CN1433403A - Solid pharmaceutical preparation - Google Patents
Solid pharmaceutical preparation Download PDFInfo
- Publication number
- CN1433403A CN1433403A CN00818730A CN00818730A CN1433403A CN 1433403 A CN1433403 A CN 1433403A CN 00818730 A CN00818730 A CN 00818730A CN 00818730 A CN00818730 A CN 00818730A CN 1433403 A CN1433403 A CN 1433403A
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- CN
- China
- Prior art keywords
- particle
- crystal
- tablet
- medicine
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000007787 solid Substances 0.000 title claims abstract description 16
- 239000000825 pharmaceutical preparation Substances 0.000 title description 2
- 239000002245 particle Substances 0.000 claims abstract description 97
- 238000002360 preparation method Methods 0.000 claims abstract description 80
- 239000013078 crystal Substances 0.000 claims abstract description 59
- 238000009826 distribution Methods 0.000 claims abstract description 54
- 230000001186 cumulative effect Effects 0.000 claims abstract description 51
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims description 157
- 239000000203 mixture Substances 0.000 claims description 66
- 239000003795 chemical substances by application Substances 0.000 claims description 43
- 239000001301 oxygen Substances 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
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- 238000000354 decomposition reaction Methods 0.000 claims description 11
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 7
- 208000008589 Obesity Diseases 0.000 claims description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims description 5
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- 102000017910 Adrenergic receptor Human genes 0.000 claims description 4
- 239000000556 agonist Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 abstract description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 23
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- 238000007327 hydrogenolysis reaction Methods 0.000 description 7
- 239000000178 monomer Substances 0.000 description 7
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 7
- 229920002554 vinyl polymer Polymers 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 6
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- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
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- 238000013019 agitation Methods 0.000 description 6
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
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- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 229940039009 isoproterenol Drugs 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910001511 metal iodide Inorganic materials 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N n-octadecyl alcohol Natural products CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002896 organic halogen compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- QMMOXUPEWRXHJS-UHFFFAOYSA-N pent-2-ene Chemical group CCC=CC QMMOXUPEWRXHJS-UHFFFAOYSA-N 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D209/16—Tryptamines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Child & Adolescent Psychology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides a solid preparation comprising a crystal of [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic acid (Compound A), especially a crystal of Compound A having a particle size of not larger than 100 mu m at the cumulative weight distribution value of 50 %, and not larger than 200 mu m at the cumulative weight distribution value of 95 %, preferably a solid preparation having the excellent stability and the content uniformity of Compound A, which is prepared by preparing granules of the crystal of Compound A with fillers, disintegrants and binders, and then followed by mixing said granules with external excipients.
Description
Technical field
The present invention relates to a kind of [3-[(2R)-[[(2R)-(3-chloro-phenyl-) 2-hydroxyethyl] amino] propyl group]-1H-indoles-7-base oxygen base] acetic acid crystal (hereinafter being sometimes referred to as compd A) and contain the medicament that the compd A crystal is made medicine, the invention particularly relates to a kind of solid preparation, wherein the size of preparation (volume), content of medicines and homogeneity and stability of drug are guaranteed, and secondly medicine is fast from the stripping of preparation.
Background technology
Compd A shows effective receptor, stimulating activity and has excellent adrenoceptor selectivity, and it can effectively prevent or treat diabetes and obesity (WO96/16938).
Compd A shows extremely effectively pharmaceutical activity, thereby when it formed composite medicine, this composition can be the low levels preparation, and promptly wherein the active compound content of per unit dosage is low.But the content that is accompanied by compd A in the preparation reduces, and a kind of phenomenon occurs, and promptly the chemical stability of compd A self greatly reduces.In addition, when the amount of the vehicle except that compd A was increased to this suitable size and makes the degree of medicament, the content of the compd A in the per unit dosage became irregular, thereby is difficult to obtain the preparation of even compd A content.In this case, wish a kind of preparation that does not have the compd A of above-mentioned shortcoming of development, and compd A can be soon from wherein stripping.
The object of the present invention is to provide a kind of preparation of compd A, it can guarantee the size (cubic content) of preparation, the content homogeneity of compd A and the stability of compd A, and compd A can be soon from wherein stripping.
The invention summary
The present invention includes following different embodiments.(1) a kind of [3-[(2R)-[[(2R)-(3-chloro-phenyl-) 2-hydroxyethyl]-amino] propyl group]-1H-indoles-7-base oxygen base] acetic acid crystal (hereinafter being sometimes referred to as " compd A crystal "); (2) a kind of [3-[(2R)-[[(2R)-(3-chloro-phenyl-) 2-hydroxyethyl]-amino] propyl group]-1H-indoles-7-base oxygen base] the acetic acid crystal, this crystal is located characteristic diffraction peak (hereinafter also being called " the I N-type waferN of compd A " sometimes) in diffraction angle (2 θ) for about 5.9 °, about 17.9 °, about 20.5 ° and about 24.0 ° on powder x-ray diffraction figure; (3) a kind of crystal of compd A, it is that 50% o'clock granularity is not more than 100 μ m in cumulative weight distribution value, is that 95% o'clock granularity is not more than 200 μ m (hereinafter being sometimes referred to as " medicine ") in cumulative weight distribution value; (4) a kind of particle of forming by the crystal of above-mentioned (3) (medicine); (5) a kind of by (a) medicine, (b) weighting agent, (c) decomposition agent and (d) particle of tackiness agent composition; (6) a kind of above-mentioned (4) particulate solid preparation that contains; (7) a kind of tablet of suppressing by the particle of above-mentioned (4); (8) a kind of by the particle of above-mentioned (4) and the tablet of external excipients compacting; (9) a kind of β
3-2 adrenoceptor agonists, this stimulant contain the crystal (medicine) of above-mentioned (3); (10) a kind of reagent for the treatment of diabetes, this reagent contain the crystal (medicine) of above-mentioned (3); (11) a kind of reagent for the treatment of obesity, this reagent contain the crystal (medicine) of above-mentioned (3).
In whole existing narration and claim, " crystal of compd A " means [3-[(2R)-[[(2R)-(3-chloro-phenyl-)-2-hydroxyethyl] amino] propyl group]-1H-indoles-7-base oxygen base] the pure crystal of vinegar, and it is as described below, based on the diffraction peak of basic x-ray diffraction pattern, the crystal of compd A can be divided into I N-type waferN (the I N-type waferN of compd A) and II N-type waferN (the II N-type waferN of compd A).I N-type waferN, II N-type waferN or these crystalline mixtures can be produced by its preparation method." crystal of compd A " comprises all these crystal.
" medicine " means the crystal of compd A recited above, and its granularity is to be not more than 100 μ m at 50% o'clock in cumulative weight distribution value, and its granularity is to be not more than 200 μ m at 95% o'clock in cumulative weight distribution value.Preferred size is to be not more than 50 μ m at 50% o'clock in cumulative weight distribution value, is to be not more than 150 μ m at 95% o'clock in cumulative weight distribution value.More preferably granularity is to be not more than 30 μ m at 50% o'clock in cumulative weight distribution value, is to be not more than 100 μ m at 95% o'clock in cumulative weight distribution value." medicine " of the present invention comprises all these.
" cumulative weight distribution value " mean by its granularity powder classification, the value that the weight adduction of each granularity that will count from the end that distributes obtains, and it is represented with the percentage ratio of powder gross weight.As a kind of method that powder (particle aggregate) mean particle size of particle size dispersion is arranged, adopt usually " cumulative weight distribution value is 50% o'clock a granularity ".In addition, " cumulative weight distribution value is 95% granularity " uses the index that adjusts coarse particles content in narration of the present invention and claim, it influences the mode of compound stripping from preparation (referring to Alfonso R.Gennard (Ed.): Particle Size Measurement and Classification (granulometry and classification), Remington ' s Pharmaceutical Sciences (Remington pharmaceutical science), 17th edition, Part 8, Chapter 89, pp 1588-1589,1985; Swithenbank, J., Beer, J.M.Taylot, D.S.Abbot, D.and McCreath, G.C.:A laser diagnostice technique for the measurement of dropletand particle size distribution (the laser calibrating technology that is used for droplet and particle size distribution measurement), AIAA Paper No.76-79 (1976); And Hayashi, S.:A lasersmall angle scattering instrument for the determination ofsize and concentration distribution in sprays (laser small-angle scattering instrument big or small and that concentration distribution is measured is used for spraying), (Hirleman, E.D.and othersEds.), Liquid particle Size Measurement Techniques (liquid granulometry technology): 2nd Volume, Philadelphia, ASTM, 1990).
The accompanying drawing summary
Fig. 1 is the powder x-ray diffraction figure of the I N-type waferN of the compd A that obtains in preparation 1.
Fig. 2 is the powder x-ray diffraction figure of the II N-type waferN of the compd A that obtains in preparation 2.
Implement optimal mode of the present invention
The crystal of compd A of the present invention can be by being shown in the method preparation of following schema.
That is to say, formula I compound (wherein R is the protecting group of phenolic hydroxyl, or-CH
2COX, X be a kind of lower alkoxyl group, benzyloxy, lower alkyl, amino, list-or two-low alkylamino or ring are amino) in the presence of alkali with formula II compound (R wherein
1Be amino protecting group, Y is a halogen atom) reaction obtains formula III compound (wherein R and R
1As top definition).The formula III compound that obtains like this obtains formula IV compound (R wherein with reductive agent reaction again
11Be hydrogen atom or amino protecting group, R such as top definition).Then, (i) as the R of formula IV protecting group (and if the R of formula IV of phenolic hydroxyl
11Be hydrogen atom, then the amino of compound IV is protected once more) time, then the protecting group of phenolic hydroxyl is optionally removed, the compound of the formula V of gained (R wherein
1As top definition) with the compound of structural formula VI (Y wherein
1Be the reactive base of alcohol, X such as top definition) reaction, optionally remove amino protecting group then to obtain compound VI I; The R that perhaps (ii) works as formula IV is-CH
2COX, R
11When being the protecting group of amino; amino protecting group is optionally removed, and obtains compound VI I (wherein X such as top definition), the compound reaction of gained compound VI I and formula VIII; the gained material through hydrogenolysis or hydrolysis, obtains the crystal of compd A effectively under acidity or alkaline condition then.
The term that is used for preparing the crystalline method of compd A of the present invention is elucidated later herein below.
" low alkyl " comprises that carbon atom is the straight or branched alkyl of 1-6, for example methyl, ethyl, propyl group, sec.-propyl, butyl and isobutyl-, preferable methyl and ethyl, more preferably methyl.
" low-alkoxy " comprises that carbon atom is the straight or branched alkoxyl group of 1-6, for example methoxyl group, oxyethyl group, propoxy-and isopropoxy, preferably methoxyl group, oxyethyl group and propoxy-, more preferably methoxyl group and oxyethyl group.
