CN103030619B - C-crystal-form 5-methyl-7-methoxyiso-flavone and preparation method, pharmaceutical compositions and application of C-crystal-form 5-methyl-7-methoxyiso-flavone - Google Patents
C-crystal-form 5-methyl-7-methoxyiso-flavone and preparation method, pharmaceutical compositions and application of C-crystal-form 5-methyl-7-methoxyiso-flavone Download PDFInfo
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Abstract
The invention discloses a C-crystal-form 5-methyl-7-methoxyiso-flavone as well as a preparation method, pharmaceutical compositions and application of the C-crystal-form 5-methyl-7-methoxyiso-flavone. In particular, the invention discloses the C-crystal-form 5-methyl-7-methoxyiso-flavone at the solid state, the preparation method of a C-crystal-form sample, various preparations and pharmaceutical compositions prepared and developed by taking the 5-methyl-7-methoxyiso-flavone as an active ingredient, and the application of the preparations and pharmaceutical compositions for prevention of cardiovascular and cerebrovascular diseases, nervous system diseases, brittle-bone diseases, inflammation and metabolic diseases as well as in other disease medicines. The molecular structural formula of the 5-methyl-7-methoxyiso-flavone is shown in the specification.
Description
Technical field
The present invention relates to and found that 5-Methyl-7-Methoxyiso-flavone has crystal type A, crystal B-type, crystal C type three kinds of forms in the solid state; Relate to the preparation method having invented three kinds of crystal form samples.The invention still further relates to the application of 5-Methyl-7-Methoxyiso-flavone different crystal forms material in the medicine of preparation control diseases of cardiovascular and cerebrovascular systems, nervous system disorders, osteoporosis, metabolic disease, inflammation and other diseases.
Background technology
5-Methyl-7-methoxy-isoflavone is the derivative of ipriflavone, and systematic chemical name is 5-Methyl-7-Methoxyiso-flavone, and molecular structure is as follows:
There are some researches show that both pharmacological activities are similar, but 5-Methyl-7-methoxy-isoflavone activity is stronger, may be used for prevention bone loss and treatment skeletal diseases.Within 1979,5-Methyl-7-methoxy-isoflavone is applied for a patent [seeing United States Patent (USP): 4163746], but after this relevant report is less.Because 5-Methyl-7-methoxy-isoflavone can increase the metabolism retention rate to trace elements such as calcium, phosphorus, potassium, nitrogen in human body, now be applied to the control senile osteoporosis of the mankind and the fodder additives such as the immunomodulator of livestock and poultry and promotor, this compound is also used by the antioxidant as food simultaneously.
At the documents such as Kitagauia [Kitagawa, Masayuki; Yamamoto, Kenjiro; Katakura, Shinichi; Kanno, Hideyuki; Yamada, Koji; Et al.; Chem.Pharm.Bull., the preparation method of different oxygen chromocor compound is wherein described 1991,39 (10): 2681-2690]:
(1) with 3,5-dimethoxy-p for raw material, react with phenyllacetyl chloride, under aluminum chloride-zinc chloride catalysis, obtain 2-hydroxyl-4-methoxyl group-6-methyldesoxybenzoins;
(2) cyclization under triethyl orthoformate, pyridine, hexahydropyridine reaction conditions, obtains 5-Methyl-7-methoxy-isoflavone.The total recovery of this synthetic route is 19%.
At document [Qian Hongsheng, Chen Limin, the Hu Weixiao of Qian Hongsheng etc.The synthesis of 5-Methyl-7-methoxy-isoflavone.Applied chemistry, 2005,22 (2): 224-227] in, relate to the preparation of different oxygen chromocor compound, and it is preventing and treating the application in the medium disease of senile osteoporosis, there is shown the novel preparation method of different oxygen chromocor compound:
(1) with 3 ,-orcin is raw material, reacts obtained 2,4-dihydroxyl-6-methyldesoxybenzoins through there is Hoesch with benzyl cyanide;
(2) 5-methyl-7-hydroxyisoflavone is obtained with morpholine catalysis and triethyl orthoformate cyclization;
(3) carry out O-with methyl-sulfate to methylate to obtain 5-Methyl-7-methoxy-isoflavone.The total recovery of this synthetic route is 26%.
Summary of the invention
The present invention starts with from the solid existence research of 5-Methyl-7-Methoxyiso-flavone compound, by crystal formation triage techniques, the raw material aspect of effective ingredient is found, finds that solid matter exists kind and status flag, crystal formation research is combined with pharmacodynamic study, for the 5-Methyl-7-Methoxyiso-flavone type solid pharmaceutical found, find, exploitation has optimal clinical curative effect provides the scientific research data on basis.
The invention provides 5-Methyl-7-Methoxyiso-flavone compound crystal type A in the solid state of knowing clearly, crystal B-type, crystal C type three kinds of crystal formations, the preparation method of three kinds of crystal form samples; The medicine finding to use the different crystal forms material of 5-Methyl-7-Methoxyiso-flavone to develop as active fraction preparation and composition thereof are for preventing and treating the clinical effect difference of diseases of cardiovascular and cerebrovascular systems, nervous system disorders, osteoporosis, metabolic disease, inflammation and other diseases, find that crystal formation can affect this solid pharmaceutical effective constituent absorption rate in vivo, change the bioavailability of this solid pharmaceutical effective constituent, thus affect the curative effect effect of medicine in clinical.
One of the object of the invention: the 5-Methyl-7-Methoxyiso-flavone crystal type A, crystal B-type, crystal C type three kinds of solid matter existences and the describing mode that do not contain crystal water or other organic crystal solvent are provided.
The object of the invention two: the preparation method that the crystal type A of 5-Methyl-7-Methoxyiso-flavone, crystal B-type, crystal C type three kinds of solid matter samples are provided.
