CN101591324B - Three crystal forms of 5-methyl-7-methoxy-isoflavone, preparation method thereof, medicine composition thereof and application - Google Patents
Three crystal forms of 5-methyl-7-methoxy-isoflavone, preparation method thereof, medicine composition thereof and application Download PDFInfo
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Abstract
The invention discloses a crystal form B of 5-methyl-7-methoxy-isoflavone, a preparation method thereof, a medicine composition thereof and application. Concretely, the invention discloses that a 5-methyl-7-methoxy-isoflavone compound has the crystal form B in a solid state; the invention relates to the preparation method of the samples of the crystal form B; and the invention relates to the application of various preparations and the medicine composition which are prepared and developed by using the substances of crystal form of 5-methyl-7-methoxy-isoflavone as active ingredients in the preventive treatment of cardiovascular and cerebrovascular diseases, nervous system diseases, osteoporosis, inflammation, metabolic diseases and other diseases. The molecule formula of the 5-methyl-7-methoxy-isoflavone is shown below.
Description
Technical field
The present invention relates to find that 5-methyl-7-methoxy-isoflavone has crystal type A, crystal B-type, three kinds of forms of crystal C type under solid state; Relate to the preparation method who has invented three kinds of crystal form samples.The invention still further relates to the application of 5-methyl-7-methoxy-isoflavone 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-methoxyl group isoflavones is the derivative of ipriflavone, cycle chemistry called after 5-Methyl-7-Methoxyiso-flavone, and molecular structure is as follows:
Pharmacological activity that there are some researches show both is similar, but 5-methyl-7-methoxyl group isoflavones activity is stronger, can be used for prevention bone loss and treatment skeletal diseases.5-methyl-7-methoxyl group isoflavones in 1979 is applied for a patent [see United States Patent (USP): 4163746], but after this relevant report is less.Because 5-methyl-7-methoxyl group isoflavones can increase the metabolism retention rate to trace elements such as calcium, phosphorus, potassium, nitrogen in human body, fodder additivess such as the immunomodulator that now is applied to preventing and treating human senile osteoporosis and livestock and poultry and promotor, this compound also is used as the antioxidant use of food simultaneously.
At documents such as Kitagauia [Kitagawa, Masayuki; Yamamoto, Kenjiro; Katakura, Shinichi; Kanno, Hideyuki; Yamada, Koji; Et al.; Chem.Pharm.Bull., wherein put down in writing the preparation method of different oxygen chromocor compound 1991,39 (10): 2681-2690]:
(1) is raw material with 3,5-dimethoxy-p, with the phenyllacetyl chloride reaction, under aluminum chloride-zinc chloride catalysis, obtains 2-hydroxyl-4-methoxyl group-6-methyl deoxybenzoin;
(2) cyclization under triethyl orthoformate, pyridine, hexahydropyridine reaction conditions obtains 5-methyl-7-methoxyl group isoflavones.The total recovery of this synthetic route is 19%.
Document [Qian Hongsheng, Chen Limin, Hu Weixiao at Qian Hongsheng etc.Synthesizing of 5-methyl-7-methoxyl group isoflavones.Applied chemistry, 2005,22 (2): 224-227] in, related to preparation and its application in the medium disease of control senile osteoporosis of different oxygen chromocor compound, wherein provided the novel preparation method of different oxygen chromocor compound:
(1) with 3 ,-orcin is raw material, makes 2,4-dihydroxyl-6-methyl deoxybenzoin through with benzyl cyanide the Hoesch reaction taking place;
(2) obtain 5-methyl-7-hydroxyisoflavone with morpholine catalysis and triethyl orthoformate cyclization;
(3) with methyl-sulfate carry out O-methylate 5-methyl-7-methoxyl group isoflavones.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-methoxy-isoflavone compound, by the crystal formation triage techniques, raw material aspect at effective ingredient seeks, finds that solid matter exists kind and status flag, crystal formation research is combined with pharmacodynamic study, the scientific research data on basis are provided for 5-methyl-7-methoxy-isoflavone type solid pharmaceutical of seeking, find, exploitation having the optimal clinical curative effect.
The invention provides the 5-methyl of knowing clearly-7-methoxy-isoflavone compound three kinds of crystal formations of crystal type A, crystal B-type, crystal C type under solid state, the preparation method of three kinds of crystal form samples; The clinical effect difference that the medicine that the different crystal forms material that find to use 5-methyl-7-methoxy-isoflavone manufactures out as activeconstituents and composition thereof are used for control diseases of cardiovascular and cerebrovascular systems, nervous system disorders, osteoporosis, metabolic disease, inflammation and other diseases, find that crystal formation can influence in vivo absorption rate of this solid pharmaceutical effective constituent, change the bioavailability of this solid pharmaceutical effective constituent, thereby influence the curative effect effect of medicine in clinical.
