CN101394838A

CN101394838A - Tablet formulations and processes

Info

Publication number: CN101394838A
Application number: CNA2007800080610A
Authority: CN
Inventors: M·K·克利斯南; R·W·卡森; M·佛拉伯; S·哈森; S·K·辛夫; A·S·纳吉
Original assignee: Wyeth LLC
Current assignee: Wyeth LLC
Priority date: 2006-03-06
Filing date: 2007-03-05
Publication date: 2009-03-25

Abstract

The present invention is directed to pharmaceutical formulations and tablet compositions of pharmacological active agents of Formula (I) that are estrogen receptor modulators, and preparative processes thereof.

Description

Tablet formulation and method

Technical field

The present invention relates to pharmaceutical preparation for the pharmacologically active agents of estrogenic agents, with and manufacture method.The invention further relates to the pharmaceutical composition that comprises pharmaceutical preparation of the present invention, with and manufacture method.

Background technology

The multiple-effect effect of estrogen in mammalian tissues obtained sufficient textual criticism, recognizes that at present estrogen can influence many tracts [Mendelsohn and Karas, New EnglandJournal of Medicine 340:1801-1811 (1999); People such as Epperson, PsychosomaticMedicine 61:676-697 (1999); Crandall, Journal of Women ' s Health ﹠amp; Gender Based Medicine 8:1155-1166 (1999); Monk and Brodaty, Dementia﹠amp; Geriatric Cognitive Disorders 11:1-10 (2000); Hurn and Macrae, Journalof Cerebral Blood Flow ﹠amp; Metabolism 20:631-652 (2000); Calvin, Maturitas 34:195-210 (2000); People such as Finking, Zeitschrift fur Kardiologie 89:442-453 (2000); Brincat, Maturitas 35:107-117 (2000); A1-Azzawi, Postgraduate Medical Journal 77:292-304 (2001) all is incorporated herein by reference it respectively].Estrogen can several means to organizing the generation effect, the mechanism of action that the clearest and the most definite quilt characterizes causes the change of genetic transcription effect for itself and estrogen receptor interact.Estrogen receptor is ligand activation transcription factor and the superfamily that belongs to nuclear hormone receptor.Other member of this family comprises Alfasone, androgen, glucocorticoid and mineralocorticoid hormone receptor.When being bonded to part, these receptors begin Dimerized and by directly be bonded on the DNA particular sequence (being called reaction component) or by interacting and the Transcription of promotor gene with other transcription factor (as AP1), it directly is bonded to specific DNA sequence [Moggs and Orphanides, EMBO Reports 2:775-781 (2001) successively; People such as Hall, Journal ofBiological Chemistry 276:36869-36872 (2001); McDonnell, Principles ofMolecular Regulation 351-361 (2000) all is incorporated herein by reference it].One class " coordination " (coregulatory) albumen also can interact with the part bind receptor, and further regulates its transcriptional activity people such as [, Endocrine Reviews 20:321-344 (1999) all is incorporated herein by reference it] McKenna.Also shown estrogen receptor can ligand dependent and the mode of dependent/non-dependent suppress Transcription [people such as Quaedackers, the Endocrinology 142:1156-1166 (2001) of NF κ B-mediation; People such as Bhat, Journal of Steroid Biochemistry ﹠amp; Molecular Biology 67:233-240 (1998); People such as Pelzer, Biochemical ﹠amp; Biophysical ResearchCommunications 286:1153-7 (2001) all is incorporated herein by reference it respectively].

Also can activate estrogen receptor by phosphorylation.This phosphorylation is mediated by somatomedin such as EGF, causes change [Moggs and Orphanides, the EMBO Reports 2:775-781 (2001) of genetic transcription effect under the situation of no part; People such as Hall, Journal ofBiological Chemistry 276:36869-36872 (2001) all is incorporated herein by reference it].

The mode that a kind of more indeterminate estrogen that is characterized influences cell is to be undertaken by so-called cell-membrane receptor.The existence of this receptoroid still has controversial, has then obtained clear and definite evidence but estrogen can bring out utmost point non-genomic reaction rapidly from cell.The molecular entity of being responsible for these effects of transduction is not clearly separated, but thinks that on evidence it becomes relevant [Levin, Journal of Applied Physiology 91:1860-1867 (2001) with the karyomorphism of estrogen receptor at least; Levin, Trends in Endocrinology ﹠amp; Metabolism 10:374-377 (1999) all is incorporated herein by reference it].

Two kinds of estrogen receptor have been found at present.First kind of estrogen receptor swelled by g before about 15 years, and it is called ER α [people such as Green, Nature 320:134-9 (1986) all is incorporated herein by reference it] at present.Second kind of estrogen receptor is in recent findings, it is called as ER β [people such as Kuiper, Proceedings of the National Academy of Sciences of theUnited States of America 93:5925-5930 (1996) all is incorporated herein by reference it].In early days the work of ER β is focused on the affinity of definition itself and various parts, and in fact observe it and ERa has some differences.ER β there is no concordance at the existing clearly blueprint of the histioid distribution of grinding tooth and its with ER α.For example in the tissue of mice and rat uterus to express ER α, the lung of mice and rat is then to express ER β [people such as Couse, Endocrinology 138:4613-4621 (1997) simultaneously; People such as Kuiper, Endocrinology 138:863-870 (1997) all is incorporated herein by reference it].Even in identical organ, ER α and ER β distribute in sectional mode.For example, in the ovary of mice, ER β highly is expressed in granular cell, then only be confined to sheath and stromal cell [Sar and Weisch, Endocrinology 140:963-971 (1999), people such as FitZpatrick, Endocrinology 140:2581-2591 (1999) all is incorporated herein by reference it].Yet, there are the example of receptor co expression and ER α and ER β can form the in vitro study evidence [people such as Cowley of heterodimer, Journal of Biological Chemistry 272:19858-19862 (1997) all is incorporated herein by reference it].

Address a lot of simulations or blocked the active chemical compound of 17 beta estradiols.Having endogenous estrogen 17 beta estradiols of rendeing a service with tool has roughly the same bioactive chemical compound to be called as " estrogen receptor agonist ".When uniting when giving with 17 beta estradiols, the chemical compound of its effect capable of blocking is called " estrogen receptor antagon ".In fact has the relation of (conti-nuum) continuously between estrogen receptor agonist and the estrogen receptor antagon, in fact some chemical compounds play estrogen receptor agonist in some tissue, organize at other and then play estrogen receptor antagon.These chemical compounds with mixed active are called as selective estrogen receptor modulators (SERMS) and can be used as effective therapeutic agent (for example, EVISTA

) [McDonnell, Journal of the Society for Gynecologic Investigation 7:S10-S15 (2000), Goldstein waits the people, Human Reproduction Update 6:212-224 (2000) all is incorporated herein by reference it].Why same compound has certain reason of cell-specific effect is not also illustrated, but thinks that it may and/or be in the proteic environment of coordination owing to the difference on the receptor configuration.

Knownly when the estrogen receptor binding partner, can adopt different configurations sometimes.Yet, just understood the consequence of these variations and its exquisite part as of late gradually.By with various part cocrystallization, can solve the three-D space structure of ER α and ER β, and clearly illustrate under the situation that estrogen receptor antagon exists, resetting of helical region 12 (helix 12) can hinder protein sequence required in receptor-coordination protein-interacting [people such as Pike, EMBO18:4608-4618 (1999) three-dimensionally; People such as Shiau, Cell 95:927-937 (1998) all is incorporated herein by reference it].In addition, display technique of bacteriophage has been used to identify in the presence of different ligands and the interactional peptide of estrogen receptor [people such as Paige, Proceedings of theNational Academy of Sciences of the United States of America 96:3999-4004 (1999) all is incorporated herein by reference it].For example, oneself identifies a kind of peptide, and it can be distinguished out and total length estrogen receptor agonist 17 beta estradiols and the bonded ER α of diethylstilbestrol.A kind of different peptide has shown can distinguish the g Luo Mifen (Clomiphene) that is bonded to ER α and ER β.Each part of these data show places one may have in different bioactive uniquenesses and the unpredictable configuration this receptor.

United States Patent (USP) the 6th, 794 has been described a kind of typical ER beta selective part in No. 403, comprises 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, and the preparation of 3-benzoxazole-5-alcohol (ERB-041) all is incorporated herein by reference it.

As mentioned above, a complete set of bioprocess of estrogen influence.In addition, difference on the sex (for example, disease incidence rate, to the reaction that stimulates etc.) has been described.Due to the difference that is interpreted as estrogen concentrations between the men and women that it is possible.Because these chemical compounds as the importance of medicament, therefore can find out that effective preparation of sending this chemical compound is very important.The present invention promptly relates to the free-revving engine of these and other.

The accompanying drawing summary

Fig. 1 has described active agents, 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-5-alcohol crystal type monohydrate (on) and the X-ray powder diffraction (XRPD) of no hydrate (descending) scheme.

Fig. 2 has described 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the thermal analysis curue of the differential scanning calorimetry (DSC) of the pure crystal type monohydrate of 3-benzoxazole-5.

Fig. 3 has described 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the thermogravimetric analysis (TGA) of the pure crystal type monohydrate of 3-benzoxazole-5.

Fig. 4 has described 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the thermal analysis curue of the differential scanning calorimetry (DSC) of the pure anhydrous crystal type of 3-benzoxazole-5.

Fig. 5 has described 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the thermogravimetric analysis (TGA) of the pure anhydrous crystal type of 3-benzoxazole-5.

Fig. 6 describes 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the isollaothermic chart of the dynamic steam absorption (DVS) of the pure crystal type monohydrate of 3-benzoxazole-5.

Fig. 7 has described 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the isollaothermic chart of the dynamic steam absorption (DVS) of the pure anhydrous crystal type of 3-benzoxazole-5.

Fig. 8 has described dog after the single dose preparation of oral 2 x 75mg, 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the average plasma levels of 3-benzoxazole-5 alcohol.

Fig. 9 has described the dissolution that mixes the ERB-041 tablet formulation that reaches the manufacturing of wet grain law technology by direct.

Figure 10 has described the dissolution by the ERB-041 tablet that contains not commensurability wetting agent composition of wet grain technology manufacturing.

Figure 11 has described the compacting figure of ERB-041 tablet.

Figure 12 has described the ERB-041 tablet formulation at the dissolution of storage one after three months.

The invention summary

The invention provides following pharmaceutical preparation, it contains:

(a) active agents with formula I of effective dose pharmaceutically:

Wherein:

R ₁Be hydrogen, hydroxyl, halogen, C _1-6Alkyl, C _1-6Trifluoroalkyl, C _3-8Cycloalkyl, C _1-6Alkoxyl, C _1-6Thrihalothaneoxy, C _1-6Alkylthio, C _1-6Sulphur oxyalkyl, C _1-6Sulfonic alkyl, C _6-10Aryl ,-NO ₂,-NR ₅R ₆,-N (R ₅) COR ₆,-CN ,-CHFCN ,-CF ₂CN, C _2-7Alkynyl, C _2-7Thiazolinyl, or have 1 to 4 heteroatomic 5-or 6-element heterocycle that is selected from O, N and S; Wherein this alkyl or alkenyl partly optional by hydroxyl ,-CN, halogen, trifluoroalkyl, thrihalothaneoxy ,-COR ₅,-CO ₂R ₅,-NO ₂,-CONR ₅R ₆,-NR ₅R ₆Or-N (R ₅) COR ₆Replace;

R ₂And R _2aBe respectively independently hydrogen, hydroxyl, halogen, C _1-6Alkyl, C _1-4Alkoxyl, C _2-7Thiazolinyl, C _2-7Alkynyl, C _1-6Trifluoroalkyl or C _1-6Thrihalothaneoxy; Wherein this alkyl or alkenyl partly optional by by hydroxyl ,-CN, halogen, trifluoroalkyl, thrihalothaneoxy ,-COR ₅,-CO ₂R ₅,-NO ₂,-CONR ₅R ₆,-NR ₅R ₆Or-N (R ₅) COR ₆Replace;

R ₃, R _3aAnd R ₄Be respectively independently hydrogen, C _1-6Thiazolinyl, the C of alkyl, a 2-7 carbon atom _2-7Alkynyl, halogen, C _1-4Alkoxyl, C _1-6Trifluoroalkyl or C _1-6Thrihalothaneoxy; Wherein this alkyl or alkenyl partly optional by by hydroxyl ,-CN, halogen, trifluoroalkyl, thrihalothaneoxy ,-COR ₅,-CO ₂R ₅,-NO ₂,-CONR ₅R ₆,-NR ₅R ₆Or-N (R ₅) COR ₆Replace;

R ₅, R ₆Be respectively independently hydrogen, C _1-6Alkyl or C _6-10Aryl;

X is O, S or NR ₇And

R ₇Be hydrogen, C _1-6Alkyl or C _6-10Aryl ,-COR ₅,-CO ₂R ₅Or-SO ₂R ₅Or its pharmaceutically acceptable salt: and

(b) carrier or excipient systems, it comprises:

(i) first diluent/filler composition accounts for about 30% to about 95% of weight of formulation;

(ii) Ren Xuan second diluent/filler composition when existing, accounts for about at the most 40% of pharmaceutical preparation weight;

(iii) the disintegrating agent composition accounts for about 0.5% to about 20% of pharmaceutical preparation weight;

(iv) adhesive ingredients accounts for about 0.5% to about 10% of pharmaceutical preparation weight;

(v) the wetting agent composition accounts for about 0.5% to about 8% of pharmaceutical preparation; And

(vi) Ren Xuan lubricant composition when existing, accounts for about 0.01% to about 5% of pharmaceutical preparation weight; Condition is that the total amount of this composition is no more than about 8% of pharmaceutical preparation weight when this pharmaceutical preparation comprises one or more compositions of the glyceride, Poloxamer 188, polyoxyethylene sorbitol fatty acid ester, castor oil derivatives, sucrose fatty acid ester, polyglycolyzed glyceride, quaternary ammonium amines chemical compound and the docusate sodium that are selected from lauryl sulfate slaine, sodium lauryl sulfate, alkylsurfuric acid slaine, Polyethylene Glycol, fatty acid ester.

The present invention further provides the pharmaceutical preparation that contains following ingredients:

(a) active agents with above-mentioned formula I of pharmacy effective dose or its pharmaceutically acceptable salt; And

(b) carrier or excipient systems, it comprises:

(i) first diluent/filler composition accounts for about 38% to about 95% of weight of formulation;

(ii) Ren Xuan second diluent/filler composition when existing, accounts for about 5% to about 25% of pharmaceutical preparation weight;

(iv) adhesive ingredients accounts for about 0.5% to about 5% of pharmaceutical preparation weight;

(v) the wetting agent composition accounts for about 1.3% to about 5% of pharmaceutical preparation; And

(vi) Ren Xuan lubricant composition when existing, accounts for about 0.01% to about 5% of pharmaceutical preparation weight; Condition is that the total amount of this composition is no more than about 5% of pharmaceutical preparation weight when this pharmaceutical preparation comprises one or more compositions that are selected from the glyceride of lauryl sulfate slaine, sodium lauryl sulfate, alkylsurfuric acid slaine, Polyethylene Glycol, fatty acid ester, Poloxamer 188, polyoxyethylene sorbitol fatty acid ester, castor oil derivatives, sucrose fatty acid ester, polyglycolyzed glyceride, quaternary ammonium amines chemical compound and docusate sodium.

(b) carrier or excipient systems, it comprises:

(iv) adhesive ingredients accounts for about 1% to about 3% of pharmaceutical preparation weight;

(v) the wetting agent composition accounts for about 1.3% to about 4% of pharmaceutical preparation; And

(vi) Ren Xuan lubricant composition when existing, accounts for about 0.01% to about 5% of pharmaceutical preparation weight; Condition is that the total amount of this composition is no more than about 4% of pharmaceutical preparation weight when this pharmaceutical preparation comprises one or more compositions that are selected from the glyceride of lauryl sulfate slaine, sodium lauryl sulfate, alkylsurfuric acid slaine, Polyethylene Glycol, fatty acid ester, Poloxamer 188, polyoxyethylene sorbitol fatty acid ester, castor oil derivatives, sucrose fatty acid ester, polyglycolyzed glyceride, quaternary ammonium amines chemical compound and docusate sodium.

The present invention further provides the method for preparing pharmaceutical preparation of the present invention, comprising:

(a) active agents and first diluent/filler, disintegrating agent and optional second diluent/filler are mixed, form preliminary mixture; With

(b) come this preliminary mixture of granulating with the aqueous solution that contains wetting agent, form the granulation mixture.

The present invention further provides the method for preparing pharmaceutical preparation of the present invention, it comprises:

(i) active agents is mixed with at least a portion first diluent/filler, form first mixture;

(ii), if desired, mix, form preliminary mixture with disintegrating agent and second diluent/filler of choosing wantonly with first mixture and remaining first diluent/filler;

This preliminary mixture of aqueous solution granulating that wetting agent is (iii) arranged with house forms the granulation mixture;

(iv) dry this granulation mixture forms the dry granulation mixture;

If (v) exist, optional lubricant mixed with this dry granulation mixture of at least a portion; With

(vi) will be from (mixture v) mixes with remaining dry granulation mixture.

(i) with first diluent/filler, the second optional diluent/filler (if existence), disintegrating agent, bonding mixture, wetting agent and active agents mix, and form first mixture; With

(ii) this first mixture of granulating randomly.

The present invention further provides the tablet that comprises pharmaceutical preparation of the present invention.

The present invention further provides the method for preparing tablet of the present invention. it comprises compacting pharmaceutical preparation of the present invention.

The present invention further provides the product of the inventive method.

In certain embodiments, this active agents is 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-5-alcohol, or its pharmaceutically acceptable salt.

Detailed Description Of The Invention

The invention provides following pharmaceutical preparation, it comprises:

(a) active agents with formula I of effective dose pharmaceutically:

Wherein:

R ₁Be hydrogen, hydroxyl, halogen, C _1-6Alkyl, C _1-6Trifluoroalkyl, C _3-8Cycloalkyl, C _1-6Alkoxyl, C _1-6Thrihalothaneoxy, C _1-6Alkylthio, C _1-6Sulphur oxyalkyl, C _1-6Sulfonic alkyl, C _6-10Aryl ,-NO ₂,-NR ₅R ₆,-N (R ₅) COR ₆,-CN ,-CHFCN ,-CF ₂CN, C _2-7Alkynyl, C _2-7Thiazolinyl, or have 1 to 4 heteroatomic 5-or 6-element heterocycle that is selected from O, N and S; Wherein this alkyl or alkenyl partly optional by hydroxyl ,-CN, halogen, trifluoroalkyl (for example, C _1-6Trifluoroalkyl), thrihalothaneoxy (for example, C _1-6Thrihalothaneoxy) ,-COR ₅,-CO ₂R ₅,-NO ₂,-CONR ₅R ₆,-NR ₅R ₆Or-N (R ₅) COR ₆Replace;

R ₂And R ₂Be respectively independently hydrogen, hydroxyl, halogen, C _1-6Alkyl, C _1-4Alkoxyl, C _2-7Thiazolinyl, C _2-7Alkynyl, C _1-6Trifluoroalkyl or C _1-6Thrihalothaneoxy; Wherein this alkyl or alkenyl partly optional by by hydroxyl ,-CN, halogen, trifluoroalkyl (for example, C _1-6Trifluoroalkyl), thrihalothaneoxy (for example, C _1-6Thrihalothaneoxy) ,-COR ₅,-CO ₂R ₅,-NO ₂,-CONR ₅R ₆,-NR ₅R ₆Or-N (R ₅) COR ₆Replace;

R ₃, R _3aAnd R ₄Be respectively independently hydrogen, C _1-6Thiazolinyl, the C of alkyl, a 2-7 carbon atom _2-7Alkynyl, halogen, C _1-4Alkoxyl, C _1-6Trifluoroalkyl or C _1-6Thrihalothaneoxy; Wherein this alkyl or alkenyl partly optional by by hydroxyl ,-CN, halogen, trifluoroalkyl (for example, C _1-6Trifluoroalkyl), thrihalothaneoxy (for example, C _1-6Thrihalothaneoxy) ,-COR ₅,-CO ₂R ₅,-NO ₂,-CONR ₅R ₆,-NR ₅R ₆Or-N (R ₅) COR ₆Replace;

R ₅, R ₆Be respectively independently hydrogen, C _1-6Alkyl or C _6-10Aryl;

X is O, S or NR ₇And

R ₇Be hydrogen, C _1-6Alkyl or C _6-10Aryl ,-COR ₅,-CO ₂R ₅Or-SO ₂R ₅

Or its pharmaceutically acceptable salt: and

(b) carrier or excipient systems, it comprises:

(v) the wetting agent composition accounts for about 0.5% to about 8% of pharmaceutical preparation weight; And

(vi) Ren Xuan lubricant composition when existing, accounts for about 0.01% to about 5% of pharmaceutical preparation weight; Condition is that the total amount of this composition is no more than about 8% of pharmaceutical preparation weight when this pharmaceutical preparation comprises one or more compositions that are selected from the glyceride of lauryl sulfate slaine, sodium lauryl sulfate, alkylsurfuric acid slaine, Polyethylene Glycol, fatty acid ester, Poloxamer 188, polyoxyethylene sorbitol fatty acid ester, castor oil derivatives, sucrose fatty acid ester, polyglycolyzed glyceride, quaternary ammonium amines chemical compound and docusate sodium.

The present invention further provides following pharmaceutical preparation, comprising:

(a) active agents with above-mentioned formula I of pharmacy effective dose or its pharmaceutically acceptable salt; With

(b) carrier or excipient systems, it comprises:

(v) the wetting agent composition accounts for about 1.3% to about 5% of pharmaceutical preparation weight; And

(b) carrier or excipient systems, it comprises:

(i) first diluent/filler composition accounts for about 38% to about 95% of pharmaceutical preparation weight;

(v) the wetting agent composition accounts for about 1.3% to about 4% of pharmaceutical preparation weight; And

The present invention further provides the pharmaceutical preparation of " category-B ", comprising:

(b) carrier or excipient systems, it comprises:

(ii) Ren Xuan second diluent/filler composition when existing, accounts for about at the most 25% of pharmaceutical preparation weight;

(iii) the disintegrating agent composition accounts for about 0.01% to about 20% of pharmaceutical preparation weight;

(iv) adhesive ingredients accounts for about 0.01% to 20% of pharmaceutical preparation weight;

(v) the wetting agent composition accounts for about 0.01% to about 20% of pharmaceutical preparation weight; And

(vi) Ren Xuan lubricant composition when existing, accounts for about 0.01% to about 10% of pharmaceutical preparation weight;

Wherein the ratio of binding agent and wetting agent is about 2:1 to about 1:1; And the ratio of disintegrating agent and binding agent is about 5:1 to 1:1.