The object of the invention three: the advantage clinical efficacy effect using the crystal formation solid matter of 5-Methyl-7-Methoxyiso-flavone to play in various diseases prevention and treatment process as medicine prepared by active constituents of medicine exploitation is provided.
The object of the invention four: the advantage clinical efficacy effect using any two or three composition in the crystal type A of 5-Methyl-7-Methoxyiso-flavone, crystal B-type, crystal C type composition to carry out combining the 5-Methyl-7-Methoxyiso-flavone mixing crystal formation solid matter sample made in any proportion to play in various diseases prevention and treatment process as medicine prepared by active constituents of medicine exploitation is provided.
The object of the invention five: provide use 5-Methyl-7-Methoxyiso-flavone crystal formation solid matter as active constituents of medicine every day dosage within the scope of 50 ~ 1000mg.
The object of the invention six: provide the crystal formation solid matter of use 5-Methyl-7-Methoxyiso-flavone to manufacture out various tablets, capsule, pill, injection, slowly-releasing or the controlled-release pharmaceutical formulation types of drug supplying Clinical practice as active constituents of medicine raw material.
The object of the invention seven: the advantage clinical treatment effect that the various pharmaceutical preparation that uses the crystal formation solid matter of 5-Methyl-7-Methoxyiso-flavone to manufacture out as active constituents of medicine raw material and pharmaceutical composition play in control diseases of cardiovascular and cerebrovascular systems, nervous system disorders, osteoporosis, metabolic disease, inflammation and other diseases is provided.
The object of the invention eight: provide 5-Methyl-7-Methoxyiso-flavone three kinds of crystal form samples absorption data in vivo, for the oral medication mode of this medicine provides scientific research data.
The object of the invention nine: provide 5-Methyl-7-Methoxyiso-flavone crystal form samples absorb in vivo with Plasma Concentration advantage crystal formation data, the crystal type A that the result of to be crystal type A > crystal C type > crystal B-type, the wherein maximum absorbance of crystal type A be about 3 times of crystal B-type of the rat gastrointestinal tract absorbed dose in the same time point under same experimental conditions indicates 5-Methyl-7-Methoxyiso-flavone is easier to play good clinical efficacy effect by gastrointestinal absorption.
The object of the invention ten: provide the specific absorption difference that 5-Methyl-7-Methoxyiso-flavone different crystal forms sample exists in vivo, needs to adopt different dosages for playing clinical efficacy when showing the different crystal forms material developing drugs utilizing 5-Methyl-7-Methoxyiso-flavone.
Technical characteristic
The crystal type A solid sample morphological specificity of 1.5-methyl-7-methoxy-isoflavone:
1.1 crystal type A solid substances that the present invention relates to 5-Methyl-7-Methoxyiso-flavone, is characterized in that the chemical purity of sample and crystal form purity are all greater than 95% and not containing crystal water or other recrystallisation solvent composition, when use powder x-ray diffraction analysis adopts CuK
adiffraction peak position 2-Theta value (°) or d value during radiation experiments condition
diffraction peak relative intensity peak height value (Height%) or peak area value (Area%) have following expression.Table 1 provides the powder x-ray diffraction peak value meter of 5-Methyl-7-Methoxyiso-flavone crystal type A solid sample.Accompanying drawing 1 provides the x-ray diffractogram of powder spectrum of 5-Methyl-7-Methoxyiso-flavone crystal type A solid sample.
The powder x-ray diffraction peak value of table 15-methyl-7-methoxy-isoflavone crystal type A solid sample
The crystal type A solid substance of the 1.2 described 5-Methyl-7-Methoxyiso-flavones that the present invention relates to, it is characterized in that chemical purity and the crystal form purity of sample are all greater than 95% and do not contain crystal water or other recrystallisation solvent composition, show as monoclinic symmetry when using single crystal X-ray diffraction structural analysis, spacer is P2
1/ c, unit cell parameters value is
α=90.00 °, β=106.97 (1) °, γ=90.00 °.Accompanying drawing 2 provides the crystal type A molecule relative configuration figure of 5-Methyl-7-Methoxyiso-flavone, accompanying drawing 3 provides 5-Methyl-7-Methoxyiso-flavone crystal type A molecule stereo structure sciagraph, and accompanying drawing 4 provides the structure cell accumulation graph of crystal type A sample molecule along a axle of 5-Methyl-7-Methoxyiso-flavone.Table 2 provides non-hydrogen atom coordinate parameters and the equivalent temperature factor values of the crystal type A molecule of 5-Methyl-7-Methoxyiso-flavone, table 3 provides the one-tenth key atomic bond long value of the crystal type A molecule of 5-Methyl-7-Methoxyiso-flavone, and table 4 provides the one-tenth key atomic bond angle value of the crystal type A molecule of 5-Methyl-7-Methoxyiso-flavone.
The crystal type A non-hydrogen atom coordinate parameters of table 25-methyl-7-methoxy-isoflavone and equivalent temperature factor values
The one-tenth key atomic bond long value of the crystal type A molecule of table 35-methyl-7-methoxy-isoflavone
One-tenth key atomic bond angle value (°) of the crystal type A molecule of table 45-methyl-7-methoxy-isoflavone
1.3 the present invention relates to the crystal type A solid substance of 5-Methyl-7-Methoxyiso-flavone, it is characterized in that endotherm(ic)peak transformation value when using dsc analysis on collection of illustrative plates is about 118.7 ° of about C.Accompanying drawing 5 provides the DSC collection of illustrative plates of 5-Methyl-7-Methoxyiso-flavone crystal type A sample.
