TW201326181A - Pharmaceutical composition containing pyrimidineone derivative - Google Patents

Abstract

This invention relates to a pharmaceutical composition containing a fused pyrimidineone derivative having the transient receptor potential modulating activity and a hydrophilic carrier.

Description

Pharmaceutical composition containing pyrimidinone derivative

The present invention relates to a pharmaceutical composition containing a pyrimidinone derivative. In particular, the present invention relates to a pharmaceutical composition comprising a fused pyrimidinone derivative having a transient receptor potential-modulating activity and a hydrophilic carrier.

The transient receptor potential (TRP) channel is a cation channel that is permeable to monovalent cations and divalent cations. The TRP channel is a large family of non-selective cation channels that have the function of helping to regulate ion current and membrane potential. The TRP family consists of six subfamilies including the transient receptor potential vanilloid type (TRPV) channel. The transient receptor potential vanilloid-3 receptor (TRPV3 receptor) is a member of this class of TRPV. Modulators of the TRPV3 receptor and compositions of such modulators are described in U.S. Patent Application Publication Nos. US 2006/0270688 and US 2007/0213321.

The commonly-assigned patent application publication No. WO 2009130560 (the '560 application) is hereby incorporated by reference in its entirety in its entirety for the disclosure of the disclosure of the disclosure of The TRPV3 receptor is modulated and can be used to treat various types of disease conditions involving the TRPV3 receptor, including inflammation and pain.

The present invention relates to a pharmaceutical composition comprising a poorly water-soluble pyrimidinone derivative and a hydrophilic carrier.

The above '560 application discloses a novel class of pyrimidinone derivatives of the formula (I) or a pharmaceutically acceptable salt thereof,

Wherein X is S or NR ^b ; Y is CR ³ ; Ring A is aryl or heteroaryl; R may be the same or different and is selected from the group consisting of hydrogen, nitro, cyano, halogen, -OR ^a , alkyl, Alkenyl, haloalkyl, cyanoalkyl or cyanoalkoxy; R ¹ and R ³ may be the same or different and are each independently selected from the group consisting of hydrogen, halogen, nitro, cyano, -COOH, alkyl, alkenyl Or alkynyl or haloalkyl; or R ¹ and R ³ together with the carbon atom to which they are attached may form a 5-7 membered ring, which may be substituted or unsubstituted, saturated, unsaturated or partially saturated, Optionally containing one or more heteroatoms selected from O, NR ^b or S; R ² is aryl or heteroaryl, each of which may be optionally mono- or polysubstituted by a substituent which is independently selected From the group consisting of halogen, hydroxy, nitro, cyano, -COOH, -NR ⁴ R ⁵ , decyl, alkyl, alkenyl, alkoxy, cyanoalkoxy, haloalkyl , haloalkoxy, cycloalkyl, cycloalkylalkyl and cycloalkyl-alkoxy; R ^a may be the same or different, selected from the group consisting of the following substances: hydrogen, alkyl, haloalkyl, cyano Alkyl, alkenyl, cycloalkyl, alkoxyalkyl, cycloalkylalkyl, substituted or unsubstituted arylalkyl, heteroarylalkyl, and heterocyclylalkyl; R ^b is selected from hydrogen, Alkyl or arylalkyl; R ⁴ and R ⁵ may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, arylalkyl, hetero An arylalkyl or heterocyclylalkyl group; and 'n' is an integer from 0 to 5 inclusive.

The above '560 application specifically discloses certain specific pyrimidinone derivatives, namely 7-{(E)-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]vinyl }-6-(4-Trifluoromethoxyphenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (same as "Compound I") or a salt thereof; 7- {(E)-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]ethenyl}-6-(4-trifluoromethylphenyl)-5H-[1,3 Thiazolo[3,2-a]pyrimidin-5-one (same as "Compound II") or a salt thereof; 4-{7-[(E)-2-(3-methoxy-2-pivaloyloxy) Phenyl)-1-vinyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-6-yl}benzonitrile (same as "Compound III") or Salt; 7-[(E)-2-(3-methoxy-2-pivaloxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy)phenyl]- 5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (same as "Compound IV") or a salt thereof; and 7-[(E)-2-(3-methoxy-2) -Pentyloxyphenyl)-1-vinyl]-6-(4-trifluoromethylphenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one ( Same as "Compound V") or a salt thereof.

Some pyrimidone derivatives of the general formula (I) have been found to be poorly soluble in water. For example, the inventors of the present invention have found, in particular, that Compound I is almost insoluble or insoluble in water (an aqueous medium having a pH ranging from 1.2 to 6.8). Accordingly, the inventors of the present invention believe that a pharmaceutical composition comprising a pyrimidinone derivative of the formula (I) (Compound I, Compound II, Compound III, Compound IV and Compound V) or a salt thereof and a hydrophilic carrier contributes to improvement The solubility of these compounds, in vitro dissolution, thereby improving the bioavailability of these compounds in the subject. Such pharmaceutical compositions contain a solid dispersion comprising a poorly water-soluble pyrimidinone derivative and a hydrophilic carrier, and such pharmaceutical compositions are contemplated herein.

Accordingly, one embodiment of the present invention provides a pharmaceutical composition comprising an active ingredient and a hydrophilic carrier selected from the group consisting of 7-{(E)-2-[2-(cyclopropyl) Methoxy)-3-methoxyphenyl]ethenyl}-6-(4-trifluoromethoxyphenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidine- 5-ketone ("Compound I") or 7-{(E)-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]ethenyl}-6-(4-trifluoro Methylphenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one ("Compound II") or 4-{7-[(E)-2-(3-A Oxy-2-p-pentyloxy)phenyl]-1-vinyl}-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-6-yl}benzonitrile ( "Compound III") or 7-[(E)-2-(3-methoxy-2-pivaloxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy) Phenyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one ("Compound IV") or 7-[(E)-2-(3-methoxy-2- Neopentyloxyphenyl)-1-vinyl]-6-(4-trifluoromethylphenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (" Compound V") or a salt thereof. Preferably, the above active ingredient is 7-{(E)-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]ethenyl}-6-(4-trifluoromethoxy Phenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one ("Compound I") or a salt thereof.

In another embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion comprising Compound I or a salt thereof and a hydrophilic carrier.

The above hydrophilic carrier in the present invention includes a surfactant, a complexing agent, a cosolvent, a polymer, and a mixture thereof. Preferably, the above hydrophilic carrier comprises a surfactant, a polymer or a mixture thereof.

In one embodiment, the invention is directed to a pharmaceutical composition wherein the weight ratio of the active ingredient to the hydrophilic carrier is from about 1:0.1 to about 1:100.

In another embodiment, the invention is directed to a pharmaceutical composition wherein the weight ratio of the active ingredient to the hydrophilic carrier is from about 1:0.5 to about 1:50. Preferably, in the above pharmaceutical composition, the weight ratio of the above active ingredient to the hydrophilic carrier is from about 1:1 to about 1:20.