These special pharmaceutical preparatioies are denoted as " category-B " pharmaceutical preparation to distinguish mutually with other medicines preparation of the present invention.

Some characteristic of the present invention have been set forth in the embodiment of this paper.This some characteristic of illustrating that the present invention describes in each independent embodiment of this paper it is emphasized that except as otherwise noted, for also can be provided in an independent embodiment by merging.On the contrary, except as otherwise noted, for simplicity and the of the present invention various characteristics of describing in the single specific embodiments of this paper also can be separated or provide in the mode of any suitable time combination.For example, some embodiments of this paper have been described the independent percentage by weight of each composition in the pharmaceutical preparation, and other embodiment of this paper has been described the chemical composition of this pharmaceutical preparation composition; Except as otherwise noted, these embodiments can also any suitable combination or the mode of inferior combination provide, and be separated in single embodiment, to provide.

In some embodiments, X is 0.

In some embodiments, R ₁Be the thiazolinyl of 2-3 carbon atom, its optional by hydroxyl, CN, halogen, trifluoroalkyl, thrihalothaneoxy ,-COR ₅,-CO ₂R ₅,-NO ₂,-CONR ₅R ₆,-NR ₅R ₆Or-N (R ₅) COR ₆Replace;

In some embodiments, this active agents is 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-5-alcohol, or its pharmaceutically acceptable salt.

In some embodiments, active agents comprises 2-(3-fluoro-4-the hydroxyphenyl)-7-vinyl-1 that accounts for pharmaceutical preparation weight about 0.01% to about 80%, 3-benzoxazole-5-alcohol, or its pharmaceutically acceptable salt.

, all disclose the substituent group of The compounds of this invention everywhere in the patent specification of the present invention with group or scope.The present invention can comprise in this group and the scope each and each member of time combination separately clearly.For example, term " C _1-6Alkyl " be used in particular for disclosing separately methyl, ethyl, C ₃Alkyl, C ₄Alkyl, C ₅Alkyl and C ₆Alkyl.

It is integer that term " n member " is generally the number n that describes the one-tenth annular atoms in the group, and wherein this number that becomes annular atoms is n.For example, piperidyl is the example of 6 element heterocycle alkyl rings, and 1,2,3, the 4-naphthane is the example of 10 Yuans naphthene groups.

Used herein alone or refer to the saturated hydrocarbyl of straight or branched with the term " alkyl " of other term and usefulness.In some embodiments, this alkyl contains 1 to 6 carbon atom.The embodiment of moieties includes, but are not limited to for example chemical group of methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, sec-butyl; More senior analog is 2-methyl-1-butene base, n-pentyl, 3-amyl group, n-hexyl, 1,2 for example, 2-trimethyl propyl group, n-heptyl, n-octyl etc.

Used herein alone or refer to two valency alkyl linking groups with the term " alkylidene " of other term and usefulness.The embodiment of alkylidene includes, but are not limited to for example ethane-1,2-two bases, propane-1,3-two bases, propane-1,2-two bases, butane-1,4-two bases, butane-1,3-two bases, butane-1,2-two bases, 2-methyl-propane-1,3-two bases etc.

Used herein alone or refer to have the alkyl of one or more carbon-to-carbon double bond with the term " thiazolinyl " of other term and usefulness.The embodiment of thiazolinyl includes, but are not limited to vinyl, positive acrylic, isopropenyl, n-butene base, secondary cyclobutenyl etc.In some embodiments, this alkenyl part contains 2 to 7 carbon atoms.

Used herein alone or refer to have the alkyl of one or more carbon-to-carbon triple bond with the term " alkynyl " of other term and usefulness.The embodiment of alkynyl includes, but are not limited to acetenyl, propine-1-base, propine-2-base etc.In some embodiments, this alkynyl partly contains 2 to 7 carbon atoms.

Used herein alone or refer to the group of formula-O-alkyl with the term " alkoxyl " of other term and usefulness.In some embodiments, this alkoxyl contains 1 to 6 carbon atom.In some embodiments, this alkoxyl contains 1 to 4 carbon atom.

Used herein alone or with the term " aryl " of other term and usefulness refer to monocycle or multi-ring (for example, having 2,3 or 4 condenses or covalent bond chain T-Ring) the aromatic hydrocarbon base section, such as, but be not limited to phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl etc.In some embodiments, this aryl contains 6 to 10 carbon atoms.

The term of Shi Yonging " carboxyl " refers to the group of formula-C (O) OH in this article.

Used herein alone or refer to non-aromatic cyclic hydrocarbon part with the term " cycloalkyl " of other term and usefulness, it can randomly contain the two or triple bond as one or more carbon-to-carbon of a part of circulus.That cycloalkyl can comprise is single-or multi-ring, the ring system of (for example, having 2,3 or 4 condenses or covalent bond chain T-Ring).Also belong to and comprise having the aromatic ring that one or more is fused to cycloalkyl ring (that is, having common key with it), for example benzo derivative of pentane, amylene, hexane etc. in the cycloalkyl definition.In some embodiments, this cycloalkyl house has 3 to 8 carbon atoms.One or more of cycloalkyl becomes the oxidized formation carbonyl of available ring carbon atom to connect.The embodiment of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cyclohexatriene base, norborny (norbornyl), nor-flat base (norpinyl), nor-base (norcamyl), the adamantyl (adamantyl) etc. driven.

Used herein alone or refer to chlorine, bromine, fluorine or iodine, be preferably fluorine with the term " halogen " of other term and usefulness.

" heterocyclic compound " of Shi Yonging refers to have 1 to 4 heteroatomic saturated, unsaturated aromatic ring of part that is selected from oxygen, nitrogen or sulfur in this article.The example of the heterocyclic compound that is fit to includes, but are not limited to furyl, pyranose, pyridine radicals, pyrimidine radicals), pyrazinyl, morpholinyl, sulfur sign indicating number quinoline base, imidazole radicals, oxazolyl, sulfur oxazolyl, thienyl or piperidines basic ring.In embodiments, this heterocycle has 5 to 6 ring memberses.

The term of Shi Yonging " hydroxyl " refers to the group of formula-OH in this article.

Use separately in this article or refer to the group of formula-S (O)-alkyl with term " sulphur oxyalkyl " speech of other term and usefulness, wherein this sulfur is connected by two keys with oxygen atom.In some embodiments, this sulphur oxyalkyl contains 1 to 6 carbon atom.

Use separately in this article or refer to formula-S (O) with the term " sulfonic alkyl " of other term and usefulness ₂The group of-alkyl, wherein this sulphur atom is connected to two oxygen atoms by two keys.In some embodiments, this sulfonic alkyl contains 1 to 6 carbon atom.

Use separately in this article or refer to the group of formula-S-alkyl with " alkylthio " of other term and usefulness.In some embodiments, this alkylthio contains 1 to 6 carbon atom.

Use separately in this article or refer to the alkyl that replaced by three fluorine atoms with the term " trifluoroalkyl " of other term and usefulness.In some embodiments, 1 to 6 carbon atom is contained in this trifluoroalkyl group.In some embodiments, this trifluoroalkyl is a trifluoromethyl.

Use separately in this article or refer to the group of formula-O-alkyl with the term " thrihalothaneoxy " of other term and usefulness, wherein the moieties of this part is replaced by three fluorine atoms.In some embodiments, this thrihalothaneoxy contains 1 to 6 carbon atom.

The term of Shi Yonging " randomly is substituted " and refers to randomly be replaced by one or more identical or different substituent group (for example, by 1,2 or 3 substituent group) in this article.When alkyl or alkenyl group was substituted, it can be replaced (for example, by 1,2 or 3 substituent group) by one or more substituent group, and it can be identical or different substituent group as mentioned above.

In some embodiments:

(a) first diluent/filler composition accounts for about 38% to about 95% of weight of formulation;

(vi) Ren Xuan lubricant composition when existing, accounts for about 0.01% to about 5% of pharmaceutical preparation weight.

In some embodiments:

(a) first diluent/filler composition accounts for about 40% to about 80% of pharmaceutical preparation weight;

(b) Ren Xuan second diluent/filler composition when existing, accounts for about at the most 20% of pharmaceutical preparation weight;

(c) disintegrating agent composition accounts for about 1% to about 10% of pharmaceutical preparation weight;

(d) adhesive ingredients accounts for about 1% to about 8% of pharmaceutical preparation weight;

(e) wetting agent composition accounts for about 1% to about 7% of pharmaceutical preparation weight; And

(f) Ren Xuan lubricant composition when existing, accounts for about 0.1% to about 5% of pharmaceutical preparation weight.

(g) active agents accounts for about 0.1% to about 50% of pharmaceutical preparation weight.

In some embodiments:

(b) Ren Xuan second diluent/filler composition when existing, accounts for about 5% to about 25% of pharmaceutical preparation weight;

(g) active agents accounts for about 0.01% to about 50% of pharmaceutical preparation weight.

In some embodiments:

(b) Ren Xuan second diluent/filler composition when existing, accounts for about 10 to about 20% of pharmaceutical preparation weight;

(c) disintegrating agent composition accounts for about 1% to about 7% of pharmaceutical preparation weight;

(d) adhesive ingredients accounts for about 1% to about 5% of pharmaceutical preparation weight;

(e) wetting agent composition accounts for about 1.3% to about 5% of pharmaceutical preparation weight; And

(f) Ren Xuan lubricant composition when existing, accounts for about 0.1% to about 2% of pharmaceutical preparation weight.

In some embodiments:

(b) Ren Xuan second diluent/filler composition when existing, accounts for about 10% to about 20% of pharmaceutical preparation weight;

(c) disintegrating agent composition accounts for about 3% to about 5% of pharmaceutical preparation weight;

(d) adhesive ingredients accounts for about 1% to about 3% of pharmaceutical preparation weight;

(e) wetting agent composition accounts for about 1.5% to about 4% of pharmaceutical preparation weight; And

(f) Ren Xuan lubricant composition when existing, accounts for about 0.1% to about 1% of pharmaceutical preparation weight.

(g) active agents accounts for about 0.1% to about 40% of pharmaceutical preparation weight.

In some embodiments:

(a) first diluent/filler composition accounts for about 60% to about 80% of pharmaceutical preparation weight;

(g) active agents accounts for about 1% to about 10% of pharmaceutical preparation weight.

In some embodiments:

(a) first diluent/filler composition accounts for about 40% to about 60% of pharmaceutical preparation weight;

(g) active agents accounts for about 0.1% to about 10% of pharmaceutical preparation weight.

In some embodiments:

(c) disintegrating agent composition accounts for about 4% of pharmaceutical preparation weight;

(d) adhesive ingredients accounts for about 2% of pharmaceutical preparation weight;

(e) wetting agent composition accounts for about 2% of pharmaceutical preparation weight; And

In some embodiments:

(g) active agents accounts for about 10% to about 30% of pharmaceutical preparation weight.

In some embodiments:

(b) Ren Xuan second diluent/filler composition when existing, accounts for about 5% to about 20% of pharmaceutical preparation weight;

(c) disintegrating agent composition accounts for about 0.5% to about 10% of pharmaceutical preparation weight;

(d) adhesive ingredients accounts for about 0.5% to about 10% of pharmaceutical preparation weight;

(e) wetting agent composition accounts for about 0.5% to about 10% of pharmaceutical preparation weight; And

In some embodiments:

(e) wetting agent composition accounts for about 1% to about 3% of pharmaceutical preparation weight; And

(g) active agents accounts for about 1% to about 35% of pharmaceutical preparation weight.

In some embodiments, active agents accounts for about 0.01% to about 80% of pharmaceutical preparation weight.In some embodiments, active agents accounts for about 0.01% to about 75% of pharmaceutical preparation weight.In some embodiments, active agents accounts for about 0.01% to about 50% of pharmaceutical preparation weight.In some embodiments, active agents accounts for about 0.1% to about 50% of pharmaceutical preparation weight.In some embodiments, active agents accounts for about 0.1% to about 40% of pharmaceutical preparation weight.In some embodiments, active agents accounts for about 0.1% to about 30% of pharmaceutical preparation weight.In some embodiments, active agents accounts for about 0.1% to about 20% of pharmaceutical preparation weight.In some embodiments, active agents accounts for about 1% to about 40% of pharmaceutical preparation weight.In some embodiments, active agents accounts for about 1% to about 35% of pharmaceutical preparation weight.In some embodiments, active agents accounts for about 1% to about 25% of pharmaceutical preparation weight.In some embodiments, active agents accounts for about 1% to about 10% of pharmaceutical preparation weight.In some embodiments, active agents accounts for about 10% to about 30% of pharmaceutical preparation weight.In some embodiments, active agents accounts for about 10% to about 35% of pharmaceutical preparation weight.In some embodiments, active agents accounts for about 5% of pharmaceutical preparation weight.In some embodiments, active agents accounts for about 25% of pharmaceutical preparation weight.

In some embodiments, the first diluent filler composition accounts for about 30% to about 95% of weight of formulation.In some embodiments, the first diluent filler composition accounts for about 38% to about 95% of weight of formulation.In some embodiments, the first diluent filler composition accounts for about 40% to about 80% of weight of formulation.In some embodiments, the first diluent filler composition accounts for about 40% to about 60% of weight of formulation.In some embodiments, the first diluent filler composition accounts for about 60% to about 80% of weight of formulation.In some embodiments, the first diluent filler composition accounts for about 45% to about 55% of weight of formulation.In some embodiments, the first diluent filler composition accounts for about 75% of weight of formulation.In some embodiments, the first diluent filler composition accounts for about 51.5% of weight of formulation.In some embodiments, the first diluent filler composition accounts for about 71.5% of weight of formulation.

In some embodiments, the second optional diluent filler composition, when existing, account for weight of formulation about at the most 40%.In some embodiments, the second optional diluent filler composition, when existing, account for weight of formulation about at the most 30%.In some embodiments, the second optional diluent filler composition, when existing, account for weight of formulation about at the most 20%.In some embodiments, the second optional diluent filler composition, when existing, account for weight of formulation about at the most 25%.In some embodiments, the second optional diluent filler composition when existing, accounts for about 10% to about 20% of weight of formulation.In some embodiments, the second optional diluent filler composition when existing, accounts for about 5% to about 25% of weight of formulation.In some embodiments, the second optional diluent filler composition when existing, accounts for about 5% to about 20% of weight of formulation.In some embodiments, the second optional diluent filler composition when existing, accounts for about 15% of weight of formulation.In some embodiments, the second optional diluent filler composition when existing, accounts for about 5% of weight of formulation.In some embodiments, the second optional diluent filler composition when existing, accounts for about 25% of weight of formulation.

In some embodiments, the disintegrating agent composition accounts for about 0.5% to about 20% of pharmaceutical preparation weight.In some embodiments, the disintegrating agent composition accounts for about 0.01% to about 20% of pharmaceutical preparation weight.In some embodiments, the disintegrating agent composition accounts for about 1% to about 10% of pharmaceutical preparation weight.In some embodiments, the disintegrating agent composition accounts for about 0.5% to about 10% of pharmaceutical preparation weight.In some embodiments, the disintegrating agent composition accounts for about 1% to about 8% of pharmaceutical preparation weight.In some embodiments, the disintegrating agent composition accounts for about 1% to about 7% of pharmaceutical preparation weight.In some embodiments, the disintegrating agent composition accounts for about 1% to about 5% of pharmaceutical preparation weight.In some embodiments, the disintegrating agent composition accounts for about 3% to about 5% of pharmaceutical preparation weight.In some embodiments, the disintegrating agent composition accounts for about 2% to about 6% of pharmaceutical preparation weight.In some embodiments, the disintegrating agent composition accounts for about 4% of pharmaceutical preparation weight.In some embodiments, the disintegrating agent composition accounts for about 2% of pharmaceutical preparation weight.In some embodiments, the disintegrating agent composition accounts for about 6% of pharmaceutical preparation weight.

In some embodiments, adhesive ingredients accounts for about 0.5% to about 10% of pharmaceutical preparation.In some embodiments, adhesive ingredients accounts for about 0.01% to about 20% of pharmaceutical preparation.In some embodiments, adhesive ingredients accounts for about 0.5% to about 10% of pharmaceutical preparation.In some embodiments, adhesive ingredients accounts for about 0.5% to about 5% of pharmaceutical preparation.In some embodiments, adhesive ingredients accounts for about 1% to about 8% of pharmaceutical preparation.In some embodiments, adhesive ingredients accounts for about 1% to about 7% of pharmaceutical preparation.In some embodiments, adhesive ingredients accounts for about 1% to about 6% of pharmaceutical preparation.In some embodiments, adhesive ingredients accounts for about 1% to about 5% of pharmaceutical preparation.In some embodiments, adhesive ingredients accounts for about 1% to about 3% of pharmaceutical preparation.In some embodiments, adhesive ingredients accounts for about 2% of pharmaceutical preparation.In some embodiments, adhesive ingredients accounts for about 1% of pharmaceutical preparation.In some embodiments, adhesive ingredients accounts for about 3 of pharmaceutical preparation.

In some embodiments, the wetting agent composition accounts for about 0.5% to about 8% of pharmaceutical preparation.In some embodiments, the wetting agent composition accounts for about 0.01% to about 10% of pharmaceutical preparation.In some embodiments, the wetting agent composition accounts for about 0.01% to about 20% of pharmaceutical preparation.In some embodiments, the wetting agent composition accounts for about 0.1% to about 20% of pharmaceutical preparation.In some embodiments, the wetting agent composition accounts for about 0.1% to about 10% of pharmaceutical preparation.In some embodiments, the wetting agent composition accounts for about 1.3% to about 5% of pharmaceutical preparation.In some embodiments, the wetting agent composition accounts for about 1.3% to about 4% of pharmaceutical preparation.In some embodiments, the wetting agent composition accounts for about 1.5% to about 5% of pharmaceutical preparation.In some embodiments, the wetting agent composition accounts for about 1.5% to about 4% of pharmaceutical preparation.In some embodiments, the wetting agent composition accounts for about 1.3% to about 5% of pharmaceutical preparation.In some embodiments, the wetting agent composition accounts for about 1% to about 8% of pharmaceutical preparation.In some embodiments, the wetting agent composition accounts for about 1% to about 7% of pharmaceutical preparation.In some embodiments, the wetting agent composition accounts for about 1% to about 6% of pharmaceutical preparation.In some embodiments, the wetting agent composition accounts for about 1% to about 3% of pharmaceutical preparation.In some embodiments, the wetting agent composition accounts for about 2% of pharmaceutical preparation.In some embodiments, the wetting agent composition accounts for about 1% of pharmaceutical preparation.In some embodiments, the wetting agent composition accounts for about 3% of pharmaceutical preparation.In some embodiments, the wetting agent composition accounts for about 4% of pharmaceutical preparation.In some embodiments, the wetting agent composition accounts for about 5% of pharmaceutical preparation.

In some embodiments, optional lubricant composition when existing, accounts for about 0.01% to about 10% of pharmaceutical preparation weight.In some embodiments, optional lubricant composition when existing, accounts for about 0.01% to about 5% of pharmaceutical preparation weight.In some embodiments, optional lubricant composition when existing, accounts for about 0.01% to about 2% of pharmaceutical preparation weight.In some embodiments, optional lubricant composition when existing, accounts for about 0.01% to about 1% of pharmaceutical preparation weight.In some embodiments, optional lubricant composition when existing, accounts for about 0.1% to about 5% of pharmaceutical preparation weight.In some embodiments, optional lubricant composition when existing, accounts for about 0.1% to about 2% of pharmaceutical preparation weight.In some embodiments, optional lubricant composition when existing, accounts for about 0.1% to about 1% of pharmaceutical preparation weight.In some embodiments, optional lubricant composition when existing, accounts for about 0.5% of pharmaceutical preparation weight.

Should be appreciated that the percentage by weight that the pharmaceutical preparation composition that is disclosed in this paper is described is meant that each composition accounts for the percentage ratio of final pharmaceutical preparation, and do not comprise any surperficial coating, as tablet coating layer or capsule.This, all the other compositions of preparation were made up of active agents at end.

In some embodiments, this pharmaceutical preparation contains the active agents from about 1mg to about 200mg.In some embodiments, this pharmaceutical preparation contains the active agents from about 1mg to about 10mg.In some embodiments, this pharmaceutical preparation contains the active agents from about 10mg to about 50mg.In some embodiments, this pharmaceutical preparation contains the active agents from about 50mg to about 100mg.In some embodiments, this pharmaceutical preparation contains the active agents from about 100mg to about 200mg.

In some embodiments, when pharmaceutical preparation comprised one or more compositions that are selected from the glyceride of lauryl sulfate slaine, sodium lauryl sulfate, alkylsurfuric acid slaine, Polyethylene Glycol, fatty acid ester, Poloxamer 188, polyoxyethylene sorbitol fatty acid ester, castor oil derivatives, sucrose fatty acid ester, polyglycolyzed glyceride, quaternary ammonium amines chemical compound and docusate sodium, the total amount of this composition was no more than about 15% of pharmaceutical preparation weight.

In some embodiments, when pharmaceutical preparation comprised one or more compositions that are selected from the glyceride of lauryl sulfate slaine, sodium lauryl sulfate, alkylsurfuric acid slaine, Polyethylene Glycol, fatty acid ester, Poloxamer 188, polyoxyethylene sorbitol fatty acid ester, castor oil derivatives, sucrose fatty acid ester, polyglycolyzed glyceride, quaternary ammonium amines chemical compound and docusate sodium, the total amount of this composition was no more than about 10% of pharmaceutical preparation weight.

In some embodiments, when pharmaceutical preparation comprised one or more compositions that are selected from the glyceride of lauryl sulfate slaine, sodium lauryl sulfate, alkylsurfuric acid slaine, Polyethylene Glycol, fatty acid ester, Poloxamer 188, polyoxyethylene sorbitol fatty acid ester, castor oil derivatives, sucrose fatty acid ester, polyglycolyzed glyceride, quaternary ammonium amines chemical compound and docusate sodium, the total amount of this composition was no more than about 8% of pharmaceutical preparation weight.

In some embodiments, when pharmaceutical preparation comprised one or more compositions that are selected from the glyceride of lauryl sulfate slaine, sodium lauryl sulfate, alkylsurfuric acid slaine, Polyethylene Glycol, fatty acid ester, Poloxamer 188, polyoxyethylene sorbitol fatty acid ester, castor oil derivatives, sucrose fatty acid ester, polyglycolyzed glyceride, quaternary ammonium amines chemical compound and docusate sodium, the total amount of this composition was no more than about 5% of pharmaceutical preparation weight.