The crystal type A solid substance of 1.4 5-Methyl-7-Methoxyiso-flavones that the present invention relates to, it is characterized in that when using infrared spectra to analyze 3073.6, 3049.0, 3014.2, 2981.3, 2967.6, 2929.1, 2839.5, 2410.1, 2234.5, 2090.8, 2042.6, 1951.9, 1880.7, 1758.6, 1722.5, 1636.6, 1600.8, 1563.8, 1496.9, 1482.3, 1453.5, 1441.2, 1411.6, 1377.7, 1329.9, 1366.2, 1316.2, 1281.1, 1259.9, 1216.7, 1195.2, 1180.6, 1139.3, 1071.9, 1027.8, 1014.7, 998.6, 970.8, 954.5, 926.7, 914.3, 859.3, 829.4, 805.4, 755.4, 697.9, 665.8, 646.6, 632.9, 618.3, 578.9, 563.7, 543.3, 531.7, 504.2, 489.3, 456.9, 435.8, 409.2cm
-1place has absorption peak to exist, wherein 3073.6,3049.0,3014.2,2981.3,2410.1,2090.8,2042.6,1951.9,1758.6,1563.8,1441.2,1316.2,1281.1,1259.9,1195.2,1180.6,1139.3,1027.8,1014.7,970.8,926.7,914.3,829.4,697.9,646.6,578.9,489.3,456.9,435.8,409.2cm
-1peak is the crystal type A solid substance characteristic absorbance peak position presenting 5-Methyl-7-Methoxyiso-flavone.Accompanying drawing 6 provides the infrared absorpting light spectra of 5-Methyl-7-Methoxyiso-flavone crystal type A sample.
The crystal type A solid substance of 1.5 5-Methyl-7-Methoxyiso-flavones that the present invention relates to, is characterized in that melting point values when using melting point apparatus to carry out sample analysis is about 118 ~ 119 ° of C.
1.6 preparation methods that the invention still further relates to the crystal type A sample of 5-Methyl-7-Methoxyiso-flavone, first use methyl alcohol, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, ether, methylene dichloride, normal hexane, hexanaphthene, dioxane, DMF, sherwood oil, 5-Methyl-7-Methoxyiso-flavone sample dissolves completely and through envrionment temperature 4 ° of C ~ 60 ° C by the single solvent of n-propyl alcohol or water at ° C temperature of 15 ° of C ~ 50, ambient moisture 10% ~ 75%, the 5-Methyl-7-Methoxyiso-flavone crystal type A solid substance that recrystallization preparation technology under normal pressure or vacuum experiment condition obtains.
Or, first use methyl alcohol, ethanol, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, ether, methylene dichloride, normal hexane, hexanaphthene, dioxane, DMF, sherwood oil, any two or more in n-propyl alcohol or water different sorts solvent combine the mixed solvent system made and to be dissolved completely by 5-Methyl-7-Methoxyiso-flavone sample at ° C temperature of 15 ° of C ~ 50 and through envrionment temperature 4 ° of C ~ 60 ° C through different ratio, ambient moisture 10% ~ 75%, the 5-Methyl-7-Methoxyiso-flavone crystal type A solid substance that recrystallization preparation technology under normal pressure or vacuum experiment condition obtains.
The crystal B-type solid sample morphological specificity of 2.5-methyl-7-methoxy-isoflavone:
The crystal B-type solid matter of the 2.1 described 5-Methyl-7-Methoxyiso-flavones that the present invention relates to, is characterized in that the chemical purity of sample and crystal form purity are all greater than 95% and not containing crystal water or other recrystallisation solvent composition, adopt CuK when using powder x-ray diffraction analysis
adiffraction peak position 2-Theta value (°) or d value during radiation experiments condition
diffraction peak relative intensity peak height value (Height%) or peak area value (Area%) have following expression.Table 5 provides the powder x-ray diffraction peak value meter of 5-Methyl-7-Methoxyiso-flavone crystal B-type solid sample, and accompanying drawing 7 provides the x-ray diffractogram of powder spectrum of the crystal B-type solid sample of 5-Methyl-7-Methoxyiso-flavone.
The powder x-ray diffraction peak value of table 55-methyl-7-methoxy-isoflavone crystal B-type solid sample
The crystal B-type solid matter of 2.2 5-Methyl-7-Methoxyiso-flavones that the present invention relates to, it is characterized in that chemical purity and the crystal form purity of sample are all greater than 95% and do not contain crystal water or other recrystallisation solvent composition, show as monoclinic symmetry when using single crystal X-ray diffraction structural analysis, spacer is P2
1/ n, unit cell parameters value is
α=90.00 °, β=101.861 °, γ=90.00 °.Accompanying drawing 8 provides 5-Methyl-7-Methoxyiso-flavone crystal B-type molecule stereo structure sciagraph, accompanying drawing 9 provides the structure cell accumulation graph of crystal B-type sample molecule along b axle of 5-Methyl-7-Methoxyiso-flavone, table 6 provides 5-Methyl-7-Methoxyiso-flavone crystal B-type non-hydrogen atom coordinate parameters and equivalent temperature factor values, table 7 provides the one-tenth key atomic bond long value of the crystal B-type molecule of 5-Methyl-7-Methoxyiso-flavone, and table 8 provides the one-tenth key atomic bond angle value of the crystal B-type molecule of 5-Methyl-7-Methoxyiso-flavone.
Table 65-methyl-7-methoxy-isoflavone crystal B-type non-hydrogen atom coordinate parameters and equivalent temperature factor values
The one-tenth key atomic bond long value of table 75-methyl-7-methoxy-isoflavone crystal B-type molecule
One-tenth key atomic bond angle value (°) of the crystal B-type molecule of table 85-methyl-7-methoxy-isoflavone
The crystal B-type solid matter of 2.3 5-Methyl-7-Methoxyiso-flavones that the present invention relates to, it is characterized in that use dsc analysis time collection of illustrative plates on endotherm(ic)peak transformation value about 108.2 ° of C and 118.2 ° about C.Accompanying drawing 10 provides the DSC collection of illustrative plates of 5-Methyl-7-Methoxyiso-flavone crystal B-type sample.
