle relaxants, Anti-anginal agents, non-steroidal anti-asthmatics, opioid analgesics, sedatives, sex hormones and stimulants.

Some examples of sparingly soluble compounds are sparingly soluble cannabinoid agonists, inverse agonists and antagonists. Some examples of these compounds are disclosed in International Publication Nos. WO 01/70700, WO 02/076949, WO 03/026647, WO 03/026648, WO 03/027076, WO 2005/074920 The compounds described in WO 2005/080345, WO 2005/118553 and WO 2006/087355, for example, (4S) -3- (4 4-phenyl-N '-( 1-piperidinyl-sulfonyl) -1H-pyrazole-1-carboximidamide and International Patent Publication (4S) -3- (4-chlorophenyl) -N - [(4-chlorophenyl) sulfonyl] -4,5-dihydro-N'- (4S) -3- (4-chlorophenyl) -4,5-dihydro-N-methyl-4- < RTI ID = 0.0 > Phenyl-N '- [[4- (trifluoromethyl) phenyl] sulfonyl] -1H-pyrazole-1-carboximidamide.

The refractory compound in the composition of the present invention preferably has a log P of less than 10, more preferably less than 5, even more preferably less than 2.5, in an amount of 0.05 to 50% w / w or more of the total weight of the composition , Preferably from 0.05 to 10% w / w, or from 0.05 to 5% w / w, or from 0.05 to 1% w / w.

In the constitution of the present invention, the "auxiliary substance" is a substance capable of forming a micelle upon contact with water, or a substance having a positive effect on the stability of the micelle when the micelle is formed, for example, Or a mixture of a surfactant and a co-solvent.

In the present invention, "micelle" means a complex of surfactant molecules having a kraft point and a critical micelle concentration or higher in aqueous solution (see Rompp Online Dictionary). According to IUPAC, surfactants in solution often form associative colloids. That is, they tend to form aggregates of colloidal size, which are in equilibrium with the molecules or ions from which they are formed. These aggregates are called micelles.

The kraft point means a temperature at which the water solubility of the surfactant rises sharply (more precisely, a narrow temperature range). At that temperature, the solubility of the surfactant becomes equal to the critical micelle concentration. This can be measured by a sudden change in the slope of the logarithm of the solubility versus t or 1 / T. There is a relatively small range of surfactant concentration, below which no substantial micelles are detected, and at a substantially lower limit above which all additional surfactant molecules form micelles. When plotted against the concentration, many properties of the surfactant solution appear to vary at different rates above and below the corresponding range. By extrapolating these properties up and down in such a range until they cross, a known value as the critical micelle concentration (critical micelle concentration) can be obtained (see IUPAC Compendium of Chemical Terminology, Goldbook).

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

In the configuration of the present invention, the "average size" means a value obtained by a dynamic light scattering method (e.g., a photocorrelation spectroscopy (PCS), a laser diffraction (LD), a low angle laser light scattering means an effective average diameter measured by a laser light scattering, an intermediate angle laser light scattering (MALLS), a light shielding method (e.g., the Coulter method), rheology or a microscope (light or electron). By " effective average particle size less than about xnm ", it is meant that at least 90% of the particles have a weight average particle size less than about xnm, as measured by the techniques described above.

The composition according to the invention may comprise at least 10% or at least 30% or at least 50% of a surfactant and may comprise up to 99.95% of a surfactant. Optionally, the composition also contains at least one co-solvent and / or at least one co-surfactant.

In the case of pharmaceutical compositions, the surfactants and any co-surfactants that may be used are described in M. M. Rieger, "Surfactants ", Chapter 8 in Pharmaceutical Dosage Forms, Marcel Dekker Inc., (1993), p. 285-359. A preferred surfactant is a surfactant having an HLB value greater than 8. The most preferred surfactants are polyoxyethylene stearates such as Solutol®, polyoxyethylene sorbitan fatty acid esters such as Tween®, polyoxyethylene castor oil derivatives such as Chremophor®, vitamin E TPGS, nonionic Polyoxyethylene-polyoxypropylene block copolymers such as Poloxamer, water-soluble long chain organic phosphate esters such as Arlatone, and inulin lauryl carbamates such as Inutec SP1.

In the case of pharmaceutical compositions, any co-solvent used is preferably a pharmaceutically acceptable non-volatile cosolvent, wherein the vapor pressure is less than 0.50 mm Hg at 25 ° C. The pharmaceutical composition comprises an oil component formulation based on a surfactant and a cosolvent as the oil component formulation, which is a solubilization type IV of the lipid formulation classification system (LFCS) (see specification number < 12 >) as defined by Pouton And therefore the oil is specifically excluded as a cosolvent in the present invention. LFCS Type II formulation (SEDDS / SMEDDS with water soluble component), LFCS Type IIIB formulation (water soluble component and low oil content), LFCS Type I formulation (non-dispersible; Are also excluded.

Examples of non-volatile cosolvents include alkylene glycols such as polyethylene glycol (PEG), propylene glycol, diethylene glycol monoethyl ether, glyceryl triacetate, benzyl alcohol; Polyhydric alcohols 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 nonvolatile co-solvents in the present invention are the copolymers of ethylene oxide of the general formula (HOCH ₂ CH ₂ ) _n OH (where n is the number of units which are also numbers defining the average molecular weight (mw) of the polymer) PEG which is a polymer.

The form of the PEG useful in the present invention can be classified according to its material state, i.e., whether the material is in solid or liquid form at room temperature and pressure. In the context of the present invention, "liquid PEG" means a PEG having a molecular weight (m.w.) such that the material can be in a liquid state at room temperature and room pressure. For example, it is a PEG having an average molecular weight of less than 800 Daltons. PEG 400 (molecular weight about 380 to 420 Dalton), PEG 600 (molecular weight about 570 to 630 Dalton), and mixtures thereof are particularly useful. PEG is commercially available from Dow Chemical (Danbury, Conn.) Under the product CARBOWAX SENTRY line.