In some embodiments, when pharmaceutical preparation comprised one or more compositions that are selected from the glyceride of lauryl sulfate slaine, sodium lauryl sulfate, alkylsurfuric acid slaine, Polyethylene Glycol, fatty acid ester, Poloxamer 188, polyoxyethylene sorbitol fatty acid ester, castor oil derivatives, sucrose fatty acid ester, polyglycolyzed glyceride, quaternary ammonium amines chemical compound and docusate sodium, the total amount of this composition was no more than about 4% of pharmaceutical preparation weight.

In some embodiments, when pharmaceutical preparation comprised one or more compositions that are selected from the glyceride of lauryl sulfate slaine, sodium lauryl sulfate, alkylsurfuric acid slaine, Polyethylene Glycol, fatty acid ester, Poloxamer 188, polyoxyethylene sorbitol fatty acid ester, castor oil derivatives, sucrose fatty acid ester, polyglycolyzed glyceride, quaternary ammonium amines chemical compound and docusate sodium, the total amount of this composition was no more than about 7% or about 6% of pharmaceutical preparation weight.

In some embodiments; when comprising one or more, pharmaceutical preparation is selected from the lauryl sulfate slaine; sodium lauryl sulfate; the alkylsurfuric acid slaine; Polyethylene Glycol; the glyceride of fatty acid ester; polyoxyethylene-polypropylene copolymer; polyoxyethylene alkyl ether; the alkylsurfuric acid slaine; the polyoxyethylene sorbitol fatty acid ester; castor oil derivatives; sucrose fatty acid ester; polyglycolyzed glyceride; the quaternary ammonium amines chemical compound; LABRASOL; octyl group caproyl polyethyleneglycol glyceride; during the composition of polyoxy ethylization vegetable oil and docusate sodium, the total amount of this composition is no more than about 15% of pharmaceutical preparation weight.

In some embodiments; when comprising one or more, pharmaceutical preparation is selected from the lauryl sulfate slaine; sodium lauryl sulfate; the alkylsurfuric acid slaine; Polyethylene Glycol; the glyceride of fatty acid ester; polyoxyethylene-polypropylene copolymer; polyoxyethylene alkyl ether; the alkylsurfuric acid slaine; the polyoxyethylene sorbitol fatty acid ester; castor oil derivatives; sucrose fatty acid ester; polyglycolyzed glyceride; the quaternary ammonium amines chemical compound; LABRASOL; octyl group caproyl polyethyleneglycol glyceride; during the composition of polyoxy ethylization vegetable oil and docusate sodium, the total amount of this composition is no more than about 10% of pharmaceutical preparation weight.

In some embodiments; when comprising one or more, pharmaceutical preparation is selected from the lauryl sulfate slaine; sodium lauryl sulfate; the alkylsurfuric acid slaine; Polyethylene Glycol; the glyceride of fatty acid ester; polyoxyethylene-polypropylene copolymer; polyoxyethylene alkyl ether; the alkylsurfuric acid slaine; the polyoxyethylene sorbitol fatty acid ester; castor oil derivatives; sucrose fatty acid ester; polyglycolyzed glyceride; the quaternary ammonium amines chemical compound; LABRASOL; octyl group caproyl polyethyleneglycol glyceride; during the composition of polyoxy ethylization vegetable oil and docusate sodium, the total amount of this composition is no more than about 8% of pharmaceutical preparation weight.

In some embodiments; when comprising one or more, pharmaceutical preparation is selected from the lauryl sulfate slaine; sodium lauryl sulfate; the alkylsurfuric acid slaine; Polyethylene Glycol; the glyceride of fatty acid ester; polyoxyethylene-polypropylene copolymer; polyoxyethylene alkyl ether; the alkylsurfuric acid slaine; the polyoxyethylene sorbitol fatty acid ester; castor oil derivatives; sucrose fatty acid ester; polyglycolyzed glyceride; the quaternary ammonium amines chemical compound; LABRASOL; octyl group caproyl polyethyleneglycol glyceride; during the composition of polyoxy ethylization vegetable oil and docusate sodium, the total amount of this composition is no more than about 7% or about 6% of pharmaceutical preparation weight.

In some embodiments; when comprising one or more, pharmaceutical preparation is selected from the lauryl sulfate slaine; sodium lauryl sulfate; the alkylsurfuric acid slaine; Polyethylene Glycol; the glyceride of fatty acid ester; polyoxyethylene-polypropylene copolymer; polyoxyethylene alkyl ether; the alkylsurfuric acid slaine; the polyoxyethylene sorbitol fatty acid ester; castor oil derivatives; sucrose fatty acid ester; polyglycolyzed glyceride; the quaternary ammonium amines chemical compound; LABRASOL; octyl group caproyl polyethyleneglycol glyceride; during the composition of polyoxy ethylization vegetable oil and docusate sodium, the total amount of this composition is no more than about 5% of pharmaceutical preparation weight

In some embodiments; when comprising one or more, pharmaceutical preparation is selected from the lauryl sulfate slaine; sodium lauryl sulfate; the alkylsurfuric acid slaine; Polyethylene Glycol; the glyceride of fatty acid ester; polyoxyethylene-polypropylene copolymer; polyoxyethylene alkyl ether; the alkylsurfuric acid slaine; the polyoxyethylene sorbitol fatty acid ester; castor oil derivatives; sucrose fatty acid ester; polyglycolyzed glyceride; the quaternary ammonium amines chemical compound; LABRASOL; octyl group caproyl polyethyleneglycol glyceride; during the composition of polyoxy ethylization vegetable oil and docusate sodium, the total amount of this composition is no more than about 4% of pharmaceutical preparation weight

In some embodiments, the ratio of disintegrating agent composition and adhesive ingredients is that about 5:1 is to about 1:1.In some embodiments, the ratio of disintegrating agent composition and adhesive ingredients for about 5:1 to about 1.5:1, about 5:1 about 2:1, about 5:1 about 2.5:1 or about 5:1 about 3:1 extremely extremely extremely.In some embodiments, the ratio of disintegrating agent composition and adhesive ingredients for about 4:1 to about 1.5:1, about 4:1 about 2:1, about 4:1 about 2.5:1 or about 4:1 about 3:1 extremely extremely extremely.In some embodiments, the ratio of disintegrating agent composition and adhesive ingredients is that about 3:1 is to about 1:1.In some embodiments, the ratio of disintegrating agent composition and adhesive ingredients is that about 2:1 is to about 1:1.In some embodiments, the ratio of disintegrating agent composition and adhesive ingredients for about 3:1 to about 1.5:1, about 3:1 about 2:1, about 2.5:1 about 1:1 or about 2.5:1 about 1:1 extremely extremely extremely.In some embodiments, the ratio of disintegrating agent composition and adhesive ingredients for about 6:1 to about 1:6, about 6:1 to about 5:1, about 6:1 about 4:1, about 6:1 about 3:1, about 6:1 about 2:1, about 6:1 about 1:1 extremely extremely extremely extremely.In some embodiments, the ratio of disintegrating agent composition and adhesive ingredients is about 5:1, about 4:1, about 3:1 or about 2:1.

In some embodiments, the disintegrating agent composition is about 3:1 about 1:3 extremely with the wetting agent components in proportions.In some embodiments, the disintegrating agent composition is about 3:1 about 1:1 extremely with the wetting agent components in proportions.In some embodiments, the disintegrating agent composition is about 2:1 about 1:1 extremely with the wetting agent components in proportions.In some embodiments, the disintegrating agent composition with the wetting agent components in proportions for about 3:1 to about 1:2, about 3:1 extremely about 1.5:1 or about 2.5:1 extremely about 1.5:1.In some embodiments, the disintegrating agent composition with the wetting agent components in proportions for about 1:1 to about 1:3, about 1:1.5 about 1:3, about 1:2 about 1:3 or about 1:2.5 about 1:3 extremely extremely extremely.In some embodiments, the disintegrating agent composition with the wetting agent components in proportions be about 1:1, about 2:1, about 1:2, about 3:1, about 1:3.

In some embodiments, the disintegrating agent composition is about 6:1:1 about 1:1:1 extremely with adhesive ingredients and wetting agent components in proportions.In some embodiments, the disintegrating agent composition with adhesive ingredients and wetting agent components in proportions be about 5:1:1.In some embodiments, the disintegrating agent composition with adhesive ingredients and wetting agent components in proportions be about 4:1:1.In some embodiments, the disintegrating agent composition with adhesive ingredients and wetting agent components in proportions be about 3:1:1.In some embodiments, the disintegrating agent composition with adhesive ingredients and wetting agent components in proportions be about 2:1:1.

In some embodiments, the ratio of wetting agent composition and adhesive ingredients is about 3:1 or still less; Or pharmaceutical preparation comprises microcrystalline Cellulose, calcium phosphate, starch, pregelatinized Starch, aluminum silicate slaine, carbonic acid metal salt at least about 5%.In some embodiments, the ratio of wetting agent composition and adhesive ingredients is about 2:1 or still less; Or pharmaceutical preparation comprises microcrystalline Cellulose, calcium phosphate, starch, pregelatinized Starch, aluminum silicate slaine, carbonic acid metal salt at least about 5%.In some embodiments, the ratio of wetting agent composition and adhesive ingredients is about 1:1 or still less; Or pharmaceutical preparation comprises microcrystalline Cellulose, calcium phosphate, starch, pregelatinized Starch, aluminium silicate slaine, carbonic acid metal salt at least about 5%.When being used in combination with the term ratio, term " still less " refers to lower ratio (being that 2:1 is lower than 3:1).

In some embodiments, can contain each optional composition in the said preparation.

In some embodiments, each composition only contains a kind of material.

In some embodiments, each composition contains a kind of different material.

The term of Shi Yonging " first diluent/filler composition " refers to dilute active agents to desired concn and/or can be used as one or more material of the carrier of this active agents in this article.In some embodiments, this first diluent/filler composition comprises one or more filler.In some embodiments, this first diluent/filler composition comprises one or more diluent materials.In some embodiments, this first diluent/filler composition is one or more material that can be used as diluent and filler.In some embodiments, this first diluent/filler composition comprises at least a material that improves the mechanical strength and/or the compressibility of pharmaceutical composition of the present invention.

In some embodiments, this first diluent/filler composition comprises one or more mannitol, lactose, sucrose, maltodextrin, Sorbitol, xylitol, cellulose powder, microcrystalline Cellulose, carboxymethyl cellulose, carboxyethyl cellulose, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, methyl hydroxyethylcellulose, starch, Explotab, pregelatinized Starch, calcium phosphate, carbonic acid metal salt, metal-oxide or aluminum silicate slaine.

In some embodiments, this first diluent/filler comprises mannitol or lactose.

In some embodiments, this first diluent/filler comprises mannitol.

The term of Shi Yonging " second diluent/filler composition " refers to dilute active agents to desired concn and/or can be used as one or more material of the carrier of this active agents in this article.In some embodiments, this second diluent/filler composition comprises one or more filler.In some embodiments, this second diluent/filler composition comprises one or more diluent materials.In some embodiments, this second diluent/filler composition is one or more material that can be used as diluent and filler.In some embodiments, this second diluent/filler composition comprises at least a material that improves the mechanical strength and/or the compressibility of pharmaceutical composition of the present invention.

In some embodiments, this optional second diluent/filler composition is if comprise one or more mannitol, lactose, sucrose, maltodextrin, Sorbitol, xylitol, cellulose powder, microcrystalline Cellulose, carboxymethyl cellulose, carboxyethyl cellulose, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, methyl hydroxyethylcellulose, starch, pregelatinized Starch, Explotab, calcium phosphate, carbonic acid metal salt, metal-oxide or aluminum silicate slaine when existing.

In some embodiments, this optional second diluent/filler composition is if comprise microcrystalline Cellulose when existing.

One or more material of the term of Shi Yonging " disintegrating agent composition " the pharmaceutical composition water of liquid in the body (or contain) disintegrate in water of referring to promote to comprise pharmaceutical preparation of the present invention in this article.In some embodiments, this disintegrating agent composition comprises one or more cross-linking sodium carboxymethyl cellulose, carboxymethylcellulose calcium, crospovidone, alginic acid, sodium alginate, potassium alginate, calcium alginate, ion exchange resin, the effervescent system based on food acids and alkaline carbonic acid salt component, clay, Pulvis Talci, starch, pregelatinized Starch, Explotab, cellulose bits, carboxymethyl cellulose, hydroxypropyl cellulose, calcium silicates, carbonic acid metal salt, sodium bicarbonate, calcium citrate, or calcium phosphate.

In some embodiments, this disintegrating agent composition comprises cross-linking sodium carboxymethyl cellulose.

The term of Shi Yonging " adhesive ingredients " refers to increase one or more material of the mechanical strength and/or the compressibility of the pharmaceutical composition that comprises pharmaceutical preparation of the present invention in this article.In some embodiments, this adhesive ingredients comprises one or more polyethylene Pyrrolizidine ketone, copolyvidone, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, crosslinked poly-(acrylic acid), arabic gum, acacin (gum acacia), gum tragacanth, lecithin, casein, polyvinyl alcohol, gel or Kaolin.

In some embodiments, this adhesive ingredients comprises polyethylene Pyrrolizidine ketone.

In some embodiments, this adhesive ingredients comprises 30 POVIDONE K 30 BP/USP 12, K17, K25, K30, K60, K90 or K120.

In some embodiments, this adhesive ingredients comprises 30 POVIDONE K 30 BP/USP 25.

In some embodiments, this adhesive ingredients does not comprise Kaolin.In some embodiments, this adhesive ingredients does not comprise hydroxypropyl cellulose or hydroxypropyl emthylcellulose.

Only this adhesive ingredients comprises one or more polyethylene Pyrrolizidine ketone in some embodiments of category-B pharmaceutical preparation, copolyvidone, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, crosslinked poly-(acrylic acid), arabic gum, acacin, gum tragacanth, lecithin, casein, polyvinyl alcohol, gel, Kaolin, cellulose, methylcellulose, hydroxy methocel, carboxymethyl cellulose, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxyethyl-cellulose, methyl hydroxyethylcellulose, silicified microcrystalline cellulose, starch, maltodextrin, dextrin, microcrystalline Cellulose or Sorbitol.

The term of Shi Yonging " wetting agent composition " refers to increase one or more material of the water penetration of the pharmaceutical composition that comprises pharmaceutical preparation of the present invention in this article.In another aspect, should " wetting agent composition " refer to increase one or more material of this active agents water of liquid in the body (or contain) stripping in water.Again on the other hand in, should " wetting agent composition " refer to after using pharmaceutical composition of the present invention and preparation, can to increase one or more material of the bioavailability of active agents.

In some embodiments, this wetting agent composition comprises one or more lauryl sulfate slaine; Polyethylene Glycol; the glyceride of fatty acid ester; polyoxyethylene-polyoxypropylene copolymer; polyoxyethylene-alkyl ether; the alkylsurfuric acid slaine; the polyoxyethylene sorbitol fatty acid ester; castor oil derivatives; sucrose fatty acid ester; polyglycolyzed glyceride; the quaternary ammonium amines chemical compound; LABRASOL; octyl group caproyl polyethyleneglycol glyceride; the polyethoxylated vegetable oil; the polyethoxylated sterin; the polyethoxylated cholesterol; the polyethoxylated fatty acid glyceride; the polyethoxylated fatty acid ester; sulfosuccinate; taurine ester or docusate sodium.

In some embodiments, this wetting agent composition comprises one or more polyoxyethylene-polyoxypropylene copolymer; polyoxyethylene-alkyl ether; the alkylsurfuric acid slaine; the polyoxyethylene sorbitol fatty acid ester; castor oil derivatives; sucrose fatty acid ester; polyglycolyzed glyceride; the quaternary ammonium amines chemical compound; LABRASOL; octyl group caproyl polyethyleneglycol glyceride; the stearyl polyethyleneglycol glyceride; inferior oleoyl polyethyleneglycol glyceride; the oleoyl polyethyleneglycol glyceride; the polyethoxylated vegetable oil; the polyethoxylated fatty acid glyceride; polyethoxylated fatty acid ester or docusate sodium.In some embodiments, this wetting agent composition comprises the alkylsurfuric acid slaine.In some embodiments, this wetting agent composition comprises the lauryl sulfate slaine.In some embodiments, this wetting agent composition comprises sodium lauryl sulfate.

The term of Shi Yonging " lubricant composition " refers to help avoid one or more material of the powder flowbility that the equipment that adheres to pharmaceutical preparation and/or work in-process improve preparation in the course of processing in this article.In some embodiments, this optional lubricant composition is if comprise one or more stearic acid, Metallic stearates, sodium stearyl fumarate, fatty acid, aliphatic alcohol, fatty acid ester, behenic acid glyceride, mineral oil, vegetable oil, paraffin, leucine, silicon dioxide, silicic acid, Pulvis Talci, methyl glycol fatty acid ester, Polyethylene Glycol, polypropylene glycol, poly alkylene glycol or sodium chloride when existing.In some embodiments, this optional lubricant composition is if comprise Metallic stearates when existing.In some embodiments, this optional lubricant composition is if comprise one or more zinc stearate, calcium stearate, magnesium stearate or sodium stearate when existing.In some embodiments, this optional lubricant composition is if comprise magnesium stearate when existing.

In some embodiments:

(a) this first diluent/filler composition comprises one or more mannitol, lactose, sucrose, maltodextrin, Sorbitol, xylitol, cellulose powder, microcrystalline Cellulose, carboxymethyl cellulose, carboxyethyl cellulose, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, methyl hydroxyethylcellulose, starch, Explotab, pregelatinized Starch, calcium phosphate, carbonic acid metal salt, metal-oxide or aluminum silicate slaine;

(b) this optional second diluent/filler composition is if comprise one or more mannitol, lactose, sucrose, maltodextrin, Sorbitol, xylitol, cellulose powder, microcrystalline Cellulose, carboxymethyl cellulose, carboxyethyl cellulose, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, methyl hydroxyethylcellulose, starch, Explotab, pregelatinized Starch, calcium phosphate, carbonic acid metal salt, metal-oxide or aluminum silicate slaine when existing;

(c) this disintegrating agent composition comprises one or more cross-linking sodium carboxymethyl cellulose, carboxymethylcellulose calcium, crospovidone, alginic acid, sodium alginate, potassium alginate, calcium alginate, ion exchange resin, the effervescent system based on food acids and alkaline carbonic acid salt component, clay, Pulvis Talci, starch, pregelatinized Starch, Explotab, cellulose bits, carboxymethyl cellulose, hydroxypropyl cellulose, calcium silicates, carbonic acid metal salt, sodium bicarbonate, calcium citrate, or calcium phosphate;

(d) this adhesive ingredients comprises one or more polyethylene Pyrrolizidine ketone, copolyvidone, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, crosslinked poly-(acrylic acid), arabic gum, acacin, gum tragacanth, lecithin, casein, polyvinyl alcohol, gel or Kaolin;

(e) this wetting agent composition comprises one or more lauryl sulfate slaine, Polyethylene Glycol, the glyceride of fatty acid ester, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene-alkyl ether, the alkylsurfuric acid slaine, the polyoxyethylene sorbitol fatty acid ester, castor oil derivatives, sucrose fatty acid ester, polyglycolyzed glyceride, the quaternary ammonium amines chemical compound, LABRASOL, octyl group caproyl polyethyleneglycol glyceride, the stearyl polyethyleneglycol glyceride, inferior oleoyl polyethyleneglycol glyceride, the oleoyl polyethyleneglycol glyceride, the polyethoxylated vegetable oil, the polyethoxylated sterin, the polyethoxylated cholesterol, the polyethoxylated fatty acid glyceride, the polyethoxylated fatty acid ester, sulfosuccinate, taurine ester or docusate sodium; And

(f) this optional lubricant composition is if comprise one or more stearic acid, Metallic stearates, sodium stearyl fumarate, fatty acid, aliphatic alcohol, fatty acid ester, behenic acid glyceride, mineral oil, vegetable oil, paraffin, leucine, silicon dioxide, silicic acid, Pulvis Talci, methyl glycol fatty acid ester, Polyethylene Glycol, polypropylene glycol, poly alkylene glycol or sodium chloride when existing.

In some embodiments:

(d) this adhesive ingredients comprises one or more polyethylene Pyrrolizidine ketone, copolyvidone, crosslinked poly-(acrylic acid), lecithin, casein, polyvinyl alcohol or gel;

(e) this wetting agent composition comprises one or more polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene-alkyl ether, the alkylsurfuric acid slaine, the polyoxyethylene sorbitol fatty acid ester, castor oil derivatives, sucrose fatty acid ester, polyglycolyzed glyceride, the quaternary ammonium amines chemical compound, LABRASOL, octyl group caproyl polyethyleneglycol glyceride, the stearyl polyethyleneglycol glyceride, inferior oleoyl polyethyleneglycol glyceride, the oleoyl polyethyleneglycol glyceride, the polyethoxylated vegetable oil, the polyethoxylated fatty acid glyceride, polyethoxylated fatty acid ester or docusate sodium; And

In some embodiments:

(a) this first diluent/filler composition comprises mannitol;

(b) this optional second diluent/filler composition is if comprise microcrystalline Cellulose when existing;

(c) this disintegrating agent composition comprises cross-linking sodium carboxymethyl cellulose;

(d) this adhesive ingredients comprises polyethylene Pyrrolizidine ketone;

(e) this wetting agent composition comprises sodium lauryl sulfate; And

(f) this optional lubricant composition is if comprise magnesium stearate when existing.

In some embodiments of category-B pharmaceutical preparation only:

(d) this adhesive ingredients comprises one or more polyethylene Pyrrolizidine ketone, copolyvidone, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, crosslinked poly-(acrylic acid), arabic gum, acacin, gum tragacanth, lecithin, casein, polyvinyl alcohol, gel, Kaolin, cellulose, methylcellulose, hydroxy methocel, carboxymethyl cellulose, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxyethyl-cellulose, methyl hydroxyethylcellulose, silicified microcrystalline cellulose, starch, maltodextrin, dextrin, microcrystalline Cellulose or Sorbitol;

(e) this wetting agent composition comprises one or more lauryl sulfate slaine, Polyethylene Glycol, the glyceride of fatty ester, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene-alkyl ether, the alkylsurfuric acid slaine, the polyoxyethylene sorbitol fatty acid ester, castor oil derivatives, sucrose fatty acid ester, polyglycolyzed glyceride, the quaternary ammonium amines chemical compound, LABRASOL, octyl group caproyl polyethyleneglycol glyceride, the stearyl polyethyleneglycol glyceride, inferior oleoyl polyethyleneglycol glyceride, the oleoyl polyethyleneglycol glyceride, the polyethoxylated vegetable oil, the polyethoxylated sterin, the polyethoxylated cholesterol, the polyethoxylated fatty acid glyceride, the polyethoxylated fatty acid ester, sulfosuccinate, taurine ester or docusate sodium; And

As institute is understood, some compositions of pharmaceutical preparation of the present invention have multiple function.For example, but the given double as of principal component is diluent/filler and disintegrating agent.In this type of the example, given principal component can be regarded as having single function at some, even it has multiple function in nature.