The crystal B-type solid matter of 2.4 5-Methyl-7-Methoxyiso-flavones that the present invention relates to, it is characterized in that when using the KBr compressing tablet of infrared spectra to analyze 3080.3, 3001.0, 2967.7, 2925.2, 2842.4, 1823.8, 1721.2, 1635.8, 1622.5, 1602.4, 1566.5, 1494.1, 1483.0, 1453.3, 1411.1, 1383.1, 1366.1, 1330.6, 1311.7, 1296.3, 1279.9, 1255.1, 1219.4, 1190.8, 1136.9, 1073.2, 1030.3, 1017.6, 983.0, 956.4, 909.3, 857.3, 826.3, 804.1, 785.7, 759.3, 701.5, 694.4, 664.1, 641.8, 634.1, 619.4, 609.3, 586.0, 563.4, 544.3, 531.8, 504.2, 497.7, 438.8cm
-1place has absorption peak to exist, wherein 3080.3,3001.0,2925.2,2842.4,1823.8,1622.5,1602.4,1566.5,1383.1,1296.3,1255.1,1219.4,1190.8,909.3,857.3,826.3,785.7,759.3,701.5,586.0,497.7cm
-1peak is the crystal B-type solid matter characteristic absorbance peak position presenting 5-Methyl-7-Methoxyiso-flavone.Accompanying drawing 11 provides the infrared absorpting light spectra of 5-Methyl-7-Methoxyiso-flavone crystal B-type sample.
The crystal B-type solid matter of 2.5 5-Methyl-7-Methoxyiso-flavones that the present invention relates to, is characterized in that melting point values when using melting point apparatus to carry out sample analysis is about 118 ~ 119 ° of C.
2.6 preparation methods that the present invention relates to the crystal B-type sample of 5-Methyl-7-Methoxyiso-flavone, first use methyl alcohol, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, ether, methylene dichloride, normal hexane, hexanaphthene, dioxane, DMF, sherwood oil, 5-Methyl-7-Methoxyiso-flavone sample dissolves completely and through envrionment temperature 4 ° of C ~ 60 ° C by the single solvent of n-propyl alcohol or water at ° C temperature of 15 ° of C ~ 50, ambient moisture 10% ~ 75%, the 5-Methyl-7-Methoxyiso-flavone crystal B-type solid matter that recrystallization preparation technology under normal pressure or vacuum experiment condition obtains.
Or, first use methyl alcohol, ethanol, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, ether, methylene dichloride, normal hexane, hexanaphthene, dioxane, DMF, sherwood oil, any two or more in n-propyl alcohol or water different sorts solvent combine the mixed solvent system made and to be dissolved completely by 5-Methyl-7-Methoxyiso-flavone sample at ° C temperature of 15 ° of C ~ 50 and through envrionment temperature 4 ° of C ~ 60 ° C through different ratio, ambient moisture 10% ~ 75%, the 5-Methyl-7-Methoxyiso-flavone crystal B-type solid matter that recrystallization preparation technology under normal pressure or vacuum experiment condition obtains.
The crystal C type solid sample morphological specificity of 3.5-methyl-7-methoxy-isoflavone:
The crystal C type solid matter of 3.1 5-Methyl-7-Methoxyiso-flavones that the present invention relates to, is characterized in that the chemical purity of sample and crystal form purity are all greater than 95% and not containing crystal water or other recrystallisation solvent composition, adopt CuK when using powder x-ray diffraction analysis
adiffraction peak position 2-Theta value (°) or d value during radiation experiments condition
diffraction peak relative intensity peak height value (Height%) or peak area value (Area%) have following expression.Table 9 provides the powder x-ray diffraction peak value meter of 5-Methyl-7-Methoxyiso-flavone crystal C type sample, and accompanying drawing 12 provides the x-ray diffractogram of powder spectrum of 5-Methyl-7-Methoxyiso-flavone crystal C type sample.
The powder x-ray diffraction peak value of table 95-methyl-7-methoxy-isoflavone crystal C type sample
The crystal C type solid matter of 3.2 5-Methyl-7-Methoxyiso-flavones that the present invention relates to, it is characterized in that when using infrared spectra to analyze 3225.9, 3058.5, 3024.0, 2969.4, 2930.5, 2839.0, 2740.2, 2592.3, 2501.1, 2417.3, 2235.0, 2094.4, 2046.6, 1948.1, 1882.1, 1804.6, 1719.9, 1637.5, 1600.7, 1561.7, 1482.9, 1449.8, 1411.9, 1377.7, 1310.6, 1279.7, 1257.5, 1216.1, 1184.6, 1137.0, 1071.9, 1029.8, 1017.6, 999.2, 984.9, 973.9, 955.7, 899.1, 859.1, 824.1, 803.9, 754.4, 695.8, 664.6, 640.5, 619.0, 609.5, 581.0, 563.8, 544.3, 531.0, 504.8, 438.5cm
-1place has absorption peak to exist, wherein 3225.9,3058.5,3024.0,2740.2,2592.3,2501.1,2417.3,2094.4,2046.6,1948.1,1804.6,1719.9,1561.7,1449.8,1257.5,1184.6,973.6,899.1,824.1,581.0cm
-1peak is the crystal C type solid matter characteristic absorbance peak position presenting 5-Methyl-7-Methoxyiso-flavone.Accompanying drawing 13 provides the infrared absorpting light spectra of 5-Methyl-7-Methoxyiso-flavone crystal C type sample.
The crystal C type solid matter of 3.3 5-Methyl-7-Methoxyiso-flavones that the present invention relates to, is characterized in that melting point values when using melting point apparatus to carry out sample analysis is about 118 ~ 119 ° of C.