In the context of the present invention, "solid PEG" means a PEG having a molecular weight such that the material can be in a solid state at room temperature and room pressure. For example, PEG with an average molecular weight range of 900 to 20,000 Daltons is a solid PEG. A particularly useful solid PEG is a PEG having a molecular weight of 3,350 daltons (molecular weight of about 3015 to about 3685 Dalton) to 8,000 Dalton (molecular weight of about 7,000 to 9,000 Dalton). Particularly useful as solid PEG are PEG 3350, PEG 4000 (molecular weight about 3,600 to 4,400 Dalton), PEG 8000, and mixtures thereof.

When replacing liquid PEG (eg PEG 400) with solid PEG (eg PEG 4000), the resulting drug-surfactant-cosolvent mixture should be heated to 80 ° C. The cake from the lyophilization of the PEG 4000 product was found to be more rigid than when using PEG 400, but surprisingly, the release behavior was found to be unchanged when PEG 400 was replaced with PEG 4000.

When present, the formulations comprise the co-solvent in an amount of 0.01 to 99.95% w / w, preferably 10.0 to 90.0% w / w, most preferably 20.0 to 70.0% w / w.

The water-soluble carrier (also referred to as a matrix) may be any polymeric material that is water soluble. The matrix material can be considered to be water soluble if more than one part of the matrix material can be dissolved in 10 to 30 parts of water (see definition according to USP 24, page 2254).

In the case of pharmaceutical compositions, the water-soluble carrier should be pharmaceutically acceptable. Examples of pharmaceutically acceptable carriers useful in the present invention include alkylcelluloses such as methylcellulose; Hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose; Hydroxyalkyl alkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropyl-methylcellulose; Carboxyalkylcelluloses such as carboxymethylcellulose; Alkali metal salts of carboxyalkylcelluloses, such as sodium carboxymethylcellulose; Carboxyalkyl alkylcelluloses such as carboxymethylethylcellulose; Carboxyalkylcellulose esters; Starch; Pectin, such as sodium carboxymethylamylopectin; Chitin derivatives such as chitosan; Polysaccharides such as alginic acid, alkali metal salts and ammonium salts thereof; Carrageenan, galactomannan, tragacanth, agar-agar, gum arabic, guar gum and xanthan gum; Polyacrylic acids and their salts; Polymethacrylic acid and its salts, methacrylate copolymer; Polyvinyl alcohol; Polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone and vinyl acetate; Polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide.

Unlisted polymers that are pharmaceutically acceptable and have suitable physicochemical properties as defined above are equally 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 render it water-soluble. HPMC having a degree of methoxy substitution of from about 0.8 to about 2.5 and a degree of hydroxypropylmethyl substitution of from about 0.05 to about 3.0 is generally water-soluble. The degree of methoxy substitution means the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. The degree of hydroxy-propyl molar substitution refers to the average number of moles of propylene oxide reacted with each anhydroglucose unit of the cellulose molecule. Hypromellose is a US-adopted name for hydroxypropylmethylcellulose.

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 flavorings, colorants, binders, fillers, filler-binders, lubricants, disintegration aids and / or other pharmaceutically acceptable additives .

The process for the preparation of the compositions according to the invention comprises the preparation of micellar aqueous solutions of poorly soluble compounds by enclosing these micelles in a drying step into a carrier, for example a water-soluble matrix of a pharmaceutically acceptable carrier. Micelles containing poorly soluble compounds are produced by the use of one or more surfactants. In some cases, one or more co-solvents may also be included.

In another aspect of the invention, a micellar solution comprising a poorly soluble compound is prepared by dissolving the poorly soluble compound in at least one surfactant. Dissolving means that the insoluble compound is substantially monomolecularly dispersed, that is, not less than 95%, preferably not less than 98%, more preferably not less than 99%, even more preferably not less than 99.5% Or more, and most preferably, 99.9% or more is monomolecularly dispersed. If desired, one or more co-solvents may be added. In one aspect of the invention, by applying energy, the molecules can be completely distributed by heating, blending, or mixing the components. When the components form a molecularly dispersed system, they are mixed with the aqueous phase to form a micellar solution. The aqueous phase may contain a carrier, e. G., A dissolved matrix of a pharmaceutically acceptable carrier, or the aqueous matrix of the carrier is subsequently dissolved in a micellar solution. The mixture is dried to obtain a solid powder. The powder may be used as such or may be further processed by mixing with other excipients.

In another aspect of the invention, the composition according to the present invention promotes the absorption of the poorly soluble drug by forming a solution of the drug in a micelle when the composition is administered.

A further aspect of the invention is that the composition, e. G., A solid powder, is mixed with a solid gelatin capsule, such as even a hard gelatin capsule, such as PEG 400, glycerol, polyoxyl 35 castor oil (e.g. Cremophor EL.RTM.), Propylene glycol, diethylene glycol monoethyl ether (For example, Transcutol P®), sorbitan monooleate (eg, Span 80®) and excipients known to be non-emissive, and can be processed into a capsule filling powder .

Lyophilization is not usually a production method used for large-scale production, and is generally applied only to highly unstable drugs, for example, proteins. Spray drying is more convenient and more suitable for large scale production. Thus, spray drying was tested as a drying method for the micellar solution according to the present invention and found to be very suitable for production. Since a high vapor pressure flammable cosolvent is not used, the production of spray dried powder can be carried out with standard equipment without any special protection against explosion. In addition, the micelle solution is stable for several hours without precipitation of the drug, and in some cases, for several days. Irrespective of the drying method used, a dissolution test is presented in which approximately the same dissolution rate can be obtained.

Particle size analysis using laser diffraction was performed to test the effect of the drying step on the particle size of the micelle, indicating that the particle sizes after spray drying and after redistribution from the spray dried powder were of the same order of magnitude . From this result, it can be concluded that the drying process does not change the size of the generated micelle.

The process of the present invention is not limited to surfactant-co-solvent mixtures. If the micelle solution of the poorly soluble compound can be obtained in the presence of a pharmaceutically acceptable carrier in which the micelle solution is dissolved, the resulting micelle solution can be processed according to the present invention.

The pharmaceutical compositions according to the present invention may be further processed into solid dosage forms for any route of administration. Particularly interesting forms of administration are granules, compressed (immediate release) tablets for oral delivery, tablets or oral tablets and powders or granules filled hard gelatin capsules or capsules.