One of the object of the invention: the 5-methyl-7-methoxy-isoflavone crystal type A, crystal B-type, three kinds of solid matter existences of crystal C type and the describing mode that do not contain crystal water or other organic crystal solvent are provided.
Two of the object of the invention: crystal type A, the crystal B-type of 5-methyl-7-methoxy-isoflavone, the preparation method of three kinds of solid matter samples of crystal C type are provided.
Three of the object of the invention: provide the crystal formation solid matter that uses 5-methyl-7-methoxy-isoflavone to prevent and treat the advantage clinical efficacy effect of bringing into play in the process as the medicine of active constituents of medicine exploitation preparation at various diseases.
Four of the object of the invention: provide any two or three composition in the crystal type A that uses 5-methyl-7-methoxy-isoflavone, crystal B-type, the crystal C type composition to make up 5-methyl-7-methoxy-isoflavone mixings crystal formation solid matter sample medicine that exploitation prepares as active constituents of medicine of making by arbitrary proportion and prevent and treat the advantage clinical efficacy effect of bringing into play in the process at various diseases.
Five of the object of the invention: provide use 5-methyl-7-methoxy-isoflavone crystal formation solid matter as active constituents of medicine every day dosage in 50～1000mg scope.
Six of the object of the invention: provide the crystal formation solid matter that uses 5-methyl-7-methoxy-isoflavone to manufacture out various tablets, capsule, pill, injection, slowly-releasing or controlled-release pharmaceutical formulation types of drug for clinical use as the active constituents of medicine raw material.
Seven of the object of the invention: the advantage clinical treatment effect that provides various pharmaceutical preparations that the crystal formation solid matter that uses 5-methyl-7-methoxy-isoflavone develops as the active constituents of medicine feedstock production and pharmaceutical composition in control diseases of cardiovascular and cerebrovascular systems, nervous system disorders, osteoporosis, metabolic disease, inflammation and other diseases, to bring into play.
Eight of the object of the invention: provide 5-methyl-three kinds of crystal form samples of 7-methoxy-isoflavone absorption data in vivo, for the oral medication mode of this medicine provides the scientific research data.
Nine of the object of the invention: provide 5-methyl-7-methoxy-isoflavone crystal form samples absorb in vivo with Plasma Concentration advantage crystal formation data, the rat gastrointestinal tract absorbed dose in the identical time point under same experimental conditions is crystal type A＞crystal C type＞crystal B-type, wherein the maximum absorbance of crystal type A is that about 3 times result of crystal B-type has shown that the crystal type A of 5-methyl-7-methoxy-isoflavone is easier to bring into play clinical efficacy effect preferably by gastrointestinal absorption.
Ten of the object of the invention: the specific absorption difference that the 5-methyl-7-methoxy-isoflavone different crystal forms sample exists in vivo is provided, need have adopted different dosages for the performance clinical efficacy when showing the different crystal forms material developing drugs of utilizing 5-methyl-7-methoxy-isoflavone.
Technical characterictic
1.5-the crystal type A solid sample morphological specificity of methyl-7-methoxy-isoflavone:
1.1 the present invention relates to the crystal type A solid substance of 5-methyl-7-methoxy-isoflavone, it is characterized in that the chemical purity of sample and crystal formation purity are all greater than 95% and do not contain crystal water or other recrystallisation solvent composition, when using powder x-ray diffraction analysis to adopt CuK
αDiffraction peak position 2-Theta value during the radiation experiments condition (°) or the d value
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-methoxy-isoflavone crystal type A solid sample.Accompanying drawing 1 provides the x-ray diffractogram of powder spectrum of 5-methyl-7-methoxy-isoflavone crystal type A solid sample.
The powder x-ray diffraction peak value of table 1 5-methyl-7-methoxy-isoflavone crystal type A solid sample
1.2 the crystal type A solid substance of the described 5-methyl-7-methoxy-isoflavone that the present invention relates to, it is characterized in that the chemical purity of sample and crystal formation purity are all greater than 95% and do not contain crystal water or other recrystallisation solvent composition, show as monoclinic symmetry when using the structural analysis of monocrystalline X-ray diffraction, spacer is P2
1/ c, the 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-methoxy-isoflavone, accompanying drawing 3 provides 5-methyl-7-methoxy-isoflavone crystal type A molecule stereo structure sciagraph, and accompanying drawing 4 provides the crystal type A sample molecule of 5-methyl-7-methoxy-isoflavone along the structure cell accumulation graph of a axle.Table 2 provides non-hydrogen atom coordinate parameters and the equivalent temperature factor values of the crystal type A molecule of 5-methyl-7-methoxy-isoflavone, table 3 provides the one-tenth key atomic bond long value of the crystal type A molecule of 5-methyl-7-methoxy-isoflavone, and table 4 provides the one-tenth key atom bond angle value of the crystal type A molecule of 5-methyl-7-methoxy-isoflavone.