" single-or two-low alkylamino " comprise, for example methylamino-, dimethylamino, ethylamino, methylethyl amino, diethylin, third amino, isopropylamino and dipropyl amino, preferred methylamino-, dimethylamino, ethylamino, diethylin and dipropyl amino, more preferably dimethylamino and diethylin.
" ring is amino " comprises that 5 yuan-7 yuan rings are amino, for example pyrrolidyl, morpholinyl, piperidyl and homopiperidinyl, preferably pyrrolidyl, morpholinyl and piperidyl, more preferably pyrrolidyl and piperidyl.
" protecting group of phenolic hydroxyl and amino protecting group " can be generally used for the organic synthesis field protecting group (for example, T.W.Greene, D.G.M.Muts, Protective Groupsin Organic Synthesis (protecting group in the organic synthesis), John Wiley ﹠amp; Sons, Inc, Second Edition, 1991, p 143-170 and is p.309-385), and comprise the easy substituting group of removing with reduction or hydrolysis.The combination of the protecting group of the protecting group of phenolic hydroxyl and amino should be selected like this, and promptly in them optionally removes.
" protecting group of phenolic hydroxyl " comprises; for example; methyl, methoxyl methyl, methoxy (ethoxy) methyl, THP trtrahydropyranyl, phenacyl, allyl group, sec.-propyl, the tertiary butyl, benzyl, diphenyl methyl, trityl group, ethanoyl, pivaloyl, benzoyl, methoxycarbonyl, 2; 2; 2-trichloro-ethoxycarbonyl and benzyl oxygen base carbonyl; preferable methyl, the tertiary butyl, benzyl, diphenyl methyl, trityl group and allyl group, more preferably methyl, benzyl, diphenyl methyl and trityl group.
" amino protecting group " comprises; for example methoxycarbonyl, ethoxycarbonyl, 2; 2; 2-trichloro-ethoxycarbonyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), vinyl oxygen carbonyl; 9-fluorenylmethyloxycarbonyl, formyl radical, ethanoyl, trifluoroacetyl group, benzoyl, phthalimido, ptoluene-sulfonyl, benzenesulfonyl, methane sulfonyl and benzyl; preferred tertiary butoxy carbonyl, carbobenzoxy-(Cbz), 9-fluorenylmethyloxycarbonyl, ethanoyl; and trifluoroacetyl group, more preferably tertbutyloxycarbonyl, carbobenzoxy-(Cbz) and 9-fluorenylmethyloxycarbonyl.
" alcohol active group " comprise, for example halogen atom, low alkyl group sulfonyloxy (for example methane sulfonyl, ethane alkylsulfonyl) and aryl-sulfonyl oxygen (for example phenylsulfonyloxy, right-tosyloxy).
" halogen atom " is fluorine atom, chlorine atom, bromine atoms or iodine atom, preferred chlorine atom.
To prepare the crystalline method of compd A than sets forth in detail below.
Operation AThe preparation of the compound of formula III:
But the compound of the compound through type I of formula III is in the compound prepared in reaction that has in the presence of the alkali in a kind of suitable solvent with structural formula II.
Alkali comprises, for example sodium hydride, metal alkoxide, Grignard reagent, lithium alkylide, sodium amide and lithium dialkyl amides or the like.In general, under a kind of indole derivatives is having in the presence of the alkali situation with a kind of nucleophilicity reagent react, obtain 1-substitution compound and 3-substitution compound.Because Grignard reagent is widely used in and preferably obtains the 3-substitution compound, also preferred Grignard reagent in this operation.
Grignard reagent comprises methyl magnesium chlorine, methyl magnesium bromine, ethyl magnesium bromide, tertiary butyl magnesium chlorine, phenyl magnesium chlorine or the like, preferable methyl magnesium bromine and tertiary butyl magnesium chlorine.The common usage quantity of Grignard reagent is about the 1-8 mole by 1 mole of formula I compound, preferred 2-4 mole.
Reaction is usually carried out preferred-20 ℃-Yue 0 ℃ under-50 ℃ approximately-Yue 30 ℃ temperature.Reaction is preferably carried out in the atmosphere of rare gas element such as nitrogen or argon.In addition, inorganic reagent such as zinc chloride, aluminum chloride, cupric bromide etc. can add in the reaction system.Solvent can be aromatic hydrocarbon (for example benzene, toluene etc.), ether (for example diethyl ether, tetrahydrofuran (THF) etc.), chloroform and methylene dichloride, and these solvents should adopt anhydrous type.
The compound of formula II can be produced with inorganic halides (for example phosphorus pentachloride, phosphorus trichloride, phosphorus tribromide or the like) or Organohalogen compounds (for example phosphoryl chloride, thionyl chloride, oxalyl chloride, phosgene etc.) reaction in suitable solvent by the alpha amino acid of amido protecting.Used halid amount is about the 1-5 mole by 1 mole of raw material, preferred 1-2.5 mole.Can be with N, dinethylformamide or HMPA are added in the reaction system.Reaction is usually carried out under about 0 ℃-Yue 200 ℃ temperature, preferably carries out under about 25 ℃-Yue 130 ℃ temperature.Solvent can be aromatic hydrocarbon (for example benzene, toluene etc.) or halon (for example chloroform, methylene dichloride etc.).
Process BThe preparation of the compound of formula IV:
The compound of formula IV can be by reducing the compound of formula III in suitable solvent with appropriate reductant.Reductive agent can be, for example lithium aluminium hydride, two (second methoxy (ethoxy))-sodium aluminum hydride, sodium borohydride, lithium borohydride, hydroboration calcium, diboron hexahydride, diisobutyl aluminium hydride or the like, preferred hydroboration basic metal.R is-CH
2The reduction of the compound III of COX should be adopted and not reduce the reductive agent of carbonyl of R.The amount of used reductive agent is about the 2-6 mole by the compound of 1 mole of formula III, preferred 3-4 mole.Reduction temperature can change with the reductive agent that is adopted, but usually in about-80 ℃-Yue 150 ℃ scope, preferred about 25 ℃-Yue 150 ℃ scope.Solvent can be ether (for example diethyl ether, tetrahydrofuran (THF) etc.), toluene, chloroform, methylene dichloride, methyl alcohol, ethanol, Virahol, acetonitrile, water or the like according to used reductive agent type selecting.
In process B, R is the protecting group of phenolic hydroxyl if obtain wherein, R
11Be the compound of the formula IV of hydrogen atom, then this compound is at the operation C of its amino group below being used for after protection again.
The introducing of amino protecting group is (for example to be undertaken by the ordinary method in the synthetic field of peptide; Nobuo IZUMIYA etc., Fundamentals and Experiments of PeptideSynthesis (peptide synthetic basis and experiment), Maruzene; 1985, p.16-40).R wherein for example
11For compound and the di-t-butyl acid carbonate of the formula IV of hydrogen atom reacts the compound that obtains formula IV, wherein R under a kind of The suitable solvent and room temperature
11It is tertbutyloxycarbonyl.
In addition, in process B, R is if obtain wherein-CH
2COX, R
11Be the compound of the formula IV of amino protecting group, then this compound can be directly used in operation E.
Once more, in process B, R is if obtain wherein-CH
2COX, R
11Be the compound of the formula IV of hydrogen atom, then this compound is the same with the compound of formula VII, and can directly use operation F.
Operation CThe preparation of the compound of formula V:
R wherein
11Be amino protecting group, R is that the removal of protecting group of phenolic hydroxyl of compound IV of the protecting group of phenolic hydroxyl is undertaken by reduction or hydrolysis, and it should be according to the type selecting of the protecting group that will remove.
Reduction is removed by hydrogenolysis or is adopted metal-powder such as zinc powder to carry out.
Hydrogenolysis is carried out in nitrogen atmosphere having in the presence of palladium on catalyzer such as the carbon, palladium hydroxide, platinum oxide etc.Reaction usually under about 20 ℃-Yue 80 ℃ temperature under atmospheric pressure or be lower than under the normal atmosphere and carry out.Can adopt ammonium formiate, formic acid, hexamethylene ring, hydrazine etc. to carry out the catalytic hydrogen transfer reduction.Solvent can be alcohols (for example methyl alcohol, ethanol etc.), vinyl acetic monomer, acetic acid, water etc., and these solvents can use separately or use with the form of two or more mixtures in these solvents.
Hydrolysis is to carry out under acidic conditions or alkaline condition in a kind of suitable solvent.Temperature of reaction can change by the type of the protecting group of intending removing, but it is usually in about 0 ℃-Yue 150 ℃ of scopes, preferably in about 20 ℃-Yue 100 ℃ of scopes.Solvent can be alcohols (for example methyl alcohol, ethanol etc.), acetonitrile, water, N, and dinethylformamide etc., these solvents can use separately or use with the form of two or more mixtures of these solvents.Alkali can be alkali metal hydroxide (for example, sodium hydroxide, potassium hydroxide etc.), and organic bases (for example piperidines, piperazine etc.), and acid can be spirit of salt, Hydrogen bromide, trifluoracetic acid, sulfuric acid, formic acid, acetic acid, methylsulfonic acid etc.
Step D and operation EThe preparation of the compound of formula VII:
The compound of formula VII prepares (step D) from the compound of formula V by step D and E:
The compound of the compound of formula V and formula VI carries out addition reaction in The suitable solvent.Temperature of reaction can change according to the type of used initial compounds, and it is usually in about 50 ℃-Yue 200 ℃ scope.Solvent can be aromatic hydrocarbon (for example benzene, toluene etc.), ketone (for example acetone, methyl ethyl ketone etc.), ethers (for example tetrahydrofuran (THF), diox etc.), alcohols (for example ethanol, Virahol etc.), acetonitrile, N, dinethylformamide, 1,3-dimethyl-2-imidazolone etc., and these solvents can use separately or use with two or more form of mixtures of these solvents.
Reaction is preferably carried out having in the presence of the alkali, alkali can be, for example mineral alkali such as alkaline carbonate (for example yellow soda ash, salt of wormwood etc.), alkali metal hydrocarbonate (as sodium bicarbonate, saleratus), alkali metal hydroxide (for example sodium hydroxide, potassium hydroxide etc.), or organic bases such as triethylamine, Tributylamine, N-methylmorpholine etc.If adopt wherein Y
1Be that the compound of the formula VI of chlorine atom or bromine atoms then reacts can be by adding alkaline metal iodide (for example sodium iodide, potassiumiodide etc.), or halogenated tetra-allkylammonium (for example four-just-butyl ammonium chloride etc.) and steadily carrying out.
Utilize this reaction, wherein R is-CH
2The Compound I of COX can prepare by similar mode from the compound of hydrogen-oxygen indoles and formula VI.(operation E):
The protecting group preparation of the amino of the compound that the compound of formula VII can prepare in step D by selective removal.
Amino protecting group is removed by reduction or hydrolysis, and it should be according to the type selecting of the protecting group of intending removing.