In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion comprising Compound I or a salt thereof and a hydrophilic carrier, wherein the weight ratio of the above Compound I or a salt thereof to the above hydrophilic carrier is about 1:1 to about 1:10.

In another embodiment, the present invention is directed to a pharmaceutical composition comprising a solid dispersion comprising Compound I or a salt thereof, poloxamer, hydroxypropyl methylcellulose, and lauric acid polyethylene glycol Lauroyl macrogolglycerides.

In another embodiment, the present invention is directed to a pharmaceutical composition comprising a solid dispersion comprising Compound I or a salt thereof, poloxamer, hydroxypropyl methylcellulose, and lauric acid polyethylene glycol Glycerides, their weight ratios are approximately 1:1:1:2, respectively.

In another embodiment, the invention is directed to a pharmaceutical composition wherein the above active ingredient is present in an amount from about 1% w/w to about 70% w/w. Preferably, the above active ingredient is present in an amount from about 1% w/w to about 50% w/w, more preferably in an amount from about 5% w/w to about 25% w/w.

In a specific embodiment, the present invention relates to a pharmaceutical composition comprising from about 5% w/w to about 25% w/w of Compound I or a salt thereof as an active ingredient, about 5% w/w to About 25% w/w of poloxamer, about 5% w/w to about 25% w/w of hydroxypropyl methylcellulose and about 5% w/w to about 50% w/w of lauric acid Polyethylene glycol glyceride.

In one embodiment, the present invention relates to a pharmaceutical composition comprising Compound I or a salt thereof and a hydrophilic carrier for oral administration; wherein, when it contains 900 mL of 0.1 N HCl and 1% (w/v) In the U.S. Pharmacopoeia Type II device of sodium dodecyl sulphate (SLS), when the temperature is maintained at about 37 ± 0.5 ° C and stirred at 75 rpm, the drug composition is released at least 75% within 60 minutes. Compound I or a salt thereof contained therein. Preferably, the composition releases 85% of the compound I or a salt thereof contained under the conditions specified above.

In another embodiment, the present invention relates to a pharmaceutical composition wherein the above Compound I or a salt thereof is partially present in an amorphous form. In one embodiment, at least about 10% of the compound I or a salt thereof contained in the above pharmaceutical composition is in an amorphous form. Preferably, from about 10% to about 50%, or more preferably from about 15% to about 40%, of the compound I or a salt thereof contained in the above pharmaceutical composition is an amorphous form.

In one embodiment, the invention relates to a method of treating a disease condition in a subject associated with modulation of a TRPV3 receptor, wherein the method comprises: administering to the subject a pharmaceutical composition comprising an active ingredient and a hydrophilic carrier, The above active ingredient is selected from the group consisting of Compound I, Compound II, Compound III, Compound IV and Compound V or a salt thereof. Preferably, the above active ingredient is Compound I or a salt thereof.

In another embodiment, the invention relates to a method of treating a disease condition in a subject associated with modulation of a TRPV3 receptor, wherein the method comprises: administering to the subject a pharmaceutical composition comprising a solid dispersion, the solid The dispersion comprises Compound I or a salt thereof and a hydrophilic carrier.

In another embodiment, the invention relates to the use of a pharmaceutical composition for treating a disease condition associated with TRPV3 receptor modulation in a subject, the use comprising: administering to the subject a pharmaceutical composition comprising a solid dispersion, The solid dispersion comprises Compound I or a salt thereof and a hydrophilic carrier.

In another embodiment, the invention relates to a pharmaceutical composition for treating a disease condition in a subject associated with TRPV3 receptor modulation, the treatment comprising: administering to the subject a pharmaceutical composition comprising a solid dispersion, the solid dispersion The body comprises Compound I or a salt thereof and a hydrophilic carrier.

In another embodiment, the present invention provides a process for the preparation of the above pharmaceutical composition, which comprises preparing a solid dispersion of Compound I or a salt thereof and a hydrophilic carrier, and formulating the above solid dispersion into a suitable dosage form . The above method comprises: preparing a solid dispersion of Compound I or a salt thereof and a hydrophilic carrier, converting the solid dispersion into a granule preparation, and formulating the granules into a dosage form suitable for oral administration.

The invention also provides the following aspects:

(1) One containing the active ingredient 7-{(E)-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]ethenyl}-6-(4-trifluoromethoxy A pharmaceutical composition of phenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one ("Compound I") or a salt thereof and a hydrophilic carrier.

(2) A pharmaceutical composition comprising a solid dispersion comprising Compound I or a salt thereof and a hydrophilic carrier.

(3) The pharmaceutical composition according to the above (1) or (2), wherein the hydrophilic carrier comprises a surfactant, a complexing agent, a cosolvent, a polymer, and a mixture thereof.

(4) The pharmaceutical composition according to the above (1) or (2), wherein the hydrophilic carrier is a surfactant, and the surfactant is selected from the group consisting of poloxamer, polyoxyethylene sorbitan ester, and polyoxyethylene. Sorbitan ester, polyglycerol-6-dioleate, polyethylene glycol-15 hydroxystearate, diethylene glycol monoethyl ether, propylene glycol dicaprylate/dicaprate, lecithin, phospholipid, Polyethylene glycol glyceride laurate, polyethylene glycol glyceride oleate and polyethylene glycol glyceride caprylate or a mixture thereof.

(5) The pharmaceutical composition according to the above (1) or (2), wherein the hydrophilic carrier is a complexing agent, and the complexing agent is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, Hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin-neutralized polyacrylic acid, cross-linked acrylic acid copolymer or a mixture thereof.

(6) The pharmaceutical composition according to the above (1) or (2), wherein the hydrophilic carrier is a cosolvent, and the cosolvent is selected from the group consisting of ethanol, propanol, isopropanol, propylene glycol, polyethylene glycol, and Methyl chloride, dimethyl isosorbide, ethyl lactate, N-methylpyrrolidone, tetrahydrofuran polyglycol ether, glycerol monodecanoate, glycerol dicarboxylate, triglyceride monooleate, polyglycerol oleic acid A mixed diester of an ester, caprylic/capric acid and propylene glycol, ethyl oleate, glycerol monooleate, vitamin ETPGS, alpha-tocopherol or a mixture thereof.

(7) The pharmaceutical composition according to the above (1) or (2), wherein the hydrophilic carrier is a polymer, and the polymer is selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, Hydroxyethyl cellulose, carrageenan or a mixture thereof.

(8) The pharmaceutical composition according to the above (1) or (2), wherein the weight ratio of the above active ingredient to the hydrophilic carrier is from about 1:0.1 to about 1:100.

(9) The pharmaceutical composition according to the above (1) or (2), wherein the weight ratio of the above active ingredient to the above hydrophilic carrier ranges from about 1:0.5 to about 1:50.