The term of Shi Yonging " alginic acid " refers to obtain the natural hydrophilic colloid polysaccharide from various Sargassums in this article, or its synthetic modification polysaccharide.

The term of Shi Yonging " sodium alginate " refers to alignic sodium salt in this article, and it is formed by alginic acid and the reaction that contains the sodium of alkali such as sodium hydroxide or sodium carbonate.The term of Shi Yonging " potassium alginate " refers to alignic potassium salt in this article, and it is obtained by the reaction of alginic acid with the potassium that contains alkali such as potassium hydroxide or potassium carbonate.The term of Shi Yonging " calcium alginate " refers to alignic calcium salt in this article, and it is formed by alginic acid and the reaction that contains the calcium of alkali such as calcium hydroxide or calcium carbonate.The sodium alginate, calcium alginate and the potassium alginate that are fit to include, but are not limited to R.C.Rowe and P.J.Shesky, and those described in the medical excipient handbook (2006) the 5th edition all are incorporated herein by reference it.The sodium alginate that is fit to is including, but not limited to Kelcosol (being obtained by ISP), Kelfone LVCR and HVCR (being obtained by ISP), Manucol (being obtained by ISP) and Protanol (being obtained by FMCBiopolymer).

The term of Shi Yonging " calcium silicates " refers to the silicate of calcium in this article.

The term of Shi Yonging " calcium phosphate " refers to single alkali calcium phosphate, two alkali calcium phosphate or three alkali calcium phosphates in this article.

Cellulose, cellulose bits, cellulose powder, microcrystalline Cellulose, silicified microcrystalline cellulose, carboxyethyl cellulose, carboxymethyl cellulose, hydroxyethyl-cellulose, methyl hydroxyethylcellulose, hydroxy methocel, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, methylcellulose, sodium carboxymethyl cellulose and carboxymethylcellulose calcium are including, but not limited to R.C.Rowe and P.J.Shesky, described in the medicine excipient handbook (2006) the 5th edition those all are incorporated herein by reference it.The cellulose of Shi Yonging refers to native cellulose in this article.Term " cellulose " also refers to be passed through a molecular weight and/or a chain modified cellulose, refers in particular to the cellulose of lower molecular weight.Term " cellulose " further refers to connected by chemical modification the cellulose of chemical functional group such as carboxyl, hydroxyl, hydroxyl alkylidene or carboxylic alkylidene.The term of Shi Yonging " carboxylic alkylidene " refers to group or its salt of formula-alkylidene-C (O) OH in this article.The term of Shi Yonging " hydroxyl alkylidene " refers to the group of formula-alkylidene-OH in this article.

Be used for suitable cellulose powder of the present invention and include, but are not limited to Arbocel (obtaining), Sanacel (obtaining) and Solka-Floc (obtaining) by InternationalFiber Corp by CFF GmbH by JRSPharma.

The microcrystalline Cellulose that is fit to includes, but are not limited to Avicel pH series (being obtained by FMCBiopolymer), Celex (being obtained by ISP), Celphere (being obtained by Asahi Kasei), Ceolus KG (supply is from Asahi Kasei) and Aivapur (supply is from JRS Pharma).

The term of Shi Yonging " silicified microcrystalline cellulose " refers to the composite homogeneity physical mixture of silicon dioxide and microcrystalline Cellulose in this article.The silicified microcrystalline cellulose that is fit to includes, but are not limited to ProSolv (being obtained by JRS Pharma).

The term of Shi Yonging " sodium carboxymethyl cellulose " refers to formula Na in this article ^+-O-C (O)-CH ₂-the base that dangles (pending group) be connected to this cellulosic cellulose ether via ehter bond.The sodium carboxymethyl cellulose polymer that is fit to includes, but are not limited to Akucell (being obtained by Akzo Nobel), Aquasorb (being obtained by Hercules), Blanose (being obtained by Hercules), Finnfix (being obtained by Noviant), Nymel (being obtained by Noviant) and Tylose CB (being obtained by Clariant).

The term of Shi Yonging " carboxymethylcellulose calcium " refers to formula-CH in this article ₂-O-C (O)-O ^-1/2Ca ²⁺Dangle the base be connected to this cellulosic cellulose ether via ehter bond.

The term of Shi Yonging " carboxymethyl cellulose " refers to formula-HO-C (O)-CH in this article ₂-the carboxymethyl that dangles be connected to cellulosic cellulose ether via ehter bond.The carboxymethylcellulose calcium polymer that is fit to includes, but are not limited to Nymel ZSC (being obtained by Noviant).

The term of Shi Yonging " carboxyethyl cellulose " speech refers to formula-HO-C (O)-CH in this article ₂-CH ₂-the carboxymethyl that dangles be connected to cellulosic cellulose ether via ehter bond.

The term of Shi Yonging " hydroxyethyl-cellulose " refers to formula-HO-CH in this article ₂-CH ₂-the ethoxy that dangles be connected to cellulosic cellulose ether via ehter bond.The hydroxyethyl-cellulose that is fit to includes, but are not limited to Cellosize HEC (being obtained by DOW), Natrosol (being obtained by Hercules) and Tylose PHA (being obtained by Clariant).

The term of Shi Yonging " methyl hydroxyethylcellulose " speech refers to formula-CH in this article ₃-O-CH ₂-CH ₂-the methoxyethyl that dangles be connected to cellulosic cellulose ether via ehter bond.The hydroxyethyl-cellulose methyl ester that is fit to includes, but are not limited to Culminal MHEC series (being obtained by Hercules) and Tylose series (being obtained by Shin Etsu).

The term of Shi Yonging " hydroxypropyl cellulose " or " hypromellose " refer to have the cellulose of hydroxypropyl of dangling in this article, and it comprises height and low-substituted hydroxypropyl cellulose.In some embodiments, this hydroxypropyl cellulose has about 5% to about 25% hydroxypropyl.The hydroxypropyl cellulose that is fit to includes, but are not limited to Klucel series (being obtained by Hercules), Methocel series (being obtained by Dow), Nisso HPC series (being obtained by Nisso), Metolose series (being obtained by Shin Etsu) and LH series and comprises LHR-11, LH-21, LH-31, LH-20, LH-30, LH-22 and LH-32 (being obtained by Shin Etsu).

The term of Shi Yonging " methylcellulose " refers to have the cellulose of methoxyl group of dangling in this article.The methylcellulose that is fit to includes, but are not limited to Culminal MC (being obtained by Hercules).

The term of Shi Yonging " ethyl cellulose " refers to have the cellulose of ethyoxyl of dangling in this article.The ethyl cellulose that is fit to includes, but are not limited to Aqualon (being obtained by Hercules).

The term of Shi Yonging " octyl group caproyl polyethyleneglycol glyceride " refers to mainly syntheticly or mainly be derived from the polyglycolyzed glyceride of the chemical compound of capric acid and sad mixture by capric acid and sad mixture in this article, and this is synthetic but other fatty acid or the chemical compound that is derived from other fatty acid also can be used for.The octyl group caproyl polyethyleneglycol glyceride that is fit to includes, but are not limited to Labrasol ^TM(obtaining) by Gattefoss é.

The term of Shi Yonging " carboxymethylcellulose calcium " refers to the cross-linked copolymer of carboxymethylcellulose calcium in this article.

The term of Shi Yonging " copolyvidone " refers to the copolymer of polyethylene Pyrrolizidine ketone and vinylacetate in this article, but wherein this Vinyl Acetate Monomer partial hydrolysis.The copolyvidone polymer that is fit to includes, but are not limited to Kolidon VA 64 (by BASF acquisition, Luviskol VA (being obtained by BASF), Plasdone S-630 (being obtained by ISP) and Majsao CT (being obtained by Cognis).

The term of Shi Yonging " cross-linking sodium carboxymethyl cellulose " refers to the cross linked polymer of sodium carboxymethyl cellulose in this article.

The term of Shi Yonging " crospovidone " refers to the cross linked polymer of polyethylene Pyrrolizidine ketone in this article.The crospovidone polymer that is fit to includes, but are not limited to Polyplasdone XL-10 (being obtained by ISP) and Kolidon CL and CL-M (being obtained by BASF).

The term of Shi Yonging " crosslinked poly-(acrylic acid) " refers to the polymerizing acrylic acid thing that is crosslinked in this article.This cross linked polymer can contain other monomer except that acrylic acid.In addition, the carboxyl that dangles on the cross linked polymer can partially or completely be neutralized and be formed the pharmaceutically acceptable salt of polymer.In some embodiments, this crosslinked poly-(acrylic acid) is neutralized by ammonia or sodium hydroxide.Crosslinked poly-(acrylic acid) polymer that is fit to includes, but are not limited to Carbopol series (being obtained by Noveon).

Can disengage the combination of the excipient of the food acids of carbon dioxide and basic carbonate after the term of Shi Yonging " based on the effervescent system of food acids and alkaline carbonic acid salt component " refers to use in this article.The effervescent system that is fit to is for utilizing food acids (for example citric acid, tartaric acid, malic acid, fumaric acid, lactic acid, adipic acid, ascorbic acid, acid, aspartic, arabo-ascorbic acid, glutamic acid and succinic acid) and alkaline carbonic acid salt component (for example sodium bicarbonate, calcium carbonate, magnesium carbonate, potassium carbonate, ammonium carbonate etc.).

In this article separately or the term " fatty acid " that is used in combination " refer to saturated or undersaturated aliphatic acid.In some embodiments, this fatty acid is the mixture of different fatty acids.In some embodiments, this fatty acid has average about 8 to about 30 carbon atoms.In some embodiments, this fatty acid has average about 8 to about 24 carbon atoms.In some embodiments, this fatty acid has average about 12 to about 18 carbon atoms.The fatty acid that is fit to comprises, but be not limited to stearic acid, lauric acid, myristic acid, sinapic acid, Palmic acid, palmitoleic acid, capric acid, sad, oleic acid, linoleic acid, linolenic acid, hydroxy stearic acid, 12-hydroxy stearic acid, whale base stearic acid, isostearic acid, sesquialter oleic acid, sesquialter-9-octadecanoid acid, sesquialter isostearic acid, behenic acid, isobehenic acid and arachic acid, or its mixture.

The term " fatty acid " ester of Shi Yonging in this article " refer to formed chemical compound between fatty acid and the hydroxy-containing compounds.In some embodiments, this fatty acid ester is the sugar ester of fatty acid.In some embodiments, this fatty acid ester is the glyceride of fatty acid.In some embodiments, this fatty acid ester is an ethoxylated fatty acid ester.

Term " aliphatic alcohol " independent in this article or that use in conjunction with other term refers to saturated or undersaturated aliphatic alcohol.In some embodiments, this aliphatic alcohol is the mixture of different aliphatic alcohol.In some embodiments, this aliphatic alcohol has average about 8 to about 30 carbon atoms.In some embodiments, this aliphatic alcohol has average about 8 to about 24 carbon atoms.In some embodiments, this aliphatic alcohol has average about 12 to about 18 carbon atoms.The aliphatic alcohol that is fit to comprises, but be not limited to stearyl alcohol, lauryl alcohol, palmityl alcohol, palmityl acid, spermol, decanol, capryl alcohol, oleyl alcohol, inferior linolenyl alcohol (linolenyl alcohol), Semen arachidis hypogaeae oleyl alcohol (arachidonic alcohol), behenyl alcohol, different behenyl alcohol, selachyl alcohol .alpha.-hexadecylglyceryl ether and inferior oleyl alcohol (linoleyl alcohol), or its mixture.

The term of Shi Yonging " gel " refers to any material that boils skeleton, ligament and/or skin that is derived from animal in this article, or is derived from the material that is known as agar of Sargassum.Term " gel " also refers to any synthesis modification thing of natural gel.The gel that is fit to comprises, but be not limited to Byco (obtaining) and Cryogel and Instagel (obtaining) by Tessenderlo by the Croda chemistry, and R.C.Rowe and P.J.Shesky, the material described in the medical excipient handbook (2006) the 5th edition all is incorporated herein by reference it.

The glyceride of the term " fatty acid " of Shi Yonging in this article " refer to the list of fatty acid-, two-or triglyceride.The glyceride of this fatty acid can randomly be replaced by sulfonic group or its pharmaceutically acceptable salt.The suitable fatty acid that forms the glyceride of fatty acid includes, but are not limited to fatty acid as herein described.The glyceride that can be used for fatty acid of the present invention includes, but are not limited to single nutmeg acid glyceride: Nikkol ^TMMGM (obtaining) by Nikko; Glyceryl monooleate: Peceol ^TM(obtaining), Hodag by Gattefoss é ^TMGMO-D, Nikkol ^TMMGO (Nikko); Single oleic acid/glyceryl linoleate: Olicine ^TM(obtaining) by Gattefoss é; Single glyceryl linoleate: Maisine ^TM35-1 (Gattefoss é), MYVEROL ^TM18-92, Myverol ^TM18-06 (obtaining) by Eastman; Castor oil acid glyceride: Softigen ^TM701 (obtaining), Hodag by Goldschmidt ^TMGMR-D (obtaining), Aldo by Calgene ^TMMR (obtaining) by Lonza; Glyceryl monolaurate: ALDO MLD (obtaining), Hodag by Lonza ^TMGML (obtaining) by Calgene; Monopalmitin: Emalex ^TMGMS-P (obtaining) by Nihon; Behenic acid glyceride: Compritol ^TM888 ATO (Gattesfosse); Glyceryl monooleate: Aldo MO (obtaining), Atlas by Lonza ^TMG-695 (obtaining), Monomuls by Uniqema ^TM90-018 (obtaining), Perceol by Cognis ^TM(obtaining), Stepan by Gattefoss é ^TMGMO (obtaining), Rylo by the Stepan product ^TMSeries (obtaining), Dimodan by Danisco ^TMSeries (obtaining), Emuldan by Danisco ^TM(obtaining), ADM by Danisco ^TMDMG-40,70 and 100 (obtaining) by ADM; Glyceryl monostearate: Imwitor ^TM900 (obtaining), Lipo by Sasol ^TMGMS 410,450 and 600 (obtaining), Rita by the Lipo chemistry ^TMGMS (obtaining), Stepan by Rita company ^TMGMS (obtaining), Tegin by the Stepan product ^TM(obtaining), Kessco by Goldschmidt ^TMGMS (obtaining), Capmul by Akzo Nobel ^TMGMS (obtaining), Myvaplex by Abitec ^TM(obtaining), Cutina by Eastman ^TMGMS, Aldo MS (obtaining), Nikkol by Lonza ^TMMGS series (obtaining) by Nikko; Glyceryl palmitostearate: Precirol ^TMATOJ (obtaining) by Gattefoss é; Single glyceryl dioleate: Capmul ^TMGMO-K (obtaining) by Abitec; Palmic acid/tristerin: Cutina ^TMMD-A, ESTAGEL-G18; Acetoglyceride: LaneginTM EE (obtaining) by Grunau GmbH; Glyceryl laurate ester: Monomuls ^TM90-45 (obtaining), Aldo by Cognis ^TMMLD (obtaining) by Lonza; Citric acid/lactic acid/oleic acid/glyceryl linoleate; Caprylin: Capmul ^TMMCMC8 (obtaining) by Abitec; Glycerol is sad/decanoin: Capmul ^TMMCM (obtaining) by Abitec; Sad single, Diglyceride; Caprylic/capric glyceride; Single-and diacetyl group monoglyceride: Myvacet ^TM9-45,9-40 and 9-08 (obtaining), Lamegin by Eastman ^TM(obtaining) by Brenntag; Glyceryl monostearate: Aldo ^TMMS (obtaining), Lipo by Lonza ^TMGMS (obtaining) by the Lipo chemistry; Myvaplex ^TM(obtaining) by Eastman; The lactate of list, Diglyceride: Lamegin ^TMGLP (obtaining) by Brenntag; GLYCERYL DILAURATE: CapmulGDL (obtaining) by Abitec; Glyceryl dioleate: Capmul ^TMGDO (obtaining) by Abitec; And the glyceride of fatty acid:

39/01,33/01 and 43/01 (obtaining) by Gattefoss é.Other fatty glyceride that is fit to includes, but are not limited to glyceryl monostearate, single glyceryl isostearate, single myristin, glyceryl monooleate, monostearate two glyceride, behenic acid glyceride and single isostearic acid two glyceride.

The term of Shi Yonging " arabic gum " refers to natural or synthetic modification arabic gum in this article.The term of Shi Yonging " gum tragacanth " refers to natural or synthetic modification gum tragacanth in this article.The term of Shi Yonging " acacin " speech refers to natural or synthetic modification acacin in this article.The term of Shi Yonging " casein " refers to natural or synthetic modification casein in this article.The term of Shi Yonging " Kaolin " refers to natural or synthetic modified kaolin clay in this article.The arabic gum, gum tragacanth, acacin, casein and the Kaolin that are fit to include, but are not limited to R.C.Rowe and P.J.Shesky, and the material described in the medical excipient handbook (2006) the 5th edition all is incorporated herein by reference it.

The term of Shi Yonging " ion exchange resin " refers to pharmaceutically acceptable and can be weak acid, weak base, strong acid or alkaline ion exchange resin in this article.The ion exchange resin that is fit to includes, but are not limited to Amberlite ^TMIRP64, IRP88 and IRP69 (obtaining) and Duolite by Rohm and Haas ^TMAP143 (obtaining) by Rohm and Haas.In some embodiments, this ion exchange resin contains acrylic acid, methacrylic acid or sulfonic acid polystyrene or its esters.In some embodiments, this ion exchange resin draws g woods potassium resin (polacrilin potassium) or Cholestyramine resin (cholestyramine) for poly-divinylbenzene acrylic resin (polacrilex), ripple.

The term of Shi Yonging " LABRASOL " refers to mainly syntheticly or mainly be derived from the polyglycolyzed glyceride of lauric chemical compound by lauric acid in this article, and this is synthetic but other fatty acid or the chemical compound that is derived from other fatty acid also can be used for.The LABRASOL that is fit to includes, but are not limited to

44/14 (obtaining) by Gattefoss é.

The term " lecithin of Shi Yonging refers to natural or synthetic lecithin or can be by purified phospholipid in this article.The lecithin that is fit to includes, but are not limited to be derived from the lecithin of ovum or soybean phospholipid, for example egg lecithin, egg phosphatide acyl ethanolamine, phosphatidic acid, plant monogalactosyl diglyceride (hydrogenation) or plant digalactosyl diglyceride (hydrogenation) etc.Other useful lecithin includes, but are not limited to phosphatidylcholine and derivant, PHOSPHATIDYL ETHANOLAMINE and derivant thereof, Phosphatidylserine and derivant thereof, or polymerization lipid, and wherein hydrophilic polymer system conjugation is to the head base of this lipid.Further the lecithin that is fit to comprises; but be not limited to two caproyls-L-α-lecithin, two caprylyls-L-α-lecithin, two capryl-L-α-lecithin, two dodecanoyl-L-α-lecithin, two four capryl-L-α-lecithin, two hexadecanoyl group-L-α-lecithin, two octadecanoyl-L-α-lecithin, dioleoyl-L-α-lecithin, two inferior oleoyl-L-α-lecithin, α-palmityl, beta-oil acyl group-L-α-lecithin, L-α-glycerol PC etc.Can be used for commercially available lecithin of the present invention and include, but are not limited to LSC 5050 and 6040 (obtaining), Phosal by Avatar company ^TM50 PG and 53 MCT (obtaining), Phospholipon by U.S. lecithin company ^TM100H, 90G, 90H and 80 (obtaining), sunflower type lecithin: Lecistar by U.S. lecithin company ^TMSun 100 and 200 (obtaining), Semen sojae atricolor type lecithin: Greencithin by SternChemie ^TM(obtaining) and Semen Glycines type lecithin: Yellothin by SternChemie ^TMMaterial described in (being obtained by SternChemie), and R.C.Rowe and P.J.Shesky, medical excipient handbook (2006) the 5th edition all is incorporated herein by reference it.

The term of Shi Yonging " inferior oleoyl polyethyleneglycol glyceride " refers to mainly syntheticly or mainly be derived from the polyglycolyzed glyceride of linoleic chemical compound by linoleic acid in this article, and this is synthetic but other fatty acid or the chemical compound that is derived from other fatty acid also can be used for.The inferior oleoyl polyethyleneglycol glyceride that is fit to includes, but are not limited to Labrafil ^TMM 2125 CS (obtaining) by Gattefoss é.

The mannitol that is fit to includes, but are not limited to PharmMannidex (being obtained by Cargill), Pearlitol (being obtained by Roquette) and Mannogem (being obtained by SPI Polyols).

The term of Shi Yonging " alkylsurfuric acid slaine " finger-type is formed in the slaine between alkylsurfuric acid salt compound and the inorganic base in this article.In some embodiments, this alkylsurfuric acid slaine has about 8 to about 18 carbon atoms.In some embodiments, this alkylsurfuric acid slaine is the lauryl sulfate slaine.In some embodiments, this alkylsurfuric acid slaine is a sodium lauryl sulfate.

The term of Shi Yonging " aluminum silicate slaine " refers to any slaine of aluminum silicate in this article, including, but not limited to aluminum metasilicic acid magnesium.The aluminum metasilicic acid magnesium that is fit to includes, but are not limited to Neusilin (being obtained by the Fuji chemistry), Pharmsorb (being obtained by Engelhard) and Veegum (being obtained by the R.T.Vanderbilt company limited).In some embodiments, this aluminum silicate slaine is a bentonite.

The term of Shi Yonging " carbonic acid metal salt " refers to any carbonic acid metal salt in this article, including, but not limited to sodium carbonate, calcium carbonate and magnesium carbonate, and zinc carbonate.

The term of Shi Yonging " metal-oxide " refers to any metal-oxide in this article, including, but not limited to calcium oxide or magnesium oxide.

The term of Shi Yonging " Metallic stearates " refers to stearic slaine in this article.In some embodiments, this stearic slaine is calcium stearate, zinc stearate or magnesium stearate.In some embodiments, this stearic acid metal is a magnesium stearate.

The term of Shi Yonging " mineral oil " refers to not refining and refining (gently) mineral oil in this article.The mineral oil that is fit to includes, but are not limited to Avatech ^TMLevel (obtaining), Drakeol by Avatar company ^TMLevel (obtaining), Sirius by Penreco ^TMLevel (obtaining) and Citation by Shell ^TMLevel (obtaining) by Avater company.