The crystal type A non-hydrogen atom coordinate parameters of table 2 5-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 3 5-methyl-7-methoxy-isoflavone
The one-tenth key atom bond angle value of the crystal type A molecule of table 4 5-methyl-7-methoxy-isoflavone (°)
1.3 the present invention relates to the crystal type A solid substance of 5-methyl-7-methoxy-isoflavone, it is characterized in that the endotherm(ic)peak transformation value on the collection of illustrative plates is about about 118.7 ℃ when using dsc analysis.Accompanying drawing 5 provides the DSC collection of illustrative plates of 5-methyl-7-methoxy-isoflavone crystal type A sample.
1.4 the crystal type A solid substance of the 5-that the present invention relates to methyl-7-methoxy-isoflavone 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
-1The place 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
-1The peak is the crystal type A solid substance characteristic absorbance peak position that presents 5-methyl-7-methoxy-isoflavone.Accompanying drawing 6 provides the infrared absorpting light spectra of 5-methyl-7-methoxy-isoflavone crystal type A sample.
1.5 the crystal type A solid substance of the 5-that the present invention relates to methyl-7-methoxy-isoflavone, the melting point values when it is characterized in that using the fusing point instrument to carry out sample analysis is about 118～119 ℃.
1.6 the invention still further relates to the preparation method of the crystal type A sample of 5-methyl-7-methoxy-isoflavone, use methyl alcohol earlier, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, ether, methylene dichloride, normal hexane, hexanaphthene, dioxane, DMF, sherwood oil, the single solvent of n-propyl alcohol or water dissolves 5-methyl-7-methoxy-isoflavone sample under 15 ℃～50 ℃ temperature and fully through 4 ℃～60 ℃ of envrionment temperatures, ambient moisture 10%～75%, 5-methyl-7-methoxy-isoflavone crystal type A solid substance that recrystallization preparation technology under normal pressure or the vacuum experiment condition obtains.
Perhaps, use methyl alcohol earlier, ethanol, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, ether, methylene dichloride, normal hexane, hexanaphthene, dioxane, DMF, sherwood oil, any mixed solvent system that two or more are made through the combination of different proportionings in n-propyl alcohol or the water different sorts solvent dissolves 5-methyl-7-methoxy-isoflavone sample under 15 ℃～50 ℃ temperature and fully through 4 ℃～60 ℃ of envrionment temperatures, ambient moisture 10%～75%, 5-methyl-7-methoxy-isoflavone crystal type A solid substance that recrystallization preparation technology under normal pressure or the vacuum experiment condition obtains.
2.5-the crystal B-type solid sample morphological specificity of methyl-7-methoxy-isoflavone:
2.1 the crystal B-type solid matter of the described 5-methyl-7-methoxy-isoflavone that the present invention relates to is characterized in that the chemical purity of sample and crystal formation purity are all greater than 95% and do not contain crystal water or other recrystallisation solvent composition, when using powder x-ray diffraction analysis to adopt CuK
αDiffraction peak position 2-Theta value during the radiation experiments condition (°) or the d value
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-methoxy-isoflavone 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-methoxy-isoflavone.
The powder x-ray diffraction peak value of table 5 5-methyl-7-methoxy-isoflavone crystal B-type solid sample
2.2 the crystal B-type solid matter of the 5-that the present invention relates to methyl-7-methoxy-isoflavone, it is characterized in that the chemical purity of sample and crystal formation purity are all greater than 95% and do not contain crystal water or other recrystallisation solvent composition, show as monoclinic symmetry when using the structural analysis of monocrystalline X-ray diffraction, spacer is P2
1/ n, the unit cell parameters value is
α=90.00 °, β=101.861 °, γ=90.00 °.Accompanying drawing 8 provides 5-methyl-7-methoxy-isoflavone crystal B-type molecule stereo structure sciagraph, accompanying drawing 9 provides the crystal B-type sample molecule of 5-methyl-7-methoxy-isoflavone along the structure cell accumulation graph of b axle, table 6 provides 5-methyl-7-methoxy-isoflavone 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-methoxy-isoflavone, and table 8 provides the one-tenth key atom bond angle value of the crystal B-type molecule of 5-methyl-7-methoxy-isoflavone.
Table 6 5-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 7 5-methyl-7-methoxy-isoflavone crystal B-type molecule
The one-tenth key atom bond angle value of the crystal B-type molecule of table 8 5-methyl-7-methoxy-isoflavone (°)
2.3 the crystal B-type solid matter of the 5-that the present invention relates to methyl-7-methoxy-isoflavone is characterized in that the endotherm(ic)peak transformation value on the collection of illustrative plates is about about 108.2 ℃ and 118.2 ℃ when using dsc analysis.Accompanying drawing 10 provides the DSC collection of illustrative plates of 5-methyl-7-methoxy-isoflavone crystal B-type sample.