Reduction is removed to be by hydrogenolysis or to utilize metal-powder such as zinc powder carries out.
Hydrogenolysis is carried out in nitrogen atmosphere having in the presence of palladium on catalyzer such as the carbon, palladium hydroxide, platinum oxide etc.Temperature of reaction is barometric point or negative pressure in about 20 ℃-Yue 80 ℃ of air pressure usually.In addition, also can adopt hydrogen sources such as ammonium formiate, formic acid, tetrahydrobenzene, hydrazine to carry out the catalytic hydrogen transfer reduction.Solvent can be alcohols (for example methyl alcohol, ethanol etc.), vinyl acetic monomer, acetic acid, water etc., and these solvents can use separately or use with two or more form of mixtures of these solvents.
Hydrolysis is being carried out in suitable solvent under acidic conditions or the alkaline condition.Temperature of reaction can change according to the type of the protecting group of intend removing, and it is usually at about 0 ℃-Yue 150 ℃, preferred about 20 ℃-Yue 100 ℃.Solvent can be alcohols (for example methyl alcohol, ethanol etc.), acetonitrile, water, N, dinethylformamide etc., and also these solvents can use separately or two or more form of mixtures of these solvents is used.Alkali can be alkali metal hydroxide (for example sodium hydroxide, potassium hydroxide etc.), or organic bases such as piperidines, piperazine etc.Acid can be spirit of salt, Hydrogen bromide, trifluoracetic acid, sulfuric acid, formic acid, acetate, oxalic acid, methanesulfonic etc.
Operation F and operation GThe preparation of the compound of formula IX:
The compound of formula IX can prepare by operation F and G from the compound of structural formula VII.(operation F):
The reaction in suitable solvent or in solvent-free of the compound of the compound of formula VII and formula VIII.
Temperature of reaction can change according to the type of initial compounds, usually at about 20 ℃-Yue 150 ℃, preferably at about 25 ℃-Yue 100 ℃, solvent can be aromatic hydrocarbon (for example benzene, toluene etc.), ketone (for example acetone, methyl ethyl ketone etc.), ethers (for example tetrahydrofuran (THF), diox etc.), alcohols (for example ethanol, Virahol etc.), acetonitrile, dimethyl oxidation sulphur, N, dinethylformamide and 1,3-dimethyl-2-imidazolone, and these solvents can use separately or use with the form of two or more mixtures of these solvents.In reaction system, can add trimethyl silyl ethanamide or two trimethyl silyl ethanamide.
In this reaction, can adopt its acid salt to replace the compound of formula VII, and the acid salt of compound VI I can be with the salt of the salt of mineral acid such as hydrochloride, hydrobromide etc. or with organic acid salt such as oxalate, maleate, fumarate etc.If the present invention adopts acid salt, then be reflected under the existence of alkali and carry out.Alkali comprises, for example mineral alkali such as alkali metal hydrocarbonate (for example sodium bicarbonate, saleratus etc.) and alkaline carbonate (for example yellow soda ash, salt of wormwood etc.), or organic bases such as triethylamine, Tributylamine, diisopropylethylamine, N-methylmorpholine etc.(operation G):
The compound of formula IX can be by making the compound (removing X is outside the low alkyl group) that obtains among the operation F again through the hydrogenolysis in suitable solvent, and perhaps the hydrolysis under acid or alkaline condition prepares.
Hydrogenolysis have catalyzer for example the palladium on the carbon, palladium hydroxide, platinum oxide etc. in the presence of, in nitrogen atmosphere, carry out.React on about 20 ℃-Yue 80 ℃ and under atmospheric pressure or under the negative pressure carry out.Can adopt such as hydrogen sources such as ammonium formiate, formic acid, tetrahydrobenzene, hydrazines and realize the catalytic hydrogen transfer reduction.Solvent can be alcohols (for example methyl alcohol, ethanol etc.), vinyl acetic monomer, acetic acid, water etc., and these solvents can use separately or use with two or more the form of mixture of these solvents.
Hydrolysis is carried out in solvent under acidity or alkaline condition.Temperature of reaction can change according to the type of initial compounds, and it is usually at about 0 ℃-Yue 150 ℃, preferably at about 20 ℃-Yue 80 ℃.Solvent can be the alcohols (mixture of), diox, water or these solvents such as methyl alcohol, ethanol, Virahol for example.Acid comprises, for example mineral acid such as spirit of salt, Hydrogen bromide, hydroiodic acid HI, sulfuric acid etc. and organic acid such as formic acid, acetate, trifluoracetic acid, right-toluenesulphonic acids, methylsulfonic acid etc.Alkali comprises alkali metal hydroxide (for example sodium hydroxide, potassium hydroxide etc.) and alkaline carbonate (for example yellow soda ash, salt of wormwood etc.).
The crystal of the compd A that obtains like this is the I N-type waferN of compd A, and the characteristic diffraction peak appears at diffraction angle (2 θ) and is about 5.9 °, 17.9 °, 20.5 ° and about 24.0 ° and locates in x-ray diffractogram of powder.
The I N-type waferN of compd A recrystallization from solvent such as methyl alcohol, appear at diffraction angle (2 θ) and be about 5.9 °, 17.5 °, 20.8 ° and 23.3 ° (II N-type waferN of compd A) to obtain its characteristic diffraction peak of a kind of crystal, but the I N-type waferN of compd A prepares easily at industrial II N-type waferN than compd A.
In preparation of the present invention, be that 50% o'clock granularity is no more than 100 μ m and is the compd A crystal useful as drug that 95% o'clock granularity is not more than 200 μ m in cumulative weight distribution value in cumulative weight distribution value.Be that 50% o'clock granularity is not more than 50 μ m and is the crystal that 95% o'clock granularity is not more than 150 μ m in cumulative weight distribution value in cumulative weight distribution value preferably, being more preferably in cumulative weight distribution value is that 50% o'clock granularity is not more than 30 μ m and is the crystal that 95% o'clock granularity is not more than 100 μ m in cumulative weight distribution value.When the medicine of above-mentioned requirements is satisfied in use, can obtain medicine can be therefrom can very fast stripping preparation.In addition, because medicine can also obtain with the form of congeries sometimes, then the content of these congeries should be less than 50% in medicine, and is almost single size-grade distribution.
The granularity of medicine (cumulative weight distribution value be 50% and 95% o'clock) is measured with the ordinary method of measuring the medicament granularity, for example use standard sieve point-score, settling process, light scattering method, imaging analysis method etc., but measuring method should be not limited to these methods.
Satisfying this medicine of above-mentioned requirements can and/or select the synthetic milling method afterwards of compd A to obtain by selective freezing condition in the compd A building-up process.For example, after compd A is synthetic, available beater grinder, fluid energy pulverizer, planet ball pulverizer, vibrating ball pulverizer, conisphere pulverizer, roller mill or thin bar pulverizer under the condition selected according to the pulverizer that adopts with compd A powder process to obtain medicine.Granularity that can be by the control compd A in the building-up process of compd A and gather rate and obtain medicine, perhaps by with the precipitation dissolution of crystals in the building-up process in suitable solvent such as water or organic solvent etc., again with gained solution in the postcritical fluid of carbon dioxide under selected condition spraying drying or drying obtain medicine.
Pharmaceutical preparation for the medication preparation expection that obtains like this needs preparation to contain the particle of this medicine.
In addition, particle be except that can containing (a) medicine, (b) weighting agent, (c) decomposition agent and (d) the tackiness agent, but also can contain antiseize paste or lubricant etc.
Because the vehicle of non-medicine directly contacts with medicine, should adopt the vehicle compatible with medicine, and introduces medicine with them with suitable ratio, guarantee stability of drug in this way in particle.Vehicle in the particle except that medicine comprises, for example weighting agent, decomposition agent and tackiness agent, and still, if desired, antiseize paste, lubricant etc. also can be used as vehicle.
The consumption of the vehicle in the particle except that medicine is generally 500 weight parts or lower by 1 weight part medicine, preferred 300 weight parts or lower, more preferably 100 weight parts or lower.
Weighting agent comprises for example lactose, cereal starch, sucrose, trehalose, D-N.F,USP MANNITOL, tetrahydroxybutane, maltose alcohol and ethyl cellulose.Decomposition agent comprises for example low hydroxypropylcellulose, carboxymethylcellulose calcium and the crosslinked-carmethose that replaces.Tackiness agent comprises for example hydroxypropylcellulose, Vltra tears, amylopectin, Polyvinylpyrolidone (PVP), gelatin and carmethose.
Antiseize paste and lubricant comprise for example Magnesium Stearate, hydrogenated castor oil, light body anhydrous silicic acid and talcum.If the employing Magnesium Stearate, then consumption is counted 1 weight %-5 weight % by the total formulation weight amount, preferred 1 weight %-4 weight %, and more preferably consumption is 1.5 weight %-3 weight %.
The particulate preparation should prepare the premix powder of medicine and part or all of weighting agent in advance, follows screening or efflorescence, then remaining vehicle is added wherein, and if desired, then granulation or adjustment mixture size guarantee that in this way content of medicines is even.
Mixing and screening are carried out with 24-60 purpose sieve with hand getting, perhaps adopt the screening plant with suitable mixing ability, and for example vibrator carries out.Mix and efflorescence employing powder-making machine, for example beater grinder carries out.
The granulation of wetting of fluidised bed granulator, mixer granulator or high shear granulator is for example adopted in granulation.
The particulate granularity that makes like this is to be not more than 350 μ m at 50% o'clock and is to be not more than 1400 μ m at 95% o'clock in cumulative weight distribution value in cumulative weight distribution value usually.The granularity of preferred particulates is 50% should be not more than 300 μ m and be to be not more than 1000 μ m at 95% o'clock in cumulative weight distribution value in cumulative weight distribution value.More preferably the particulate granularity is more suitablely to be not more than 250 μ m and to be 95% o'clock more suitable 800 μ m that are not more than in cumulative weight distribution value in 50% o'clock in cumulative weight distribution value.The particle that employing has preferred size has guaranteed the content of medicines homogeneity more.
The granularity of medicine (cumulative weight distribution value be 50% and 95% o'clock) be to measure with the ordinary method of measuring the medicament granularity, for example adopt standard sieve point-score, settling process, light scattering method, imaging analysis method or the like, but measuring method is not limited to these methods.
Solid preparation of the present invention contains the particle that obtains in such a way.Solid preparation can be for example tablet, capsule, granula, powder, suppository or external preparation such as adhesive tape.
Solid preparation can only contain particle, but contain in the low levels preparation of 2mg or lower medicine at every dose unit, should increase the volume (weight) of preparation with mode in the particle that outer vehicle is added to, so that guaranteeing medicine has enough stability and guarantees that it has suitable size (general diameter is 4-10mm, heavy 25-300mg).
The vehicle such as the weighting agent of using in can be used on granules preparation, decomposition agent, tackiness agent, outer vehicle can adopt crystalline cellulose to make weighting agent.