3.4. the invention still further relates to the preparation method of the crystal C type sample of 5-Methyl-7-Methoxyiso-flavone, use the crystal type A sample of 5-Methyl-7-Methoxyiso-flavone to be raw materials, adopt the 5-Methyl-7-Methoxyiso-flavone crystal C type solid matter that physical mechanics lattice damage and molecular transposition rotating crystal method are prepared 5-Methyl-7-Methoxyiso-flavone crystal C type solid matter or prepared by the pressure condition of change physics, temperature condition.
Or, first use methyl alcohol, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, ether, methylene dichloride, normal hexane, hexanaphthene, dioxane, DMF, sherwood oil, 5-Methyl-7-Methoxyiso-flavone sample dissolves or uses methyl alcohol by n-propyl alcohol or water single solvent completely, ethanol, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, ether, methylene dichloride, normal hexane, hexanaphthene, dioxane, DMF, sherwood oil, any two or more in n-propyl alcohol or water different sorts solvent combine the mixed solvent system made and are dissolved completely by 5-Methyl-7-Methoxyiso-flavone sample at ° C temperature of 15 ° of C ~ 60 and adopt cold spray method to prepare 5-Methyl-7-Methoxyiso-flavone crystal C type solid matter fast again through different ratio.
4. the crystal formation composition of crystalline form of 5-methyl-7-methoxy-isoflavone, dosage and pharmaceutical preparations composition feature:
The mixing crystal formation solid matter of 4.1 1 kinds of 5-Methyl-7-Methoxyiso-flavones, containing in 5-Methyl-7-Methoxyiso-flavone crystal type A composition, crystal B-type composition, crystal C type composition at least 2 kinds.
4.2 the invention still further relates to pharmaceutical composition, using 5-Methyl-7-Methoxyiso-flavone crystal formation solid matter as active constituents of medicine, containing at least one in 5-Methyl-7-Methoxyiso-flavone crystal type A composition, crystal B-type composition, crystal C type composition or mixing crystal formation composition.
4.3 pharmaceutical compositions that the present invention relates to, using 5-Methyl-7-Methoxyiso-flavone crystal formation solid matter as active constituents of medicine, every day, dosage was within the scope of 50 ~ 1000mg.
4.4 the present invention relates to employ 5-Methyl-7-Methoxyiso-flavone crystal formation solid matter develops preparation pharmaceutical preparation as active constituents of medicine, containing at least one in 5-Methyl-7-Methoxyiso-flavone crystal type A composition, crystal B-type composition, crystal C type composition or 5-Methyl-7-Methoxyiso-flavone mixing crystal formation composition, described pharmaceutical preparation can be the various types of drug preparations such as tablet, capsule, pill, injection, slowly-releasing or controlled release.
The pharmacodynamic profile of 5.5-methyl-7-methoxy-isoflavone different crystal forms composition:
The control diseases of cardiovascular and cerebrovascular systems that 5.1 5-Methyl-7-Methoxyiso-flavone that the present invention relates to three kinds crystal form samples are played in vivo by Oral administration, nervous system disorders, osteoporosis, metabolic disease, the effect of inflammation and other diseases, it is characterized in that three kinds of crystal formation solid matters detect all in blood after rat oral gavage administration this material exist result indicate 5-Methyl-7-Methoxyiso-flavone three kinds of crystal-form substances all can be rapidly absorbed into blood and whole body play control diseases of cardiovascular and cerebrovascular systems, nervous system disorders, osteoporosis, metabolic disease, inflammation and other diseases play clinical treatment effect.
Absorption difference that 5.2 5-Methyl-7-Methoxyiso-flavone that the present invention relates to three kinds crystal-form substances exist the in vivo opposite sex, to is characterized in that under same experimental conditions showing that the crystal type A of 5-Methyl-7-Methoxyiso-flavone is easier to the clinical efficacy effect of being made the most of the advantage by gastrointestinal absorption in the result of the specific absorption of rat 5-Methyl-7-Methoxyiso-flavone in blood of same time point to be crystal type A > crystal C type > crystal B-type, wherein crystal type A maximum absorbance be about 3 times of crystal B-type after gastric infusion.Table 10 provides and utilizes HPLC method to measure 5-Methyl-7-Methoxyiso-flavone three kinds of crystal form samples content value in rat plasma, and Figure 14 provides and utilizes HPLC method to measure 5-Methyl-7-Methoxyiso-flavone three kinds of crystal form samples content in rat plasma.
Table 10HPLC method measures 5-Methyl-7-Methoxyiso-flavone three kinds of crystal form samples content in rat plasma
5.3. the present invention relates to A type composition, crystal B-type composition, the crystal C type composition of 5-Methyl-7-Methoxyiso-flavone crystalline substance, and using-methyl-7-methoxy-isoflavone crystal-form substances as the various pharmaceutical compositions of active constituents of medicine, the clinical treatment effect in preparation control diseases of cardiovascular and cerebrovascular systems, nervous system disorders, osteoporosis, metabolic disease, inflammation and other diseases.By the route of administration of oral pharmaceutical, need to adopt different dosages for playing clinical efficacy when the specific absorption difference results that 5-Methyl-7-Methoxyiso-flavone different crystal forms sample exists in vivo shows the different crystal forms material developing drugs utilizing 5-Methyl-7-Methoxyiso-flavone.