2.4 the crystal B-type solid matter of the 5-that the present invention relates to methyl-7-methoxy-isoflavone is characterized in that when the KBr compressing tablet that uses infrared spectra is analyzed 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
-1The place 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
-1The peak is the crystal B-type solid matter characteristic absorbance peak position that presents 5-methyl-7-methoxy-isoflavone.Accompanying drawing 11 provides the infrared absorpting light spectra of 5-methyl-7-methoxy-isoflavone crystal B-type sample.
2.5 the crystal B-type solid matter of the 5-that the present invention relates to methyl-7-methoxy-isoflavone, the melting point values when it is characterized in that using the fusing point instrument to carry out sample analysis is about 118～119 ℃.
2.6 the present invention relates to the preparation method of the crystal B-type sample of 5-methyl-7-methoxy-isoflavone, use methyl alcohol earlier, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, ether, methylene dichloride, normal hexane, hexanaphthene, dioxane, DMF, sherwood oil, the single solvent of n-propyl alcohol or water dissolves 5-methyl-7-methoxy-isoflavone sample under 15 ℃～50 ℃ temperature and fully through 4 ℃～60 ℃ of envrionment temperatures, ambient moisture 10%～75%, 5-methyl-7-methoxy-isoflavone crystal B-type solid matter that recrystallization preparation technology under normal pressure or the vacuum experiment condition obtains.
Perhaps, use methyl alcohol earlier, ethanol, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, ether, methylene dichloride, normal hexane, hexanaphthene, dioxane, DMF, sherwood oil, any mixed solvent system that two or more are made through the combination of different proportionings in n-propyl alcohol or the water different sorts solvent dissolves 5-methyl-7-methoxy-isoflavone sample under 15 ℃～50 ℃ temperature and fully through 4 ℃～60 ℃ of envrionment temperatures, ambient moisture 10%～75%, 5-methyl-7-methoxy-isoflavone crystal B-type solid matter that recrystallization preparation technology under normal pressure or the vacuum experiment condition obtains.
3.5-the crystal C type solid sample morphological specificity of methyl-7-methoxy-isoflavone:
3.1 the crystal C type solid matter of the 5-that the present invention relates to methyl-7-methoxy-isoflavone is characterized in that the chemical purity of sample and crystal formation purity are all greater than 95% and do not contain crystal water or other recrystallisation solvent composition, when using powder x-ray diffraction analysis to adopt CuK
αDiffraction peak position 2-Theta value during the radiation experiments condition (°) or the d value
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-methoxy-isoflavone crystal C type sample, and accompanying drawing 12 provides the x-ray diffractogram of powder spectrum of 5-methyl-7-methoxy-isoflavone crystal C type sample.
The powder x-ray diffraction peak value of table 9 5-methyl-7-methoxy-isoflavone crystal C type sample
3.2 the crystal C type solid matter of the 5-that the present invention relates to methyl-7-methoxy-isoflavone 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
-1The place 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
-1The peak is the crystal C type solid matter characteristic absorbance peak position that presents 5-methyl-7-methoxy-isoflavone.Accompanying drawing 13 provides the infrared absorpting light spectra of 5-methyl-7-methoxy-isoflavone crystal C type sample.
3.3 the crystal C type solid matter of the 5-that the present invention relates to methyl-7-methoxy-isoflavone, the melting point values when it is characterized in that using the fusing point instrument to carry out sample analysis is about 118～119 ℃.
3.4. the invention still further relates to the preparation method of the crystal C type sample of 5-methyl-7-methoxy-isoflavone, the crystal type A sample that uses 5-methyl-7-methoxy-isoflavone is the preparation raw material, adopts physical mechanics lattice damage and molecular transposition rotating crystal method to prepare 5-methyl-7-methoxy-isoflavone crystal C type solid matter or by the pressure condition that changes physics, 5-methyl-7-methoxy-isoflavone crystal C type solid matter that temperature condition prepares.
Perhaps, use methyl alcohol earlier, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, ether, methylene dichloride, normal hexane, hexanaphthene, dioxane, DMF, sherwood oil, n-propyl alcohol or water single solvent dissolve 5-methyl-7-methoxy-isoflavone sample fully or 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 mixed solvent system that two or more are made through the combination of different proportionings in n-propyl alcohol or the water different sorts solvent dissolves 5-methyl-7-methoxy-isoflavone sample fully under 15 ℃～60 ℃ temperature and adopts the cold spray method to prepare 5-methyl-7-methoxy-isoflavone crystal C type solid matter fast again.