A tablet is a conventional form of a solid dosage form used for administration of a pharmaceutical composition. However, until now, it is difficult to produce tablets from liquid or semi-solid formulations containing insoluble drugs in their solubilized (i.e., dissolved) form. One procedure used in the preparation of such tablets is the absorption of a liquid drug or drug solution on a selected carrier (see Spireas et al., Powdered solution technology: principles and mechanisms, Pharm. Res. -1358, 1992). However, a common drawback of the resulting powders is its poor fluidity 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 the powders produced by spray drying, exhibit very good flowability. The anhydrous powder may be mixed with the pharmaceutical excipient in an anhydrous state. The resulting powder mixture can be directly filled into capsules, but can also be compressed into tablets. The tablets obtained exhibited very rapid drug release, and the release rate was comparable to the rate of capsule formulation of similarly structured powder. Particularly, when granulated fumed silica (such as AEROPERL 300) is used as a filler in the present invention, very rapid disintegration of the tablet and hence excellent drug release is obtained.

Tablets produced according to the present invention exhibit far superior drug release than those obtained with standard approaches (e.g., melt-extruded or liquid-filled capsules).

When comparing the release profiles of the formulations produced by melt-extrusion with the tablet formulations produced in accordance with the present invention, only heterogeneous tablets are obtained, since it is very difficult to powder the solidified masses obtained by melt extrusion And that only 60% of the drug was released after 20 minutes, compared to when the formulation according to the invention was used with more than 80% release.

The production of liquid filled capsules is another state of the art technology for providing dosage forms that can be used to administer pharmaceutical compositions. When the molten drug-surfactant-co-solvent (PEG 4000) mixture is filled into hard gelatine capsules that are solidified for drug release studies, the molten drug-surfactant-cosolvent mixture is compatible with the capsule shell . However, these capsules also exhibited relatively slow drug release. After 20 minutes, only 52% of the drug was released. Thus, drug release from formulations according to the present invention that is greater than 80% released is superior to drug release from conventional liquid filled capsules known in the art.

Although lyophilisation is not routinely used in large scale production, it can also be used according to the invention for the production of powders which can be compressed into tablets. Freeze drying may be used if only a limited amount of drug is used (e.g. in the initial development step) and the tablets according to the invention are desired. It has been found that lyophilized powder can be successfully compressed into tablets without the addition of additional excipients. These "unformulated" tablets exhibited a promising drug release of about 62%, which could certainly be elevated after 20 minutes by adding a standard tabletting excipient.

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

In a first aspect,

a) dissolving the poorly soluble active substance in an auxiliary substance or a mixture of auxiliary substances;

b) optionally adding at least one further auxiliary material to the solution obtained in step (a);

c) mixing the solution obtained in step (a) or (b) with water to form nanosized micelles;

d) dissolving the matrix-forming material in the mixture obtained in step (c); And

e) drying the mixture obtained in step (d) to obtain a solid pharmaceutical composition, wherein the micelle is encapsulated in a matrix-forming material. will be.

In a further aspect,

a) dissolving the poorly soluble active substance in an auxiliary substance or a mixture of auxiliary substances;

b) optionally adding at least one further auxiliary material to the solution obtained in step (a);

c) dissolving the matrix-forming material in water;

d) mixing the solution obtained in step (a) or (b) with the solution obtained in step (c) to form nanosized micelles; And

e) drying the mixture obtained in step (d) to obtain a solid pharmaceutical composition, wherein the micelle is encapsulated in a matrix-forming material. will be.

In a further aspect,

a) dissolving the poorly soluble active substance in an auxiliary substance or a mixture of auxiliary substances;

b) dissolving the solution obtained in step (a) in water to form nanosized micelles;

c) optionally adding at least one further auxiliary material to the solution obtained in step (b);

d) dissolving the matrix-forming material in the solution obtained in step (b) or (c); And

e) drying the mixture obtained in step (d) to obtain a solid pharmaceutical composition, wherein the micelle is encapsulated in a matrix-forming material. will be.

In another aspect,

a) dissolving an auxiliary material or a mixture of auxiliary materials in water to form nano-sized micelles;

b) dissolving the poorly soluble active substance in the solution obtained in step (a), wherein the obtained solution contains micelles containing the poorly soluble active substance;

c) optionally adding at least one further auxiliary material to the solution obtained in step (b);

d) dissolving the matrix-forming material in the solution obtained in step (b) or (c); And

e) drying the mixture obtained in step (d) to obtain a solid pharmaceutical composition, wherein the micelle is encapsulated in a matrix-forming material. will be.

In another aspect,

a) dissolving an auxiliary material or a mixture of auxiliary materials in water;

b) dissolving the poorly soluble active substance in the solution obtained in step (a);

c) adding at least one additional auxiliary material to the solution obtained in step (b) to form a solution containing micelles comprising the poorly soluble active material;

d) dissolving the matrix-forming material in a solution containing micellar active material obtained in step (c); And

e) drying the mixture obtained in step (d) to obtain a solid pharmaceutical composition, wherein the micelle is encapsulated in a matrix-forming material. will be.

When applying the above methods, the micelle may be formed in step (a), step (b), step (c) or step (d). For example, the micelle may be formed in step (a) 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). In this case, the micelle does not contain a poorly soluble active substance, and the poorly soluble active substance is included in the micelle in step (b). Alternatively, the micelle may be formed in step (b) when the surfactant is contacted with water in step (b). As a third alternative, if the micelle is not formed in step (a) or (b), the micelle is formed in step (c). In this case, the surfactant is first added in step (c) and / or the surfactant is contacted with water in step (c). As a fourth alternative, if the surfactant is first contacted with water in step (d), the micelle is formed in step (d).

In another aspect,

A) mixing the poorly soluble active substance, the auxiliary substance or the mixture of auxiliary substances, optionally one or more additional auxiliary substances, a matrix-forming substance and water to form nanosized micelles, and

B) drying the mixture obtained in step (A) to obtain a solid pharmaceutical composition, wherein the micelle is encapsulated in a matrix-forming material, to a process for preparing a solid pharmaceutical composition as described above will be.