(10) The pharmaceutical composition according to the above (1) or (2), wherein the weight ratio of the above active ingredient to the hydrophilic carrier ranges from about 1:1 to about 1:20.

(11) A pharmaceutical composition comprising a solid dispersion comprising Compound I or a salt thereof and a hydrophilic carrier, wherein the weight ratio of the above Compound I or a salt thereof to the above hydrophilic carrier is about 1:1 It is about 1:10.

(12) The pharmaceutical composition according to the above (11), wherein the hydrophilic carrier comprises poloxamer, polyoxyethylene sorbitan ester, polyethoxylated castor oil, lauric acid polyethylene glycol glyceride, poly Vinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or a mixture thereof.

(13) The pharmaceutical composition according to the above (11), wherein the hydrophilic carrier comprises poloxamer, lauric acid polyethylene glycol glyceride, and hydroxypropylmethylcellulose or a mixture thereof.

(14) A pharmaceutical composition comprising a solid dispersion comprising Compound I or a salt thereof, poloxamer, hydroxypropylmethylcellulose, and polyethylene glycol glyceride.

(15) The pharmaceutical composition according to the above (14), wherein the weight ratio of the compound I or a salt thereof, the poloxamer, the hydroxypropylmethylcellulose, and the polyethylene glycol laurate is about 1: 1:1:2.

(16) The pharmaceutical composition according to any of the preceding paragraphs, wherein the compound I or a salt thereof is present in an amount of from about 1% w/w to about 70% w/w.

(17) The pharmaceutical composition according to any of the preceding paragraphs, wherein the compound I or a salt thereof is present in an amount of from about 1% w/w to about 50% w/w.

(18) The pharmaceutical composition according to any of the preceding paragraphs, wherein the compound I or a salt thereof is present in an amount of from about 5% w/w to about 25% w/w.

(19) A pharmaceutical composition comprising: (a) from about 5% w/w to about 25% w/w of Compound I or a salt thereof; (b) from about 5% w/w to about 25% w /w of poloxamer; (c) from about 5% w/w to about 25% w/w of hydroxypropyl methylcellulose; and (d) from about 5% w/w to about 50% w/w The lauric acid polyethylene glycol glyceride.

(20) A pharmaceutical composition comprising the compound I or a salt thereof, wherein at least about 10% of the compound I or a salt thereof contained in the pharmaceutical composition is present in an amorphous form.

(21) The pharmaceutical composition according to the above (20), wherein about 10% to about 50% of the compound I or a salt thereof contained in the above pharmaceutical composition is in an amorphous form.

(22) A pharmaceutical composition according to any of the preceding paragraphs, wherein the above composition is suitable for oral administration.

(23) A pharmaceutical composition comprising Compound I or a salt thereof and a hydrophilic carrier suitable for oral administration, wherein when it contains 900 mL of 0.1 N HCl and 1% (w/v) of dodecyl sulfate In the U.S. Pharmacopoeia Type II device of sodium, when the test is carried out at a temperature of about 37 ± 0.5 ° C and stirred at 75 rpm, the drug composition releases at least 75% of the compound I or a salt thereof contained therein within 60 minutes.

(24) The pharmaceutical composition according to the above (23), wherein the pharmaceutical composition releases at least 85% of the compound I or a salt thereof.

(25) A method of treating a disease condition in a subject associated with modulation of a TRPV3 receptor, the method comprising administering to the subject the above-described pharmaceutical composition according to any of the above (1) to (24).

(26) Use of the pharmaceutical composition according to any one of the above (1) to (24) for the manufacture of a medicament for treating a disease condition in which a subject is involved in the regulation of TRPV3 receptor.

(27) A pharmaceutical composition according to any one of the above (1) to (24), for use in the treatment of a disease condition in which a subject is associated with TRPV3 receptor modulation.

(28) A method of producing a pharmaceutical composition according to the above (1) to (24), which comprises: (a) preparing a solid dispersion of the compound I or a salt thereof and a hydrophilic carrier; and (b) dispersing the above solid The body preparation is in a suitable dosage form.

A method of producing a pharmaceutical composition according to the above (1) to (24), which comprises: (a) preparing a solid dispersion of Compound I or a salt thereof and a hydrophilic carrier; (b) converting the above solid dispersion into particles Formulation; and (c) formulating the above granules into a dosage form suitable for oral administration.

[detailed description]

The present invention relates to a pharmaceutical composition comprising a solid dispersion comprising a pyrimidone derivative of the formula (I) which is poorly soluble in water and a hydrophilic carrier.

The terms used herein are as defined below. In the event of a conflict between the definitions set forth in this application and the definitions set forth in the prior provisional application claiming priority, the definitions in this application shall control.

The above '560 application specifically discloses certain specific pyrimidinone derivatives, i.e., 7-{(E)-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]vinyl }-6-(4-Trifluoromethoxyphenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (same as "Compound I") or a salt thereof; 7- {(E)-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]ethenyl}-6-(4-trifluoromethylphenyl)-5H-[1,3 Thiazolo[3,2-a]pyrimidin-5-one (same as "Compound II") or a salt thereof; 4-{7-[(E)-2-(3-methoxy-2-pivaloyloxy) Phenyl)-1-vinyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-6-yl}benzonitrile (same as "Compound III") or Salt; 7-[(E)-2-(3-methoxy-2-pivaloxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy)phenyl]- 5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (same as "Compound IV") or a salt thereof; and 7-[(E)-2-(3-methoxy-2) -Pentyloxyphenyl)-1-vinyl]-6-(4-trifluoromethylphenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one ( Same as "Compound V") or a salt thereof.

In particular, Compound I was found to be almost insoluble or insoluble in water (i.e., an aqueous medium having a pH ranging from 1.2 to 6.8), slightly soluble in methanol, very slightly soluble in ethanol, and readily soluble in acetone, dichloromethane and chloroform.

Herein, the above term "solid dispersion" means a preparation in which an active ingredient is dispersed in a hydrophilic carrier domain in a molecular state or in the form of microparticles. The above solid dispersions in the context of the present invention improve the solubility of the above active ingredients (and in turn improve the dissolution rate).

The pyrimidinone derivatives of the present invention (including Compound I, Compound II, Compound III, Compound IV, and Compound V) may be in an amorphous form, or a crystalline form, or a mixture thereof.

The term "active ingredient" as used herein (which may be used interchangeably with "active", or "active substance", or "drug") includes a pyrimidinone derivative selected from the group consisting of Compound I, Compound II. , Compound III, Compound IV and Compound V (comprising one or more of their salts, analogs, derivatives, polymorphs, solvates, single isomers, enantiomers, metabolites, prodrugs and mixture).

The term "treating" or "treatment" as used herein also includes "prophylaxis", "mitigation", "prevention", "improvement" in a subject. "" or "suppression" of a disease condition.