Accompanying drawing explanation
The x-ray diffractogram of powder spectrum of Figure 15-methyl-7-methoxy-isoflavone crystal type A solid sample
Figure 25-methyl-7-methoxy-isoflavone crystal type A molecule relative configuration figure
Figure 35-methyl-7-methoxy-isoflavone crystal type A molecule stereo structure sciagraph
Figure 45-methyl-7-methoxy-isoflavone crystal type A sample molecule is along the structure cell accumulation graph of a axle
The DSC collection of illustrative plates of Figure 55-methyl-7-methoxy-isoflavone crystal type A sample
The infrared absorpting light spectra of Figure 65-methyl-7-methoxy-isoflavone crystal type A sample
The x-ray diffractogram of powder spectrum of Figure 75-methyl-7-methoxy-isoflavone crystal B-type solid sample
Figure 85-methyl-7-methoxy-isoflavone crystal B-type molecule stereo structure sciagraph
Figure 95-methyl-7-methoxy-isoflavone crystal B-type sample molecule is along the structure cell accumulation graph of b axle
The DSC collection of illustrative plates of Figure 105-methyl-7-methoxy-isoflavone crystal B-type sample.
The infrared absorpting light spectra of Figure 115-methyl-7-methoxy-isoflavone crystal B-type sample
The x-ray diffractogram of powder spectrum of Figure 125-methyl-7-methoxy-isoflavone crystal C type sample
The infrared absorpting light spectra of Figure 135-methyl-7-methoxy-isoflavone crystal C type sample
Figure 14 HPLC method measures 5-Methyl-7-Methoxyiso-flavone three kinds of crystal form samples content in rat plasma
Embodiment
For technical scheme of the present invention is better described, spy provides following examples, but the present invention is not limited to this.
Embodiment 1
The crystal type A sample preparation methods 1 of 5-Methyl-7-Methoxyiso-flavone:
5-Methyl-7-Methoxyiso-flavone crystal type A sample preparation methods, it is characterized in that first using that 5-Methyl-7-Methoxyiso-flavone sample dissolves completely by methanol solvate under 15 ~ 25 ° of C normal temperature states, control temperature in 45 ° of C utilize vacuum filtration or revolve steaming method by the solvent rapid filtration under suction in sample or evaporate to dryness, sample again drying technique finally prepare the crystal type A solid sample of 5-Methyl-7-Methoxyiso-flavone.
The crystal type A sample preparation methods 2 of 5-Methyl-7-Methoxyiso-flavone:
5-Methyl-7-Methoxyiso-flavone crystal type A sample preparation methods, it is characterized in that first using methyl alcohol add proportion of ethanol for 3:1 be configured to mixing solutions after under 15 ~ 25 ° of C normal temperature states, 5-Methyl-7-Methoxyiso-flavone sample is dissolved completely, control temperature in 45 ° of C utilize vacuum filtration or revolve steaming method by the solvent rapid filtration under suction in sample or evaporate to dryness, sample again drying technique finally prepare the crystal type A solid sample of 5-Methyl-7-Methoxyiso-flavone.
Need the problem illustrated: owing to having 19 kinds and use the solvent of two kinds or more combination to have hundreds of for the preparation of 5-Methyl-7-Methoxyiso-flavone crystal type A sample for the preparation of the single organic solvent of 5-Methyl-7-Methoxyiso-flavone crystal type A sample, often kind of organic solvent boiling point values is different, different to 5-Methyl-7-Methoxyiso-flavone sample solubility, cause use to prepare 5-Methyl-7-Methoxyiso-flavone crystal type A sample under different solvents condition time its experiment the variate-value such as envrionment temperature, humidity, time, pressure all there is some difference property and constant interval scope.
Embodiment 2
The crystal B-type sample preparation methods 1 of 5-Methyl-7-Methoxyiso-flavone:
5-Methyl-7-Methoxyiso-flavone crystal B-type sample preparation methods, it is characterized in that first with tetrahydrofuran (THF) or dichloromethane solvent under 15 ~ 25 ° of C normal temperature states, 5-Methyl-7-Methoxyiso-flavone sample is dissolved completely, control temperature in 45 ° of C utilize vacuum filtration or revolve steaming method by the solvent rapid filtration under suction in sample or evaporate to dryness, sample again drying technique finally prepare the crystal B-type solid sample of 5-Methyl-7-Methoxyiso-flavone.
The crystal B-type sample preparation methods 2 of 5-Methyl-7-Methoxyiso-flavone:
5-Methyl-7-Methoxyiso-flavone crystal B-type sample preparation methods, it is characterized in that first with methylene dichloride add ethyl acetate ratio be under 15 ~ 25 ° of C normal temperature states, 5-Methyl-7-Methoxyiso-flavone sample is dissolved completely after 1:1 is configured to mixing solutions, control temperature in 50 ° of C utilize vacuum filtration or revolve steaming method by the solvent rapid filtration under suction in sample or evaporate to dryness, sample again drying technique finally prepare the crystal B-type solid sample of 5-Methyl-7-Methoxyiso-flavone.
Need the problem illustrated: owing to having 19 kinds and use the solvent of two kinds or more combination to have hundreds of for the preparation of 5-Methyl-7-Methoxyiso-flavone crystal B-type sample for the preparation of the single organic solvent of 5-Methyl-7-Methoxyiso-flavone crystal B-type sample, often kind of organic solvent boiling point values is different, different to 5-Methyl-7-Methoxyiso-flavone sample solubility, cause use to prepare 5-Methyl-7-Methoxyiso-flavone crystal B-type sample under different solvents condition time its experiment the variate-value such as envrionment temperature, humidity, time, pressure all there is some difference property and constant interval scope.
Embodiment 3
The crystal C type sample preparation methods 1 of 5-Methyl-7-Methoxyiso-flavone:
5-Methyl-7-Methoxyiso-flavone crystal C type sample preparation methods, it is characterized in that using 5-Methyl-7-Methoxyiso-flavone crystal type A solid sample as raw materials, adopt the preparation technology of high-temperature fusion quenching again to obtain 5-Methyl-7-Methoxyiso-flavone crystal C type solid matter.