The drying step may be performed by lyophilization, spray drying or freeze spray drying. The most preferred drying method is spray drying.

The powder formed by applying one of the above methods is free flowing and even when the amount of matrix forming material is very low, for example less than 50%, less than 30%, less than 20% or less than 10% It is stable and free-flowing when heated above the melting point of the auxiliary material. In this powder, micelles are present as in the initial micellar aqueous solution, but they are now incorporated into the solid matrix and are therefore stable. When dissolved in water, an initial aqueous solution of micelles is formed again (see FIG. 1).

The dried product may be further processed into granules, compressed tablets, tablets or buccal tablets, or the dried composition may be filled into capsules or capsules in powder or granular form with the aid of conventional methods and devices .

It is an advantage of the present invention that a thermostable solid composition of a poorly soluble active compound having a very high bioavailability can be obtained. A bioavailability study (in male beagle dogs) of a formulation comprising compound 1 (SLV330), a poorly soluble compound, was performed. The relative bioavailability of the composition according to the invention in male beagle dogs was found to be about 6 times higher relative to the relative bioavailability of the composition comprising the microparticulated active compound (see Table 2).

Although the present invention has been developed on the basis of active materials that can be used in the medical field, the principles can be used in other technical fields where nanoscale particles have an advantage, and the invention is thus not limited to its use in the medical field .

The following examples are merely intended to further illustrate the present invention in more detail, and thus these examples provided herein are not to be construed as limiting the scope of the invention in any way.

Example  1. Materials and Methods

Materials: Polyethylene glycol (eg PEG 400 and PEG 4000), polyoxyethylene sorbitan monooleate (eg Polysorbat 80®), Macrogol-15 hydroxystearate (eg Solutol® HS 15), anhydrous citric acid, Mannitol, hydroxypropyl methylcellulose (e.g. HPMC E5), d-alpha-tocopheryl polyethylene glycol 1000 (vitamin E TPGS), sodium dodecyl sulfate (SDS), polyvinylpolyprolidone (PVP- Aryl fumarate (eg Pruv®), microcrystalline cellulose (MCC) and granulated fused silica (eg Aerophe 300®) were obtained from conventional sources.

Compound 1: (4S) -3- (4-Chlorophenyl) -4,5-dihydro-N-methyl-4-phenyl-N '-( 1-piperidinyl- sulfonyl) 1-carboximidamide was prepared as described in International Publication No. WO 03/026648.

Compound 2: (4S) -3- (4-Chlorophenyl) -N - [(4-chlorophenyl) sulfonyl] -4,5-dihydro-N'- 1-carboximidamide was prepared as described in International Publication No. WO 02/076949.

Compound 3: (4S) -3- (4-Chlorophenyl) -4,5-dihydro-N-methyl- -1H-pyrazole-1-carboximidamide was prepared as described in International Publication No. WO 02/076949.

Way:

Plasma samples were analyzed according to the following procedure. Internal standard (20 [mu] l, 250 ng / ml) was added to the thawed plasma sample (20 [mu] l). The sample was then subjected to protein precipitation using methanol (210.). The samples were mixed, centrifuged (5 min, 3400 rpm, room temperature) and transferred to a 96 well plate with 50 占 퐇 of the resulting supernatant. Formic acid (0.2%, 150 [mu] l) was added to each well. The extracts were mixed, centrifuged (5 min, 3400 rpm, nominal 4 ° C) and submitted to LC-MS / MS analysis on a Waters Acquity UPLC connected to Applied Biosystems API 4000. The mass spectrometer was operated on a Turbo IonSpray positive and the analytical column was Waters Acquity BEH Phenyl 1.7 μm, 100 mm × 2.1 mm (id). Concentrations of Compound 1 and QC samples in the calibration standard were determined using a quadratic regression using the reciprocal (1 / x) of the concentration at the time of weighing. Data were collected and processed using Applied Biosystems / MDS Sciex Analyst ™ software 1.4.1.

Example  2. Compound 1 formulation ( FD PEG  400)

50 mg of Compound 1, a poorly soluble drug, was weighed into a glass injection vial. Thereafter, a solution containing 66.34% (w / w) PEG 400, 16.58% (w / w) Polysorbat 80, 16.58% (w / w) Solutol.HS 15 and 0.5% anhydrous citric acid 950 mg of a surfactant-co-solvent mixture was added to the vial. After the drug was completely dissolved, 4 ml of an aqueous mannitol solution (10% w / w) was added to the vial and the contents were thoroughly mixed. Then, within 5 seconds, the vial was supplied to 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) at -80 ° C and 0.050 mbar for 48 hours. A fluffy cake was obtained.

Example  3. Compound 1 formulation ( FD PEG  4000)

50 mg of the poorly soluble drug (Compound 1) was weighed into a glass injection vial. Thereafter, a solution containing 66.34% (w / w) PEG 4000, 16.58% (w / w) Polysorbate 80, 16.58% (w / w) Solutol HS 15 and 0.5% anhydrous citric acid 950 mg of a surfactant-co-solvent mixture was added to the vial. The mixture was stored in an oven at &lt; RTI ID = 0.0 &gt; 80 C &lt; / RTI &gt; until the drug was completely dissolved. Then, 4 ml of heated (80 ° C) aqueous mannitol solution (10% w / w) was added to the vial and the contents were mixed thoroughly until the solids content was dissolved. Then, within 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) at -80 ° C and 0.050 mbar for 48 hours. A cake which can be easily pulverized with a spatula was obtained.

Example  4. Compound 1 formulation ( SD PEG  4000)

13.7 g of the poorly soluble drug (Compound 1) was weighed into a glass flask. Thereafter, a solution containing 66.34% (w / w) PEG 4000, 16.58% (w / w) Polysorbate 80, 16.58% (w / w) Solutol HS 15 and 0.5% anhydrous citric acid 260 g of a surfactant-co-solvent mixture was added to the flask. The mixture was stored in an oven at &lt; RTI ID = 0.0 &gt; 80 C &lt; / RTI &gt; until the drug was completely dissolved. 1 g of this molten solution was mixed with 250 ml of an aqueous solution of hydroxypropylmethylcellulose (HPMC Grad E5, 0.016% w / w). The resulting solution was then spray dried using a Mini Spray Dryer Buchi 191 (Buchi, Switzerland). The air flow was 600 l / h, the inlet temperature was 150 ° C, the inhaler was set at 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.