In order to guarantee the homogeneity of medicament contg, the content of outer vehicle is counted the 0.01-100 weight part by 1 weight part particle, and preferred amounts is the 0.10-50 weight part, more preferably the 0.15-10 weight part.
In formulated, for mixing with the particle that contains medicine, outer vehicle can be only beyond the mixture of vehicle use, perhaps adjust to the granularity identical with particle in extrinsic agent granulation or with its size after use.For the big I of granulating or adjust outer vehicle adopts hydroxypropylcellulose, Vltra tears, amylopectin, Polyvinylpyrolidone (PVP), gelatin, carmethose as tackiness agent.Composite grain and outside during vehicle, can adopt antiseize paste and/or lubricant.
Particle can be without mixing compacting, to obtain dry-coated patch agent or multilayer tablet with outer vehicle.In this case, outer vehicle can be for example crystalline cellulose and/or low-substituted hydroxypropyl cellulose and Magnesium Stearate and/or hydrogenated castor oil.In addition, also can adopt light body anhydrous silicic acid and/or talcum.If desired, hydroxypropylcellulose, Vltra tears or amylopectin can be used as tackiness agent.
With particle or particle and outside the mixture of vehicle when making tablet; Magnesium Stearate or hydrogenated castor oil should be added in the mixture of particle or particle and outer vehicle; its amount is 1 weight %-5 weight %; with the adhesion that prevents from the compression film-making, to occur easily; the mixture that makes like this is with suitable pelleter compression film-making, so that the tablet that obtains expecting.
In addition, for the intensity of covering bad taste, increase tablet, the comfortableness when improving mouthfeel and increasing use, but the suitable component of polymer of tablet coated that makes in a manner described; So that the tablet that obtains filming.This component of polymer can be Vltra tears, hydroxypropylcellulose, Natvosol, methyl hydroxyethylcellulose, methylcellulose gum, ethyl cellulose, carmethose, Polyvinylpyrolidone (PVP), polyvinyl alcohol, polyoxyethylene glycol, dimethyl aminoethyl first acrylate-alkylmethacrylate polymer and ethyl propylene acid esters-methyl first acrylate copolymer for example.If desired; can add the softening agent of component of polymer to the coated agent, for example propylene glycol, glycerine, polyoxyethylene glycol, Vanay, triethyl citrate, Triethyl citrate acetate, diethyl phthalate, diethyl sebate, acetylated monoglyceride, Viscotrol C or whiteruss.Secondly, for against sunshine and improvement identifiability, can in Liniment, add suitable tinting material.Tinting material can be for example water-soluble synthetic colour as yellow No. 4 and yellow No. 5, blue No. 1, blue No. 2 etc. and their aluminium color lake, talcum, titanium oxide, ferric oxide, calcium sulfate, lime carbonate or add riboflavin, fuchsin, turmeric pigment.In addition, in order to increase palatability, also can add sweeting agent or spices.
Once more, can be converted into sugar coated tablet for reaching same purpose tablet recited above.Sugared coated agent can be made up of lime carbonate, talcum or titanium oxide except major ingredient sucrose or sorbyl alcohol, also contain for example gelatin, Acacia, polyvinyl alcohol etc. in addition, or derivatived cellulose such as amylopectin, Vltra tears etc. are as tackiness agent, if desired, also can add water-soluble synthetic dyestuff as yellow No. 4, yellow No. 5, blue No. 1, blue No. 2 etc., and their aluminium color lake, talcum, titanium oxide, ferric oxide, calcium sulfate, lime carbonate or riboflavin, fuchsin, turmeric pigment etc.Once more, in order to improve palatability, can add sweeting agent or spices equally.
The mixture of particle or particle and outer vehicle can be directly formed to thin granular preparation, granular preparation or powder formulation, is shaped to capsule preparations in the ' Yanming ' capsules for clearing of perhaps they being packed into.In this case, outer vehicle can be for example lactose, cereal starch, sucrose, trehalose, D-mannitol, red tinea alcohol, maltitole and/or ethyl cellulose and Magnesium Stearate and/or hydrogenated castor oil.Secondly, can adopt the anhydrous silicic acid and/or the talcum of light body equally.Under the situation of granular preparation, after granulation, can add the weighting agent that hydroxypropylcellulose, Vltra tears, amylopectin, Polyvinylpyrolidone (PVP), gelatin or carmethose are made granular preparation.
If also need, make tablet become the tablet that continues release, then contain the particle of medicine or the paint coating of the release that tablet is used the may command medicine, it is made up of with oil polymerization composition or grease, to obtain the continuous release tablet of storage type.Paint can be for example beeswax, carnauba wax, hexadecanol, hexadecyl stearyl alcohol, phosphatide fat and oil, resin (for example shellac), cellulose ester (for example ethyl cellulose) and acrylate.If desired, can in paint, add propylene glycol, glycerine, polyoxyethylene glycol, Vanay, triethyl citrate, Triethyl citrate acetate, diethyl phthalate, diethyl sebate, acetylated monoglyceride, Viscotrol C or whiteruss softening agent as component of polymer.Once more, the particle of control medicament release can be pressed into tablet.
Here can obtain a kind of occurring matrix type extended release preparation, its mode is the component that the control medicament is discharged, and component of polymer as described above or fat mix in the operation of producing particle and tablet with weighting agent with oil.Secondly, if desired, the particle of this sustained release can be pressed into tablet.
The solid preparation of the present invention that obtains like this can be packed, and if desired, in the bottle of can pack into bubble shape bag, heat-sealing bag or suitable material, but should not be limited to these several packings.Once more, if desired, solid preparation of the present invention can with suitable siccative, encapsulate together as silica gel.The pharmacology test
Once studied the influence of medicine of the present invention to the human body receptor.
The height indicator body β that lets others have a look at
3-and β
2The clone of-suprarenal gland receptor is pressed disclosed method preparation among the WO 96/16938.The height indicator body β that lets others have a look at
1The clone of-adrenoceptor is pressed the preparation of WO 00/44721 disclosed method.
TestHuman body β
3-adrenoceptor-stimulating activity:
Human body β
3-adrenoceptor-highly represent clone CHO/pKREX10-36 is with the MEM-DulbeccoShi medium and add 10% foetal calf serum and the G-418 of 200 μ g/ml cultivated 2-3 days.Cell was peeled off with the salt solution cultivation under 37 ℃ with phosphate buffered that contains 0.5mM EDTA in 10 minutes after removing medium.By centrifugal collection CHO/pKREX10-36 cell, and in the 3-of L-xitix that contains 1mM and 1mM isobutyl--1-methyl-xanthic Hanks damping fluid (ICN Biomedicals) suspension, its concentration is about 5 * 10
5Cell/ml.This suspension (100 μ l) and test compound mix in same damping fluid (500 μ l), and cultivate 30 minutes down at 37 ℃, boil 5 minutes then with termination reaction.After reaction mixture was centrifugal, the cAMP that utilizes cAMP EIA system (Amersham) to measure in the clear liquid measured.
Equally, to the height indicator body β that lets others have a look at
2-adrenoceptor utilizes CHO/pKREX 21-8, perhaps to the height indicator body β that lets others have a look at
1-adrenoceptor utilizes CHO/pKREX 23-30, measures the cAMP number in the same way, rather than utilizes the height indicator body β that lets others have a look at
3The CHO/pKREX 10-36 of-adrenoceptor.
When reaction mixture adds 10
-5The isoproterenol of M or when not adding fully, the quantity of cAMP is represented this preparation medicine (10 with 100% and 0% respectively
-6-10
-11M) maximum relatively reaction table is shown interior activity (I.A.).EC
50Value is for reaching the concentration of the required test compound of 50% cAMP accumulation, and it is with the least square regression analytical method calculating of each compound concentrations-response curve.
The results are shown in table 1.
Table 1
Annotate:
*Medicine;
*(-)-isoproterenol.
| Test compound | Human body β 3-，β 2-and β 1-adrenoceptor-stimulating activity | |||||
| ??????β 3-acceptor | ????????β 2-acceptor | ?????????β 1-acceptor | ||||
| EC 50(nM) | ??I.A.(％) | ??EC 50(nM) | ??I.A.(％) | ??EC 50(nM) | ????I.A.(％) | |
| A * | 0.27 | ??110 | ??21 | ??45 | ??3.5 | ????83 |
| IP ** | 10 | ??100 | ??4.2 | ??100 | ??0.46 | ????100 |
In this test, has low EC
50The compound of value and high I.A value is considered to have strong human body receptor,-stimulating activity.Therefore, can find out clearly that the medicine proof of this preparation has strong human body β from table 1
3The stimulating activity of-adrenoceptor, but it is to human body β
2-and β
1The stimulating activity of-adrenoceptor but quite a little less than.
The above results shows that medicine of the present invention is expected as human body β
3The exciting agent of-adrenoceptor, and have excellent adrenoceptor selectivity.
Medicine of the present invention is as β
3-adrenoceptor-exciting agent can be effective to prevention or treatment obesity, diabetes, hyperlipemia, acute bowel syndromes, acute or chronic dysentery, pollakiuria, the enuresis, urinary stone etc.In addition, medicine of the present invention can effectively improve the symptom such as stomachache, gastric disorder causing nausea, vomiting, epigastrium disease, digestion association ulcer, acute or chronic gastritis, courage dyskinesia, cholecystitis etc. equally.
If with medicine of the present invention as β
3The exciting agent of-adrenoceptor, then it can be oral, administered parenterally or rectal administration, but preferred oral approach.The dosage of medicine of the present invention can change according to route of administration, condition, patient age or purpose (prevention or treatment) etc., but usually at 0.0002mg/kg/ days-0.02mg/kg/ days, preferably at 0.001mg/kg/ days-0.02mg/kg/ days.
Embodiment
The present invention will be with following preparation, test and embodiment sets forth in detail in addition, but should not be so limited.
Preparation 1The crystal formulations of compd A:
The evaluation of compound is revolved mensuration by ultimate analysis, mass spectroscopy, infrared (IR) absorption spectrum, proton magnetic resonance (PMR) (1H-NMR) spectrum and light.Optical purity is determined with HPLC (high performance liquid chromatography).
Following abbreviation can be used for simplified illustration.