The crystal C type sample preparation methods 2 of 5-Methyl-7-Methoxyiso-flavone:
5-Methyl-7-Methoxyiso-flavone crystal C type sample preparation methods, it is characterized in that first using n-butanol solvent to be dissolved completely by 5-Methyl-7-Methoxyiso-flavone sample under 15 ~ 25 ° of C normal temperature states, then adopt cold spray method to prepare 5-Methyl-7-Methoxyiso-flavone crystal C type solid matter fast.
Need the problem illustrated: owing to having 19 kinds and use the solvent of two kinds or more combination to have hundreds of for the preparation of 5-Methyl-7-Methoxyiso-flavone crystal C type sample for the preparation of the single organic solvent of 5-Methyl-7-Methoxyiso-flavone crystal C type sample, often kind of organic solvent boiling point values is different, different to 5-Methyl-7-Methoxyiso-flavone sample solubility, cause use to prepare 5-Methyl-7-Methoxyiso-flavone crystal C type sample under different solvents condition time its experiment the variate-value such as envrionment temperature, humidity, time, pressure all there is some difference property and constant interval scope.
Embodiment 4
5-Methyl-7-Methoxyiso-flavone three kinds of crystal form samples are at rat body absorption comparison in difference:
Adopt male SD rat (body weight: 198 ± 3g), after fasting 12h, gavage gives compound 5-Methyl-7-Methoxyiso-flavone crystal type A, crystal B-type and crystal C type respectively.Various crystal form samples per os gives 200mg/Kg.After administration 5,15,30,60 minutes, ball rear vein beard was got blood and is about 0.5ml, by blood in the centrifugal 30min of 4500rpm, drew upper plasma.Add acetonitrile by 1:2, draw supernatant after the centrifugal 20min of vortex oscillation 1min, 13400rpm, carry out HPLC mensuration.
HPLC testing conditions: detection system is Aligent1100, chromatographic column is Aligent Zorbax EclipseXDB-C8, (150 × 4.6mm, 5um), moving phase is methyl alcohol: water (60:40), and sample size is 20ul, flow velocity is 1ml/min, and determined wavelength is 254nm.
Detected result shows: the 5-Methyl-7-Methoxyiso-flavone having prototype detected in blood, and the absorption of different crystal forms 5-Methyl-7-Methoxyiso-flavone compound in rat body exists notable difference; Wherein brilliant A and brilliant C can be observed enterohepatic circulation result.Detected result shows: all proto-drug can be detected in rat serum after the administration of three kinds of crystal formation different oxygen flavones, and the absorption of different crystal forms compound in rat body exists notable difference; Experimentally results presumption, the different oxygen flavones of 5-methyl-7-methoxy before by intestinal absorption namely by metabolism.
Embodiment 5
The dosage 1 of 5-Methyl-7-Methoxyiso-flavone crystal type A medicinal composition:
The pharmaceutical composition that a kind of crystal type A sample of use 5-Methyl-7-Methoxyiso-flavone as described in claim 1 manufactures as active constituents of medicine, it is characterized in that the activeconstituents using the crystal type A of 5-Methyl-7-Methoxyiso-flavone as medicine, daily dosage is 300mg, can be prepared into 3 times/each 1 100mg every day, every day 2 times/each 1 150mg, 1 time/each 1 300mg common or slow control formula tablet type.
The dosage 2 of 5-Methyl-7-Methoxyiso-flavone mixing crystal formation medicinal composition:
The pharmaceutical composition that a kind of use 5-Methyl-7-Methoxyiso-flavone mixing crystal form samples as described in claim 20 manufactures as active constituents of medicine, it is characterized in that the activeconstituents of biased sample as medicine of the three kinds of crystal formations using 5-Methyl-7-Methoxyiso-flavone, wherein crystal type A accounts for 50%, crystal B-type accounts for 30%, crystal C type accounts for 20%, daily dosage is 600mg, can be prepared into 3 times/each 1 200mg every day, every day 2 times/each 1 300mg, 1 time/each 1 600mg common or slow control formula tablet type.
Need the problem illustrated: the 5-Methyl-7-Methoxyiso-flavone crystal formation pharmaceutical composition that the present invention relates to has multifactor impact perhaps on the dosage of effective constituent, such as: the purposes for prevention and therapy is different, ill character is different from severity, the difference of Gender, age, body weight, route of administration, administration number of times, therapeutic purpose are different, absorption between crystal form samples and Plasma Concentration are not equal, cause the present invention to have 50 ~ 1000mg change value in a big way on the every per daily dose using 5-Methyl-7-Methoxyiso-flavone crystal formation composition.Different 5-Methyl-7-Methoxyiso-flavone crystal formation effective constituent total dose schemes should be formulated according to the prevention of reality from treatment different situations demand during use, and can be divided into repeatedly or single administration mode complete.
Embodiment 6
The preparation method 1 of 5-Methyl-7-Methoxyiso-flavone crystal type A medicinal composition formulation-tablet:
The method for preparing tablet thereof of the combined pharmaceutical formulation of a kind of use as described in claim 23, it is characterized in that use as the 5-Methyl-7-Methoxyiso-flavone crystal type A sample in claim 1 as active constituents of medicine, use several vehicle as the adjunct ingredient preparing medicinal composition tablet, proportioning makes the tablet samples of every sheet containing 5-Methyl-7-Methoxyiso-flavone crystal formation composition 50 ~ 300mg according to a certain percentage, and following table provides the formula of conventional tablet:
The bulk drug of 5-Methyl-7-Methoxyiso-flavone crystal type A tablet composition medicine and accessory formula
By the method that the 5-Methyl-7-Methoxyiso-flavone crystal type A sample of some amount and excipients are prepared into tablet formulation be: by several excipients and bulk drug Homogeneous phase mixing, add 1% sodium cellulose glycolate solution and make soft material in right amount, sieving wet grain of granulating dries the whole grain that sieves, and adds Magnesium Stearate and talcum powder mixes compressing tablet and get final product.