The term "TRPV3 receptor modulation" as used herein also includes inhibition, antagonism, inverse agonism, agonism, reverse antagonism, and activation of the TRPV3 receptor.

The above term "subject" includes mammals such as humans and other animals such as domestic animals (eg, domestic pets, including cats and dogs) and non-live animals (eg, wild animals). Preferably, the subject is a human.

In one embodiment, the invention provides a pharmaceutical composition comprising an active ingredient and a hydrophilic carrier selected from the group consisting of 7-{(E)-2-[2-(cyclopropyl) Methoxy)-3-methoxyphenyl]ethenyl}-6-(4-trifluoromethoxyphenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidine- 5-ketone (Compound I) or 7-{(E)-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]ethenyl}-6-(4-trifluoromethyl Phenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (Compound II) or 4-{7-[(E)-2-(3-methoxy-2) -Pentyloxy)phenyl)-1-vinyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidin-6-yl}benzonitrile (Compound III) or 7-[(E)-2-(3-Methoxy-2-pivalyloxyphenyl)-1-vinyl]-6-[4-(trifluoromethoxy)phenyl]-5H- [1,3]thiazolo[3,2-a]pyrimidin-5-one (Compound IV) or 7-[(E)-2-(3-methoxy-2-pivaloxyphenyl)- 1-vinyl]-6-(4-trifluoromethylphenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (Compound V) or a salt thereof. Preferably, the above active ingredient is 7-{(E)-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]ethenyl}-6-(4-trifluoromethoxy Phenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (Compound 1) or a salt thereof.

In another embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion comprising Compound I or a salt thereof and a hydrophilic carrier.

The above pharmaceutical composition of the present invention includes a pharmaceutical composition for oral administration, intravenous administration, transdermal administration, transmucosal administration, nasal administration and the like.

The above pharmaceutical compositions for oral administration may be in various dosage forms such as tablets, capsules, granules (same as "beads" or "particles" or "pellets". ), solutions, suspensions, emulsions, powders, dry syrups, and the like. The above capsules may include granules/pellets/microgranules/microtablets/microcapsules containing the active ingredient.

The above pharmaceutical composition for parenteral administration includes a solution for intravenous, subcutaneous or intramuscular injection/infusion, a suspension for intramuscular or subcutaneous injection, an emulsion for intramuscular or subcutaneous injection, and the like. Implants, but are not limited to this.

The above-mentioned pharmaceutical composition for transdermal or transmucosal administration includes, but is not limited to, a patch, a gel, a cream, an ointment and the like.

In one embodiment, the invention is directed to a pharmaceutical composition wherein the weight ratio of the active ingredient to the hydrophilic carrier is from about 1:0.1 to about 1:100.

In another embodiment, the invention is directed to a pharmaceutical composition wherein the weight ratio of the active ingredient to the hydrophilic carrier is from about 1:0.5 to about 1:50. Preferably, in the above pharmaceutical composition, the weight ratio of the above active ingredient to the hydrophilic carrier is from about 1:1 to about 1:20.

In one embodiment, the present invention includes a pharmaceutical composition comprising a solid dispersion comprising the active ingredient Compound I or a salt thereof and a hydrophilic carrier, wherein the weight ratio of the above Compound I or a salt thereof to the above hydrophilic carrier It is about 1:1 to about 1:10.

In another embodiment, the present invention is directed to a pharmaceutical composition comprising a solid dispersion comprising Compound I or a salt thereof, poloxamer, hydroxypropyl methylcellulose, and lauric acid polyethylene glycol Glyceride.

In another embodiment, the present invention is directed to a pharmaceutical composition comprising a solid dispersion comprising Compound I or a salt thereof, poloxamer, hydroxypropyl methylcellulose, and lauric acid polyethylene glycol Glycerides, their weight ratios are approximately 1:1:1:2, respectively.

In another embodiment, the invention is directed to a pharmaceutical composition wherein the above active ingredient is present in an amount from about 1% w/w to about 70% w/w. Preferably, the above active ingredient is present in an amount from about 1% w/w to about 50% w/w, more preferably in an amount from about 5% w/w to about 25% w/w.

In a specific embodiment, the present invention relates to a pharmaceutical composition comprising from about 5% w/w to about 25% w/w of Compound I or a salt thereof as an active ingredient, about 5% w/w to About 25% w/w of poloxamer, about 5% w/w to about 25% w/w of hydroxypropyl methylcellulose and about 5% w/w to about 50% w/w of lauric acid Polyethylene glycol glyceride.

The above term "hydrophilic carrier" means one or more pharmaceutical excipients which, when mixed with a compound selected from the group consisting of Compound I, Compound II, Compound III, Compound IV and Compound V, are capable of increasing the above compounds Water solubility; the above hydrophilic carrier generally includes a surfactant, a complexing agent, a cosolvent, a polymer, and a mixture thereof.

In the context of the present invention, the above hydrophilic carrier includes a surfactant, a complexing agent, a cosolvent, a polymer, and a mixture thereof. Preferably, the above hydrophilic carrier comprises a surfactant, a polymer or a mixture thereof.

Surfactants suitable for use in the present invention include, but are not limited to, poloxamers, cetrimide, cetyltrimethylammonium bromide (CTAB), polyoxyethylene sorbitan esters (also known as POLYSORBATE or TWEEN), polyoxyethylene castor oil (CREMOPHOR), methyl glucose sesquistearate, PEG-20 methyl glucoside sesquistearate, Steareth-21, polyethylene glycol-20 sorbose Alcoholic anhydride monostearate, polyethylene glycol-60 sorbitan monostearate, polyethylene glycol-80 sorbitan monostearate, Steareth-20, Ceteth-20, PEG- 100 stearate, sodium stearyl sarcosinate, hydrogenated lecithin, sodium cocoyl glyceryl sulfate, sodium stearyl sulfate, sodium stearyl sulphate, PEG-20 glycerin single hard Fatty acid ester, sucrose monostearate, sucrose polystearate, polyglyceryl-10 stearate, polyglycerol-10 myristate, Steareth-10, oleyl-3 phosphate DEA salt , oleyl polyether-10 phosphate DEA salt, PPG-5 cetyl polyether-10 phosphate sodium salt, PPG-5 cetyl polyether-10 phosphate potassium salt, Steareth-2, PEG-5 soybean Sterol oil, PEG -10 soy sterol oil, cetyl phosphate diethanolamine, polyglycerol-6-dioleate (Pleurol Olique CC 497), polyethylene glycol-15 hydroxystearate (Solutol HS 15), two Transcutol P, propylene glycol dicaprylocaprate (Labrafac PG), dioctyl bis(2-ethylhexyl) sulfosuccinate (Docusate) Sodium), propylene glycol monocaprylate (Capryol PGMC), lecithin, sorbitan monostearate, diethylene glycol monostearate, glyceryl monostearate, etc., polyoxyglycerides (eg Lauric acid polyglycol glyceride (referred to as GELUCIRE), oleic acid polyethylene glycol glyceride (referred to as LABRAFIL) and caprylic acid polyethylene glycol glyceride (referred to as LABRASOL), phospholipids and their mixture. Preferably, poloxamers and hydrophilic grades of GELUCIRE (e.g., GELUCIRE 44/14) are found to be suitable for use in the present invention.