The term of Shi Yonging " oleoyl polyethyleneglycol glyceride " refers to mainly be synthesized or mainly be derived from by oleic acid the polyglycolyzed glyceride of oleic chemical compound in this article, but should synthesize the chemical compound that also can use other fatty acid or be derived from other fatty acid.The oleoyl polyethyleneglycol glyceride that is fit to includes, but are not limited to Labrafil ^TMM1944CS (obtaining) by Gattefoss é.

The term of Shi Yonging " GREMAPHOR GS32 " finger-type becomes the chemical compound from ethoxylated castor oil in this article, and wherein at least one being linked as of Polyethylene Glycol is covalently linked to this Oleum Ricini.This Oleum Ricini can be hydrogenated or not hydrogenation.The synonym of GREMAPHOR GS32 includes, but are not limited to polyoxy Oleum Ricini, hydrogenation polyoxy Oleum Ricini, Oleum Ricini polyethyleneglycol glyceride, hydroxy stearic acid polyethyleneglycol glyceride, polyoxy 35 Oleum Ricini and polyoxy 40 castor oil hydrogenated.The GREMAPHOR GS32 that is fit to includes, but are not limited to Nikkol ^TMHCO series (being obtained by Nikko chemistry company limited) is as Nikkol HCO-30, HC-40, HC-50 and HC-60 (being respectively Polyethylene Glycol-30 castor oil hydrogenated, Polyethylene Glycol-40 castor oil hydrogenated, Polyethylene Glycol-50 castor oil hydrogenated and Polyethylene Glycol-60 castor oil hydrogenated); Emulphor ^TMEL-719 (40 moles of ethoxylated castor oils are obtained by the Stepan product); Cremophore ^TMSeries (obtaining) by BASF, it comprises Cremophore RH40, RH60 and EL35 (being respectively Polyethylene Glycol 40 castor oil hydrogenated, Polyethylene Glycol 60 castor oil hydrogenated and Polyethylene Glycol 35 castor oil hydrogenated); And

RO and HRE series (obtaining) by Cognis PharmaLine.Other castor oil derivatives that is fit to comprises R.C.Rowe and P.J.Shesky, and person described in the medical excipient handbook (2006) the 5th edition all is incorporated herein by reference it.

The term of Shi Yonging " polyethoxylated cholesterol " finger-type becomes chemical compound or its mixture from the ethoxylation cholesterol in this article.In some embodiments, the polyoxyethylene of this chemical compound or mixture partly has about 2 to about 200 ethylene oxide monomers.In some embodiments, the polyoxyethylene of this chemical compound or mixture partly has about 2 to about 100 ethylene oxide monomers.In some embodiments, the polyoxyethylene of this chemical compound or mixture partly has about 2 to about 50 ethylene oxide monomers.In some embodiments, the polyoxyethylene of this chemical compound or mixture partly has about 5 to about 30 ethylene oxide monomers.

The term of Shi Yonging " polyethoxylated fatty acid ester " refers to be derived from the monoesters or the dibasic acid esters of ethoxylated fatty acid in this article, or its mixture.This polyethoxylated fatty acid ester also can contain free fatty and Polyethylene Glycol.The fatty acid that is used to form the polyethoxylated fatty acid ester include, but are not limited to as herein described those.The polyethoxylated fatty acid ester that is fit to includes, but are not limited to Emulphor ^TMVT-679 (8.3 moles of ethoxylation stearic acid are obtained by the Stepan product); Alkasurf ^TMCO series (obtaining) by Alkaril; Polyethylene Glycol 15 hydroxy stearic acid esters; Solutol ^TMHS15 (obtaining) by BASF; And being set forth in R.C.Rowe and P.J.Shesky, the Myrj 45 in the medical excipient handbook (2006) the 5th edition all is incorporated herein by reference it.

The term of Shi Yonging " polyethoxylated sorbitol ester " refers to be derived from chemical compound or its mixture of ethoxylation sorbitol ester in this article.The term of Shi Yonging " sorbitol ester " refers to be derived from the chemical compound of esterification of Sorbitol and at least a fatty acid or the mixture of chemical compound in this article.The fatty acid that is used to produce the polyethoxylated sorbitol ester includes, but are not limited to person described herein.In some embodiments, the polyoxyethylene of this chemical compound or mixture partly has about 2 to about 200 ethylene oxide monomers.In some embodiments, the polyoxyethylene of this chemical compound or mixture partly has about 2 to about 100 ethylene oxide monomers.In some embodiments, the polyoxyethylene of this chemical compound or mixture partly has about 4 to about 80 ethylene oxide monomers.In some embodiments, the polyoxyethylene of this chemical compound or mixture partly has about 4 to about 40 ethylene oxide monomers.In some embodiments, the polyoxyethylene of this chemical compound or mixture partly has about 4 to about 20 ethylene oxide monomers.The polyethoxylated sorbitol ester that is fit to includes, but are not limited to Tween ^TMSeries (obtaining) by Uniqema, it comprises Tween20 (POE (20) is sorbityl monododecanoate), 21 (POE (4) is sorbityl monododecanoate), 40 (POE (20) Sorbitol monopalmitates), 60 (POE (20) Sorbitol monostearates), 60K (POE (20) Sorbitol monostearate), 61 (POE (4) Sorbitol monostearates), 65 (POE (20) Sorbitol tristearates), 80 (POE (20) sorbitol monooleates), 80K (POE (20) sorbitol monooleate), 81 (POE (5) sorbitol monooleates) and 85 (POE (20) Sorbitol trioleates).Use abbreviation in this article " POE " refer to polyoxyethylene.Numeral after the POE abbreviation refers to the number of ethylene oxide repeated monomer in the chemical compound.Other polyethoxylated sorbitol ester that is fit to comprises and is set forth in R.C.Rowe and P.J.Shesky, and the polyoxyethylene sorbitol fatty acid ester in the medical excipient handbook (2006) the 5th edition all is incorporated herein by reference it.

The term of Shi Yonging " polyethoxylated sterin " refers to be derived from the chemical compound of ethoxylation sterin molecule in this article, or the mixture of chemical compound.The polyethoxylated sterin that is fit to includes, but are not limited to the PEG-24 cholesterol ethers; Solulan ^TMC-24 (obtaining) by Amerchol; The PEG-30 cholestanol, Nikkol ^TMDHC (obtaining) by Nikko; Phytosterol, GENEROL ^TMSeries (obtaining) by Henkel; The PEG-25 phytosterol, Nikkol ^TMBPSH-25 (obtaining) by Nikko; PEG-5 Semen Glycines sterin, Nikkol ^TMBPS-5 (obtaining) by Nikko; PEG-10 Semen Glycines sterin, Nikkol ^TMBPS-10 (obtaining) by Nikko; PEG-20 Semen Glycines sterin, Nikkol ^TMBPS-20 (obtaining) by Nikko; And PEG-30 Semen Glycines sterin, Nikkol ^TMBPS-30 (obtaining) by Nikko.The term of Shi Yonging " PEG " refers to Polyethylene Glycol in this article.

The term of Shi Yonging " polyethoxylated vegetable oil " finger-type becomes from the chemical compound of ethoxylation vegetable oil or the mixture of chemical compound in this article, and wherein at least one being linked as of Polyethylene Glycol is covalently linked to this vegetable oil.In some embodiments, this fatty acid has about 12 to about 18 carbon atoms.In some embodiments, the quantity of ethoxylation is from about 2 to about 200, about 5 to 100, about 10 to about 80, about 20 to about 60, or about 12 to about 18 ethylene glycol repeated monomers.This vegetable oil can be hydrogenated or not hydrogenation.The polyethoxylated vegetable oil that is fit to includes, but are not limited to Cremaphor ^TMEL or RH series (obtaining) by BASF; Emulphor ^TMEL-719 (obtaining) and Emulphor by the Stepan product ^TMEL-620P (obtaining) by GAF.

The term of Shi Yonging " Polyethylene Glycol " speech refers to contain formula-O-CH in this article ₂-CH ₂-the polymer of ethylene glycol monomer.The Polyethylene Glycol that is fit to has a free hydroxyl group at each end of polymer molecule, or has one or more hydroxyl through low alkyl group such as methyl institute etherificate.But also can use polyethyleneglycol derivative with etherificate carboxyl.Be used for the polymer that Polyethylene Glycol of the present invention can be any chain length or molecular weight and comprises side chain.In some embodiments, the mean molecule quantity of Polyethylene Glycol is from about 200 to about 9,000.In some embodiments, the mean molecule quantity of Polyethylene Glycol is from about 200 to about 5,000.In some embodiments, the mean molecule quantity of Polyethylene Glycol is from about 200 to about 900.In some embodiments, the mean molecule quantity of Polyethylene Glycol is about 400.The Polyethylene Glycol that is fit to includes, but are not limited to Polyethylene Glycol-200, Polyethylene Glycol-300, Polyethylene Glycol-400, Polyethylene Glycol-600 and Polyethylene Glycol-900.Number in the title behind the dash line refers to the mean molecule quantity of this polymer.In some embodiments, this Polyethylene Glycol is a Polyethylene Glycol-400.The Polyethylene Glycol that is fit to includes, but are not limited to Carbowax ^TMAnd Carbowax ^TMSentry series (obtaining) by Dow; Lipoxol ^TMSeries (obtaining) by Brenntag; Lutrol ^TMSeries (obtaining) and Pluriol by BASF ^TMSeries (obtaining) by BASF.

The term of Shi Yonging " polyglycolyzed glyceride " finger-type becomes the esterification from Polyethylene Glycol, glycerol and fatty acid in this article; The transesterigfication of glyceride and Polyethylene Glycol; Or the product of the oxyethylation of glyceride and fatty acid.The term of Shi Yonging " polyglycolyzed glyceride ester " can be in addition or is further referred to the monoesters of monoglyceride, Diglyceride and/or triglyceride and Polyethylene Glycol and/or the mixture of dibasic acid esters in this article.Poly-ethanol two is changed glyceride and the Polyethylene Glycol that glyceride can be derived from fatty acid as herein described, fatty acid.Fatty acid side chain on glyceride, monoesters or the dibasic acid esters can be any chain length and can be saturated or unsaturated.Polyglycolyzed glyceride can contain other material as pollutant or side-product, such as, but be not limited to Polyethylene Glycol, glycerol and fatty acid.

In some embodiments, this polyglycolyzed glyceride is LABRASOL, stearyl polyethyleneglycol glyceride, inferior oleoyl polyethyleneglycol glyceride, oleoyl polyethyleneglycol glyceride or octyl group caproyl polyethyleneglycol glyceride.

The term of Shi Yonging " polyoxyethylene-alkyl ether " refers to polyoxyethylated monoalkyl or dialkyl ether in this article, or its mixture.In some embodiments, this polyoxyethylene-alkyl ether is a polyoxyethylene aliphatic alcohol ether.

The term of Shi Yonging " polyoxyethylene aliphatic alcohol ether " finger-type is formed in monoether or the bis ether between Polyethylene Glycol and the aliphatic alcohol in this article, or its mixture.The aliphatic alcohol that is used to produce polyoxyethylene aliphatic alcohol ether includes, but are not limited to person described herein.In some embodiments, the polyoxyethylene of this molecule partly has about 2 to about 200 ethylene oxide monomers.In some embodiments, the polyoxyethylene of this molecule partly has about 2 to about 100 ethylene oxide monomers.In some embodiments, the polyoxyethylene of this molecule partly has about 4 to about 50 ethylene oxide monomers.In some embodiments, the polyoxyethylene of this molecule partly has about 4 to about 30 ethylene oxide monomers.In some embodiments, this polyoxyethylene aliphatic alcohol ether comprises ethoxylation stearyl alcohol, spermol and cetyl stearyl alcohol (spermaceti aryl alcohol).The polyoxyethylene aliphatic alcohol ether that is fit to includes, but are not limited to Brij ^TMThe surfactant of series (obtaining) by Uniqema, it comprises Brij 30,35,52,56,58,72,76,78,93Veg, 97,98 and 721; Cremophor ^TMA series (obtaining) by BASF, it comprises Cremophor A6, A20 and A25; Emulgen ^TMSeries (by Kao company air ticket), it comprises Emulgen 104P, 123P, 210P, 220,320P and 409P; Ethosperse ^TM(by the Lonza air ticket), it comprises Ethosperse 1A4,1A12, TDAa6, S120 and G26; Ethylan ^TMSeries (obtaining) by Brenntag, it comprises Ethylan D252,253,254,256,257,2512 and 2560; Plurafac ^TMSeries (obtaining) by BASF, it comprises Plurafac RA20, RA30, RA40, RA43 and RA340; Ritoleth ^TMAnd Ritox ^TMSeries (obtaining) by Rita company; Volpo ^TMSeries (obtaining) by Croda, it comprises Volpo N10, N20, S2, S10, C2, C20, CS10, CS20, L4 and L23; And Texafor ^TMSeries, it comprises Texafor A1P, AP, A6, A10, A14, A30, A45 and A60.Other polyoxyethylene aliphatic alcohol ether that is fit to includes, but are not limited to the stearic alcohol ether of Polyethylene Glycol (13) (steareth-13), the stearic alcohol ether of Polyethylene Glycol (14) (steareth-14), the stearic alcohol ether of Polyethylene Glycol (15) (steareth-15), the stearic alcohol ether of Polyethylene Glycol (16) (steareth-16), the stearic alcohol ether of Polyethylene Glycol (17) (steareth-17), the stearic alcohol ether of Polyethylene Glycol (18) (steareth-18), the stearic alcohol ether of Polyethylene Glycol (19) (steareth-19), the stearic alcohol ether of Polyethylene Glycol (20) (steareth-20), Polyethylene Glycol (12) isooctadecanol ether (isosteareth-12), Polyethylene Glycol (13) isooctadecanol ether (isosteareth-13), Polyethylene Glycol (14) isooctadecanol ether (isosteareth-14), Polyethylene Glycol (15) isooctadecanol ether (isosteareth-15), Polyethylene Glycol (16) isooctadecanol ether (isosteareth-16), Polyethylene Glycol (17) isooctadecanol ether (isosteareth-17), Polyethylene Glycol (18) isooctadecanol ether (isosteareth-18), Polyethylene Glycol (19) isooctadecanol ether (isosteareth-19), Polyethylene Glycol (20) isooctadecanol ether (isosteareth-20), Polyethylene Glycol (13) cetyl ether (ceteth-13), Polyethylene Glycol (14) cetyl ether (ceteth-14), Polyethylene Glycol (15) cetyl ether (ceteth-15), Polyethylene Glycol (16) cetyl ether (ceteth-16), Polyethylene Glycol (17) cetyl ether (ceteth-17), Polyethylene Glycol (18) cetyl ether (ceteth-18), Polyethylene Glycol (19) cetyl ether (ceteth-19), Polyethylene Glycol (20) cetyl ether (ceteth-20), the different cetyl ether of Polyethylene Glycol (13) (isoceteth-13), the different cetyl ether of Polyethylene Glycol (14) (isoceteth-14), the different cetyl ether of Polyethylene Glycol (15) (isoceteth-15), the different cetyl ether of Polyethylene Glycol (16) (isoceteth-16), the different cetyl ether of Polyethylene Glycol (17) (isoceteth-17), the different cetyl ether of Polyethylene Glycol (18) (isoceteth-18), the different cetyl ether of Polyethylene Glycol (19) (isoceteth-19), the different cetyl ether of Polyethylene Glycol (20) (isoceteth-20), Polyethylene Glycol (12) oleyl ether (oleth-12), Polyethylene Glycol (13) oleyl ether (oleth-13), Polyethylene Glycol (14) oleyl ether (oleth-14), Polyethylene Glycol (15) oleyl ether (oleth-15), Polyethylene Glycol (12) lauryl ether (laureth-12), the different lauryl ether of Polyethylene Glycol (12) (isolaureth-12), Polyethylene Glycol (13) cetearyl ether (ceteareth-13), Polyethylene Glycol (14) cetearyl ether (ceteareth-14), Polyethylene Glycol (15) cetearyl ether (ceteareth-15), Polyethylene Glycol (16) cetearyl ether (ceteareth-16), Polyethylene Glycol (17) cetearyl ether (ceteareth-17), Polyethylene Glycol (18) cetearyl ether (ceteareth-18), Polyethylene Glycol (19) cetearyl ether (ceteareth-19), Polyethylene Glycol (20) cetearyl ether (ceteareth-20).Numeral behind term " Polyethylene Glycol " noun refers to the number of ethylene oxide repeated monomer in the chemical compound.Polyoxyethylene aliphatic alcohol ether and other mixtures of material also can be used for the present invention.The non-limiting example of the mixture that is fit to is Arlacel ^TM165 or 165VEG (by the Uniqema air ticket), it is the mixture of glyceryl monostearate and Polyethylene Glycol-100 stearate.Other polyoxyethylene aliphatic alcohol ether that is fit to comprises and is set forth in R.C.Rowe and P.J.Shesky, and person in the medical excipient handbook (2006) the 5th edition all is incorporated herein by reference it.

The term of Shi Yonging " polyoxyethylene-fatty acid glyceride " refers to the ethoxylated fatty acid ester of glycerol in this article, or its mixture.In some embodiments, the polyoxyethylene of this molecule partly has about 2 to about 200 ethylene oxide monomers.In some embodiments, the polyoxyethylene of this molecule partly has about 2 to about 100 ethylene oxide monomers.In some embodiments, the polyoxyethylene of this molecule partly has about 4 to about 50 ethylene oxide monomers.In some embodiments, the polyoxyethylene of this molecule partly has about 4 to about 30 ethylene oxide monomers.Polyoxyethylene-the fatty acid glyceride that is fit to includes, but are not limited to PEG-20 glyceryl laurate ester, Tagat ^TML (Goldschmidt); The PEG-30 glyceryl laurate ester, Tagat ^TML2 (Goldschmidt); The PEG-15 glyceryl laurate ester, Glycerox ^TML series (Croda); The PEG-40 glyceryl laurate ester, Glycerox ^TML series (Croda); The PEG-20 tristerin, Capmul ^TMEMG (ABITEC), Aldo MS-20KFG (Lonza); The PEG-20 olein, Tagat ^TM0 (Goldschmidt); The PEG-30 olein, Tagat ^TM02 (Goldschmidt).

The term of Shi Yonging " polyoxyethylene-polyoxypropylene copolymer " refers to the copolymer of ethylene oxide monomer and propylene oxide monomer in this article.Be suitable for polyoxyethylene of the present invention-polyoxypropylene copolymer and can be any chain length or molecular weight and comprise the side chain person.This end of the chain can have a free hydroxyl group or have one or more hydroxyl through low alkyl group or carboxyl institute etherificate.This polyoxyethylene-polyoxypropylene copolymer also can comprise other monomer that is formed a part of main chain by the copolymerization combination.For example, butylene oxide can be with ethylene oxide and propylene oxide combined polymerization and is formed for polyoxyethylene of the present invention-polyoxypropylene copolymer.In some embodiments, this polyoxyethylene-polyoxypropylene copolymer based block copolymer, wherein a block is a polyoxyethylene and another block is a polyoxypropylene.Polyoxyethylene-polyoxypropylene the copolymer that is fit to includes, but are not limited to

The surfactant of series (obtaining) by BASF, surfactant Poloxamer 108,124,188,217,237,238,288,338,407,101,105,122,123,124,181,182,183,184,212,231,282,331,401,402,185,215,234,235,284,333,334,335 in its formation CTFA name and 403 group.Other polyoxyethylene-polyoxypropylene copolymer that is fit to is including, but not limited to DowFax

Nonionic surfactant (obtaining), DowFax by the Dow chemistry

N-series of surfactants (obtaining), Lutrol by the Dow chemistry ^TMSurfactant (obtaining) and Synperonic by BASF ^TMSurfactant (obtaining) by Uniqema.

The term of Shi Yonging " polyvinyl alcohol " finger-type becomes the polymer from part or all of hydrolysed polyvinyl acetate in this article.The polyvinyl alcohol that is fit to includes, but are not limited to Airvol series (being obtained by the Air product); Alcotex series (obtaining) by Synthomer; Elvanol series (obtaining) by DuPont; Gelvatol series (obtaining) by Burkard; And Gohsenol series (obtaining) by Gohsenol.

The term of Shi Yonging " polyethylene Pyrrolizidine ketone " refers to the polymer of ethylene Pyrrolizidine ketone in this article.In some embodiments, this polyethylene Pyrrolizidine ketone contains one or more additional polymerization single polymerization monomer.In some embodiments, this additional polymerization monomer is carboxylic monomer.In some embodiments, this polyethylene Pyrrolizidine ketone is polyvidone.In some embodiments, this polyethylene Pyrrolizidine ketone has 2,500 to 3,000,000 molecular weight.In some embodiments, this polyethylene Pyrrolizidine ketone is 30 POVIDONE K 30 BP/USP 12, K17, K25, K30, K60, K90 or K120.In some embodiments, this polyethylene Pyrrolizidine ketone is 30 POVIDONE K 30 BP/USP 25.The polyethylene Pyrrolizidine ketone polymer that is fit to includes, but are not limited to Kollidone ^TMSeries (obtaining) and Plasdone by BASF ^TMSeries (obtaining) by ISP.

The term of Shi Yonging " methyl glycol fatty acid ester " finger-type becomes monoether or the dibasic acid esters from propylene glycol or polypropylene glycol and fatty acid in this article, or its mixture.The fatty acid that can be used for producing the propylene glycol fatty alcohol ether includes, but are not limited to person described herein.In some embodiments, this monoesters or dibasic acid esters are derived from propylene glycol.In some embodiments, this monoesters or dibasic acid esters have about 1 to about 200 propylene oxide monomer.In some embodiments, the polypropylene glycol of this molecule partly has about 2 to about 100 propylene oxide monomer.In some embodiments, this monoesters or dibasic acid esters have about 4 to about 50 propylene oxide monomer.In some embodiments, this monoesters or dibasic acid esters have about 4 to about 30 propylene oxide monomer.The methyl glycol fatty acid ester that is fit to includes, but are not limited to propylene glycol laurate: Lauroglycol ^TMFCC and 90 (obtaining) by Gattefoss é; Propylene glycol caprylate: Capryol ^TMPGMC and 90 (obtaining) by Gatefosse; And dioctyl caproyl propylene glycol ester: Labrafac ^TMPG (obtaining) by Gatefosse.