The preparation method 2 of 5-Methyl-7-Methoxyiso-flavone crystal type A medicinal composition formulation-capsule:
The preparation method of the combined pharmaceutical formulation capsule of a kind of use as described in claim 23, it is characterized in that use as the 5-Methyl-7-Methoxyiso-flavone crystal type A sample in claim 1 as active constituents of medicine, use several vehicle as the adjunct ingredient preparing medicinal composition capsule, proportioning makes every capsule sample containing 5-Methyl-7-Methoxyiso-flavone crystal type A composition 50 ~ 300mg according to a certain percentage, and following table provides the formula of conventional capsule:
The bulk drug of 5-Methyl-7-Methoxyiso-flavone crystal type A capsule combination medicine and accessory formula
By the 5-Methyl-7-Methoxyiso-flavone crystal type A sample of some amount with the method that excipients is prepared into capsule preparations be: several excipients is mixed with 5-Methyl-7-Methoxyiso-flavone crystal type A bulk drug, add 1% sodium cellulose glycolate solution appropriate, make wet grain and dry the whole grain that sieves, add Magnesium Stearate to mix, insert capsule and obtain; Or do not use granulation step, and directly 5-Methyl-7-Methoxyiso-flavone crystal type A bulk drug is mixed with several excipients, after sieving, directly incapsulate obtained.
Claims (9)
- The crystal C type solid matter of 1.5-methyl-7-methoxy-isoflavone, is characterized in that, the chemical purity of its sample and crystal form purity are all greater than 95% and not containing crystal water or other recrystallisation solvent composition, adopt CuK when using powder x-ray diffraction analysis adiffraction peak position 2-Theta value (°) or d value during radiation experiments condition diffraction peak relative intensity peak height value (Height%) or peak area value (Area%) have following expression:
- 2. the preparation method of the crystal C type solid matter of 5-Methyl-7-Methoxyiso-flavone described in claim 1, it is characterized in that, use 5-Methyl-7-Methoxyiso-flavone crystal type A solid substance as raw materials, adopt the preparation technology of high-temperature fusion quenching again to obtain 5-Methyl-7-Methoxyiso-flavone crystal C type solid matter; The crystal type A sample of described 5-Methyl-7-Methoxyiso-flavone, show as monoclinic symmetry when using single crystal X-ray diffraction structural analysis, spacer is P2 1/ c, unit cell parameters value is α=90.00 °, β=106.97 (1) °, γ=90.00 °.
- 3. the preparation method of the crystal C type sample of 5-Methyl-7-Methoxyiso-flavone described in claim 1, it is characterized in that, first use n-butanol solvent to be dissolved completely by 5-Methyl-7-Methoxyiso-flavone sample under 15 ~ 25 DEG C of normal temperature states, then adopt cold spray method to prepare 5-Methyl-7-Methoxyiso-flavone crystal C type solid matter fast.
- 4. the mixing crystal formation solid matter of a 5-Methyl-7-Methoxyiso-flavone, it is characterized in that, containing the 5-Methyl-7-Methoxyiso-flavone crystal C type solid matter described in claim 1 and 5-Methyl-7-Methoxyiso-flavone crystal type A composition, or containing the 5-Methyl-7-Methoxyiso-flavone crystal C type solid matter described in claim 1 and 5-Methyl-7-Methoxyiso-flavone crystal B-type composition; Wherein said 5-Methyl-7-Methoxyiso-flavone crystal type A, show as monoclinic symmetry when using single crystal X-ray diffraction structural analysis, spacer is P2 1/ c, unit cell parameters value is α=90.00 °, β=106.97 (1) °, γ=90.00 °; Described 5-Methyl-7-Methoxyiso-flavone crystal B-type, the chemical purity of its sample and crystal form purity are all greater than 95% and not containing crystal water or other recrystallisation solvent composition, adopt CuK when using powder x-ray diffraction analysis adiffraction peak position 2-Theta value (°) or d value during radiation experiments condition diffraction peak relative intensity peak height value (Height%) or peak area value (Area%) have following expression:
- 5. a pharmaceutical composition, using 5-Methyl-7-Methoxyiso-flavone crystal formation solid matter as active constituents of medicine, it is characterized in that, the crystal C type solid matter containing the 5-Methyl-7-Methoxyiso-flavone described in claim 1 or the mixing crystal formation solid matter containing the 5-Methyl-7-Methoxyiso-flavone described in claim 4.
- 6. pharmaceutical composition according to claim 5, is characterized in that, 5-Methyl-7-Methoxyiso-flavone every day dosage within the scope of 50 ~ 1000mg.
- 7. pharmaceutical composition according to claim 5, is characterized in that, the formulation of described composition is tablet, capsule, pill, injection, slowly-releasing or controlled-release pharmaceutical formulation.
- 8. the application of the pharmaceutical composition of claim 5 in the medicine of preparation treatment cardiovascular and cerebrovascular diseases, osteoporosis, inflammation, metabolic disease.
- 9. the application of the 5-Methyl-7-Methoxyiso-flavone crystal C type solid matter described in claim 1 in the medicine of preparation control diseases of cardiovascular and cerebrovascular systems, nervous system disorders, osteoporosis, metabolic disease, inflammation.
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| US4163746A (en) * | 1973-07-09 | 1979-08-07 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. | Metabolic 5-methyl-isoflavone-derivatives, process for the preparation thereof and compositions containing the same |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4163746A (en) * | 1973-07-09 | 1979-08-07 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. | Metabolic 5-methyl-isoflavone-derivatives, process for the preparation thereof and compositions containing the same |
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