Complexing agents suitable for use as hydrophilic carriers in the present invention include, but are not limited to, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether -β-cyclodextrin-neutralized polyacrylic acid, cross-linked acrylic acid copolymer (such as Indion 414), sodium polystyrene sulfonate (such as Amberlite IRP-69), copolymerization of methacrylic acid crosslinked with divinylbenzene (eg Amberlite IRP-64) and Potaklin potassium, zinc acetate, calcium acetate, magnesium acetate and mixtures thereof.

Cosolvents suitable as hydrophilic carriers in the present invention include, but are not limited to, ethanol, propanol, isopropanol, propylene glycol, polyethylene glycol, dichloromethane, acetone, hexane polyol fatty acid esters, Trialkyl citrate, propylene carbonate, dimethylisosorbide, ethyl lactate, N-methylpyrrolidone, ethylene glycol monoethyl ether (transcutol), tetrahydrofuran polyglycol ether (glycofurol ), polyglycerol-10 monoglyceride and polyglycerol-10 dioleate (Caprol PGE-860), triolein monooleate (Caprol 3GO), polyglyceryl oleate (Caprol MPGO), caprylic / citric acid Mixed diester with propylene glycol (Captex 200), glycerol monocaprate and glycerol dicaprate (Capmul MCM), isostearyl isostearate, oleic acid, peppermint oil, oleic acid, soybean oil, safflower oil Corn oil, olive oil, cottonseed oil, peanut oil, sunflower oil, palm oil, rapeseed oil, ethyl oleate, glycerol monooleate, vitamin E TPGS, alpha-tocopherol acetate, and mixtures thereof.

Polymers suitable for use as hydrophilic carriers in the present invention include, but are not limited to, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, other cellulose derivatives, hydrocolloids (eg, gums) ), carrageenan and mixtures thereof.

The present invention is the above pharmaceutical composition may further comprise at least one other excipient, non-limiting examples include diluents such as microcrystalline cellulose ( "MCC"), silicide the MCC (e.g., PROSOLV ^TM), microfiber , lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, calcium hydrogen phosphate dihydrate, phosphoric acid Tricalcium, magnesium carbonate, magnesium oxide, etc.; core/beads, such as insoluble inert materials such as glass particles/beads or cerium oxide, calcium phosphate dihydrate, dicalcium phosphate, calcium sulfate dihydrate, microcrystalline cellulose a cellulose derivative; a soluble core such as a sugar sphere of sugar, such a sugar such as dextrose, lactose, mannitol, starch, sorbitol or sucrose; an insoluble inert resin material such as a spherical or nearly spherical polychlorinated Vinyl core beads, polystyrene core beads or any other pharmaceutically acceptable insoluble synthetic polymeric material core beads or the like, or mixtures thereof; binders or adhesives such as gum arabic, guar gum, alginic acid, dextrin, Maltodextrin, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (eg ), low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose (for example) ), sodium carboxymethyl cellulose, povidone (various grades) ), starch, etc.; disintegrants, such as calcium carboxymethylcellulose, croscarmellose sodium (eg Ac-Di- , ), cross-linked povidone (for example) , ), Povidone K-30, Potracin Potassium, Starch, Pregelatinized Starch, Sodium starch glycolate (eg PRIMOGEL, ); plasticizers such as butyl citrate, phosphates, phthalates, decylamines, mineral oils, fatty acids and esters, glycerol, triacetin or sugar, fatty alcohols, polyethylene A diol, a polyethylene glycol ether, a fatty alcohol such as octadecyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, myristyl alcohol, and the like. Solvents which can be used in granulation or coating layering include: water, methanol, ethanol, isopropanol, acetone, dichloromethane, dichloromethane, and the like, and mixtures thereof.

The pharmaceutical preparations described herein may further comprise any one or more of pharmaceutically acceptable glidants and lubricants (such as stearic acid, magnesium stearate, zinc stearate, talc, colloidal cerium oxide, stearin). Sodium fumarate), opacifiers, colorants and other commonly used carriers. Suitable preservatives include, for example but are not limited to, phenoxyethanol, parabens (e.g., methylparaben, propylparaben and their sodium salts), propylene glycol, sorbate/ Salts, urea derivatives (e.g., diazolindinyl urea), and the like, and mixtures thereof. Suitable buffering agents include, by way of example and not limitation, sodium hydroxide, potassium hydroxide, ammonium hydroxide, and the like, and mixtures thereof. Suitable chelating agents include mild agents such as, for example, edetic acid ("EDTA"), disodium edetate and EDTA derivatives, and the like, and mixtures thereof.

Suitable polymers as excipients include, for example but are not limited to, those known to those of ordinary skill in the art, such as gum arabic, sodium based lignosulfonate, methyl methacrylate, methyl. Acrylate copolymer, isobutyl methacrylate, ethylene glycol dimethacrylate, and the like, and mixtures thereof.

Suitable gelling/thickening agents include, for example but are not limited to, carbopol; modified cellulose derivatives; naturally occurring, synthetic or semi-synthetic gums such as xanthan gum, gum arabic And tragacanth; sodium alginate; gelatin; modified starch; cellulose polymer, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate Formates and methylcellulose; copolymers, such as copolymers of maleic anhydride and methyl vinyl ether, copolymers of colloidal cerium oxide and methacrylate derivatives, polyethylene oxide, Polyoxyethylene-polyoxypropylene copolymer, polyvinyl alcohol, and the like, and mixtures thereof.

The pharmaceutical compositions described herein may further comprise one or more suitable solvents. The above solvent may be present in the composition or may be used in the preparation of the above composition. Examples of such solvents include, but are not limited to, water, tetrahydrofuran, propylene glycol, liquid paraffin, ether, petroleum ether, alcohols (eg, methanol, ethanol, isopropanol, and higher alcohols), aromatic hydrocarbons (eg, toluene), alkanes (eg, pentane) Alkanes, hexanes and heptanes), ketones (such as acetone and methyl ethyl ketone), chlorinated hydrocarbons (such as chloroform, carbon tetrachloride, dichloromethane and dichloroethylene), acetates (such as ethyl acetate), Lipids (e.g., isopropyl myristate, diisopropyl adipate), mineral oil, and the like, and mixtures thereof.