The Fmoc:9-fluorenylmethyloxycarbonyl
Ala: alaninyl
J: coupling constant
S: single line
D: two-wire
Dd: line in pairs
T: three-way
Q: four lines
M: multi-thread
Br: broadband (1) (R)-preparation (operation 1) of 3-(2-aminopropyl)-7-benzyloxy indoles barkite
To Fmoc-D-Ala-OH (23.35g 75mmol), methylene dichloride (240ml) and N, the suspension of dinethylformamide (0.39ml) dropwise adds oxalyl chloride, and (7ml, 80mmol), mixture continues to stir one hour in room temperature with under stirring.Reaction mixture is concentrated into dried under negative pressure, obtains containing the solid of Fmoc-D-Ala-Cl, and it is without being further purified and being used for following reaction.(operation 2)
To the commercially available 7-benzyloxy indoles in methylene dichloride (100ml) (11.2g, 50mmol) under argon atmospher, to add methyl magnesium bromine (50ml, the diethyl ether solution of 3M 150mmol) in ice-cooled and the solution that stirs.This mixture is heated in room temperature, restir one hour.Add Fmoc-D-Ala-Cl that operation 1 obtains at dichloromethane solution (200ml) at ice-cooled downhill reaction mixture.This mixture is heated to room temperature, restir one hour.Add the 5% spirit of salt aqueous solution (100ml) to mixture down ice-cooled, the whole stirring 15 minutes.Isolate organic layer water (100ml) washing, and dry on anhydrous magnesium sulfate.Evaporating solvent under negative pressure is contained (R)-7-benzyloxy-3-[[2-(9-fluorenylmethyloxycarbonyl) amino] propionyl] oil of indoles, without being further purified and being used in down in the step operation.(operation 3)
In the mixture of the oil that obtains by operation 2 and acetonitrile (100ml) and 2-propyl alcohol (15.03ml) stir and room temperature under gradation interpolation sodium borohydride (5.67g, 150mmol), this mixture is through refluxing 5 hours.Reaction mixture is chilled to room temperature, and is added dropwise to methyl alcohol (100ml) to it.Reaction mixture is concentrated into dried under negative pressure.Add vinyl acetic monomer (250ml) and water (100ml) afterwards to residue, stir the mixture.Isolate organic layer, water (100ml) washing, and dry on anhydrous magnesium sulfate.Remove inorganic substance, and add oxalic acid (4.50g, 50mmol) solution in vinyl acetic monomer (45ml) to the gained material in room temperature with under stirring.The crystal that is precipitated out is collected after filtration, with vinyl acetic monomer washing and dry, obtains the title compound (11.2g, 61%) as white crystal, fusing point 206-208 ℃.
[α] D
25=-46.2 ° (c=1.0, N, dinethylformamide);
1H-NMR composes (200MHz, DMSO-d
6, δ ppm): 1.14 (3H, d, J=7Hz), 2.80 (1H, dd, J=14Hz, J=8Hz), 3.03 (1H, dd, J=14Hz, J=5Hz), 3.42 (1H, m), 5.26 (2H, s) 5.94 (4H, br), 6.75 (1H, d, J=8Hz), 6.92 (1H, t, J=8Hz), 7.11-7.22 (2H, m), 7.32-7.48 (3H, m) 7.51-7.62 (2H, m), 11.11 (1H, s).(2) (R)-preparation of 3-(uncle 2--butoxy carbonyl amino propyl group)-7-benzyloxy indoles:
(50g 135mmol), stirs this mixture (R)-3-(2-aminopropyl)-7-benzyloxy indoles barkite that (1) obtains above adding in the mixture of salt of wormwood (28g), water (500ml) and vinyl acetic monomer (250ml).Then, (29.5g, 135mmol), mixture at room temperature stirred 3 hours to add two-tert-butyl supercarbonate in ice-cold and stirred mixture.Isolate organic layer, with saturated aqueous sodium chloride (150ml) washing, dry on anhydrous magnesium sulfate.Evaporating solvent under negative pressure, and just adding-hexane (150ml) to residue.The crystal that is settled out is collected by filtering, and drying obtains the title compound (47.2g, 92%) as white crystal, fusing point 94-95 ℃.
[α] D
25=-21.0 ° (c=1.0, methyl alcohol);
1H-NMR composes (300MHz, CHCl
3, δ ppm): 1.11 (3H, d, J=6.6Hz), 1.43 (9H, s), 2.83 (1H, dd, J=14.5Hz, J=6.7Hz), 2.94 (1H, dd, J=14.5Hz, J=5.1Hz), 4.00 (1H, m), 4.44 (1H, m), 5.18 (2H, s), 6.71 (1H, d, J=7.5Hz), 6.97 (1H, d, J=2.2Hz), 7.02 (1H, t, J=7.9Hz), 7.20 (1H, s), 7.24-7.51 (5H, m), 8.30 (1H, s).
Optical purity: 98.5%ee[analysis condition: post (CHIRALPAK AD (diameter 4.6mm * 250mm: make)) by DAICEL CHEMICAL INDUSTRIES company; Mobile phase (just-hexane: Virahol=70: 30); Flow (0.8ml/min) temperature (25 ℃); Detect wavelength (254nm); The residence time (8.8min)] (3) N, N-diethyl-[3-[[(2R)-t-butoxycarbonyl amino]-propyl group]-1H-indoles-7-base oxygen base] preparation of ethanamide:
To (the R)-7-benzyloxy-3-that obtains by top (2) (2-t-butoxycarbonyl amino propyl group) indoles (10g, 26.3mmol) add 10% the palladium on carbon (0.5g) in ice-cold in methyl alcohol (100ml) and the solution that stirs, the hydrogenation 2 hours under the normal atmosphere of hydrogen and room temperature of this mixture.After the theoretical amount that has consumed hydrogen, remove catalyzer, and at the few evaporating solvent of decompression.Residue is dissolved in the acetone (60ml), and adds salt of wormwood (4.54g), N to solution, the N-diethylchloro-acetamide (4.72g, 31.6mmol) and potassiumiodide (0.55g), and mixture backflow 4 hours.With after ice-cooled, remove insolubles after filtration, the vapourisation under reduced pressure solvent.Add chloroform (100ml) and water (100ml) to residue, mixture is stirred, isolate chloroform layer and drying on anhydrous magnesium sulfate.The vapourisation under reduced pressure solvent, and to residue interpolation diisopropyl ether (30ml).The crystal that is settled out is collected by filtering, drying, obtains the title compound as white crystal, 142 ℃ of fusing points.
[α] D
25=-26.3 ° (c=1.0, methyl alcohol);
1H-NMR composes (300MHz, CDCl
3, δ ppm): 1.10 (3H, d, J=6.6Hz), 1.17 (3H, t, J=7.1Hz), 1.22 (3H, t, J=7.1Hz), 1.43 (9H, s), 2.83 (1H, dd, J=14.1Hz, J=7.0Hz), 2.94 (1H, dd, J=14.1Hz, J=5.1Hz), 3.34 (2H, q, J=7.1Hz), 3.44 (2H, q, J=7.1Hz), 3.99 (1H, br), 4.45 (1H, br), 4.80 (2H, s), 6.67 (1H, d, J=7.7Hz), 6.99 (1H, t, J=7.9Hz), 7.10 (1H, s), 7.30 (1H, d, J=7.9Hz), 9.41 (1H, s).
Optical purity:＞99%ee[analysis condition: post (CHIRALPAK AD (diameter 4.6mm * 250mm: make)) by DAICEL CHEMICAL INDUSTRIES company; Mobile phase (just-hexane: Virahol=50: 50); Flow (0.8ml/min); Temperature (25 ℃); Detect wavelength (254nm); The residence time (6.6min)] (4) N, N-diethyl-[3-(2R)-aminopropyl]-1H-indoles-7-base oxygen base] preparation of ethanamide:
To the N that obtains from top (3), the N-diethyl-[3-[[(2R)-tertbutyloxycarbonyl-amino]-1H-indoles-7-base oxygen base] ethanamide (12g, 29.7mmol) (10.71g, 119mmol), this mixture refluxed 2 hours to add oxalic acid in the solution in acetonitrile (120ml).Mixture is with ice-cooled, and the crystal that is settled out is collected by filtering, and washs with acetonitrile.Add 10% wet chemical (50ml) and chloroform (120ml) to the gained crystal, mixture is stirred.Isolate chloroform layer and drying on anhydrous magnesium sulfate.Evaporating solvent under negative pressure, and to residue interpolation dipropyl ether (30ml).The crystal that is precipitated out is collected by filtering, and drying obtains the title compound (6.84g, 75%) as white crystal, 133 ℃ of fusing points.
[α] D
25=-46.3 ° (c=1.0, methyl alcohol);
1H-NMR composes (300MHz, CDCl
3, δ ppm): 1.16 (3H, d, J=6.6Hz), 1.17 (3H, t, J=7.1Hz), 1.22 (3H, t, J=7.1Hz), 1.40-2.00 (2H, br), 2.64 (1H, dd, J=14.1Hz, J=8.2Hz), 2.86 (1H, dd, J=14.1Hz, J=5.0Hz), 3.18 (1H, m), 3.35 (2H, q, J=7.1Hz), 3.44 (2H, q, J=7.1Hz), 4.80 (2H, s), 6.68 (1H, d, J=7.5Hz), 6.99 (1H, t, J=7.9Hz), 7.05 (1H, s), 7.28 (1H, d, J=8.0Hz), 9.42 (1H, s).
Optical purity:＞99ee[analysis condition: post (CHIRALPAK AD (diameter 4.6mm * 250mm: make)) by DAICEL CHEMICAL INDUSTRIES company; Mobile phase (just-and hexane: Virahol: diethylamine=85: 15: 0.8); Flow (1.0ml/min); Temperature (25 ℃); Detect wavelength (254nm); The residence time (19.9min)].(5) N, N-diethyl-[3-[(2R)-[[(2R)-(3-chloro-phenyl-)-2-hydroxyethyl] amino] propyl group]-1H-indoles-7-base oxygen base] preparation of ethanamide:
To the N that obtains by top (4), the N-diethyl-[3-[(2R)-aminopropyl]-1H-indoles-7-base oxygen base] ethanamide (21g, 69.2mmol) (11.77g, 76.1mmol), this mixture refluxed 5 hours to add (R)-3-chloro-styrene oxide compound in the solution in acetonitrile (42ml).Mixture is with ice-cooled, and adds diisopropyl ether (168ml) to it.The crystal that is settled out is collected by filtering, and drying obtains the title compound (16.99g, 54%) as white crystal.On the other hand, the filtrate of containing unreacted initial substance under reduced pressure is concentrated into dried, and adds acetonitrile (21ml) and (R)-3-chloro-styrene oxide compound (1.07g again in residual, 6.9mmol), mixture refluxed 6 hours, and mixture is with ice-cooled, and to its interpolation diisopropyl ether (63ml).The crystal that is settled out is collected by filtering, and drying obtains title compound (2.86g, 9%), fusing point 120-121 ℃.