Example  5. Compound 1 formulation ( SD TPGS )

1.0 g of the poorly soluble drug (Compound 1) was weighed into a flask. 20.0 g of heated (80 占 폚) Vitamin E TPGS containing 0.5% anhydrous citric acid (w / w) was added to the flask. The mixture was stored in an oven at &lt; RTI ID = 0.0 &gt; 80 C &lt; / RTI &gt; 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, 0.016% w / w). The resulting solution was then spray dried using a Mini Spray Dryer Buchi 191 (Buchi, Switzerland). The air flow was 600 l / h, the inlet temperature was 150 ° C, the inhaler was set at 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 example shows that the present invention is not limited to surfactant-cosolvent mixtures. Once the aqueous solution of the poorly soluble compound is obtained in the presence of a pharmaceutically acceptable carrier in which the aqueous solution is dissolved, the resulting solution of the micelle is processed according to the present invention.

Example  6. Particle size of Compound 1 formulation ( SD PEG  4000)

The particle size of the drug micelles was measured before and after spray drying using a laser pneumatic crawler LS 13 320 (Beckman Coulter, Fullerton, CA, USA) equipped with a Coulter aqueous liquid module. The actual refractive index of the fluid was set at 1.33 (water). In the case of the sample, the actual refractive index was set to 1.46, and the virtual refractive index was set to 0.01. 50 mg of the poorly soluble drug (Compound 1) was weighed into a glass injection vial. Thereafter, 950 mg of heated (80 캜) surfactant containing 66.67% (w / w) PEG 4000, 16.67% (w / w) Polysorbat 80 and 16.67% (w / -Copolymer mixture was added to the vial. The mixture was stored in an oven at &lt; RTI ID = 0.0 &gt; 80 C &lt; / RTI &gt; 1 g of this molten solution was mixed with 250 ml of an aqueous solution of hydroxypropylmethylcellulose (HPMC Grad E5, 0.016% w / w). The particle size of the resulting micellar solution measured when the volume was weighed to 95% diameter d by laser diffraction was 345 nm. 1.4 g of a drug (containing 50 mg of Compound 1) containing the powder produced according to Example 3 was dissolved in 250 ml of water. The particle size of the resulting micellar solution measured when the volume was weighed to 95% diameter by laser diffraction was 254 nm.

Example  7. Compound 1 FD  Purification of powder

The powder produced from Example 3 was compressed into a two-sided tablet having a diameter of 12.5 mm using an experimental hydraulic press and a compaction pressure of 100 bar was applied for 40 seconds.

Example  8. Compound 1 SD  Purification of powder

325 mg of the powder produced according to Example 4 was mixed with 325 mg of granulated hydrophilic fused silica (AEROPERL® 300/30, Degussa AG, Germany) and 125 mg of polyvinylpyrrolidone (Kollidon® CL, BASF, Germany) &Lt; / RTI &gt; The mixture was then compressed into a two-sided tablet having a diameter of 12.5 mm using an experimental hydraulic press and a consolidation pressure of 40 bar was applied for 2 seconds.

Example  9. Compound 1 PEG  400 capsules ( FD ) Emission profile

The powder produced according to Example 2 was filled into hard gelatine capsules. The drug content in one capsule was 25 mg. The dissolution test was performed according to USP II. The vessel was filled with 900 ml of 0.1 M HCl containing 0.5% w / v sodium dodecyl sulfate at 37.5 [deg.] C. The paddle speed was set at 50 rpm for the first 90 minutes and then the paddle speed was increased to 150 rpm for an additional 30 minutes. 10 ml of a sample was taken through a 0.22 탆 filter at 0 min, 5 min, 10 min, 20 min, 30 min, 45 min, 60 min, 90 min and 120 min. All experiments were performed 3 times and the mean ± covariance of these 3 tests was plotted as a function of time. The drug content in the sample was determined by HPLC. After 20 minutes, approximately 95% of the drug was released.

Example  10. Compound 1 PEG  4000 capsules ( FD ) Emission profile

The powder resulting from Example 3 was filled into hard gelatin capsules. The drug content in one capsule was 25 mg. The dissolution test was performed according to USP II. The vessel was filled with 900 ml of 0.1 M HCl containing 0.5% w / v sodium dodecyl sulfate at 37.5 [deg.] C. The paddle speed was set at 50 rpm for the first 90 minutes and then the paddle speed was increased to 150 rpm for an additional 30 minutes. 10 ml of a sample was taken through a 0.22 탆 filter at 0 min, 5 min, 10 min, 20 min, 30 min, 45 min, 60 min, 90 min and 120 min. All experiments were performed 3 times and the mean ± covariance of these 3 tests was plotted as a function of time. The drug content in the sample was determined by HPLC. After 20 minutes, approximately 85% of the drug was released.

Example  11. Compound 1 PEG  4000 capsules ( SD ) Emission profile

650 mg of powder produced according to Example 4 was filled into hard gelatin capsules. The drug content in one capsule was 25 mg. The dissolution test was carried out according to USP II. The vessel was filled with 900 ml of 0.1 M HCl containing 0.5% w / v sodium dodecyl sulfate at 37.5 [deg.] C. The paddle speed was set at 50 rpm for the first 90 minutes and then the paddle speed was increased to 150 rpm for an additional 30 minutes. 10 ml of a sample was taken through a 0.22 탆 filter at 0 min, 5 min, 10 min, 20 min, 30 min, 45 min, 60 min, 90 min and 120 min. All experiments were performed 3 times and the mean ± covariance of these 3 tests was plotted as a function of time. The drug content in the sample was determined by HPLC. After 20 minutes, approximately 85% of the drug was released.