In one embodiment, the present invention relates to a pharmaceutical composition comprising Compound I or a salt thereof and a hydrophilic carrier for oral administration; wherein, when it contains 900 mL of 0.1 N HCl and 1% (w/v) In the U.S. Pharmacopoeia Type II device of sodium lauryl sulfate, when the test is carried out at a temperature of about 37 ± 0.5 ° C and stirred at 75 rpm, the drug composition releases at least 75% of the compound I contained within 60 minutes. Or its salt. Preferably, the pharmaceutical composition releases at least 85% of the compound I or a salt thereof contained under the conditions specified above. The percentage (%) of active substance release was measured by using an HPLC method compared to a standard solution.

In another embodiment, the present invention relates to a pharmaceutical composition wherein the above Compound I or a salt thereof is partially present in an amorphous form. In one embodiment, at least about 10% of the compound I or a salt thereof contained in the above pharmaceutical composition is in an amorphous form. Preferably, from about 10% to about 50%, or more preferably from about 15% to about 40%, of the compound I or a salt thereof contained in the above pharmaceutical composition is an amorphous form.

In one embodiment, the invention relates to a method of treating a disease condition in a subject associated with modulation of a TRPV3 receptor, wherein the method comprises administering to the subject a pharmaceutical composition comprising an active ingredient and a hydrophilic carrier, The active ingredient is selected from the group consisting of Compound I, Compound II, Compound III, Compound IV and Compound V or salts thereof. The above pharmaceutical composition may be in the form of a solid dispersion. Preferably, the above active ingredient is Compound I or a salt thereof.

In another embodiment, the invention relates to a method of treating a disease condition in a subject associated with TRPV3 receptor modulation, wherein the method comprises administering to the subject a drug comprising Compound I or a salt thereof and a hydrophilic carrier Composition.

In another embodiment, the invention contemplates the use of a pharmaceutical composition for treating a disease condition in a subject associated with TRPV3 receptor modulation, the use comprising administering to the subject a compound I or a salt thereof and a hydrophilic carrier Drug composition.

In another embodiment, the invention relates to a pharmaceutical composition for treating a disease condition in a subject associated with modulation of TRPV3 receptor, the treatment comprising administering to the subject a pharmaceutical composition comprising a solid dispersion, the solid dispersion Compound I or a salt thereof and a hydrophilic carrier are included.

Non-limiting examples of disease conditions associated with TRPV3 receptor modulation as described above in the context of the present invention include inflammation, irritable bowel syndrome, Crohn's disease, psoriasis, eczema, dermatitis, post-herpetic neuralgia (flaps) Rash), incontinence, bladder incontinence, overactive bladder, cystitis, fever, hot flashes, cough, migraine, joint pain, heartache caused by ischemic myocardium, acute pain, chronic pain, neuropathic pain, postoperative pain, Pain caused by neuralgia (eg, post-herpetic neuralgia or trigeminal neuralgia), pain due to diabetic neuropathy, toothache and cancer pain, inflammatory pain conditions (such as arthritis and osteoarthritis), muscle weakness Sign, non-insulin dependent diabetes and breast cancer.

In another embodiment, the present invention provides a method for preparing a pharmaceutical composition comprising: preparing a solid dispersion of Compound I or a salt thereof and a hydrophilic carrier; and formulating the above solid dispersion into a suitable dosage form . The above method comprises: preparing a solid dispersion of Compound I or a salt thereof and a hydrophilic carrier, converting the solid dispersion into a granule preparation; and formulating the granules into a dosage form suitable for oral administration.

Preferably, the above method comprises dispersing the above pyrimidinone derivative in a hydrophilic carrier using techniques such as hot melt dispersion, spray drying, granulation and coating.

The above particles may be formed by any known method using one or more operations such as dry granulation, wet granulation, and extrusion spheronization. In one embodiment, the granulation described above is carried out in equipment such as a planetary mixer, a rapid mixing granulator (RMG), a fluidized bed processor, and the like. A fluidized bed processor with an attached spray device at the top or bottom has been found to be particularly useful. In general, the above active ingredient may be dissolved or dispersed in an organic solvent, optionally with a binder and/or a solubilizing agent, and the solution may be sprayed onto a substrate containing a pharmaceutically acceptable excipient. Granulation. The resulting granules can be further compressed into tablets or filled into capsules using techniques known in the art. Alternatively, tablets may be prepared by a direct compression process using a powder mixture.

The above pharmaceutical compositions of the present invention can be prepared by a variety of other processes and techniques known to those skilled in the art to achieve the desired in vitro drug release profile. A specific process implementation includes one of the following:

1. Direct compression using suitable punches and dies, which are mounted on a suitable rotary tablet press.

2. Injection molding or compression molding using a suitable mold installed in the compression unit.

3. Compress after granulation.

4. Extrude into the mold in the form of a paste or cut the extrudate into strips.

5. Form a solid dispersion by evaporating the solvent.

6. Form a solid dispersion by hot melt technique.

7. Prepare the suspension by high pressure homogenization.

The following examples are provided to enable those skilled in the art to practice the invention and are merely illustrative of the invention. The above embodiments should not limit the scope of the invention.

Example

Example 1: Solubility data for Compound I and various hydrophilic carriers and solubility data for solid dispersion compositions at 25 °C.

Compound I and a hydrophilic carrier were mixed according to the ratios in Table 1. Prepare buffer according to the United States Pharmacopoeia. The equivalent of Compound I (100 mg) was added to various buffers (100 ml) in the presence of various hydrophilic carriers. The sample was sonicated for 15 minutes. The solid dispersion composition form of Compound I was also evaluated for its solubility by a similar procedure. Quantification was carried out by comparison with a standard solution on HPLC. The above assay provides the relative amount (mg/ml) of the drug in the sample solution. The results obtained were extrapolated to indicate the solubility in 900 ml of buffer. The data thus obtained are shown in Table 1.

A brief analysis of the solubility of Compound I:

Preparation of Test Solution: Compound I (100 mg) was added to various buffers (100 ml) in the presence of various surfactants. The sample was sonicated for 15 minutes. Evaluation was carried out by comparison with a standard solution by an analytical method on high performance liquid chromatography (HPLC).

Mobile phase:

A mixture of 0.01 M ammonium acetate buffer and acetonitrile at a ratio of 20:80% v/v.

Thinner:

A mixture of water and acetonitrile in a ratio of 20:80 v/v.

Chromatographic conditions:

Column: Hypersil BDS C18, 150 × 4.6mm, 5μm

Flow rate: 1.0 ml/min

Detection: UV detection at 330 nm

Column temperature: 25 ° C

Injection volume: 50μl

Running time: 10 minutes

Retention time: about 5 minutes

Example 2: Pharmaceutical composition containing Compound I and various hydrophilic carriers

Production method:

1. Disperse hydroxypropyl methylcellulose in isopropanol with stirring.

2. Add dichloromethane to the dispersion obtained in step 1 with stirring.

3. Dissolve Compound I in a mixture of dichloromethane and isopropanol.

4. Add poloxamer 407 to the solution obtained in step 3 with stirring to obtain a transparent dispersion.

5. On a water bath, Gelucire 44/14 is heated to melt and added to the dispersion obtained in step 4.

6. The dispersion obtained in step 5 was added to the dispersion obtained in the step 2 under stirring to obtain a transparent dispersion.