4. the crystal formation composition of crystalline form of 5-methyl-7-methoxy-isoflavone, dosage and pharmaceutical preparations composition feature:
4.1 the mixing crystal formation solid matter of 5-methyl-7-methoxy-isoflavone contains in 5-methyl-7-methoxy-isoflavone crystal type A composition, crystal B-type composition, the crystal C type composition at least 2 kinds.
4.2 the invention still further relates to pharmaceutical composition,, contain 5-methyl-7-methoxy-isoflavone crystal type A composition, crystal B-type composition, crystal C type composition or mix in the crystal formation composition at least a as active constituents of medicine with 5-methyl-7-methoxy-isoflavone crystal formation solid matter.
4.3 the pharmaceutical composition that the present invention relates to, so that the 5-methyl-7-methoxy-isoflavone crystal formation solid matter is as active constituents of medicine, every day, dosage was in 50～1000mg scope.
4.4 the use that the present invention relates to 5-methyl-7-methoxy-isoflavone crystal formation solid matter develop the pharmaceutical preparation of preparation as active constituents of medicine, contain in 5-methyl-7-methoxy-isoflavone crystal type A composition, crystal B-type composition, crystal C type composition or 5-methyl-7-methoxy-isoflavone mixing crystal formation composition at least aly, described pharmaceutical preparation can be various types of drug preparations such as tablet, capsule, pill, injection, slowly-releasing or controlled release.
5.5-the pharmacodynamic profile of methyl-7-methoxy-isoflavone different crystal forms composition:
5.1 the control diseases of cardiovascular and cerebrovascular systems that the 5-that the present invention relates to methyl-three kinds of crystal form samples of 7-methoxy-isoflavone are brought into play in vivo by the oral administration mode, 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 after the rat oral gavage administration, all in blood, detect this material exist the result to show that 5-methyl-three kinds of crystal-form substances of 7-methoxy-isoflavone all can be absorbed to enter blood and at whole body performance control diseases of cardiovascular and cerebrovascular systems, nervous system disorders, osteoporosis, metabolic disease, inflammation and the effect of other diseases performance clinical treatment.
5.2 the absorption difference opposite sex that the 5-that the present invention relates to methyl-three kinds of crystal-form substances of 7-methoxy-isoflavone exist in vivo, it is characterized in that under same experimental conditions through be crystal type A＞crystal C type＞crystal B-type in the specific absorption of rat 5-methyl-7-methoxy-isoflavone in blood of identical time point behind the gastric infusion, wherein the crystal type A maximum absorbance is that about 3 times result of crystal B-type shows that the crystal type A of 5-methyl-7-methoxy-isoflavone is easier to the clinical efficacy effect of making the most of the advantage by gastrointestinal absorption.Table 10 provides and utilizes the HPLC method to measure 5-methyl-three kinds of crystal form samples of 7-methoxy-isoflavone content value in rat plasma, and Figure 14 provides and utilizes the HPLC method to measure 5-methyl-three kinds of crystal form samples of 7-methoxy-isoflavone content in rat plasma.
Table 10HPLC method is measured 5-methyl-three kinds of crystal form samples of 7-methoxy-isoflavone content in rat plasma
5.3. the present invention relates to the 5-methyl-A type composition of 7-methoxy-isoflavone crystalline substance, crystal B-type composition, crystal C type composition, and with-methyl-7-methoxy-isoflavone crystal-form substances various pharmaceutical compositions as 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, when showing the different crystal forms material developing drugs of utilizing 5-methyl-7-methoxy-isoflavone, the specific absorption difference result that the 5-methyl-7-methoxy-isoflavone different crystal forms sample exists in vivo need adopt different dosages for the performance clinical efficacy.
Description of drawings
The x-ray diffractogram of powder spectrum of Fig. 1 5-methyl-7-methoxy-isoflavone crystal type A solid sample
Fig. 2 5-methyl-7-methoxy-isoflavone crystal type A molecule relative configuration figure
Fig. 3 5-methyl-7-methoxy-isoflavone crystal type A molecule stereo structure sciagraph
Fig. 4 5-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 Fig. 5 5-methyl-7-methoxy-isoflavone crystal type A sample
The infrared absorpting light spectra of Fig. 6 5-methyl-7-methoxy-isoflavone crystal type A sample
The x-ray diffractogram of powder spectrum of Fig. 7 5-methyl-7-methoxy-isoflavone crystal B-type solid sample
Fig. 8 5-methyl-7-methoxy-isoflavone crystal B-type molecule stereo structure sciagraph
Fig. 9 5-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 10 5-methyl-7-methoxy-isoflavone crystal B-type sample.
The infrared absorpting light spectra of Figure 11 5-methyl-7-methoxy-isoflavone crystal B-type sample
The x-ray diffractogram of powder spectrum of Figure 12 5-methyl-7-methoxy-isoflavone crystal C type sample
The infrared absorpting light spectra of Figure 13 5-methyl-7-methoxy-isoflavone crystal C type sample
Figure 14 HPLC method is measured 5-methyl-three kinds of crystal form samples of 7-methoxy-isoflavone content in rat plasma
Embodiment
Be better explanation technical scheme of the present invention, the spy provides following examples, but the present invention is not limited to this.