Example  12. Compound 1 PEG  4000 tablets ( SD ) Emission profile

Drug release from the tablets produced according to Example 8 was tested. The drug content per tablet was 25 mg. The dissolution test was performed according to USP II. The vessel was filled with 900 ml of 0.1 M HCl containing 0.5% w / v sodium dodecyl sulfate at 37.5 [deg.] C. The paddle speed was set at 50 rpm for the first 90 minutes and then the paddle speed was increased to 150 rpm for an additional 30 minutes. 10 ml of a sample was taken through a 0.22 탆 filter at 0 min, 5 min, 10 min, 20 min, 30 min, 45 min, 60 min, 90 min and 120 min. All experiments were performed 3 times and the mean ± covariance of these 3 tests was plotted as a function of time. The drug content in the sample was determined by HPLC. After 20 minutes, about 82% of the drug was released.

Example  13. Spray Dry  Of compound 1 PEG  4000 tablets

In this example, comparative formulations were prepared and other formulations were made to compare the release profile of a standardized approach (e.g., melt-extrusion) with the formulations produced in accordance with the present invention. Thus, 150 mg of the poorly soluble drug (Compound 1) was weighed into a glass injection vial. Thereafter, 2850 mg of the heated (80 캜) surfactant containing 66.67% (w / w) PEG 4000, 16.67% (w / w) Polysorbat 80 and 16.67% (w / -Copolymer mixture was added to the vial. The mixture was stored in an oven at &lt; RTI ID = 0.0 &gt; 80 C &lt; / RTI &gt; The resulting solution was poured onto a glass plate and cooled to 25 ° C to solidify. The solid mass was then ground into irregular particles having a diameter of about 2 to 5 mm using a spatula. 325 mg granulated hydrophilic fumed silica (AEROPERL 300/30, Degussa AG, Germany) and 125 mg polyvinylpyrrolidone (Kollidon (R) CL, BASF, Germany) were compressed using an experimental hydraulic press and a consolidation pressure of 40 bar was applied for 2 seconds.

Example  14. Non-spray dried PEG  4000 Compound 1 dissolving tablets

Drug release from the tablets produced according to Example 13 was tested. The drug content per tablet was 25 mg. The dissolution test was performed according to USP II. The vessel was filled with 900 ml of 0.1 M HCl containing 0.5% w / v sodium dodecyl sulfate at 37.5 [deg.] C. The paddle speed was set at 50 rpm for the first 90 minutes and then the paddle speed was increased to 150 rpm for an additional 30 minutes. 10 ml of a sample was taken through a 0.22 탆 filter at 0 min, 5 min, 10 min, 20 min, 30 min, 45 min, 60 min, 90 min and 120 min. All experiments were performed 3 times and the mean ± covariance of these 3 tests was plotted as a function of time. The drug content in the sample was determined by HPLC. After 20 minutes, about 60% of the drug was released.

Example  15. PEG  4000 based compound 1 &lt; RTI ID = 0.0 &gt;

In this example, comparative formulations were prepared and other samples were produced to compare the release profiles of the standardized approaches (e.g., liquid filled capsules) with the formulations produced according to the present invention. Thus, 150 mg of the poorly soluble drug (Compound 1) was weighed into a glass injection vial. Thereafter, 2850 mg of the heated (80 캜) surfactant containing 66.67% (w / w) PEG 4000, 16.67% (w / w) Polysorbat 80 and 16.67% (w / -Copolymer mixture was added to the vial. The mixture was stored in an oven at &lt; RTI ID = 0.0 &gt; 80 C &lt; / RTI &gt; The resulting solution was filled into hard gelatin capsules (Licaps size 0, Capsugel, Belgium) and cooled to 25 캜 for solidification. All capsules were filled with 500 mg of melt mass (containing 25 mg of Compound 1).

Example  16. PEG  4000 &lt; / RTI &gt; liquid filled compound &lt; RTI ID = 0.0 &gt;

Drug release from the capsules produced according to Example 15 was tested. The drug content per tablet was 25 mg. The dissolution test was performed according to USP II. The vessel was filled with 900 ml of 0.1 M HCl containing 0.5% w / v sodium dodecyl sulfate at 37.5 [deg.] C. The paddle speed was set at 50 rpm for the first 90 minutes and then the paddle speed was increased to 150 rpm for an additional 30 minutes. 10 ml of a sample was taken through a 0.22 탆 filter at 0 min, 5 min, 10 min, 20 min, 30 min, 45 min, 60 min, 90 min and 120 min. All experiments were performed 3 times and the mean ± covariance of these 3 tests was plotted as a function of time. The drug content in the sample was determined by HPLC. After 20 minutes, about 52% of the drug was released.

Example  17. Compound 2 formulation ( SD )

250 mg of insoluble drug, Compound 2, was weighed into a glass flask. Thereafter, a solution of 9.75 (w / w) containing 66.34% (w / w) PEG 4000, 16.58% (w / w) Polysorbate 80, 16.58% (w / w) vitamin E TPGS and 0.5% g of the surfactant-co-solvent mixture was added to the flask. The mixture was stored in an oven at &lt; RTI ID = 0.0 &gt; 80 C &lt; / RTI &gt; until the drug was completely dissolved. 1 g of this molten solution was mixed with 100 ml of an aqueous solution of hydroxypropylmethylcellulose (HPMC Grad E5, 0.016% w / w). The resulting solution was then spray dried using a Mini Spray Dryer Buchi 191 (Buchi, Switzerland). The air flow was 600 l / h, the inlet temperature was 150 ° C, the inhaler was set at 80%, the feed flow rate was about 5.5 g / min, and the outlet temperature under these conditions was about 90 ° C. This procedure was repeated until the complete drug-surfactant-cosolvent mixture was processed. A free flowing powder was obtained.

Example  18. Compound 2 SD  Purification of powder

650 mg of the powder produced according to Example 17 was mixed with 450 mg of granulated hydrophilic fumed silica fumed silica 300/30, Degussa AG, Germany) and 200 mg of polyvinylpyrrolidone (Kollidon CL, BASF, Germany) . The mixture was compressed into a two-sided tablet having a diameter of 12.5 mm using an experimental hydraulic press and a consolidation pressure of 40 bar was applied for 2 seconds.