7. In a fluid bed processor, spray the dispersion obtained in step 6 onto a sugar sphere to obtain granules.

In vitro dissolution data were determined using a United States Pharmacopoeia Dissolution Test Set (Type II) in 900 ml of 0.1 N HCl at 50 rpm.

A brief analysis of the dissolution of Compound I:

The amount of Compound I eluted can be determined by high performance liquid chromatography compared to a standard solution.

Mobile phase:

A mixture of 0.01 M ammonium acetate buffer and acetonitrile at a ratio of 20:80% v/v.

Thinner:

A mixture of water and acetonitrile in a ratio of 20:80 v/v.

Chromatographic conditions:

Column: Hypersil BDS C18, 150 × 4.6mm, 5μm

Flow rate: 1.0 ml/min.

Detection: UV detection at 330 nm.

Column temperature: 25 ° C

Injection volume: 50 μl.

Running time: 10 minutes.

Retention time: about 5 minutes.

Stability data:

The resulting granules were stored in three layers of bags containing about 50 mg of granules in each bag. Each bag is packed in a high density polyethylene (HPDE) container and stored under different storage conditions. The percentage of dissolution was evaluated every 60 minutes of storage.

The in vitro dissolution data was determined using a USP dissolution test apparatus (type II) in 900 ml of 0.1 N HCl and 1% sodium lauryl sulfate at 75 rpm. After 60 minutes, the in vitro dissolution data was determined.

Examples 3-5: Pharmaceutical capsule compositions containing Compound I and various hydrophilic carriers.

Manufacturing method of Example 3:

1. Mix vitamin E TPGS, PEG 4000 and poloxamer 407 at 45 ° C and continue stirring to obtain a dispersion.

2. Add Compound I to the dispersion obtained in Step 1, maintain the temperature at about 45 ° C, and continue stirring to obtain a uniform dispersion.

3. Maintain the dispersion obtained in step 2 in its molten state and fill it in a capsule.

Manufacturing method of Example 4:

1. Mix PEG 4000, Poloxamer 407 and Gelucire 50/13 at 45 ° C and continue stirring to give a dispersion.

2. Add Compound I to the dispersion obtained in Step 1, maintain the temperature at about 45 ° C, and continue stirring to obtain a uniform dispersion.

3. Maintain the dispersion obtained in step 2 in its molten state and fill it in a capsule.

Manufacturing method of Example 5:

1. Heat Labrasol to about 45 ° C and maintain at the same temperature.

2. Add Gelucire 44/14, Vitamin E TPGS and PEG 4000 to the molten material obtained in Step 1, maintain the temperature and continue stirring to obtain a molten dispersion.

3. Add Compound I to the dispersion obtained in Step 2, maintain the temperature at about 45 ° C, and continue stirring to obtain a uniform dispersion.

4. Maintain the dispersion obtained in step 3 in its molten state and fill it into a capsule.

In vitro dissolution data were determined using a United States Pharmacopoeia Dissolution Test Set (Type II) in 900 ml of 0.1 N HCl at 50 rpm.

Example 6: A pharmaceutical composition in the form of granules containing a compound I and various hydrophilic carriers.

Production method:

1. Heat Labrasol to melt at about 45 ° C and maintain at the same temperature.

2. Disperse Gelucire 44/14, Vitamin E TPGS and PEG 4000 in the melt obtained in Step 1, maintain the temperature at about 45 ° C, and continue stirring.

3. Add Compound I to the dispersion obtained in Step 2, maintain the temperature at about 45 ° C, and continue stirring to obtain a uniform dispersion.

4. The dispersion obtained in step 3 is adsorbed onto a sugar sphere to obtain a semi-solid substance.

5. The semi-solid material of step 4 was passed through an ASTM #16 sieve to obtain granules.

6. Dry the granules obtained in step 5 and compress into tablets.

7. Alternatively, the granules obtained in step 5 are dried and filled into hard gelatin capsules.

In vitro dissolution data were determined using a United States Pharmacopoeia Dissolution Test Set (Type II) in 900 ml of 0.1 N HCl at 50 rpm.

Example 7: A capsule-formed pharmaceutical composition in the form of granules containing Compound I and various hydrophilic carriers.

Production method:

1. Disperse HPMC E5LV in a sufficient amount of isopropanol with stirring.

2. A portion of the dichloromethane was added to the dispersion obtained in step 1 with slow agitation.

3. Disperse Compound I in the remaining portion of dichloromethane.

4. Melt Gelucire 44/14, add to poloxamer 407 and mix.

5. Disperse the dispersion obtained in Step 3 in the dispersion obtained in Step 4 with stirring.

6. In a fluid bed processor, spray the dispersion obtained in step 5 onto the NP particles and fill the resulting pellets into capsules.

In vitro dissolution data were determined using a United States Pharmacopoeia Dissolution Test Set (Type II) in 900 ml of 0.1 N HCl at 50 rpm.

X-ray diffraction studies were performed on Compound I, the placebo particle composition of Example 7, and the particle composition of Example 7. The above study was carried out on a Panalytical X-ray diffractometer (model: X'Pert Pro).

The X-ray diffraction study results of Compound I are shown in Fig. 1. X-ray diffraction of the placebo particle composition of Example 7 is shown in Fig. 2, and the X-ray diffraction of the particle composition of Example 7 is shown in Fig. 3.

Therefore, it can be seen that about 15% to 20% of the compound I or the salt thereof contained in the particle composition of Example 7 is in an amorphous form.

Example 8: Pharmaceutical composition in the form of an oral solution containing Compound I and various hydrophilic carriers.

Production method:

1. Mix Labrasol, PEG 400 and Cremophor EL and continue to agitate to obtain a uniform dispersion.

2. Add Compound I to the dispersion obtained in Step 1, maintain the temperature at about 45 ° C, and continue stirring to obtain a solution.

3. Tween 80, sodium saccharin and a portion of propylene glycol were added to the solution of step 2, maintaining the temperature at about 45 ° C, and stirring was continued to obtain a uniform dispersion.

4. With slow, continuous stirring, water was added to the dispersion obtained in step 3, maintaining the temperature at about 45 ° C to obtain a solution.

5. Cool the solution from step 4 to room temperature.

6. Add strawberry flavor and make up the volume with propylene glycol.

In vitro dissolution data corresponding to an oral solution of 30 mg of Compound I was determined using a United States Pharmacopoeia dissolution test apparatus (Type II) in 900 ml of 0.1 N HCl at 50 rpm.