The crystal type A sample preparation methods 1 of 5-methyl-7-methoxy-isoflavone:
5-methyl-7-methoxy-isoflavone crystal type A sample preparation methods, it is characterized in that using earlier methanol solvate under 15～25 ℃ of normal temperature states, 5-methyl-7-methoxy-isoflavone sample dissolved fully, controls temperature in 45 ℃ utilize vacuum filtration or revolve the steaming method with the quick suction filtration of the solvent in the sample or evaporate to dryness, sample again drying technology finally prepare the crystal type A solid sample of 5-methyl-7-methoxy-isoflavone.
The crystal type A sample preparation methods 2 of 5-methyl-7-methoxy-isoflavone:
5-methyl-7-methoxy-isoflavone crystal type A sample preparation methods, it is characterized in that using earlier methyl alcohol add proportion of ethanol be configured at 3: 1 behind the mixing solutions under 15～25 ℃ of normal temperature states 5-methyl-7-methoxy-isoflavone sample dissolved fully, controls temperature in 45 ℃ utilize vacuum filtration or revolve the steaming method with the quick suction filtration of the solvent in the sample or evaporate to dryness, sample again drying technology finally prepare the crystal type A solid sample of 5-methyl-7-methoxy-isoflavone.
The problem that needs explanation: owing to have 19 kinds and use two kinds or above solvent combination that hundreds of is arranged for the preparation of 5-methyl-7-methoxy-isoflavone crystal type A sample for the preparation of the single organic solvent of 5-methyl-7-methoxy-isoflavone crystal type A sample, every kind of organic solvent boiling point value difference, to 5-methyl-7-methoxy-isoflavone sample dissolution degree difference, variate-values such as the envrionment temperature of its experiment, humidity, time, pressure all there is some difference property and constant interval scope when causing preparation 5-methyl under using the different solvents condition-7-methoxy-isoflavone crystal type A sample.
The crystal B-type sample preparation methods 1 of 5-methyl-7-methoxy-isoflavone:
5-methyl-7-methoxy-isoflavone crystal B-type sample preparation methods, it is characterized in that earlier with tetrahydrofuran (THF) or dichloromethane solvent under 15～25 ℃ of normal temperature states, 5-methyl-7-methoxy-isoflavone sample dissolved fully, controls temperature in 45 ℃ utilize vacuum filtration or revolve the steaming method with the quick suction filtration of the solvent in the sample or evaporate to dryness, sample again drying technology finally prepare the crystal B-type solid sample of 5-methyl-7-methoxy-isoflavone.
The crystal B-type sample preparation methods 2 of 5-methyl-7-methoxy-isoflavone:
5-methyl-7-methoxy-isoflavone crystal B-type sample preparation methods, it is characterized in that earlier with methylene dichloride add the ethyl acetate ratio be configured at 1: 1 behind the mixing solutions under 15～25 ℃ of normal temperature states 5-methyl-7-methoxy-isoflavone sample dissolved fully, controls temperature in 50 ℃ utilize vacuum filtration or revolve the steaming method with the quick suction filtration of the solvent in the sample or evaporate to dryness, sample again drying technology finally prepare the crystal B-type solid sample of 5-methyl-7-methoxy-isoflavone.
The problem that needs explanation: owing to have 19 kinds and use two kinds or above solvent combination that hundreds of is arranged for the preparation of 5-methyl-7-methoxy-isoflavone crystal B-type sample for the preparation of the single organic solvent of 5-methyl-7-methoxy-isoflavone crystal B-type sample, every kind of organic solvent boiling point value difference, to 5-methyl-7-methoxy-isoflavone sample dissolution degree difference, variate-values such as the envrionment temperature of its experiment, humidity, time, pressure all there is some difference property and constant interval scope when causing preparation 5-methyl under using the different solvents condition-7-methoxy-isoflavone crystal B-type sample.
The crystal C type sample preparation methods 1 of 5-methyl-7-methoxy-isoflavone:
5-methyl-7-methoxy-isoflavone crystal C type sample preparation methods, it is characterized in that using 5-methyl-7-methoxy-isoflavone crystal type A solid sample as the preparation raw material, the employing high-temperature fusion preparation technology of quenching again obtains 5-methyl-7-methoxy-isoflavone crystal C type solid matter.
The crystal C type sample preparation methods 2 of 5-methyl-7-methoxy-isoflavone:
5-methyl-7-methoxy-isoflavone crystal C type sample preparation methods, it is characterized in that using the propyl carbinol solvent under 15～25 ℃ of normal temperature states, 5-methyl-7-methoxy-isoflavone sample to be dissolved fully earlier, adopt the cold spray method to prepare 5-methyl-7-methoxy-isoflavone crystal C type solid matter fast again.