Example 19. Release profile of PEG 4000 Capsules (SD) of Compound 2

Drug release from the tablets produced according to Example 18 was tested. The drug content per tablet was 12.5 mg. The dissolution test was performed according to USP II. The vessel was filled with 900 ml of 0.1 M HCl containing 0.5% w / v sodium dodecyl sulfate at 37.5 [deg.] C. The paddle speed was set at 50 rpm for the first 90 minutes and then the paddle speed was increased to 150 rpm for an additional 30 minutes. 10 ml of a sample was taken through a 0.22 탆 filter at 0 min, 5 min, 10 min, 20 min, 30 min, 45 min, 60 min, 90 min and 120 min. All experiments were performed 3 times and the mean ± covariance of these 3 tests was plotted as a function of time. The drug content in the sample was determined by HPLC. After 20 minutes, about 92% of the drug was released.

Example  20. Compound 3 formulation ( SD TPGS )

0.2 g of the poorly soluble drug (Compound 3) was weighed into a flask. Then 1.8 g of heated (80 캜) vitamin E TPGS containing 0.5% anhydrous citric acid (w / w) was added to the flask. The mixture was stored in an oven at &lt; RTI ID = 0.0 &gt; 80 C &lt; / RTI &gt; until the drug was completely dissolved. 2 g of this molten solution was mixed with 100 ml of an aqueous solution of hydroxypropyl methylcellulose (HPMC Grad E5, 0.016% w / w). The resulting solution was then spray dried using a Mini Spray Dryer Buchi 191 (Buchi, Switzerland). The air flow was 600 l / h, the inlet temperature was 120 ° C, the inhaler was set at 80%, the feed flow rate was about 5.5 g / min and the outlet temperature under these conditions was about 80 ° C. A free flowing powder was obtained. This example shows that the present invention is not limited to surfactant-cosolvent mixtures. When an aqueous solution of the poorly soluble compound is obtained in the presence of a pharmaceutically acceptable water-soluble carrier dissolved therein, the resulting solution of the micelle is processed according to the present invention.

Example  21. Compound 1 formulation ( SD TPGS ) Increase experiment

100.0 g of the poorly soluble drug (Compound 1) was weighed into a flask. Then, 1900.0 g of heated (80 DEG C) Vitamin E TPGS containing 0.5% citric anhydride (w / w) was added to the flask. The mixture was stored in an oven at &lt; RTI ID = 0.0 &gt; 80 C &lt; / RTI &gt; and stirred until the drug was completely dissolved. 2 kg (2000.0 g) of this molten solution was mixed with 18.0 L of an aqueous solution of hydroxypropylmethylcellulose (HPMC Grad E5, 3.33% w / w). The resulting micellar solution was then spray dried using a spray drier, Niro Atomizer Mobile Minor (Niro Inc.). The inlet temperature was 250 캜, the feed flow rate was about 50 g / min, and the outlet temperature under these conditions was about 80 캜. A free flowing powder was obtained. This example shows that an increase to large equipment is also possible and produces a powder having the same properties as powders produced on a small laboratory scale.

Example  22. Example  At 21 The obtained  powder( SD TPGS ) Temperature stability measurement

The product of Example 21 (large scale production compound 1 SD TPGS) was placed in an oven at 80 占 폚 and allowed to stand for 4 weeks. No major changes in powder morphology were observed. After 4 weeks storage at 80 ℃, the free flowing powder remained intact. In contrast, the physical mixture with the same composition was already completely melted after one hour storage at 80 DEG C in the same oven.

Example  23. Male From a beagle dog  The comparative bioavailability data for four different formulations of Compound 1

A comparative bioavailability study was conducted in a crossover design to test the bioavailability of the final dosage form containing the micronized micelle according to the invention versus the other formulation forms. Four male beagle dogs were dosed with 50 mg of Compound 1 formulated into several dosage forms configured as shown in Table 1.

Composition of investigated formulations Micelle solution Microparticulate tablets Liquid filled capsules Tailored micelle purification (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 E TPGS 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 Aeropé 300® 400 27.59 Mingle 100 100 300 100 500 100 1450 100

In all cases, administering 50 mg of Compound 1 means that in some cases two doses were administered concurrently. The average plasma level after oral administration as measured according to the method described in Example 1 is shown in Fig. From these measurements, the data presented in Table 2 were obtained.

A comparative study of bioavailability for compound 1 in male beagle dogs Formulation Form C _maximum ratio Relative bioavailability Micelle solution 18 7.6 Tablets (microparticles) One One Liquid filled capsules 8 3.5 Tailored micelle purification 10 5.7

As indicated above, the relative bioavailability in male beagle dogs of compositions according to the invention (e. G. Tablets comprising the macronized micelle containing the active compound) is relatively low relative to that of the tablets containing the microparticulated active compound Which is about 6 times larger than bioavailability.

Claims (28)