The term of Shi Yonging " quaternary ammonium compound " refers to contain the chemical compound of at least one quaternary ammonium group in this article.Useful especially quaternary ammonium compound is emulsifying agent, lytic agent or the suspension hydrophobic material person who can be used in the water.Can be used for other quaternary ammonium compound of the present invention and can strengthen the bioavailability person of active agents when using to patient.The quaternary ammonium compound that is fit to comprises; but be not limited to 1; the two oleyls of 2--3-trimethyl ammonium propane, DDA, N-[1-(1; the two oily alkene oxygen bases of 2-) propyl group]-N; N; N-trimethyl ammonium chloride, 1, the two oleyls of 2--3-ethyl phosphorus choline or 3-β-[N-[(N ', N '-dimethylamino) ethane] carbamyl] cholesterol.Other quaternary ammonium compound that is fit to includes, but are not limited to Stepanquat ^TM50NF and 65NF (nalka dixylyl ammonium chloride is obtained by the Stepan product).

The Sorbitol that is fit to includes, but are not limited to PharmSorbidex E420 (being obtained by Cargill); Liponic 70-NC and 76-NC (obtaining) by the Lipo chemistry; Neosorb (obtaining) by Roquette; Partech SI (obtaining) by Merck; And Sorbogem (obtaining) by SPI Polyols.

Starch, Explotab and pregelatinized Starch include, but are not limited to R.C.Rowe and P.J.Shesky, and person described in the medical excipient handbook (2006) the 5th edition all is incorporated herein by reference it.

The term of Shi Yonging " starch " refers to that the natural or modified starch of any kind comprises in this article, but be not limited to corn starch (also being called beautiful potato broomcorn millet starch or maydis amylum), potato starch (also being called solani amylum), rice starch (also being called oryzae amylum) and wheaten starch (also being called tritici amylum) and tapioca.Term " starch " is pointer starch that molecular weight and side chain are modified also.Term " starch " further refers to connected by chemical modification the starch of chemical functional base such as carboxyl, hydroxyl, hydroxyl alkylidene or carboxylic alkylidene.The term of Shi Yonging " carboxylic alkylidene " refers to the group of formula-alkylidene-C (O) OH in this article, or its esters.The term of Shi Yonging " hydroxyl alkylidene " refers to the group of formula-alkylidene-OH in this article.

The Explotab that is fit to includes, but are not limited to Explotab (being obtained by JRS Pharma); Glycolys (obtaining) by Roquette; Primojel (obtaining) by DMV is international; And Vivastar (obtaining) by JRS Pharma.

The pregelatinized Starch that is fit to includes, but are not limited to Lycatab C and PGS (being obtained by Roquette); Merigel (obtaining) by Brenntag; National 78-1551 (obtaining) by National Starch; Spress B820 (obtaining) by GPC; And Starch 1500 (obtaining) by Colorcon.

The term of Shi Yonging " stearyl polyethyleneglycol glyceride " refers to mainly synthetic from stearic acid or mainly be derived from the polyglycolyzed glyceride of stearic chemical compound in this article, and this is synthetic but other fatty acid or the chemical compound that is derived from other fatty acid also can be used for.The stearyl polyethyleneglycol glyceride that is fit to includes, but are not limited to

50/13 (obtaining) by Gattefoss é.

The term " fatty acid " sugar ester of Shi Yonging in this article " finger-type is formed in the ester compounds between fatty acid and carbohydrate or the glycan molecule.In some embodiments, this carbohydrate is glucose, lactose, sucrose, dextrose, mannitol, xylitol, Sorbitol, maltodextrin etc.The sucrose fatty acid ester that is fit to includes, but are not limited to sucrose fatty acid ester (for example obtaining those by the Mitsubishi chemistry).

The term of Shi Yonging " sulfosuccinate " refers to formula R-O-C (O) CH in this article ₂CH (SO ₃ ^-M ⁺) two alkyl sulfosuccinic acid metal salts of C (O) OR, wherein R is an alkyl or cycloalkyl, and wherein alkyl and cycloalkyl can randomly be replaced by one or more hydroxyl, and M is metal such as sodium, potassium etc.In some embodiments, R is isobutyl group, amyl group, hexyl, cyclohexyl, octyl group, three decyls or 2-ethylhexyl.The sulfosuccinate that is fit to is Aerosol ^TMThe 2-Sulfosuccinic acid ester surfactant of series (obtaining) by Cytec.

The term of Shi Yonging " taurine ester " refers to formula R-C (O) NR '-CH in this article ₂-CH ₂-SO ₃ ^-M ⁺The alkyl taurine slaine, wherein R and R ' are alkyl or cycloalkyl, wherein alkyl and cycloalkyl can randomly be replaced by one or more hydroxyl, and M is metal such as sodium, potassium etc.In some embodiments, R is cocoyl or oleoyl.In some embodiments, R ' is methyl or ethyl.The taurine ester that is fit to includes, but are not limited to Geropon ^TMT series, it comprises Geropon ^TMTC42 and T77 (obtaining) and Hostapon by Rhodia ^TMT series (obtaining) by Clariant.

The term of Shi Yonging " vegetable oil " refers to and can be comprised triglyceride by refining, fractional distillation or hydrogenant natural or synthetic oil in this article.The vegetable oil that is fit to includes, but are not limited to Oleum Ricini, castor oil hydrogenated, Oleum sesami, Semen Maydis oil, Oleum Arachidis hypogaeae semen, olive oil, sunflower oil, safflower oil, soybean oil, benzyl benzoate, Oleum sesami, Oleum Gossypii semen and Petiolus Trachycarpi oil.Other vegetable oil that is fit to for example comprises commercially available artificial oil, but is not limited to Miglyol ^TM810 and 812 (obtaining Sweden by DynamitNobel Chicals); Neobee ^TMM5 (by Drew chemical company air ticket); Alofine ^TM(obtaining) by Jarchem industry; Lubritab ^TMSeries (obtaining) by JRS Pharma; Sterotex ^TM(by Abitec company air ticket); Softisan ^TM154 (obtaining) by Sasol; Croduret ^TM(obtaining) by Croda; Fancol ^TM(obtaining) by Fanning company; Cutina ^TMHR (obtaining) by Cognis; Simulsol ^TM(obtaining) by CJ Petrow; EmCon ^TMCO (obtaining) by Amisol company; Lipvol ^TMCO, SES and HS-K (obtaining) and Sterotex by Lipo ^TMHM (by Abitec company air ticket).Other vegetable oil that is fit to comprises and is set forth in R.C.Rowe and P.J.Shesky, and Oleum sesami, Oleum Ricini, Semen Maydis oil and Oleum Gossypii semen in the medical excipient handbook (2006) the 5th edition all are incorporated herein by reference it.

In the medical components of definition, one of skill in the art will appreciate that some preparation composition may have the above definition of this paper one class concurrently.For example, sucrose fatty acid ester also can be considered to be a kind of fatty acid ester.

The present invention also relates to the method for making pharmaceutical preparation of the present invention.In one aspect, the direct hybrid technology of this method utilization is made pharmaceutical preparation of the present invention.In yet another aspect, this method utilizes wet granulation to make pharmaceutical preparation of the present invention.Further, the present invention relates to make the dry pelletizing method of pharmaceutical preparation of the present invention.Can make the granule of pharmaceutical preparation by any comminution granulation well-known to those skilled in the art.For example, dry pelletizing method is suppressed mixed-powder by roll extrusion or " turbulent (slugging) " under the high pressure in heavy tablet machine.Wet granulation includes, but are not limited to mixed at high speed comminution granulation, single pot process, top spray comminution granulation, end spray comminution granulation, fluidisation spray granulation, extruding/round and cylinder comminution granulation.

Therefore, the present invention further provides the method for making pharmaceutical preparation of the present invention, it comprises:

(a) active agents and first diluent/filler composition, disintegrating agent composition and optional second diluent/filler composition (if existence) are mixed and form preliminary mixture; With

(b) form the granulation mixture with this preliminary mixture of aqueous solution granulating that contains the wetting agent composition.

In some embodiments, step (a) comprising:

(i) active agents is mixed with at least a portion first diluent/filler composition and form first mixture;

(ii) mix first mixture and remaining first diluent/filler composition, disintegrating agent composition and optional second diluent/filler composition (if existence) and form preliminary mixture.

In some embodiments, this aqueous solution further contains adhesive ingredients.

In some embodiments, this method further comprises:

(i) dry this granulated mixture and form the dried particles mixture; With

(ii) optional lubricant composition (if existence) is mixed with this dried particles mixture and form whole mixture.

In some embodiments, this step (ii) comprises:

(a) optional lubricant composition (if existence) is mixed with the dry granulated mixture of a part;

(b) mixture with (i) mixes with remaining dry granulated mixture.

In some embodiments, in mixer, carry out (ii) the step of (b).

The present invention further provides the method for making pharmaceutical preparation of the present invention, it comprises:

(ii) first mixture and remaining first diluent/filler composition, disintegrating agent composition and optional second diluent/filler composition (if existence) are mixed and form preliminary mixture;

(iii) form the granulation mixture with this preliminary mixture of aqueous solution granulating that contains the wetting agent composition;

(iv) dry this granulation mixture and form the dry granulation mixture;

(v) optional lubricant composition (if existence) is mixed with this dry granulation mixture of at least a portion; With

(vi) will (mixture v) mixes with remaining dry granulation mixture.

In some embodiments, this aqueous solution further contains binding agent.

(i) first diluent/filler composition, optional second diluent/filler composition (if existence), disintegrating agent composition, adhesive ingredients, wetting agent composition and active agents are mixed and form first mixture; With

(ii) this first mixture of granulating randomly.

In some embodiments, this first mixture further contains optional lubricant composition.

Method as herein described can be used for making any pharmaceutical preparation as herein described, and any combination of its embodiment and time combination.

The present invention further provides the tablet that contains pharmaceutical preparation of the present invention.Any combination of any pharmaceutical preparation as herein described and its embodiment and time combination all can be used to prepare tablet of the present invention.

The present invention further provides the method for making tablet of the present invention, comprise pharmaceutical preparation of the present invention is pressed into tablet.

In some embodiments, this is compressed to direct compacting.

In some embodiments, this compacting can produce the tablet of about 7Kp to about 13Kp hardness.In some embodiments, this tablet has the hardness of about 7Kp to about 13Kp.

The method of manufacturing tablet as herein described can be used for making any pharmaceutical preparation as herein described, or the tablet of its combination or inferior combination.

The present invention further provides the product of the whole bag of tricks manufacturing of the present invention.

By United States Patent (USP) case numbers 6,794, the method described in 403 can be made active agents of the present invention, comprises 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, and 3-benzoxazole-5-alcohol all is incorporated herein by reference it.

Active agents of the present invention also can comprise pharmaceutically acceptable salt.The term of Shi Yonging " pharmaceutically acceptable salt " refers to by pharmaceutically acceptable acid or alkali are added the salt that chemical compound as herein described forms in this article.The phrase of Shi Yonging " pharmaceutically acceptable " refers to can be used as medicinal usage and do not produce bad interactive material with active component from toxicologic viewpoint in this article.Pharmaceutically acceptable salt, comprise single-and two-Shi salt, including, but not limited to being derived from organic and the mineral acid person, as but be not limited to acetic acid, lactic acid, citric acid, cinnamic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, oxalic acid, propanoic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, glycolic, acetone acid, methanesulfonic acid, ethyl sulfonic acid, toluenesulfonic acid, salicylic acid, benzoic acid, and known class like acceptable salt.The salt that is fit to is recited in Remington ' s Pharmaceutical Sciences, 17th ed., MackPublishing Company, Easton, Pa., 1985, p.1418 with Journal ofPharmaceutical Science, in 66,2 (1977), it all is incorporated herein by reference.

One of active agents also can be 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, in the no hydrate type of 3-benzoxazole-5-alcohol and the two kinds of crystal types of monohydrate type.Can make its crystal type by any suitable method.In some embodiments, the method for making monohydrate of the present invention comprises be settled out this monohydrate from aqueous solution.This solution further contains one or more other solvent, for example solvent that can be mixed with water.In some embodiments, this solution contains alcohol as methanol, ethanol, normal propyl alcohol or isopropyl alcohol.In some embodiments, this alcohol is ethanol.This solution contains the alcohol or the water of any proper proportion.In some embodiments, alcohol and water weight ratio for about 1:1 to about 3:1, about 1.5:1 about 2.5:1 extremely, or about 2:1.Can be in water and optional solvent by mixing 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-5-alcohol and prepare this solution.This solution can be chosen wantonly and be heated and/or stir to help the dissolving of chemical compound.Can make its precipitation by any suitable method, comprise the pH of cooling, the anti-solvent of adding or change solution, or its combination.In some embodiments, the temperature of this solution is cooled to-20 ℃ to about 50 ℃, about 0 ℃ to about 20 ℃, about 0 ℃ to about 10 ℃ or about 0 ℃ to about 5 ℃ approximately from about 65 ℃ to about 95 ℃, about 70 ℃ to about 90 ℃ or about 75 ℃ to about 80 ℃.In some embodiments, the temperature of this solution is cooled to about 0 ℃ to about 5 ℃ from about 75 ℃ to about 80 ℃.In some embodiments, this solution was kept a period of time in a medium temperature earlier before being cooled to final temperature.In some embodiments, this medium temperature is about 40 ℃ to about 60 ℃, about 45 ℃ to about 55 ℃, or about 50 ℃.

In substituting embodiment, the pH by regulator solution can be settled out this monohydrate from aqueous solution.For example, can increase the pH of this solution and cause the precipitation of monohydrate.In some embodiments, pH rises to about 9 or higher from about 7 (or lower).Can according to routine method regulate its pH, for example add alkali such as hydroxide (for example, sodium hydroxide).By to dissolving 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, add anti-solvent in the solution of 3-benzoxazole-5-alcohol and also can make this monohydrate produce precipitation.The anti-solvent that is fit to comprises water or other suchlike liquid.The solvent that is fit to comprises alcohol as methanol, ethanol, normal propyl alcohol, isopropyl alcohol, or its mixture or other and the mixable solvent of water.By with 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the anhydrous compound of 3-benzoxazole-5-alcohol in water or in the aqueous solvent (for example, ethanol/water mixture) in slurrying also can prepare this monohydrate.

In some embodiments, by making this anhydrous crystal type by the precipitation of anhydrous solution.Anhydrous solution can contain be lower than about 1%, be lower than about 0.5%, be lower than about 0.2%, be lower than about 0.1%, be lower than approximately 0.05%, or be lower than about 0.01% water.The suitable solvent that is used to precipitate this anhydrous crystal comprises hydrocarbon for example pentane, hexane, heptane etc.; Ether is diethyl ether or oxolane for example; Aromatics is benzene or toluene etc. for example; Chlorinated hydrocabon is dichloromethane etc. for example; And other organic solvent ethyl acetate etc. for example, and composition thereof.In some embodiments, this no hydras is from containing the solvent deposition of ethyl acetate.In some embodiments, this solvent further contains for example hydrocarbon of hexane.In further embodiment, the weight ratio of ethyl acetate and hydrocarbon is about 3:1 about 1:1, about 1:1 about 1:1 extremely extremely, or about 1.5:1.

The precipitation that can bring out no hydrate by any various sedimentation method of knowing.For example, cooling that can be by solution or add anti-solvent-induced precipitation.In some embodiments, the temperature of this solution is cooled to-20 ℃ to about 30 ℃, about 0 ℃ to about 10 ℃ or about 0 ℃ to about 5 ℃ approximately from about 60 ℃ to about 90 ℃, about 70 ℃ to about 85 ℃ or about 75 ℃ to about 80 ℃.In cooling procedure, this temperature can be chosen wantonly in for example about 40 ℃ to about 60 ℃ an of medium temperature (for example, about 45 ℃ to about 50 ℃) and be kept a period of time.Anti-solvent method comprises the anti-solvent that will be fit to, and for example hydrocarbon is (for example, be difficult for dissolving 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-the pentane of 5-alcohol, hexane, heptane) add dissolving 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, in the solvent of 3-benzoxazole-5-alcohol.The solvent that is fit to comprises can be partly dissolved 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-5-alcohol person, for example ethyl acetate, dichloromethane, oxolane etc. at least.

Can differentiate the special solid-state labelling of these two kinds of crystal types according to for example differential scanning calorimetry (DSC), x-ray powder diffraction (XRPD) and other solid state process.Can further measure the characteristic of the water or the solvent of this crystal type by the method for any routine, for example thermogravimetric analysis (TGA), dynamic steam absorption (DVS), DSC and other technology.DSC for example, oneself knows that observed temperature will decide according to the change speed of temperature and the particular instrument of sample preparation technology and use.Therefore, the variation of the value of the DSC thermal analysis curue of this paper record can be approximately between ± 4 ℃.For XRPD, the relative intensity at its peak depends on the fixed routine of the technology of preparing of sample, sample and the particular instrument of use.In addition, the deviation of instrument and other factors influence 2 θ values through regular meeting.Therefore, the peak of diffraction pattern is set to be changed between ± 0.2 ° approximately.Distinguishing the physical property and the X-ray data of no hydrate and monohydrate crystal type takes passages in table 1 and 2.

The data of table 2 is the water contents about crystal type, and it shows that according to TGA after measured the monohydrate crystal type contains the water content (seeing also for example Fig. 3) near theoretical water content 6.23 weight %.DSC confirms to have in the monohydrate existence of water, and it is presented at about 100 ℃ dehydration (they are different according to sample, see also for example Fig. 2).Under the contrast, no hydrate is substantially devoid of water, and it shows under TGA and is lower than 0.02% water content (Fig. 5) and lacks dehydration heat absorption (Fig. 5) under DSC.

Analyze the distinguishing characteristics that provides according to DSC and TGA, this monohydrate has the differential scanning calorimetric curve that comprises the dehydration heat absorption.In some embodiments, the included dehydration heat absorption of the differential scanning calorimetric curve that this monohydrate has occurs in about 95 ℃ to about 120 ℃, about 98 ℃ to about 118 ℃, or about 95 ℃ to about 115 ℃.In some embodiments, this monohydrate with DSC feature further comprises and occurs in about 250 ℃ dehydration heat absorption and fusion heat absorption.In further embodiment, the differential scanning discharge curve that this monohydrate has basically as shown in Figure 2.In some embodiments, this monohydrate has thermogravimetric analysis figure and is presented at about 60 ℃ to about 150 ℃ and produces about 5.0% to about 7.0%, about 5.5% to about 6.5%, or about 5.9% to about 6.4% the loss in weight.In further embodiment, this monohydrate has thermogravimetric analysis figure basically as shown in Figure 3.

The differential scanning calorimetric curve that this anhydrous crystal type has comprises and occurs in about 250 ℃ fusion heat absorption and lack the endothermic reaction that is equivalent to the incident of dewatering basically.In some embodiments, the differential scanning calorimetric curve that has of this anhydrous crystal type basically as shown in Figure 4.In further embodiment, the thermogravimetric analysis figure that this anhydrous crystal type has be presented at about 60 ℃ to about 150 ℃ of generations be lower than about 0.5%, be lower than about 0.2%, be lower than approximately 0.1%, or be lower than about 0.05% the loss in weight.Again further in the embodiment, the thermogravimetric analysis figure that this anhydrous crystal type has basically as shown in Figure 5.

It is few that the DVS data of table 2 (referring to Fig. 6 and Fig. 7) shows that the weight of two kinds of crystal types increases, and this shows that monohydrate and no hydrate type major part are non-water absorption.Under the contrast, the water solubility that is shown in two kinds of types of table 2 then has tangible difference, and monohydrate has the dissolubility that is starkly lower than no hydrate.

Two kinds of crystal types (referring to for example Fig. 1) have different XRPD figure, and can characterize each crystal type according to its unique spectrum labelling.Therefore, in some embodiments, in 2 θ, the X-ray powder diffraction figure that this monohydrate has is included in about 9.2 ° and about 12.2 ° peak.In some embodiments, in 2 θ, the X-ray powder diffraction figure that this monohydrate has is included in about 9.2 °, about 12.2 ° and about 15.2 ° peak.In further embodiment, in 2 θ, the X-ray powder diffraction figure that this monohydrate has is included in about 9.2 °, about 12.2 °, about 15.2 ° and about 24.3 ° peak.Again further in the embodiment, in 2 θ, the X-ray powder diffraction figure that this monohydrate has is included in about 9.2 °, about 12.2 °, about 15.2 °, about 24.3 °, about 25.4 ° and about 28.0 ° peak.Again further in the embodiment, the X-ray powder diffraction figure that this monohydrate has is (top) basically as shown in Figure 1.

Table 1

Table 2

	Monohydrate	No hydrate
	Monohydrate	No hydrate	TGA	6.1% water (theoretical value 6.23%)	Be lower than 0.02%
DSC	Dehydration incident: occur in approximately～114 ℃ (variations) and fuse :～250 ℃	Fuse :～250 ℃	TGA	6.1% water (theoretical value 6.23%)	Be lower than 0.02%
DSC		Fuse :～250 ℃	XRPD	9.2，12.2°2θ	8.2，10.3°2θ
DVS	0.1% increases (0-90%RH)	02% increases (0-90%RH)	XRPD	9.2，12.2°2θ	8.2，10.3°2θ
DVS	0.1% increases (0-90%RH)	02% increases (0-90%RH)	Water solubility (μ g/ml)	2.34(pH?7.11)221(pH?7.51)	10.0(pH?7.29)12.75(pH?7.70)

In some embodiments, in 2 θ, the X-ray powder diffraction figure that this no hydrate has is included at about 8.2 °, about 10.3 ° and about 14.6 ° peak.In some embodiments, in 2 θ, the X-ray powder diffraction figure that this crystal type has is included in about 8.2 °, about 10.3 °, about 14.6 °, about 15.1 ° and about 16.3 ° peak.In some embodiments, in 2 θ, the X-ray powder diffraction figure that this crystal type has is included in about 8.2 °, about 10.3 °, about 14.6 °, about 15.1 °, about 16.3 °, about 22.3 °, about 24.8 ° and about 26.7 ° peak.In further embodiment, the X-ray powder diffraction figure that this crystal type has is basically as Fig. 1 institute (bottom).

Active agents in the preparation of the present invention contains 2-(3-fluoro-4-the hydroxyphenyl)-7-vinyl-1 of no hydrate or monohydrate crystal type, 3-benzoxazole-5-alcohol.In some embodiments, this pharmaceutical preparation contains at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, at least about the monohydrate of 99.9% weight or do not have 2-(3-fluoro-4-the hydroxyphenyl)-7-vinyl-1 of hydrate crystal type, 3-benzoxazole-5-alcohol.In some embodiments, pharmaceutical preparation of the present invention contains the mixture of monohydrate and no hydrate crystal type.In some embodiments, this pharmaceutical preparation further contains additional active component such as lutein.