The problem that needs explanation: owing to have 19 kinds and use two kinds or above solvent combination that hundreds of is arranged for the preparation of 5-methyl-7-methoxy-isoflavone crystal C type sample for the preparation of the single organic solvent of 5-methyl-7-methoxy-isoflavone crystal C type sample, every kind of organic solvent boiling point value difference, to 5-methyl-7-methoxy-isoflavone sample dissolution degree difference, variate-values such as the envrionment temperature of its experiment, humidity, time, pressure all there is some difference property and constant interval scope when causing preparation 5-methyl under using the different solvents condition-7-methoxy-isoflavone crystal C type sample.
5-methyl-three kinds of crystal form samples of 7-methoxy-isoflavone absorption difference in the rat body compares:
The employing male SD rat (body weight: 198 ± 3g), behind the fasting 12h, irritate stomach respectively and give compound 5-methyl-7-methoxy-isoflavone crystal type A, crystal B-type and crystal C type.Various crystal form samples per os give 200mg/Kg.After administration 5,15,30,60 minutes, the ball rear vein beard was got the about 0.5ml of blood, and blood in the centrifugal 30min of 4500rpm, is drawn upper plasma.Added acetonitrile by 1: 2, vortex oscillation 1min draws supernatant behind the centrifugal 20min of 13400rpm, carries out HPLC and measures.
The HPLC testing conditions: detection system is Aligent 1100, and chromatographic column is Aligent Zorbax EclipseXDB-C8, (150 * 4.6mm, 5um), moving phase is methyl alcohol: water (60: 40), sample size are 20ul, flow velocity is 1ml/min, and the detection wavelength is 254nm.
Detected result shows: detect 5-methyl-7-methoxy-isoflavone that prototype is arranged in the blood, and there is notable difference in the different crystal forms 5-methyl-absorption of 7-methoxy-isoflavone compound in the rat body; Wherein brilliant A and brilliant C can be observed the enterohepatic circulation result.Detected result shows: all can detect the prototype medicine in rat serum after the administration of three kinds of different oxygen flavones of crystal formation, and there is notable difference in the absorption of different crystal forms compound in the rat body; Infer according to experimental result, the different oxygen flavones of 5-methyl-7-methoxy before by intestinal absorption namely by metabolism.
The dosage 1 of 5-methyl-7-methoxy-isoflavone crystal type A medicinal composition:
The pharmaceutical composition that a kind of crystal type A sample of the use 5-methyl-7-methoxy-isoflavone described in claim 1 manufactures as active constituents of medicine, it is characterized in that using the crystal type A of 5-methyl-7-methoxy-isoflavone as the activeconstituents of medicine, every day, dosage was 300mg, can be prepared into 3 times/each 1 100mg every day, every day 2 times/the common or slow control formula tablet type of each 1 150mg, 1 time/each 1 300mg.
The dosage 2 of 5-methyl-7-methoxy-isoflavone mixing crystal formation medicinal composition:
A kind of use 5-methyl-7-methoxy-isoflavone described in claim 20 mixes the pharmaceutical composition that crystal form samples manufactures as active constituents of medicine, it is characterized in that using the biased sample of three kinds of crystal formations of 5-methyl-7-methoxy-isoflavone as the activeconstituents of medicine, wherein crystal type A accounts for 50%, crystal B-type accounts for 30%, crystal C type accounts for 20%, every day, dosage was 600mg, can be prepared into 3 times/each 1 200mg every day, every day 2 times/the common or slow control formula tablet type of each 1 300mg, 1 time/each 1 600mg.
The problem that needs explanation: the 5-methyl that the present invention relates to-7-methoxy-isoflavone crystal formation pharmaceutical composition has many factor affecting at the dosage of effective constituent, for example: it is different with the purposes for the treatment of to be used for prevention, ill character is different with severity, the difference of patient's sex, age, body weight, route of administration, administration number of times, therapeutic purpose difference, absorption between crystal form samples and Plasma Concentration are not equal, cause the present invention at dosage every day that uses 5-methyl-7-methoxy-isoflavone crystal formation composition 50～1000mg variation value in a big way to be arranged.Should formulate different 5-methyl-7-methoxy-isoflavone crystal formation effective constituent total dose schemes with treatment different situations demand according to the prevention of reality during use, and can be divided into repeatedly or the single administration mode is finished.