A thermally stable solid composition comprising nanoscale micelles comprising a poorly soluble chemical dissolved in at least one surfactant and entrapped in a water soluble carrier, Wherein the at least one surfactant is selected from the group consisting of polyoxyethylene stearate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, vitamin E TPGS, nonionic polyoxyethylene-polyoxypropylene block copolymer, water soluble long chain organic phosphate ester and &Lt; / RTI &gt; inulin lauryl carbamate, The water- -Alkylcellulose; Hydroxyalkylcellulose; Hydroxyalkyl-alkylcellulose; Carboxyalkylcellulose; - alkali metal salts of carboxyalkylcellulose; Carboxyalkyl alkylcellulose; Carboxyalkylcellulose esters; Starch; - pectin; - chitin derivatives; - polysaccharides, alkali metal salts and ammonium salts thereof; - carrageenan, galactomanan, tragacanth, agar-agar, gum arabic, guar gum and xanthan gum; Polyacrylic acids and their salts; - polymethacrylic acid and its salts, methacrylate copolymers; Polyvinyl alcohol; - polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone and vinyl acetate; And - polyalkylene oxide &Lt; / RTI &gt; 1. A thermally stable solid pharmaceutical composition comprising nanosized micelles comprising an insoluble active material dissolved in at least one surfactant and encapsulated in a matrix of pharmaceutically acceptable water-soluble carriers, Wherein the at least one surfactant is selected from the group consisting of polyoxyethylene stearate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, vitamin E TPGS, nonionic polyoxyethylene-polyoxypropylene block copolymer, water soluble long chain organic phosphate ester and &Lt; / RTI &gt; inulin lauryl carbamate, The water- -Alkylcellulose; Hydroxyalkylcellulose; Hydroxyalkyl-alkylcellulose; Carboxyalkylcellulose; - alkali metal salts of carboxyalkylcellulose; Carboxyalkyl alkylcellulose; Carboxyalkylcellulose esters; Starch; - pectin; - chitin derivatives; - polysaccharides, alkali metal salts and ammonium salts thereof; - carrageenan, galactomanan, tragacanth, agar-agar, gum arabic, guar gum and xanthan gum; Polyacrylic acids and their salts; - polymethacrylic acid and its salts, methacrylate copolymers; Polyvinyl alcohol; - polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone and vinyl acetate; And - polyalkylene oxide &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof. 3. The composition according to claim 1 or 2, wherein the effective average particle size of the micelle is less than 1000 nm. 4. The composition of claim 3, wherein the effective average particle size of the micelle is less than 500 nm. 3. The composition of claim 1 or 2, wherein said at least one surfactant comprises at least 10% w / w. 3. The composition of claim 1 or 2, wherein the at least one surfactant is selected from the group consisting of Tween®, Chremophor®, Poloxamer®, Arlatone® and Inutec SP1®. 3. The pharmaceutical composition according to claim 1 or 2, wherein the water-soluble carrier is selected from the group consisting of methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxyethyl-methylcellulose, hydroxypropyl-methyl Cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylethylcellulose, carboxymethylamylopectin, chitosan, alginic acid, alkali metal salts and ammonium salts of alginic acid, polyethylene oxide, polypropylene oxide, and copolymers of ethylene oxide and propylene oxide &Lt; / RTI &gt; 3. The composition of claim 1 or 2 further comprising at least one co-solvent. 9. The process of claim 8, wherein the co-solvent is an alkylene glycol; Polyhydric alcohol; Polyoxyethylene; Linear polyols, 1,6-hexanediol, neopentyl glycol and methoxypolyethylene glycol; And mixtures thereof. 10. The composition of claim 9, wherein the cosolvent is selected from the group consisting of polyethylene glycol (PEG), propylene glycol, mannitol, sorbitol, xylitol, and ethylene glycol. 11. The composition of claim 10, wherein the co-solvent is polyethylene glycol (PEG) having a molecular weight of 800 Daltons or less. 12. The composition of claim 11, wherein the co-solvent is selected from the group consisting of PEG 200, PEG 400, and PEG 800. 11. The composition of claim 10, wherein the co-solvent is polyethylene glycol (PEG) having a molecular weight of 950 to 20,000 Daltons. 14. The composition of claim 13, wherein the co-solvent is selected from the group consisting of PEG 2000, PEG 3350, PEG 4000 and PEG 8000. The composition of claim 1 or 2, wherein the composition is in the form of a powder, granules, compressed tablet, tablet, mouthwash, filled capsule or filled saccase. 3. The composition according to claim 1 or 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. Claim 17 has been abandoned due to the setting registration fee. The method according to claim 16, wherein the poorly soluble active substance is (4S) -3- (4-chlorophenyl) -4,5-dihydro-N- Sulfonyl) -1H-pyrazole-1-carboximidamide. Claim 18 has been abandoned due to the setting registration fee. The method according to claim 16, wherein the poorly soluble active substance is (4S) -3- (4-chlorophenyl) -N - [(4-chlorophenyl) sulfonyl] -4,5-dihydro- 4-phenyl-1H-pyrazole-1-carboximidamide. Claim 19 is abandoned in setting registration fee. The method according to claim 16, wherein the poorly soluble active substance is (4S) -3- (4-chlorophenyl) -4,5-dihydro-N- Dimethylamino) phenyl] sulfonyl] -1H-pyrazole-1-carboximidamide. a) dissolving the poorly soluble active substance in at least one surfactant; b) mixing the solution obtained in step (a) with water to form nanosized micelles; c) dissolving the matrix-forming material in the mixture obtained in step (b); And d) drying the mixture obtained in step (c) to obtain a solid pharmaceutical composition, wherein the micelle is encapsulated in a matrix-forming material. a) dissolving the poorly soluble active substance in at least one surfactant; b) dissolving the matrix forming material in water; c) mixing the solution obtained in step (a) with the solution obtained in step (b) to form nanosized micelles; And d) drying the mixture obtained in step (c) to obtain a solid pharmaceutical composition, wherein the micelle is encapsulated in a matrix-forming material. a) dissolving the poorly soluble active substance in at least one surfactant; b) dissolving the solution obtained in step (a) in water to form nanosized micelles; c) dissolving the matrix-forming material in the solution obtained in step (b); And d) drying the mixture obtained in step (c) to obtain a solid pharmaceutical composition, wherein the micelle is encapsulated in a matrix-forming material. a) dissolving at least one surfactant in water to form nanosized micelles; b) dissolving the poorly soluble active substance in the solution obtained in step (a), wherein the obtained solution contains micelles comprising the poorly soluble active substance; c) dissolving the matrix-forming material in the solution obtained in step (b); And d) drying the mixture obtained in step (c) to obtain a solid pharmaceutical composition, wherein the micelle is encapsulated in a matrix-forming material. a) dissolving at least one surfactant in water; b) dissolving the poorly soluble active substance in the solution obtained in step (a); c) adding at least one additional surfactant to the solution obtained in step (b) to form a solution containing micelles comprising the poorly soluble active material; d) dissolving the matrix-forming material in a solution containing micellar active material obtained in step (c); And e) drying the mixture obtained in step (d) to obtain a solid pharmaceutical composition, wherein the micelle is encapsulated in a matrix-forming material. 25. The method of any one of claims 20 to 24, further comprising the step of adding at least one cosolvent. 25. The method of any of claims 20 to 24, wherein the drying step is performed in a lyophilization, spray drying, freeze spray drying, vacuum drying or a combination thereof. 25. The method of any one of claims 20 to 24, further comprising processing the solid pharmaceutical composition into granules, compressed tablets, capsules, or oral tablets. 25. The method of any one of claims 20 to 24, further comprising filling the capsule or saccharide with the solid pharmaceutical composition.

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