[α] D
25=-69.1 ° (c=1.0, methyl alcohol);
1H-NMR composes (300MHz, CDCl
3, δ ppm): 1.11 (3H, d, J=6.2Hz), 1.16 (3H, t, J=7.1Hz), 1.22 (3H, t, J=7.1Hz), 2.66 (1H, dd, J=12.2Hz, J=9.2Hz), 2.81 (2H, d, J=6.6Hz), 2.87 (1H, dd, J=12.2Hz, J=3.7Hz), 3.00 (1H, m), 3.34 (2H, q, J=7.1Hz), 3.43 (2H, q, J=7.1Hz), 4.54 (1H, m), 4.78 (2H, s), 6.65 (1H, d, J=7.3Hz), 6.98 (1H, t, J=7.9Hz), 6.99 (1H, s), and 7.12-7.30 (4H, m), 7.34 (1H, s), 9.60 (1H, s). (6) [3-[(2R)-[[(2R)-(3-chloro-phenyl-)-2-hydroxyethyl]-amino] propyl group]-1H-indoles-7-base oxygen base] preparation of acetic acid (compd A):
The N that top (5) are obtained, the N-diethyl-[3-[(2R)-[[(2R)-(3-chloro-phenyl-)-2-hydroxyethyl]-amino] propyl group]-1H-indoles-7-base oxygen base] ethanamide (4g, 8.7mmol) join potassium hydroxide (1.96g, 34.9mmol) in the solution in the aqueous ethanolic solution (32ml) 50%, this mixture refluxed 3 hours, and was cooled to room temperature.Mixture be dissolved in acetic acid (2.3g, 38.4mmol) in, and at room temperature stir and spend the night.The crystal that is settled out is collected by filtering, and drying obtains the title compound (3.1g, 88%) as white crystal, fusing point 230-231 ℃.
[α] D
25=-24.4 ° (c=1.0,1N aqueous sodium hydroxide solution);
1H-NMR composes (200MHz, DMSO-d
6, δ ppm): 0.93 (3H, d, J=7Hz), 2.61 (1H, m), 2.80-3.22 (4H, m), 4.54 (2H, s), 4.90 (1H, m), 6.48 (1H, d, J=8Hz), 6.76 (1H, t, J=8Hz), 6.89-7.02 (2H, m), 7.28-7.40 (3H, m), 7.46 (1H, s), 11.01 (1H, s).
Optical purity:＞99%ee[analysis condition: post (CHIRAL-AGP (diameter 4.0mm * 100mm: make)) by SKINWA KAKO company; Mobile phase ((20mM Na
2HPO
4+ 2mM tetrabutyl ammonium bisulfite) the aqueous solution (pH7.0): Virahol=98: 2); Flow (0.7ml/min); Temperature (30 ℃); Detect wavelength (220nm); The residence time (27.4min)].
The crystal of the compd A that obtains by this way X-ray powder diffraction instrument (the RINT1000 type is by the preparation of RIGAKU CORPARATION company), tube voltage is 30kV, tube current is 20mA, utilizes CuK
αLine is by diffraction angle (2 θ) measured X x ray diffration pattern x, and its diffractogram is shown in Fig. 1.The diffraction angle of the crystalline X-ray powder diffraction pattern of compd A is about 5.9 °, 17.9 °, 18.8 °, 20.5 °, 23.3 °, 24.0 ° and 24.9 °, has located characteristic peak at about 5.9 °, 17.9 °, 20.5 ° and 24.0 °.The value of diffraction angle (2 θ) has the standard accuracy.
Preparation 2
The preparation of the II N-type waferN of compd A:
Interpolation methyl alcohol (35ml) in the I N-type waferN (100mg) of the compd A that obtains in 1 in preparation, this mixture are dissolved in heating in 100 ℃ the water-bath.The crystal that is settled out is by filter collecting, and drying obtains the II N-type waferN of compd A.
The II N-type waferN of the compd A that obtains is by this way pressed at pipe with X-ray powder diffraction instrument (RINT ULTIMA type is made by RIGAKO CORPARATION company) and is 40kV, and tube current is to utilize CuK under the 30mA
αLine is measured x-ray diffraction pattern by diffraction angle (2 θ), and its diffractogram is shown in Fig. 2.The diffraction angle of the x-ray diffraction pattern of the II N-type waferN of compd A is about 5.9 °, 17.5 °, 19.4 °, 20.8 °, 23.3 °, 24.0 ° and 24.9 °, and characteristic peak is located about 5.9 °, 17.5 °, 20.8 ° and 23.3 ° greatly.The value of diffraction angle (2 θ) has the standard accuracy.
Preparation 3The preparation of medicine: (1) utilizes beater grinder (SampleMill AP-S, by Hosokawa Micro Corparation, Japan makes) and utilizes the sieve of aperture 0.7mm to carry out micronization the I N-type waferN for preparing the compd A that makes in 1.(2) in addition, utilizing the fluid can pulverizer (Single Truck Jet Mill FS-4, by SEISHIN ENTERPRISE company, Japan makes) the I N-type waferN of the compd A that makes in the preparation 1, be 7kgf/cm at compressed air pressure
2Under carry out micronization.(3) the various micronized particle that obtains by this way cumulative weight distribution value be 50% and 95% o'clock granularity utilize laser diffraction granularity distributional analysis instrument (HELOS ﹠amp; RODOS (trade mark) is made by the Germany of SYMPATEC company) measure, and calculate (dispersion air pressure: 1atm) with the dry air dispersion method from the cumulative particle sizes distribution of calculating according to body.(1) the crystalline granularity that obtains in is to be not more than 21 μ m at 50% o'clock and is to be not more than 75 μ m at 95% o'clock in cumulative weight distribution value in cumulative weight distribution value.(2) the crystalline granularity that obtains in is to be not more than 1.7 μ m at 50% o'clock and is to be not more than 3.8 μ m at 95% o'clock in cumulative weight distribution value in cumulative weight distribution value.All can obtain its granularity by arbitrary method of micronization is that to be not more than 100 μ m and its granularity at 50% o'clock be to be not more than the crystal of the compd A of 200 μ m at 95% o'clock in cumulative weight distribution value in cumulative weight distribution value.
Test 1The granularity of medicine:
Scheme according to table 2, to medicine or under agitation do not add water in the mixed powder of crystal, lactose, low-substituted hydroxypropyl cellulose and the hydroxypropylcellulose of micronized compd A, obtain particulate matter (mediate and granulate), latter's drying and size adjusting obtain particle.The particle that obtains like this and crystalline cellulose, light body anhydrous silicic acid and Magnesium Stearate mix, and repressedly obtain every and contain 1mg medicine or not micronized compd A crystalline tablet.Adopt beater grinder (Sample Mill AP-S, by Hosokawa Micron Corporation company, Japan makes) and utilize the aperture to be the micronized medicine of the sieve of 0.7mm or 1.0mm, perhaps utilize fluid energy pulverizer (Single Truck Jet Mill FS-4, by SEISHINENTERPRISE company, Japan makes), be 7kgf/cm at compressed air pressure
2The micronized medicine that obtains has different granularities down, and data are listed in table 3, and these medicines all are used.The solubility test of the tablet that makes like this according to complete works of the 13 edition of Japanese pharmacy (blade stirs, 50rpm, 37 ℃ in water 900ml) carries out, the observed value of the dissolution rate of the relation between drug particle size and its dissolving during with 15 minutes is evaluated.The results are shown in table 3.
Table 2
| Composition | Weight (mg) | |
| Particle | The medicine or the crystalline lactose low-substituted hydroxypropyl cellulose hydroxypropylcellulose of micronized compd A not | ??1 ??70 ??10 ??2.5 |
| Outer vehicle | The light body anhydrous silicic acid of crystalline cellulose Magnesium Stearate | ??15 ??1 ??0.5 |
| Add up to | ??100 | |
Table 3
| Method of micronization | Cumulative weight distribution value is 50% o'clock a granularity (μ m) | Cumulative weight distribution value is 95% o'clock a granularity (μ m) | Dissolution rate (%) after 15 minutes | |
| Test 1-1 | Fluid can pulverizer | 1.7 | 3.8 | ??100 |
| Test 1-2 | Beater grinder (sieve diameter 0.7mm) | 9.4 | 43 | ??97 |
| Test 1-3 | Beater grinder (sieve diameter 0.7mm) | 17 | 42 | ??100 |
| Test 1-4 | Beater grinder (sieve diameter 0.7mm) | 21 | 75 | ??99 |
| Test 1-5 | Beater grinder (sieve diameter 0.7mm) | 12.5 | 45 | ??100 |
| Test 1-6 | Beater grinder (sieve diameter 1.0mm) | 45 | 144 | ??96 |
| Simultaneous test 1-1 | Not micronization | 85 | 366 | ??60 |
Adopting cumulative weight distribution value is that 50% o'clock granularity is not more than 100 μ m and is that the tablet that medicine that 95% o'clock granularity is not more than 200 μ m is made shows that dissolution rate is 100% in the time of 15 minutes in cumulative weight distribution value, and its dissolving power is good.
Test 2Medicine and the components by weight of the vehicle except that medicine in particle:
Utilize fluidised bed granulator and drying machine to medicine (above the used medicine of test 1-3 be used to test 2-1 and simultaneous test 2-1; test 1-2 used medicine is used to test 2-2 above), the aqueous solution of the mixed powder spraying hydroxypropylcellulose of lactose and low-substituted hydroxypropyl cellulose, and granulate and dry to obtain particle.As shown in table 4, prepared three kinds of particles here, wherein the content difference of the vehicle except that medicine in particle promptly counted 82.5 weight parts (test 2-1) by 1 weight part medicine, 417 weight parts (test 2-2) and 834 weight parts (simultaneous test 2-1).Add the crystalline cellulose of fixed amount, light body anhydrous silicic acid and Magnesium Stearate to every kind of particle, and mixture is pressed into tablet.Tablet was stored 4 months under the condition of 40 ℃-75%RH (relative humidity), has measured the content of all decomposition prods that derives from medicine, and calculate its increment from original bulk.The results are shown in table 5.
Table 4
| Component | Test 2-1 | Test 2-2 | Simultaneous test 2-1 | |
| Particle | Medicine lactose low-substituted hydroxypropyl cellulose hydroxypropylcellulose | ????1 ????70 ????10 ????2.5 | ????0.2 ????70.8 ????10 ????2.5 | ??0.1 ??70.9 ??10 ??2.5 |
| Outer vehicle | The light body anhydrous silicic acid of crystalline cellulose Magnesium Stearate | ????15 ????1 ????0.5 | ????15 ????1 ????0.5 | ??15 ??1 ??0.5 |
| Add up to | ????100 | ????100 | ??100 | |
| The weight part of the vehicle in the 1 weight part drug particles except that medicine | ????82.5 | ????417 | ??834 | |
Table 5
| Test 2-1 | Test 2-2 | Simultaneous test 2-1 | |
| The increasing amount of all decomposition prods (%) | 0.20 | 0.69 | 1.45 |
In the tablet of test 2-1 and 2-2, the amount of all decomposition prods is all compared littler than the tablet of test 2-1, in the particle of simultaneous test contained vehicle except that medicine by 1 weight part medicine greater than 500 weight parts, this fact proved that the chemical stability of medicine itself is high in the tablet of test 2-1 and 2-2.