Usually, the content of this active agents in preparation of the present invention is effective dose pharmaceutically.Phrase " effective dose pharmaceutically " refers to that research worker, veterinary, doctor or other clinician can be in tissue, system, animal, individuality, patient or human amounts of bringing out the active agents of biology or medical response.Desirable biology or medical response comprise the disease (for example, prevent patient's disease, this patient is inclined to pathology or the symptom that disease takes place but produce or show disease yet) of preventing patient.Desirable biology or medical response also comprise that the patient's of the pathology of disease or symptom (that is, stop or delay further developing of pathology and/or symptom) disease has taken place or shown in inhibition.Desirable biology or medical response also comprise that the patient's of disease pathology or symptom (that is, reversing its pathology or symptom) disease has taken place or shown in alleviation.

The effective dose pharmaceutically that is used to prevent or treats specified disease can change according to the specified disease of being treated, patient's body weight, age and reaction pattern, the order of severity of disease, attending doctor's judgement etc.Usually, every day, Orally administered effective dose was about 0.01 to 1, and 000mg/kg is preferably about 0.5 to 500mg/kg, and the effective dose that is used for parenteral administration is about 0.1 to 100mg/kg, is preferably about 0.5 to 50mg/ kilogram.

Usually, can be by any suitable approach such as Orally administered this pharmaceutical preparation and compositions thereof.The oral formulations that contains solid dispersion of the present invention comprises any conventional oral form of using, and comprises tablet, capsule, contains agent, contains ingot, lozenge and oral liquid, suspension etc.Contained pharmaceutical preparation of the present invention also can be in conjunction with the mixture of other reactive compound or inert filler and/or diluent in capsule or the tablet.Be used for delay or time-delay delivery formulations or capsule that the oral formulations of this paper can be conventional.

The film coating of preparation of the present invention is known in this area, and it is made of polymer (being generally the polymer of cellulose type), coloring agent and plasticizer usually.Can contain other composition for example wetting agent, sugar, spice, oil and lubricant and can influence some characteristic of thin clothing in the film-coated preparation.The compositions of this paper and preparation also can be combined and be processed to solid, insert then in the capsule as gel capsule.

The mixture that the pharmaceutical preparation of this paper also can contain antioxidant or antioxidant is ascorbic acid for example.Spendable other antioxidant comprises sodium ascorbate and ascorbyl palmitate, chooses wantonly to be used in combination with ascorbic acid.The example of oxidation preventive content is about 0.05% to about 15% weight, about 0.5% to about 15% weight, or about 0.5% to about 5% weight.In some embodiments, this pharmaceutical preparation is substantially devoid of antioxidant.

Preparation of the present invention can be used in combination other various excipient as known in the art, dosage form, dispersant etc., it is recited in Remington ' s Pharmaceutical Sciences, the 17th edition, Mack Publishing Company, Easton, Pa., in 1985, it all is incorporated herein by reference.

For ease of more effectively understanding invention disclosed herein, provide following embodiment.Should understand these embodiment and only be used for illustrative purposes, rather than should be interpreted as limiting by any way the present invention.

Embodiment

Term " the C of Shi Yonging in this article _Max" show the maximum concentration that this active agents can reach behind the medicine in patient's blood plasma.Term " the t of Shi Yonging in this article _Max" show medicine after this active agents in patient's blood plasma, reach the required time of maximum concentration.Term " the t of Shi Yonging in this article _1/2" refer to plasma half-life, or the concentration of active agents is reduced to half C in patient's blood plasma _MaxThe required time.

The term of Shi Yonging " AUC " refers to the area under curve of the time function of plasma drug level in this article.Term " the AUC of Shi Yonging in this article _t" refer to the area under curve of plasma drug level to time point " t ".Term " the AUC of Shi Yonging in this article _{0 → ∞}" refer to the area under curve of whole curves after the unlimited time.

Embodiment 1

Preparation 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the no hydrate crystal type of 3-benzoxazole-5-alcohol

With 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the solid of 3-benzoxazole-5-alcohol (170g, 0.627 mole) is dissolved in the ethyl acetate (3946g, 23 volumes) under 75-80 ℃.At the 75-80 ℃ of solution of handling gained down with charcoal (17g).Under atmospheric pressure filtrate is concentrated into 7 volumes then, maintains under 75-80 ℃ heptane (793g, 6 volumes) is added in the slurry, be cooled to 45-50 ℃ and kept 0.5 hour then, then be cooled to 0-5 ℃ and kept 1 hour.The filtering solid, dry and obtain 87% the response rate, product purity 99.4% under 55-65 ℃ and 5-10mg Hg.

Embodiment 2

Preparation 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the monohydrate crystal type of 3-benzoxazole-5-alcohol

With 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1 of 274g, the pre-filtered ethanol of the pure and mild 1375ml of 3-benzoxazole-5-is put into 3 liters of multinecked flasks that are equipped with splash bar, condenser and temperature probe.Mixture heated was formed solution to 75-80 ℃ after 10 minutes.In 0.5 hour process of 75-80 ℃, water (688ml) is added in the solution.In 0.5 hour process, solution is cooled to 50 ℃, is keeping 0.5 hour (under about 74 ℃, beginning to occur crystallization) under 50 ℃ then.In 0.5 hour process, the suspension that forms is cooled to 0-5 ℃ then, under 0-5 ℃, kept 1 hour.By filter collecting this solid, then to be precooled to 0-5 ℃ the ethanol of washing 2 x 300ml: the clear filter cake of water (2:1 volume/volume).Following will be somebody's turn to do of 32-38 ℃ and 20-25mg Hg and the final monohydrate product of generation 281.8g (96.11% output) through the filtration cakes torrefaction 20 hours of cleaning.Water content (KF)-6.5%; TGA-6.35% water; DSC and XRPD and monohydrate have concordance.

Embodiment 3

To not have hydrate and be transformed into the monohydrate crystal type

The pH method

With anhydrous 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-5-alcohol (71mg) adds in the water of 2ml, then solution begin to become clarifying time point with the 1N sodium hydroxide with pH regulator to pH 10.After 2 hours, this solution becomes the faint yellow of muddiness.Centrifugal this solution is removed supernatant, with vacuum drying again after this precipitate air drying.The XRPD of this product and TGA and monohydrate have concordance.

The solvent/anti-solvent method

With anhydrous 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-5-alcohol (about 100mg) is dissolved in the ethanol of 3ml, slowly adds the water of 4ml afterwards till solution is muddiness.Centrifugal this solution is removed supernatant, with vacuum drying again after this precipitate air drying.The XRPD of this product and TGA and monohydrate have concordance.

The waterborne suspension method

With anhydrous 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-5-alcohol (84mg) is suspended in the water of 4.2ml, at room temperature stirs 40 hours.Centrifugal this solution is removed supernatant, then with vacuum drying again after this precipitate air drying.The mixture of its XRPD and TGA and no hydrate and monohydrate (under the TGA be 2.4% water content) has concordance.

Embodiment 4

The stability study of these two kinds of crystal types

Short-term

XRPD studies show that this monohydrate can keep down 1 hour stable at 70 ℃, but after 90 ℃ 1.5 hours partial dehydration, and 90 ℃ 1 hour after, dewater fully.

Mid-term

With the sample of monohydrate in room temperature, 56 ℃ and 70 ℃ of one weeks of storage.In the time of at room temperature, humidity maintains 0% RH.Be not controlled at the humidity under the higher temperature.

Analyze this sample by XRPD and TGA.Be stored at sample under room temperature and 56 ℃ be presented at one week the back do not have significantly dehydration.The sample that is stored under 70 ℃ did not have significantly dehydration after 1 day, but this sample is partial dehydration after 4 days.After 7 days, the sample major part that is stored under 70 ℃ is dewatered.

For a long time

The not micronize sample of monohydrate and no hydrate was stored three months under 40 ℃/75% RH.This monohydrate also is stored under 40 ℃, does not have controlled humidity.During trimestral, after 2 weeks, 1 month, 2 months and 3 months, check this sample.XRPD and TGA show that monohydrate and no hydrate were not all transformed after three months, HPLC shows that these samples all have chemical stability under test condition.

In an independent research, XRPD shows that the micronize sample of no hydrate is stored and can not change into monohydrate after three months under 25 ℃/60% RH; Yet, under 40 ℃/75%RH after the storage one month the micronize sample part change into monohydrate.Under the contrast, the not micronize sample that is stored at the no hydrate under the same terms (40 ℃/75% RH) does not show any tangible conversion.

Embodiment 5

Obtain the X-ray powder diffraction data of these two kinds of crystal types

Utilize x-ray powder diffractometer (Scintag company, Cupertino, CA) (for example obtain the X ray data, referring to Fig. 1 and table 1), it has following parameter: voltage 45kv, electric current 40.0mA, 1.80 kilowatts of power, 3 to 40 ° of sweep limitss (2 θ), 0.02 ° of scanning stride, total scanning time 22.6 minutes.

Embodiment 6

Obtain the differential scanning calorimetry data of these two kinds of crystal types

(Perkin Elmer, Norwalk CT) collect differential scanning calorimetry data (referring to Fig. 2 and 3), and it has following parameter: aerofluxus (N to utilize DSC ₂) 20ml/min, 25 to 300 ℃ of sweep limitss, 10 ℃/min of sweep speed.

Embodiment 7

Obtain the thermogravimetric analysis data of these two kinds of crystal types

(Perkin Elmer, Norwalk CT) collect thermogravimetric analysis data (referring to Figure 4 and 5), and it has following parameter: aerofluxus (N to utilize the TGA instrument ₂) 20ml/min, 25 to 300 ℃ of sweep limitss, 10 ℃/min of sweep speed.

Embodiment 8

Obtain the data of the dynamic steam absorption of these two kinds of crystal types

Utilize dynamic steam absorption instrument (Allentown, PA) water absorption (referring to Fig. 6 and 7 figure) of mensuration no hydrate of the present invention and monohydrate.This step condition is each under 0%, 30%, 52.5%, 75% and 90% RH three hours, twice complete alternation.

Embodiment 9

Contain 75mg 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the granule and the tablet of 3-benzoxazole-5-alcohol by the preparation of wet grain method

The w/w percentage ratio (% wt/wt) that utilization is shown in the composition of table 3 is the 1-7 useful in preparing drug formulations through the following steps.8-10 prepares tablet through the following steps.Each tablet contains the unit dose that is shown in table 3.

1. the aqueous solution that in pure water, prepares polyethylene Pyrrolizidine ketone (30 POVIDONE K 30 BP/USP 25) and sodium lauryl sulfate.

2. with 2-(3-fluoro-4-the hydroxyphenyl)-7-vinyl-1 of anhydrous crystal type, 3-benzoxazole-5-alcohol mixes with the mannitol (Pearlitol 200SD) of a part, by suitable screen cloth, inserts then in the high speed mixing drum.

With remaining mannitol, microcrystalline Cellulose (Avicel pH 113) and cross-linking sodium carboxymethyl cellulose by suitable screen cloth, insert in the mixing drum then and mix;

4. utilize the mixture of the solution granulation step 3 of step 1.

5. the granule of drying steps 4 is by suitable screen cloth.

6. magnesium stearate is passed through suitable screen cloth.

7. with the mixture premixing of the step 5 of magnesium stearate and equivalent, then this premix is added all the other materials of step 5 and in mixer, mix.

8. utilize tablet machine that the final mixture of step 7 is pressed into tablet.

9. 7.5% solid solution for preparing Opaglos 2.

10. the coating solution coat of capacity being made the weight of its increase in this tablet is 3.0% w/w of dry tablet weight.

Table 3

Composition % wt/wt unit dose (mg/ ingot)
Composition % wt/wt unit dose (mg/ ingot)	Anhydrous crystal type 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1.3-benzoxazole-5-alcohol 25.0 75.0 mannitols (Pearlitol 200SD) ^a51.5 154.5 microcrystalline celluloses (Avicel pH 113), 15.0 45.0 Ac-Di-Sols, 4.0 12.0 PVPs (30 POVIDONE K 30 BP/USP 25), 2.0 6.0 NaLSs, 2.0 6.0 dolomols, 0.5 1.5 pure water^b--total amount 100.0% 300.0
Film coating Opaglos 2, green 97,W11,753 3.0 9.0

A adjusts the addition of mannitol if total amount does not reach 100.0%.

B uses during the course, but is not present in final tablet product.

Embodiment 10

Prepare 2-(3-fluoro-4-the hydroxyphenyl)-7-vinyl-1 that contains 25% weight, the preparation and the tablet of 3-benzoxazole-5-alcohol by wet grain method

Step 1-7 by embodiment 9 utilizes composition w/w percentage ratio (%wt/wt) useful in preparing drug formulations that is shown in table 4.Step 8-10 by embodiment 9 prepares this tablet.

Table 4

Composition % wt/wt
Composition % wt/wt	Anhydrous crystal type 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzene 25.0 Kai oxazole-5-alcohol mannitol (Pearlitol 200SD) ^a48.5 microcrystalline Cellulose (Avicel pH 113) 15.0 polyethylene Pyrrolizidine ketone (30 POVIDONE K 30 BP/USP 25) 2.0 cross-linking sodium carboxymethyl celluloses 4.0 sodium lauryl sulfates 5.0 magnesium stearate 0.5 pure water ^b-total amount 100.0%

A adjusts the addition of mannitol if total amount does not reach 100.0%.

B uses during the course, but is not present in final tablet product.

Embodiment 11

Step 1-7 by embodiment 9 utilizes composition w/w percentage ratio (%wt/wt) useful in preparing drug formulations that is shown in table 5.Step 8-10 by embodiment 9 prepares this tablet.

Table 5

Composition % wt/wt
Composition % wt/wt	Anhydrous crystal type 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-5-alcohol 25.0 mannitols (Pearlitol 200SD) ^a51.5 microcrystalline Cellulose (Avicel pH 113) 15.0 polyethylene Pyrrolizidine ketone (30 POVIDONE K 30 BP/USP 25) 2.0 cross-linking sodium carboxymethyl celluloses 4.0 sodium lauryl sulfates 2.0 magnesium stearate 0.5 pure water ^b-total amount 100.0%

A adjusts the addition of mannitol if total amount does not reach 100.0%.

B uses during the course, but is not present in final tablet product.

Embodiment 12

Step 1-7 by embodiment 9 utilizes composition w/w percentage ratio (%wt/wt) useful in preparing drug formulations that is shown in table 6.Step 8-10 by embodiment 9 prepares this tablet.

Table 6

Composition % wt/wt
Composition % wt/wt	Anhydrous crystal type 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-5-alcohol 25.0 mannitols (Pearlitol 200SD) ^a53.5 microcrystalline Cellulose (Avicel pH 113) 15.0 polyethylene Pyrrolizidine ketone (30 POVIDONE K 30 BP/USP 25) 2.0 cross-linking sodium carboxymethyl celluloses 4.0 sodium lauryl sulfates 0.0 magnesium stearate 0.5 pure water ^b-total amount 100.0%

A adjusts the addition of mannitol if total amount does not reach 100.0%.

B uses during the course, but is not present in final tablet product.

Embodiment 13

Prepare 2-(3-fluoro-4-the hydroxyphenyl)-7-vinyl-1 that contains 25mg, the preparation and the tablet of 3-benzoxazole-5-alcohol by wet grain method

Step 1-7 by embodiment 9 utilizes composition w/w percentage ratio (%wt/wt) useful in preparing drug formulations that is shown in table 7.Step 8-10 by embodiment 9 prepares this tablet.Each tablet contains the unit dose that is shown in table 7.

Table 7

Composition % wt/wt unit dose (mg/ ingot)
Composition % wt/wt unit dose (mg/ ingot)	Anhydrous crystal type 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-5-alcohol 25.0 25.0 mannitols (Pearlitol 200SD) ^a51.5 51.5 microcrystalline Cellulose, (Avicel pH 113) 15.0 15.0 cross-linking sodium carboxymethyl celluloses 4.0 4.0 polyethylene Pyrrolizidine ketone, (30 POVIDONE K 30 BP/USP 25) 2.0 2.0 sodium lauryl sulfates 2.0 2.0 magnesium stearate 0.5 0.5 pure water ^b--total amount 100.0% 100.0
Film coating Opaglos 2, green 97,W11,753 3.0 3.0

A adjusts the addition of mannitol if total amount does not reach 100.0%.

B uses during the course, but is not present in final tablet product.

Embodiment 14

Prepare 2-(3-fluoro-4-the hydroxyphenyl)-7-vinyl-1 that contains 5mg, the preparation and the tablet of 3-benzoxazole-5-alcohol by wet grain method

Step 1-7 by embodiment 9 utilizes composition w/w percentage ratio (%wt/wt) useful in preparing drug formulations that is shown in table 8.Step 8-10 by embodiment 9 prepares this tablet.Each tablet contains the unit dose that is shown in table 8.

Table 8

Composition % wt/wt unit dose (mg/ ingot)
Composition % wt/wt unit dose (mg/ ingot)	Anhydrous crystal type 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-5-alcohol 5.0 5.0 mannitols (Pearlitol 200SD) ^a71.5 71.5 microcrystalline celluloses (Avicel pH 113), 15.0 15.0 Ac-Di-Sols, 4.0 4.0 PVPs (30 POVIDONE K 30 BP/USP 25), 2.0 2.0 NaLSs, 2.0 2.0 dolomols, 0.5 0.5 pure water^b--total amount 100.0% 300.0
Film coating Opaglos 2, green 97,W11,753 3.0 3.0

A adjusts the addition of mannitol if total amount does not reach 100.0%.

B uses during the course, but is not present in final tablet product.

Embodiment 15

Prepare 2-(3-fluoro-4-the hydroxyphenyl)-7-vinyl-1 that contains 150mg, the preparation and the tablet of 3-benzoxazole-5-alcohol by wet grain method

Step 1-7 by embodiment 9 utilizes composition w/w percentage ratio (%wt/wt) useful in preparing drug formulations that is shown in table 9.Step 8-10 by embodiment 9 prepares this tablet.Each tablet contains the unit dose that is shown in table 9.

Table 9

Composition % wt/wt unit dose (mg/ ingot)
Composition % wt/wt unit dose (mg/ ingot)	Anhydrous crystal type 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-5-alcohol 25.0 150.0 mannitols (Pearlitol 200SD) ^a51.5 309.0 microcrystalline Cellulose, (Avicel pH 113) 15.0 90.0 cross-linking sodium carboxymethyl celluloses 4.0 24.0 polyethylene Pyrrolizidine ketone, (30 POVIDONE K 30 BP/USP 25) 2.0 12.0 sodium lauryl sulfates 2.0 12.0 magnesium stearate 0.5 3.0 pure water ^b--total amount 100.0% 600.0
Film coating Opaglos 2, green 97,W11,753 3.0 18.0

A adjusts the addition of mannitol if total amount does not reach 100.0%.

B uses during the course, but is not present in final tablet product.

Embodiment 16

Contain 75mg 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the tablet of 3-benzoxazole-5-alcohol

The pharmaceutical preparation and the tablet that prepare this embodiment by the method for embodiment 9.With OpadryAMB, the yellow Opaglos 2 that replaces is green.

Embodiment 17

Contain 5mg 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the tablet of 3-benzoxazole-5-alcohol

Utilize the w/w percentage ratio (%wt/wt) of the composition of embodiment 13 to prepare pharmaceutical preparation and the tablet of this embodiment by the method for embodiment 9, with Opadry AMB, the yellow Opaglos 2 that replaces is green.

Embodiment 18

Contain 25mg 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the tablet of 3-benzoxazole-5-alcohol

Utilize the composition w/w percentage ratio (%wt/wt) of embodiment 14 to prepare pharmaceutical preparation and the tablet of this embodiment by the method for embodiment 9, with Opadry AMB, Huang replaces Opaglos 2, and is green.

Embodiment 19

Contain 150mg 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the tablet of 3-benzoxazole-5-alcohol

Utilize the composition w/w percentage ratio (%wt/wt) of embodiment 15 to prepare pharmaceutical preparation and the tablet of this embodiment by the method for embodiment 9, with Opadry AMB, Huang replaces Opaglos 2, and is green.

Embodiment 20

Contain 25mg 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the tablet of 3-benzoxazole-5-alcohol by the direct mixing method preparation

Be shown in the pharmaceutical preparation that the composition w/w percentage ratio (% wt/wt) of table 10 prepares this embodiment by the follow procedure utilization.

1. with Lactis Anhydrous, microcrystalline Cellulose (Avicel pH 112), cross-linking sodium carboxymethyl cellulose, sodium lauryl sulfate, silicon dioxide (Syloid 244) and anhydrous crystal type 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-5-alcohol is inserted in the PK blender, mixes 5 to 10 minutes;

2. magnesium stearate is added in the mixture of step 1 remix 2 minutes;

3. utilize tablet machine that the mixture of step 2 is pressed into tablet.

Table 10

Composition % wt/wt
Composition % wt/wt	Anhydrous crystal type 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-5-alcohol 25.0 Lactis Anhydrouses, 49.5 microcrystalline celluloses (Avicel pH 113) 15.0 Ac-Di-Sols, 4.0 NaLSs, 5.0 silica (Syloid 244) 1.0 dolomols 0.5 total amount 100.0%

Embodiment 21

Prepare 2-(3-fluoro-4-the hydroxyphenyl)-7-vinyl-1 that contains 25% weight, the tablet of 3-benzoxazole-5-alcohol by direct mixing method

Be shown in the pharmaceutical preparation that the composition w/w percentage ratio (%wt/wt) of table 11 prepares this embodiment by the follow procedure utilization.

1. with Lactis Anhydrous, microcrystalline Cellulose (Avicel pH 112), cross-linking sodium carboxymethyl cellulose, sodium lauryl sulfate, silicon dioxide (Syloid 244), sodium carbonate and anhydrous crystal type 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-5-alcohol is inserted in the PK blender, mixes 5 to 10 minutes;

2. magnesium stearate is added in the mixture of step 1 remix 2 minutes;

3. utilize tablet machine that the mixture of step 2 is pressed into tablet.