The preparation method 1 of 5-methyl-7-methoxy-isoflavone crystal type A medicinal composition formulation-tablet:
A kind of method for preparing tablet thereof that uses the combined pharmaceutical formulation described in claim 23, it is characterized in that using as the methyl of the 5-in the claim 1-7-methoxy-isoflavone crystal type A sample as active constituents of medicine, use several vehicle as the adjunct ingredient of preparation medicinal composition tablet, proportioning is made every tablet samples that contains 5-methyl-7-methoxy-isoflavone crystal formation composition 50～300mg according to a certain percentage, and following table provides the prescription of conventional tablet:
Bulk drug and the accessory formula of 5-methyl-7-methoxy-isoflavone crystal type A tablet medicinal composition
With the 5-methyl-7-methoxy-isoflavone crystal type A sample of some amount with the method that the vehicle auxiliary material is prepared into tablet formulation be: several vehicle auxiliary materials are evenly mixed with bulk drug, add 1% sodium cellulose glycolate solution and make soft material in right amount, sieving granulates wet dries the whole grain that sieves, and adds Magnesium Stearate and talcum powder and mixes compressing tablet namely.
The preparation method 2 of 5-methyl-7-methoxy-isoflavone crystal type A medicinal composition formulation-capsule:
A kind of preparation method who uses the combined pharmaceutical formulation capsule described in claim 23, it is characterized in that using as the methyl of the 5-in the claim 1-7-methoxy-isoflavone crystal type A sample as active constituents of medicine, use several vehicle as the adjunct ingredient of preparation medicinal composition capsule, proportioning is made every capsule sample that contains 5-methyl-7-methoxy-isoflavone crystal type A composition 50～300mg according to a certain percentage, and following table provides the prescription of conventional capsule:
Bulk drug and the accessory formula of 5-methyl-7-methoxy-isoflavone crystal type A capsule combination medicine
The method that 5-methyl-7-methoxy-isoflavone crystal type A sample and the vehicle auxiliary material of some amount is prepared into capsule preparations is: several vehicle auxiliary materials and 5-methyl-7-methoxy-isoflavone crystal type A bulk drug are mixed, it is an amount of to add 1% sodium cellulose glycolate solution, make wet grain oven dry and sieve whole, add Magnesium Stearate and mix, insert capsule and make; Or do not use granulation step, and and directly 5-methyl-7-methoxy-isoflavone crystal type A bulk drug and several vehicle auxiliary material are mixed, after sieving, directly incapsulate and make.
Claims (8)
1.5-the crystal B-type solid matter of methyl-7-methoxy-isoflavone is characterized in that, its chemical purity and crystal formation purity are all greater than 95% and do not contain crystal water or other recrystallisation solvent composition, when using powder x-ray diffraction analysis to adopt CuK
aDiffraction peak position 2-Theta value during the radiation experiments condition (°) or the d value
Diffraction peak relative intensity peak height value (Height%) or peak area value (Area%) have following expression:
2. the preparation method of the crystal B-type sample of the methyl of 5-described in the claim 1-7-methoxy-isoflavone, it is characterized in that, earlier with tetrahydrofuran (THF) or dichloromethane solvent under 15～25 ℃ of normal temperature states, 5-methyl-7-methoxy-isoflavone sample dissolved fully, controls temperature in 45 ℃ utilize vacuum filtration or revolve the steaming method with the quick suction filtration of the solvent in the sample or evaporate to dryness, sample again drying technology finally prepare the crystal B-type solid sample of 5-methyl-7-methoxy-isoflavone.
3. the preparation method of the crystal B-type sample of the methyl of 5-described in the claim 1-7-methoxy-isoflavone, it is characterized in that, earlier with methylene dichloride add the ethyl acetate ratio be configured at 1: 1 behind the mixing solutions under 15～25 ℃ of normal temperature states 5-methyl-7-methoxy-isoflavone sample dissolved fully, controls temperature in 50 ℃ utilize vacuum filtration or revolve the steaming method with the quick suction filtration of the solvent in the sample or evaporate to dryness, sample again drying technology finally prepare the crystal B-type solid sample of 5-methyl-7-methoxy-isoflavone.
4. a pharmaceutical composition, is characterized in that as active constituents of medicine with 5-methyl-7-methoxy-isoflavone crystal formation solid matter, contains the crystal B-type of the 5-methyl-7-methoxy-isoflavone described in the claim 1.
5. according to the pharmaceutical composition of claim 4, it is characterized in that, 5-methyl-7-methoxy-isoflavone every day dosage in 50～1000mg scope.
6. according to the pharmaceutical composition of claim 4, it is characterized in that the formulation of described composition is tablet, capsule, pill, injection, slowly-releasing or controlled-release pharmaceutical formulation.
7. the application of the pharmaceutical composition of claim 4 in the medicine of preparation treatment cardiovascular and cerebrovascular diseases, osteoporosis, inflammation, metabolic disease.
8. the application of the methyl of the 5-described in the claim 1-7-methoxy-isoflavone crystal B-type composition 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 |
|---|---|---|---|---|
| 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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