Test 3
The weight proportion of composing of particle Chinese traditional medicine and the vehicle except that medicine:
According to the scheme of table 6, in the mixed powder of lactose and low-substituted hydroxypropyl cellulose, add the solution of hydroxypropylcellulose in pure water to obtain particulate matter (mediate and granulate), particulate matter drying and size adjusting obtain outer excipient granule.
Table 6
| Form | Weight (mg) | |
| Outer excipient granule | Lactose low-substituted hydroxypropyl cellulose hydroxypropylcellulose | ????71 ????10 ????2.5 |
| Add up to | ????83.5 | |
Mixed powder to medicine (testing 1-4's above being used for), lactose and low-substituted hydroxypropyl cellulose adds the aqueous solution of hydroxypropylcellulose in purifying to obtain particulate matter (mediate and granulate), and drying and size adjusting obtain particle.From these particles, obtain 4 kinds of particles, wherein the content of the vehicle except that medicine in particle is different, by 1 weight part medicine as being 416.5 weight parts (tests 3-1, test 3-2), 1001 weight parts (simultaneous test 3-1), 1251.5 weight parts (simultaneous test 3-2).In 4 kinds of particles, add the outer excipient granule that obtains according to last table 6 scheme, crystalline cellulose, the tablet (test 3-1) that light body water silicic acid and Magnesium Stearate, every of the repressed one-tenth of this mixture contain the 0.1mg medicine and count the outer vehicle of 1.87 weight parts by 1 weight part medicine, the tablet (test 3-2) that contains the 0.2mg medicine and count the outer vehicle of 2.59 weight parts by 1 weight part medicine, the tablet (simultaneous test 3-1) that contains the 0.1mg medicine and count the outer vehicle of 0.20 weight part by 1 weight part medicine, with the tablet (simultaneous test 3-2) that contains the 0.2mg medicine and count the outer vehicle of 0.2 weight part by 1 weight part medicine.These tablets were stored one month under the condition of 40 ℃-75%RH (relative humidity), and the content of all decomposition prods that derives from medicine is measured with the HPLC (high performance liquid chromatography) instrument, and calculates its increasing amount from original bulk.The results are shown in table 8.
Table 7
| Component | Test 3-1 | Test 3-2 | Simultaneous test 3-1 | Simultaneous test 3-2 | |
| Particle | The low hydroxypropylcellulose hydroxypropylcellulose that replaces of medicine lactose | ????0.1 ????35.4 ????5 ????1.25 | ????0.2 ????70.8 ????10 ????2.5 | ??0.1 ??85.1 ??12 ??3 | ????0.2 ????212.8 ????30 ????7.5 |
| Outer vehicle | The light body anhydrous silicic acid of outer excipient granule crystalline cellulose Magnesium Stearate | ????58.45 ????18 ????1.2 ????0.6 | ????167 ????45 ????3 ????1.5 | ??- ??18 ??1.2 ??0.6 | ????- ????45 ????3 ????1.5 |
| Add up to (mg) | ????120 | ????300 | ??120 | ????300 | |
| The weight part of the vehicle in the 1 weight part drug particles except that medicine | ????416.5 | ????416.5 | ??1001 | ????1251.5 | |
| The weight part of 1 weight part particle China and foreign countries vehicle | ????1.87 | ????2.59 | ??0.20 | ????0.20 | |
Table 8
| Test 3-1 | Test 3-2 | Simultaneous test 3-1 | Simultaneous test 3-2 | |
| The increment (%) of whole degradation productions | 0.75％ | 0.83％ | 1.31％ | 1.76％ |
In the tablet of test 3-1 and 3-2, all the comparison of the generation of degradation production is lacked than the tablet of test 3-1 and 3-2, and this fact proved, the chemical stability height of test 3-1 and 3-2 tablet Chinese traditional medicine itself.
Test 4Pre-mixing in the granules preparation:
According to the scheme of table 9, once respectively contained the tablet of 0.05mg medicine (top test 1-5 is used).If medicine utilizes mixing screen (50 purposes stainless steel sift=test 3-1) in advance or utilizes nodulizer (beater grinder=test 3-2) to mix and micronization with lactose when the preparation particle, and adds low-substituted hydroxypropyl cellulose and hydroxypropylcellulose to it.Under agitation water is added mixture, obtain particulate matter (mediate and granulate), drying and size adjusting obtain particle.Add crystalline cellulose, light body anhydrous silicic acid and Magnesium Stearate in the particle that this mode obtains, and mix, mixture is pressed into tablet.The content homogeneity of the tablet that this mode obtains detects (be lower than in view of the above 15% result think meet the demands) according to the content uniformity test in complete works of the 13 edition of the Japanese medicine.The results are shown in table 10.
Table 9
| Form | Weight (mg) | |
| Particle | Medicine lactose low-substituted hydroxypropyl cellulose hydroxypropylcellulose | ????0.05 ????17.7 ????2.5 ????0.625 |
| Outer vehicle | The light body anhydrous silicic acid of crystalline cellulose Magnesium Stearate | ????3.75 ????0.25 ????0.125 |
| Add up to | ????25 | |
Table 10
| Test 4-1 | Test 4-2 | |
| Method for pre mixing | Stainless steel sift | Beater grinder |
| Uniformity of dosage units (%) | ??10.0 | ??4.0 |
In the uniformity of dosage units test of complete works of the 13 edition of Japanese medicine, be lower than that 15% result is considered to meet the demands.Since the uniformity testing of the tablet of test 4-1 and 4-2 as a result both all below 15%, so the homogeneity of medicament contg is retained in the tablet.
Embodiment 1
According to the scheme of table 11, once respectively contained the tablet of 1mg medicine (as mentioned above, used in test 1-3).If when the preparation particle, medicine utilizes beater grinder to mix with lactose in advance and sieves, and adds low-substituted hydroxypropyl cellulose and hydroxypropylcellulose to it.Water under agitation is added to obtains particle in the mixture (mediate to granulate, drying and size adjusting obtain granularity and be to be not more than 250 μ m at 50% o'clock and be to be not more than the particle of 600 μ m at 95% o'clock in cumulative weight distribution value in cumulative weight distribution value.The particle that obtains like this mixes the repressed one-tenth tablet of mixture with crystalline cellulose, light body anhydrous silicic acid and Magnesium Stearate.The tablet that obtains like this has suitable size and uniformity of dosage units, and has kept stability of drug, and the dissolving of medicine from tablet is fast.
Table 11
Embodiment 2
| Form | Weight (mg) | |
| Particle | Medicine lactose low-substituted hydroxypropyl cellulose hydroxypropylcellulose | ??1 ??70 ??10 ??2.5 |
| Outer vehicle | The light body anhydrous silicic acid of crystalline cellulose Magnesium Stearate | ??15 ??1 ??0.5 |
| Add up to | ??100 | |
According to the scheme of table 12, obtained respectively containing the tablet of 0.1mg medicine (above-mentioned test 1-5's).When the preparation particle, medicine mixes with lactose with beater grinder in advance and sieves, and adds low-substituted hydroxypropyl cellulose and hydroxypropylcellulose to it.Water is under agitation added mixture, obtain particulate matter (mediate granulate), drying and size adjusting obtain having granularity and are to be not more than 250 μ m at 50% o'clock and are to be not more than the particle of 600 μ m at 95% o'clock in cumulative weight distribution value in cumulative weight distribution value.The particle that obtains like this mixes the repressed one-tenth tablet of mixture with crystalline cellulose, light body anhydrous silicic acid and Magnesium Stearate.The tablet that obtains like this has suitable size and uniformity of dosage units, and has kept stability of drug, and medicine dissolves from tablet soon.
Table 12
Embodiment 3
| Form | Weight (mg) | |
| Particle | Medicine lactose low-substituted hydroxypropyl cellulose hydroxypropylcellulose | ??1 ??35.3 ??5 ??1.25 |
| Outer vehicle | The light body anhydrous silicic acid of crystalline cellulose Magnesium Stearate | ??7.5 ??0.5 ??0.25 |
| Add up to | ??50 | |
According to the scheme of table 13, obtained respectively containing the tablet of 0.05mg medicine (being used in above-mentioned test 1-5's).When the preparation particle, medicine mixes with lactose with beater grinder in advance and sieves, and adds low-substituted hydroxypropyl cellulose and hydroxypropylcellulose to it.Water is under agitation added mixture, obtain particulate matter (mediate granulate), it is that 50% o'clock granularity is not more than 250 μ m and is the particle that 95% o'clock granularity is not more than 600 μ m in cumulative weight distribution value that drying and size adjusting obtain having in cumulative weight distribution value.The particle that obtains like this mixes the repressed one-tenth tablet of mixture with crystalline cellulose, light body anhydrous silicic acid and Magnesium Stearate.The tablet that obtains like this has suitable size and uniformity of dosage units, and has kept stability of drug, and medicine dissolves from tablet soon.
Table 13
Embodiment 4
| Form | Weight (mg) | |
| Particle | Medicine lactose low-substituted hydroxypropyl cellulose hydroxypropylcellulose | ????0.05 ????17.7 ????2.5 ????0.625 |
| Outer vehicle | The light body anhydrous silicic acid of crystalline cellulose Magnesium Stearate | ????3.75 ????0.25 ????0.125 |
| Add up to | ????25 | |
According to the scheme of table 14, obtained respectively containing the 0.2g medicine tablet of (being used for above-mentioned test 1-3's).Mixed powder to medicine, low-substituted hydroxypropyl cellulose and hydroxypropylcellulose under agitation adds water, obtains granularity and is worth in the cumulative weight distribution and was not more than 350 μ m at 50% o'clock and is worth the particle that was not more than 1000 μ m at 95% o'clock in the cumulative weight distribution.The particle that obtains like this mixes the repressed one-tenth tablet of mixture with crystalline cellulose, light body anhydrous silicic acid and Magnesium Stearate.The tablet that obtains like this has suitable size and uniformity of dosage units, has kept stability of drug, and medicine dissolves from tablet soon.
Table 14
Embodiment 5
| Form | Weight (mg) | |
| Particle | Medicine lactose low-substituted hydroxypropyl cellulose hydroxypropylcellulose | ??0.2 ??70.8 ??10 ??2.5 |
| Outer vehicle | The light body anhydrous silicic acid of crystalline cellulose Magnesium Stearate | ??15 ??1 ??0.5 |
| Add up to | ??100 | |
Scheme according to table 15, to the mixed powder spraying hydroxypropylcellulose of medicine (being used for above-mentioned test 1-4's), lactose and the low hydroxypropylcellulose that replaces solution at pure water, obtain particulate matter (fluidized bed granulation), drying and size adjusting obtain particle.The particle that obtains like this mixes with crystalline cellulose, light body water silicic acid, and the repressed one-tenth of mixture respectively contains the tablet of 0.5mg medicine.The tablet that obtains like this has suitable size and uniformity of dosage units, has kept stability of drug, and medicine dissolves from tablet soon.