Table 11

Composition % wt/wt
Composition % wt/wt	Anhydrous crystal type 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole 25.0-5-alcohol Lactis Anhydrous 47.5 microcrystalline celluloses (Avicel pH 113) 14.4 Ac-Di-Sol 3.84 NaLSs, 4.8 sodium carbonate, 4.0 silica (Syloid 244) 0.96 dolomol 0.5 total amount 100.0%

Embodiment 22-39

Prepare 2-(3-fluoro-4-the hydroxyphenyl)-7-vinyl-1 that contains 25% weight, the granule and the tablet of 3-benzoxazole-5-alcohol by wet grain method

Make granule and the tablet of embodiment 22-39 with the batch of 300.0g by sodium lauryl sulfate (SLS), polyethylene Pyrrolizidine ketone (PVP), cross-linking sodium carboxymethyl cellulose (Cros.Na) and the microcrystalline Cellulose (Avicel pH 113) that utilizes w/w percentage ratio as shown in table 12 by follow procedure.The 2-of each embodiment among the embodiment 22-39 (3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the percentage ratio of 3-benzoxazole-5-alcohol is 25.0% w/w.The percentage ratio of the magnesium stearate in granule and the tablet is 0.5%.Each embodiment has the mannitol of different weight percentage, and it is the percentage ratio from 100% deduction SLS, PVP, cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose and magnesium stearate.Multiply by the gravimetric value that the 300.0g total lot amount calculates each composition by w/w percentage ratio.

1. take by weighing respectively and be used for 300g mannitol (Pearlitol 200 SD), microcrystalline Cellulose (Avicel pH 113), sodium lauryl sulfate, cross-linking sodium carboxymethyl cellulose, polyethylene Pyrrolizidine ketone (30 POVIDONE K 30 BP/USP 25), magnesium stearate and 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1 in batches, 3-benzoxazole-5-alcohol.

2. by being dissolved in, sodium lauryl sulfate then adds 10% solution that polyethylene Pyrrolizidine ketone prepares sodium lauryl sulfate and polyethylene Pyrrolizidine ketone (30 POVIDONE K 30 BP/USP 25) in the pure water.

3. the mannitol (Pearlitol 200 SD) of 73g is directly imported in the Diosna granulator by the #16 screen cloth.

In bag with 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-5-alcohol mixes with the 36g mannitol.

5. the mixture of step 4 is directly imported in the granulator by the #16 screen cloth.

6. remaining mannitol is directly imported in the Gral granulator by the #16 screen cloth.

7. microcrystalline Cellulose (Avicel pH 113) is directly imported in the granulator by the #16 screen cloth.

8. making cross-linking sodium carboxymethyl cellulose pass through the #16 screen cloth directly imports in the granulator.

9. use plow set with all material dry mixed 2 minutes with low speed.

10. utilize pump with plow set with the slow-speed of revolution in 3 minutes with this mixture of solution granulating of step 2 and close chipper.

11. utilize the percentage ratio of the required water of following formula count particlesization:

12. finish after the granulating, utilize plow with the slow-speed of revolution with granule 30 seconds of other remix and open chipper.

13. be shown under the inlet temperature of following table this granule of fluid bed drying until till 100 ℃ of its LOD during with Computrac wet analysis instrument analytic sample are lower than 1-2%.

14. the dried particles that utilizes Comil grinding steps 13 to be obtained.

15. the granule of step 14 is changed in the PK-mixer, quickens to stir 5 minutes under the rod not starting.

16. the output according to step 15 is calculated the quantity (3kg needs the magnesium stearate of 1.5g in batches in theory) of mixing required magnesium stearate eventually.

17. make magnesium stearate pass through the #20 screen cloth, with the granulate mixture premixing of the step 14 of about equivalent.

18. premix is changed in the PK-mixer of step 15, quickens to mix 2 minutes under the rod not starting;

19. the mixture of step 18 is inserted in the refrigerator that contains desiccant with till preventing that light and dampness are when carrying out tabletting;

20. take by weighing the quantity that is used for the required final mixture of step 20 tabletting;

21. be equipped with 0.225 for making required tablet, utilizing " x 0.6 " rotary tablet machine of improvement capsule sheet instrument, adjust the mixture of its pressure according to following explanation on demand with pressing step 20.

Tablet properties

Tablet weight: target 300mg ± 3.75% (288.75-311.25mg)

Average (n=10) ± 1.875% (2943.75-3056.25mg)

Tablet hardness: target 10Kp (scope 7-13Kp)

Table 12 ^A-c

Embodiment	％SLS	％PVP	％Cros.Na	％Avicel?pH?113	Baking temperature (℃)
Embodiment	％SLS	％PVP	％Cros.Na	％Avicel?pH?113	Baking temperature (℃)	22	1	1	2	25	60
23	3	1	2	5	60	22	1	1	2	25	60
23	3	1	2	5	60	24	3	3	2	5	60
25	2	2	4	15	70	24	3	3	2	5	60
25	2	2	4	15	70	26	1	3	2	25	80
27	3	1	2	25	80	26	1	3	2	25	80
27	3	1	2	25	80	28	1	3	6	25	60
29	1	3	6	5	80	28	1	3	6	25	60
29	1	3	6	5	80	30	3	3	6	25	80
31	1	1	6	5	60	30	3	3	6	25	80
31	1	1	6	5	60	32	3	1	6	25	60
33	2	2	4	15	70	32	3	1	6	25	60
33	2	2	4	15	70	34	3	3	6	5	60
35	3	3	2	25	60	34	3	3	6	5	60
35	3	3	2	25	60	36	3	1	6	5	80
37	1	3	2	5	60	36	3	1	6	5	80
37	1	3	2	5	60	38	1	1	2	5	80
39	1	1	6	25	80	38	1	1	2	5	80

A is for each sample: adjust anhydrous crystal 2-(3-fluoro-4-the hydroxyphenyl)-7-vinyl-1 of 25.0% w/w that is contained in each sample, 3-benzoxazole-5-alcohol; The magnesium stearate of 0.5% w/w; And mannitol (Pearlitol 200SD) to make its total amount be 100% w/w

Embodiment 40

Measure it at the intravital pharmacokinetic parameter of dog after the

embodiment

10,20 of single administration 150mg and 21

9 female dogs of 12 years old (7.0-11.8 kilogram) are divided into three groups with 3 every group.With 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1 of the 150mg of single dose, 3-benzoxazole-5-alcohol uses for each dog.It is one of following three kinds to provide 2 x 75mg, used pharmaceutical preparation to be selected from in 9 dogs every: (1) embodiment 10 tablets; (2) embodiment 20 tablets; Or (3) embodiment 21 tablets.Dog is overnight by fasting before administration.Gathered blood sample on the 0.5th, 1,2,3,4,6,8,12 and 24 hour after 0 (before administration) and administration, separated plasma also detects 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the content of 3-benzoxazole-5-alcohol.With 2-(3-fluoro-4-the hydroxyphenyl)-7-vinyl-1 that records, the time function of the mean plasma concentration of 3-benzoxazole-5-alcohol after draw (referring to Fig. 8) with administration.

Carry out each dog plasma 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the non-locellus pharmacokinetic analysis of the concentration-time curve of 3-benzoxazole-5-alcohol (WinNonlin, Model 200).Measure the pharmacokinetic parameter of each dog: AUC then from the dog plasma Cot curve _{0 → ∞}, C _Max, t _MaxAnd t _1/2(referring to table 13).

Table 13

	Embodiment 10 (n=3)	Embodiment 20 (n=3)	Embodiment 21 (n=3)
	Embodiment 10 (n=3)	Embodiment 20 (n=3)	Embodiment 21 (n=3)	AUC ₀(ng. hour/ml)	2409(814)	1401(567)	2272(1585)
C _max(ng/ml)	406(289)	318(198)	321(62.7)	AUC ₀(ng. hour/ml)	2409(814)	1401(567)	2272(1585)
C _max(ng/ml)	406(289)	318(198)	321(62.7)	t _max(hour)	2.00(0.00)	2.50(3.04)	2.33(3.18)
t _1/2(hour)	4.70(0.67)	3.75(2.01)	4.53(3.99)	t _max(hour)	2.00(0.00)	2.50(3.04)	2.33(3.18)

Bracket inner digital is a standard deviation

Embodiment 41

In human bioavailability research, measure the pharmacokinetic parameter of embodiment 9 (75mg 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-5-alcohol)

Use three kinds of preparations to 30 women under the fasting state in the crossing research at random in three stages, then accept one of three kinds of preparations and high fat breakfast (1/3 accepts embodiment 9 tablets) at random quadravalence section patient.Carry out individual blood plasma 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1, the non-locellus pharmacokinetic analysis of the concentration-time curve of 3-benzoxazole-5-alcohol, and measure each women's pharmacokinetic parameter: AUC _{0 → ∞}, C _Max, t _MaxAnd t _1/2(please see table 15).Its result takes passages in table 14.

Table 14

	Fasting state	Fasting state	The feed state
	Fasting state	Fasting state	The feed state	C _max(ng/ml)	46.1(20.7)	50.2(24.5)	35.3(51.7)
t _max(hour)	1.4(1.8)	1.1(1.2)	3.8(3.7)	C _max(ng/ml)	46.1(20.7)	50.2(24.5)	35.3(51.7)
t _max(hour)	1.4(1.8)	1.1(1.2)	3.8(3.7)	t _1/2(hour)	25.1(15.6)	23.3(9.1)	26.4(11.4)
AUC _t(ng hour/ml)	211(74)	233(99)	169(84)	t _1/2(hour)	25.1(15.6)	23.3(9.1)	26.4(11.4)
AUC _t(ng hour/ml)	211(74)	233(99)	169(84)	AUC _0→∞(ng hour/ml)	227(85)	245(99)	181(93)

Bracket inner digital is a standard deviation

Embodiment 42

Embodiment

10,20 and 21 stripping curve

Under 50rpm, utilize the dissolution medium of the 0.1N hydrochloric acid that contains 0.25% Tween 80 to produce external stripping curve according to American Pharmacopeia method II (slurry formula).Test sample was at 15,30,45,60,90,120 and 150 minutes drug level.Its result takes passages in Fig. 9.

Embodiment 43

Embodiment 10,11 and 12 stripping curve

Under 50rpm, utilize the dissolution medium of the 0.1N hydrochloric acid that contains 0.25% Tween 80 to produce external stripping curve according to American Pharmacopeia method II (slurry formula).Test sample was at 15,30,45,60,90,120 and 150 minutes drug level.Its result takes passages in Figure 10.

Embodiment 44

Embodiment 10,11 and 12 compaction curve figure

Produce its compaction curve figure by the hardness number under the various pressure of tabletting period detecting.Need to utilize automatic interface (Korsch PMA) to obtain the compacting data in the whole tabletting process with tablet machine (Korsch XL 100).Utilize the hardness of Schleuniger 8E hardness tester mensuration with the tablet of various compression stress manufacturings.Its result takes passages in Figure 11.

Embodiment 45

Embodiment 9 stores the stripping curve of 1-3 during individual month down at 25 ℃ and 40 ℃

The tablet of embodiment 9 storage 1 month and 3 months under 25 ℃ and 60% relative humidity was stored 1 month, 2 months and 3 months under 40 ℃ and 75% relative humidity.Be determined at the stripping curve of this tablet behind the storage then.Under 50rpm, utilize the dissolution medium of the 0.1N hydrochloric acid that contains 0.25%Tween 80 to produce external stripping curve according to American Pharmacopeia method II (slurry formula).Test sample was at 15,30,45,60,90,120 and 150 minutes drug level.Its result takes passages in Figure 12.

Embodiment 46

Measure the particulate geometric mean diameter of embodiment 22-39

Before tabletting, utilize USP program 786 to measure the particle diameter of each granulating pharmaceutical preparation of embodiment 22-39.Twice particle diameter test is carried out in every batch of pharmaceutical preparation.It the results are shown in table 15.

Table 15

Embodiment	Particle diameter (mm)	Can suppress index (%)	Q15 (% release)	Brittleness (%)
Embodiment	Particle diameter (mm)	Can suppress index (%)	Q15 (% release)	Brittleness (%)	22	145.8	27.27	64.6	0.03
23	245.3	34.18	45.4	0.15	22	145.8	27.27	64.6	0.03
23	245.3	34.18	45.4	0.15	24	251.3	40.51	37.1	-
25	160.5	28.17	62.3	0.11	24	251.3	40.51	37.1	-
25	160.5	28.17	62.3	0.11	26	145.8	30.56	47	0.02
27	145.4	30	31.5	0.1	26	145.8	30.56	47	0.02
27	145.4	30	31.5	0.1	28	133.3	31.88	55.2	0.1
29	167.6	28.77	54.9	0.07	28	133.3	31.88	55.2	0.1
29	167.6	28.77	54.9	0.07	30	138.2	29.58	61	0.02
31	167.8	26.09	71.2	0.09	30	138.2	29.58	61	0.02
31	167.8	26.09	71.2	0.09	32	137.7	27.94	65.8	0.05
33	163.3	30.56	-	-	32	137.7	27.94	65.8	0.05
33	163.3	30.56	-	-	34	163.9	30	64.1	0.07
35	148.4	30.14	23.1	0.02	34	163.9	30	64.1	0.07
35	148.4	30.14	23.1	0.02	36	163.4	32	47	0.14
37	171.8	38.75	13.5	0.13	36	163.4	32	47	0.14
37	171.8	38.75	13.5	0.13	38	173.2	28.77	45.5	0.15
39	139	29.85	63.7	0.1	38	173.2	28.77	45.5	0.15

Embodiment 47

But measure the particulate briquettability index of embodiment 22-39

But calculate its briquettability index from the bulk density and the tap density of toppling over.By the known weight powder is poured on the graduated cylinder, measures the volume that mixture of powders occupies then and calculate its bulk density.Tap density is for beaing number of times compacted powder mixture afterwards according to the measured density of similar densimeter algorithm with default.Its result takes passages in table 15.

Embodiment 48

Measure the dissolution rate (Q15) of the tablet of embodiment 22-39

Under 50rpm, utilize the dissolution medium of the 0.1N hydrochloric acid that contains 0.25% Tween 80 to produce the stripping curve of the tablet of embodiment 22-39 according to American Pharmacopeia slurry formula method.Utilize HPLC stability indication assay at the 15th minute sample.The meltage of medicine when Q15 is illustrated in 15 minutes.Its result takes passages in table 15.

Embodiment 49

Measure the brittleness of the tablet of embodiment 22-39

Utilize American Pharmacopeia program 1216 to measure the brittleness of the tablet of embodiment 22-39 in the mode of every sample determination three times.

The application requires the U.S. Provisional Application serial number the 60/780th of submission on March 6th, 2006, the United States Patent (USP) provisional application row sequence number the 60/797th that No. 045 and on May 4th, 2006 propose, 503 priority all is incorporated herein by reference its disclosed separately content.

Except that method as herein described, those skilled in the art can be from the clear understanding of above-mentioned explanation other various modification methods of the present invention.This type of modification method also still falls within the scope of additional claims.The various lists of references that the application quoted comprise that patent, public publication and journal article all are incorporated herein by reference.

Claims

1. pharmaceutical preparation, it comprises:

(a) active agents with formula I of effective dose pharmaceutically:

Wherein:

R ₅, R ₆Be respectively independently hydrogen, C _1-6Alkyl or C _6-10Aryl;

X is O, S or NR ₇And

Or its pharmaceutically acceptable salt: and

(b) carrier or excipient systems, it comprises:

(vi) Ren Xuan lubricant composition when existing, accounts for about 0.01% to about 5% of pharmaceutical preparation weight; Condition is that the total amount of this composition is no more than about 8% of pharmaceutical formulation weight when this pharmaceutical formulation comprises one or more compositions of the glyceride, Poloxamer 188, polyoxyethylene sorbitol fatty acid ester, castor oil derivatives, sucrose fatty acid ester, polyglycolyzed glyceride, quaternary ammonium amines chemical compound and the docusate sodium that are selected from lauryl sulfate slaine, sodium lauryl sulfate, alkylsurfuric acid slaine, Polyethylene Glycol, fatty acid ester.

2. the pharmaceutical preparation of claim 1, wherein said active agents account for about 0.01% to about 80% of pharmaceutical preparation weight.

3. claim 1 or 2 pharmaceutical preparation, wherein:

4. the pharmaceutical preparation of claim 1, wherein:

5. the pharmaceutical preparation of claim 1, wherein:

(e) wetting agent composition accounts for about 1.5% to 4% of pharmaceutical preparation weight;

(f) Ren Xuan lubricant composition when existing, accounts for about 0.1% to about 1% of pharmaceutical preparation weight; And

6. the pharmaceutical preparation of claim 1, wherein:

(e) wetting agent composition accounts for about 2% of pharmaceutical preparation weight;

7. the pharmaceutical preparation of claim 1, wherein:

8. each pharmaceutical preparation of claim 1 to 7, wherein:

(b) Ren Xuan second diluent/filler composition is if comprise one or more mannitol, lactose, sucrose, maltodextrin, Sorbitol, xylitol, cellulose powder, microcrystalline Cellulose, carboxymethyl cellulose, carboxyethyl cellulose, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, methyl hydroxyethylcellulose, starch, pregelatinized Starch, Explotab, calcium phosphate, carbonic acid metal salt, metal-oxide or aluminum silicate slaine when existing;

(e) this wetting agent composition comprises one or more lauryl sulfate slaine, Polyethylene Glycol, the glyceride of fatty acid ester, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene-alkyl ether, the alkylsurfuric acid slaine, the polyoxyethylene sorbitol fatty acid ester, castor oil derivatives, sucrose fatty acid ester, polyglycolic acid glycerol, the quaternary ammonium amines chemical compound, LABRASOL, octyl group caproyl polyethyleneglycol glyceride, the stearyl polyethyleneglycol glyceride, inferior oleoyl polyethyleneglycol glyceride, the oleoyl polyethyleneglycol glyceride, the polyethoxylated vegetable oil, the polyethoxylated sterin, the polyethoxylated cholesterol, the polyethoxylated fatty acid glyceride, the polyethoxylated fatty acid ester, sulfosuccinate, taurine ester or docusate sodium; And

9. each pharmaceutical preparation of claim 1 to 8, wherein:

(d) this adhesive ingredients comprises one or more polyethylene Pyrrolizidine ketone, copolyvidone, crosslinked poly-(acrylic acid), lecithin, casein, polyvinyl alcohol or gel; And

(e) this wetting agent composition comprises one or more polyoxyethylene-polyoxypropylene copolymer; polyoxyethylene-alkyl ether; the alkylsurfuric acid slaine; the polyoxyethylene sorbitol fatty acid ester; castor oil derivatives; sucrose fatty acid ester; polyglycolyzed glyceride; the quaternary ammonium amines chemical compound; LABRASOL; octyl group caproyl polyethyleneglycol glyceride; the stearyl polyethyleneglycol glyceride; inferior oleoyl polyethyleneglycol glyceride; the oleoyl polyethyleneglycol glyceride; the polyethoxylated vegetable oil; the polyethoxylated fatty acid glyceride; polyethoxylated fatty acid ester or docusate sodium.

10. each pharmaceutical preparation of claim 1 to 9, wherein:

(a) this first diluent/filler composition comprises mannitol;

(d) this adhesive ingredients comprises polyethylene Pyrrolizidine ketone;

(e) this wetting agent composition comprises sodium lauryl sulfate; And

11. a pharmaceutical preparation comprises:

(b) carrier or excipient systems, it comprises:

(vi) Ren Xuan lubricant composition when existing, accounts for about 0.01% to about 5% of pharmaceutical preparation weight; Condition is that the total amount of this composition is no more than about 5% of pharmaceutical preparation weight when this pharmaceutical preparation comprises one or more compositions that are selected from the glyceride of lauryl sulfate slaine, sodium lauryl sulfate, alkylsurfuric acid slaine, Polyethylene Glycol, fatty acid ester, Poloxamer188, polyoxyethylene sorbitol fatty acid ester, castor oil derivatives, sucrose fatty acid ester, polyglycolyzed glyceride, quaternary ammonium amines chemical compound and docusate sodium.

12. the pharmaceutical preparation of claim 11, wherein:

13. the pharmaceutical preparation of claim 11 or 12, wherein:

14. the pharmaceutical preparation of claim 11, wherein:

(a) this first diluent/filler composition comprises mannitol;

(d) this adhesive ingredients comprises polyethylene Pyrrolizidine ketone;

(e) this wetting agent composition comprises sodium lauryl sulfate; And

15. each pharmaceutical preparation of claim 11 to 14, wherein active agents accounts for about 0.01% to about 80% of pharmaceutical preparation weight.

16. a pharmaceutical preparation comprises:

(b) carrier or excipient systems, it comprises:

17. the pharmaceutical preparation of claim 16, wherein:

18. the pharmaceutical preparation of claim 16 or 17, wherein:

19. the pharmaceutical preparation of claim 16, wherein:

(a) this first diluent/filler composition comprises mannitol;

(d) this adhesive ingredients comprises polyethylene Pyrrolizidine ketone;

(e) this wetting agent composition comprises sodium lauryl sulfate; And

20. each pharmaceutical preparation of claim 16 to 19, wherein active agents accounts for about 0.01% to about 80% of pharmaceutical preparation weight.

21. each pharmaceutical preparation of claim 1-20, wherein active agents is 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazole-5-alcohol, or its pharmaceutically acceptable salt.

22. a tablet comprises each pharmaceutical preparation of claim 1-21.

23. each the method for pharmaceutical preparation of preparation claim 1-21 comprises:

24. the method for claim 23, wherein (a) comprising:

(ii), if desired, mix, form preliminary mixture with disintegrating agent and second diluent/filler of choosing wantonly with first mixture and remaining first diluent/filler.

25. the method for claim 23 or 24, wherein said aqueous solution further comprises adhesive ingredients.

26. each method of claim 23 to 25 further comprises:

(i) dry this granulation mixture forms the dry granulation mixture;

If (ii) exist, optional lubricant is mixed with this dry granulation mixture to form final mixture.

27. the method for claim 26 wherein (ii) further comprises:

(a) if exist, optional lubricant is mixed with this dry granulation mixture of at least a portion; With

(b) will mix with remaining dry granulation mixture from the mixture of (i).

28. the method for claim 27, wherein (b) carries out in mixer.

29. the method for claim 23 comprises:

(ii) first mixture and remaining first diluent/filler composition, disintegrating agent composition (if desired) and optional second diluent/filler composition (if existence) are mixed and form preliminary mixture;

(iv) dry this granulation mixture and form the dry granulation mixture;

(vi) will (mixture v) mixes (if desired) with remaining dry granulation mixture.

30. the method for claim 29, wherein this aqueous solution further comprises adhesive ingredients.

31. each the method for pharmaceutical preparation of preparation claim 1 to 21 comprises:

(ii) this first mixture of granulating randomly.

32. the method for claim 31, wherein this first mixture further contains optional lubricant composition.

33. each the product of method preparation of claim 23 to 32.

34. prepare the method for tablet, comprise each the pharmaceutical preparation of compacting claim 1 to 21.

35. the method for claim 34 further is included in this pharmaceutical preparation of compacting and grinds this pharmaceutical preparation before.

36. the method for claim 34 or 35, wherein this is compressed to direct compacting.