Example 9: A pharmaceutical composition comprising Compound I and various hydrophilic carriers.

Production method:

1. Heat Labrasol to melt at about 45 ° C and maintain at the same temperature.

2. Disperse Gelucire 44/14 and Vitamin E TPGS in the molten material obtained in Step 1, maintain the temperature at about 45 ° C, and continue to stir.

3. Add Compound I to the dispersion obtained in Step 2, maintain the temperature at about 45 ° C, and continue stirring to obtain a uniform dispersion.

4. Maintain the dispersion obtained in step 3 in its molten state and fill it into a capsule.

Example 10: Pharmaceutical composition comprising Compound I and various hydrophilic carriers.

Production method:

1. Mix propylene glycol, glycerin and ethanol at about 45 ° C with constant stirring to give a homogeneous dispersion.

2. PEG 4000 was added to the dispersion obtained in Step 1 under continuous stirring at about 45 ° C to obtain a uniform dispersion.

3. Maintain the temperature at about 45 ° C, add compound I, and mix with the dispersion obtained in step 2 to obtain a uniform dispersion.

4. Slowly add 0.5% methylcellulose suspension to the dispersion obtained in Step 3 with continuous stirring until a homogeneous dispersion is obtained and the resulting dispersion is cooled to room temperature.

Comparative Examples A-D: Tablets or capsules containing the particles of Compound I.

Example 11: Pharmaceutical composition of a tablet-form composition containing Compound I.

Production method:

1. Hydroxypropyl methylcellulose (Hypromellose) was dispersed in isopropanol under constant stirring.

2. Dichloromethane was added to the dispersion obtained in Step 1, and stirred to obtain a clear solution.

3. Dissolve Compound I in the above solution with constant stirring.

4. Gelucle 44/14 and Poloxamer 407 were melted and added to the above solution with constant stirring.

5. In a fluid bed processor, spray the mixture from step 4 onto the sugar spheres using a bottom spray.

6. The dried granules are passed through an ASTM 30# sieve and mixed with Avicel 102, Ac-di-sol and Aerosil, and finally lubricated with magnesium stearate.

7. The granules of the above step 6 are formulated into tablets, and the resulting tablets are suitably coated.

In vitro dissolution data were determined using a United States Pharmacopoeia Dissolution Test Set (Type II) in 900 ml of 0.1 N HCl at 50 rpm.

Stability study:

The resulting tablets were placed under accelerated stability conditions. The amount of Compound I eluted can be determined by high performance liquid chromatography compared to a standard solution.

Chromatographic conditions:

Column: Hypersil BDS C-18, 150 x 4.6 mm, 5 μm

Flow rate: 1.0 ml/min

Detection: UV detection at 330 nm

Column temperature: 25 ° C

Injection volume: 50μl

Running time: 10 minutes

Retention time: about 5 minutes

In vitro dissolution studies using US Pharmacopoeia II (paddle equipment) in 900 ml dissolution medium (ie, 0.1 N HCl and 1% (w/v) sodium lauryl sulfate) at 37 ± 0.5 ° C, 75 rpm Take 60 minutes.

The substances involved (i.e., the maximum value of individual impurities and the total amount of impurities) were determined by high performance liquid chromatography, and the tests were carried out under storage conditions (by high performance liquid chromatography).

The drug composition of Example 11 was subjected to an X-ray diffraction study. The above study was carried out on a Panalytical X-ray diffractometer (model: X'Pert Pro). The obtained X-ray diffraction pattern is shown in Fig. 4.

Example 12: Systemic exposure of Compound I composition in dogs

The above systemic exposure study was performed in Beagle dogs at a single dose of 10 mg/kg. The above animals are administered by oral gavage. The pharmacokinetic data obtained are shown in Table 2.

The disclosures of all publications, patents, and patent applications are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the

Figure 1 shows X-ray diffraction data of Compound I.

Figure 2 shows an X-ray diffraction pattern of the placebo particle composition of Example 7.

Fig. 3 shows X-ray diffraction data of the particle composition of Example 7.

Fig. 4 shows X-ray diffraction data of the drug composition of Example 11.

Claims (10)

One containing the active ingredient 7-{(E)-2-[2-(cyclopropylmethoxy)-3-methoxyphenyl]vinyl}-6-(4-trifluoromethoxyphenyl) A pharmaceutical composition of -5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one ("Compound I") or a salt thereof and a hydrophilic carrier. A pharmaceutical composition comprising a solid dispersion comprising the compound I or a salt thereof and a hydrophilic carrier. The pharmaceutical composition of claim 1 or 2, wherein the hydrophilic carrier comprises a surfactant, a complexing agent, a co-solvent, a polymer, and a mixture thereof. The pharmaceutical composition according to claim 1 or 2, wherein the hydrophilic carrier is a surfactant, and the surfactant is selected from the group consisting of poloxamer, polyoxyethylene sorbitan ester, and polyoxyethylene sorbitan ester. , polyglyceryl-6-dioleate, polyethylene glycol-15-hydroxystearate, diethylene glycol monoethyl ether, propylene glycol dicaprylate/dicaprate, lecithin, phospholipid, lauric acid polyethyl Glycol glycerides, oleic acid polyethylene glycol glycerides and caprylic acid phthalic acid polyethylene glycol glycerides or mixtures thereof. The pharmaceutical composition according to claim 1 or 2, wherein the hydrophilic carrier is a complexing agent, and the complexing agent is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl- Β-cyclodextrin, sulfobutylether-β-cyclodextrin-neutralized polyacrylic acid, cross-linked acrylic acid copolymer or a mixture thereof. The pharmaceutical composition according to claim 1 or 2, wherein the hydrophilic carrier is a cosolvent, and the cosolvent is selected from the group consisting of ethanol, propanol, isopropanol, propylene glycol, polyethylene glycol, dichloromethane, and Methyl isosorbide, ethyl lactate, N-methylpyrrolidone, tetrahydrofuran polyglycol ether, glycerol monocaprate, glycerol dicaprate, triolein monoglyceride, polyglyceryl oleate, octanoic acid / A mixed diester of citric acid and propylene glycol, ethyl oleate, glycerol monooleate, vitamin E TPGS, alpha-tocopherol or a mixture thereof. The pharmaceutical composition according to claim 1 or 2, wherein the hydrophilic carrier is a polymer, and the polymer is selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, and hydroxyethylcellulose. , carrageenan or a mixture thereof. The pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of the above active ingredient to the above hydrophilic carrier ranges from about 1:0.1 to about 1:100. The pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of the above active ingredient to the above hydrophilic carrier ranges from about 1:0.5 to about 1:50. The pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of the above active ingredient to the above hydrophilic carrier ranges from about 1:1 to about 1:20.