Table 15
Embodiment 6
| Form | Weight (mg) | |
| Particle | Medicine lactose low-substituted hydroxypropyl cellulose hydroxypropylcellulose | ????0.5 ????84.7 ????12 ????3 |
| Outer vehicle | The light body anhydrous silicic acid of crystalline cellulose Magnesium Stearate | ????18 ????1.2 ????0.6 |
| Add up to | ????120 | |
Scheme according to table 16, the solution of mixed powder spraying hydroxypropylcellulose in pure water to medicine (used), lactose, low-substituted hydroxypropyl cellulose at above-mentioned test 1-4, obtain particulate matter (fluidized bed granulation), drying and size adjusting obtain particle.The particle that obtains like this mixes with outer excipient granule, crystalline cellulose and light body water silicic acid, and the repressed one-tenth of mixture respectively contains the tablet of 0.5mg medicine.The tablet that obtains like this has suitable size and uniformity of dosage units, has kept stability of drug, and medicine dissolves from tablet soon.
Table 16
Embodiment 7
| Form | Weight (mg) | |
| Particle | Medicine lactose low-substituted hydroxypropyl cellulose hydroxypropylcellulose | ????0.5 ????169.39 ????24 ????6 |
| Outer vehicle | The light body anhydrous silicic acid of crystalline cellulose Magnesium Stearate | ????36 ????2.4 ????1.2 |
| Add up to | ????240 | |
According to the scheme of table 7, the solution of mixed powder spraying hydroxypropylcellulose in pure water to lactose and low-substituted hydroxypropyl cellulose obtains particulate matter (fluidized bed granulation), and drying and size adjusting obtain outer excipient granule.
Table 17
| Form | Weight (mg) | |
| Outer excipient granule | Lactose low-substituted hydroxypropyl cellulose hydroxypropylcellulose | ??71 ??10 ??2.5 |
| Add up to | ??83.5 | |
Scheme according to table 18, the solution of mixed powder spraying hydroxypropylcellulose in pure water to medicine (in above-mentioned test 1-4, using), lactose and low-substituted hydroxypropyl cellulose, obtain particulate matter (fluidized bed granulation), drying and size adjusting obtain particle.The particle that obtains like this mixes with the outer excipient granule that obtains according to table 17 scheme, crystalline cellulose and light body water silicic acid, and the repressed one-tenth of mixture respectively contains the tablet of 0.1mg medicine.The tablet that obtains like this has suitable size and uniformity of dosage units, has kept stability of drug, and medicine dissolves from tablet soon.
Table 18
Embodiment 8
| Form | Weight (mg) | |
| Particle | Medicine lactose low-substituted hydroxypropyl cellulose hydroxypropylcellulose | ????0.1 ????35.4 ????5 ????1.25 |
| Outer vehicle | The light body anhydrous silicic acid of outer excipient granule crystalline cellulose Magnesium Stearate | ????58.45 ????18 ????1.2 ????0.6 |
| Add up to | ????120 | |
Scheme according to table 19, the solution of mixed powder spraying hydroxypropylcellulose in pure water to medicine (used), lactose and low-substituted hydroxypropyl cellulose at above-mentioned test 1-4, obtain particulate matter (fluidized bed granulation), drying and size adjusting obtain particle.The particle that obtains like this mixes with outer excipient granule, crystalline cellulose and light body water silicic acid, and the repressed one-tenth of mixture respectively contains the tablet of 0.2mg medicine.The tablet that obtains like this has suitable size and uniformity of dosage units, has kept stability of drug, and medicine dissolves from tablet soon.
Table 19
| Form | Weight (mg) | |
| Particle | Medicine lactose low-substituted hydroxypropyl cellulose hydroxypropylcellulose | ??0.2 ??70.8 ??10 ??2.5 |
| Outer vehicle | The light body anhydrous silicic acid of outer excipient granule crystalline cellulose Magnesium Stearate | ??167 ??45 ??3 ??1.5 |
| Add up to | ??300 | |
Industrial applicibility
Have granularity and distribute in cumulative weight that be not more than 100 μ m 50% the time and distribute the crystal (medicine of the present invention) that is not more than the compounds of this invention A of 200 μ m 95% time in cumulative weight can be as the raw material of preparation. Medicine of the present invention shows strong β3-adrenocepter-stimulating activity, and it is selective to have an excellent adrenocepter, therefore, it can be used for prevention or treatment obesity or diabetes. The preparation that contains medicine of the present invention is a kind of preparation of excellence, it is characterized in that, the uniformity of the size of preparation (volume), medicament contg and the stability of medicine are guaranteed, and the stripping of medicine from preparation is fast.
Claims (17)
1. one kind [3-[(2R)-[[(2R)-(3-chloro-phenyl-)-2-hydroxyethyl]-amino] propyl group]-1H-indoles-7-base oxygen base] crystal of acetic acid.
2. one kind [3-[(2R)-[[(2R)-(3-chloro-phenyl-)-2-hydroxyethyl]-amino] propyl group]-1H-indoles-7-base oxygen base] crystal of acetic acid, this crystal is positioned at diffraction angle (2 θ) and is about 5.9 °, 17.9 °, 20.5 ° and 24.0 ° and has located characteristic peak on the X-ray powder diffraction pattern.
3. the crystal of claim 1, wherein, its granularity is worth to be not more than 100 μ m at 50% o'clock and to be worth in the cumulative weight distribution in the cumulative weight distribution and was not more than 200 μ m at 95% o'clock.
4. particle of forming by the crystal of claim 3.
5. the particle of claim 4, this particle by the crystal of (a) claim 3, (b) weighting agent, (c) decomposition agent and (d) tackiness agent form.
6. the particle of claim 5, wherein, the gross weight of weighting agent, decomposition agent and tackiness agent is by the crystal of 1 weight part claim 3, less than 500 weight parts.
7. solid preparation, said preparation contains the particle of claim 4.
8. the solid preparation of claim 7, said preparation comprises outer vehicle.
9. the solid preparation of claim 7, wherein, the crystalline content of claim 3 is that every dose unit is less than 2mg.
10. the solid preparation of claim 7, said preparation is figure of tablet.
11. a tablet, this tablet are to make by the particle compressing tablet of claim 4.
12. the tablet of claim 11, wherein the crystalline content of claim 3 is that every dose unit is not more than 2mg.
13. a tablet, this tablet are vehicle outside adding by the particle to claim 4, then the mixture compressing tablet are made.
14. the tablet of claim 13, wherein the crystalline content of claim 3 is that every dose unit is not more than 2mg.
15. β
3-2 adrenoceptor agonists, this stimulant contain right and require 3 crystal.
16. containing right, a medicament for the treatment of diabetes, this medicament require 3 crystal.
17. containing right, a medicament for the treatment of obesity, this medicament require 3 crystal.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP339547/1999 | 1999-11-30 | ||
| JP33954799 | 1999-11-30 | ||
| US09/661,577 US6458824B1 (en) | 1999-11-30 | 2000-09-14 | Solid preparation |
| US09/661,577 | 2000-09-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1433403A true CN1433403A (en) | 2003-07-30 |
Family
ID=26576443
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00818730A Pending CN1433403A (en) | 1999-11-30 | 2000-11-24 | Solid pharmaceutical preparation |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP1235801A2 (en) |
| JP (1) | JP2003515587A (en) |
| CN (1) | CN1433403A (en) |
| AU (1) | AU1550501A (en) |
| CA (1) | CA2391646A1 (en) |
| CZ (1) | CZ20021833A3 (en) |
| HU (1) | HUP0203865A3 (en) |
| IL (1) | IL149635A0 (en) |
| MX (1) | MXPA02005326A (en) |
| NO (1) | NO20022541L (en) |
| NZ (1) | NZ519086A (en) |
| PL (1) | PL356468A1 (en) |
| SK (1) | SK7362002A3 (en) |
| WO (1) | WO2001040182A2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1514869A1 (en) * | 2002-06-12 | 2005-03-16 | Sumitomo Pharmaceuticals Company, Limited | Indole, indazole, and benzazole derivative |
| EP1574220A4 (en) * | 2002-12-17 | 2006-01-18 | Wakunaga Pharma Co Ltd | Light-blocking agent and film-forming composition |
| RS57561B1 (en) * | 2004-01-20 | 2018-10-31 | Novartis Ag | Direct compression formulation and process |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR9509827A (en) * | 1994-11-29 | 1997-09-30 | Dainippon Pharmaceutical Co | Indole derivatives |
| JPH11255743A (en) * | 1998-03-06 | 1999-09-21 | Dainippon Pharmaceut Co Ltd | Production of optically active indole derivative and intermediate for producing the same |
-
2000
- 2000-11-24 EP EP00977904A patent/EP1235801A2/en not_active Withdrawn
- 2000-11-24 JP JP2001541868A patent/JP2003515587A/en not_active Withdrawn
- 2000-11-24 SK SK736-2002A patent/SK7362002A3/en not_active Application Discontinuation
- 2000-11-24 AU AU15505/01A patent/AU1550501A/en not_active Abandoned
- 2000-11-24 CA CA002391646A patent/CA2391646A1/en not_active Abandoned
- 2000-11-24 CN CN00818730A patent/CN1433403A/en active Pending
- 2000-11-24 IL IL14963500A patent/IL149635A0/en unknown
- 2000-11-24 HU HU0203865A patent/HUP0203865A3/en unknown
- 2000-11-24 WO PCT/JP2000/008283 patent/WO2001040182A2/en not_active Application Discontinuation
- 2000-11-24 CZ CZ20021833A patent/CZ20021833A3/en unknown
- 2000-11-24 MX MXPA02005326A patent/MXPA02005326A/en not_active Application Discontinuation
- 2000-11-24 NZ NZ519086A patent/NZ519086A/en unknown
- 2000-11-24 PL PL00356468A patent/PL356468A1/en not_active Application Discontinuation
-
2002
- 2002-05-29 NO NO20022541A patent/NO20022541L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU1550501A (en) | 2001-06-12 |
| EP1235801A2 (en) | 2002-09-04 |
| SK7362002A3 (en) | 2003-02-04 |
| NO20022541D0 (en) | 2002-05-29 |
| CZ20021833A3 (en) | 2003-02-12 |
| NZ519086A (en) | 2003-11-28 |
| WO2001040182A2 (en) | 2001-06-07 |
| JP2003515587A (en) | 2003-05-07 |
| NO20022541L (en) | 2002-07-29 |
| CA2391646A1 (en) | 2001-06-07 |
| WO2001040182A3 (en) | 2002-06-27 |
| PL356468A1 (en) | 2004-06-28 |
| MXPA02005326A (en) | 2003-02-12 |
| IL149635A0 (en) | 2002-11-10 |
| HUP0203865A2 (en) | 2003-03-28 |
| HUP0203865A3 (en) | 2004-05-28 |
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| PB01 | Publication | ||
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| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |