CN101906101A - Rotundine crystal B-type solid matter and preparation method as well as applications - Google Patents
Rotundine crystal B-type solid matter and preparation method as well as applications Download PDFInfo
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Abstract
The invention discloses a novel crystal-type state of rotundine solid chemical matter, which is shown as the formula (I), a preparation method of the novel crystal-type sample, and superior clinical therapeutic action of the novel crystal-type matter of the rotundine as active components in the preparation and the development of various formulations and medicament compositions for preventing and treating pains caused by various reasons, including headache, cramp, labour pains, and the like, and diseases caused by pains, such as insomnia, arrhythmia, and the like. Compared with the traditional officinal crystal-type solid matter (Crystal A type), the two types of novel crystal-type solid matter of the rotundine have higher absorption and blood concentration. Different crystal-type matter can influence the absorption speed and the blood concentration in an organism as well as the bioavailability of the active components of the medicaments, and thereby influencing the preventive and therapeutic effect of the medicaments in clinical applications.
Description
Technical field
The present invention relates to the crystal B-type material of Rotundine, belong to medical technical field.
Background technology
Rotundine, chemical name are 2,3,9,10-tetramethoxy-5,8,13, and 13a-tetrahydrochysene-6H-dibenzo [a, g] thiazine, specific optical rotation is-290 °～-300 °, structural formula is as follows:
Rotundine is " 2005 editions two ones of Chinese pharmacopoeia
[1]Record types of drugs, this medicine has Rotundine tablet (339 pages), rotundine hydrochloride tablet (536 pages), rotundine sulfate injection liquid (339 pages) at present.Because existing, Rotundine medicine self absorbs relatively poor defective, thus just developed the rotundine hydrochloride tablet, to promote its absorption.
Be published in the 1977th page of Acta Crystallographica Section C 1998 the 54th the 12nd phase of volume about " (-)-Tetrahydropalmatine Monohydrate " article to one piece by literature search
[2], put down in writing the crystalline structure of Rotundine crystal type A, belong to the rhombic system symmetry, spacer is P2
12
12
1, the unit cell parameters value is
Molecule number Z=4 in α=β=γ=90 °, structure cell.
In Chinese patent ZL 02130672.9, put down in writing " be used to ease pain and quit drug abuse the pharmaceutical composition that contains Rotundine " of people such as Gong Zehui invention
[3]Wherein, relate to a kind of pharmaceutical composition of easing pain and/or quitting drug abuse of being used to, comprised the opiate receptor full agonist of the significant quantity of easing pain or the Rotundine of opiate receptor partial agonist and analgesia significant quantity during its feature.This pharmaceutical composition analgesic activity is strong, and untoward reactions such as habituation are little.
In Chinese patent CN 1125572A (publication number), put down in writing " a kind of making method of " Luotongding " pain-killing tablet " of Zou Guifa invention
[4]Wherein, related to a kind of making method of Rotundine controlled release tablet, advantage such as have analgesic activity, fluctuation is little, makes patient's comfort time lengthening, and toxic side effect is little.
In Chinese patent CN 1778300A (publication number), put down in writing people such as Zhang Xuemei invention " a kind of Rotundine orally disintegrating tablet and preparation method thereof "
[5]Wherein, related to a kind of Rotundine orally disintegrating tablet and preparation method thereof, these orally disintegrating tablet characteristics are to need not drinking-water, and it is big to have solved supplementary product consumption, water insoluble, leaves the problem of insoluble substance after the disintegration, and this disintegrating tablet sheet is heavy moderate, and dissolution rate is fast, available conventional tablet machine large-scale commercial production.
In in Chinese patent CN 1634056A (publication number), put down in writing Wang Liqiang, Liang Jintian invention " Rotundine orally disintegrating tablet preparation and preparation method thereof "
[6]Wherein, related to a kind of Rotundine disintegrating tablet formulation and preparation method thereof, this method need not specific installation, adopts common tabletting machine, and technology is simple, and cost is low.
In Chinese patent CN 1704058A (publication number), put down in writing people such as Zhang Wenwei invention " Rotundine slow releasing capsule and preparation method thereof "
[7]Wherein, related to a kind of Rotundine slow releasing capsule and preparation method thereof, this invention preparation only need be taken medicine once every day, and it is long to have the analgesic activity time, characteristics such as toxic side effect is low.
In Chinese patent CN 1704059A (publication number), put down in writing people such as Zhang Wenwei invention " Rotundine orally disintegrating tablet and preparation method thereof "
[8]Wherein, related to a kind of Rotundine orally disintegrating tablet and preparation method thereof, this invention preparation process is simple, easy administration, need not use water delivery service, in the oral cavity, run into just disintegration or dissolving rapidly of saliva, critical patient under especially suitable those dysphagias, water intaking inconvenience or the particular surroundings such as old man, children, coma patient medication.
In Chinese patent CN 1706383A (publication number), put down in writing people such as Zhang Wenwei invention " Rotundine dispersible tablet and preparation method thereof "
[9]Wherein, related to a kind of Rotundine dispersible tablet and preparation method thereof, the technical characterstic of this invention is to adopt direct compression technology or wet granule compression tablet prepared Rotundine dispersible tablet, this invention preparation easy administration, mouthfeel is good, and stripping is rapid, the bioavailability height, rapid-action, be particularly suitable for the critical patient medication under old man, children, dysphagia person or the particular surroundings.
In Chinese patent CN 1726914A (publication number), put down in writing high " slow release tablet of rotundine and the production technique thereof " that very waits people's invention forever
[10]Wherein, related to a kind of slow release tablet of rotundine and preparation method thereof.
In Chinese patent CN 1490007A (publication number), put down in writing people such as Qian Jin invention " dripping pills of tetrahydropalmatini sulfas and preparation method thereof "
[11]Wherein, related to a kind of method that micronizing and pill production technology prepare tetrahydropalmatine sulfate of using, can reach and improve the molten diffusing speed of disintegration, can contain clothes or swallow, onset is rapid, improves medicine stability, reduces supplementary product consumption, reduce production costs purpose easy to carry and use.
Put down in writing " the improving one's methods of preparation tetrahydropalmatine " of Colleges Of Traditional Chinese Medicine Of Guangxi's invention among the state patent CN 86108482A (publication number)
[12]Wherein, thus having related to a kind of muriatic Diluted Alcohol solution of palmatine and solution of potassium borohydride of adopting participates in the method that reduction reaction prepares tetrahydropalmatine.
In Chinese patent CN 1068113A (publication number), put down in writing to hold to preserve and given birth to " is the method for feedstock production tetrahydropalmatine with methyl catechol " of waiting people's invention
[13]Wherein, having related to a kind of is starting raw material with the methyl catechol, through methylate, the method for the complete synthesis tetrahydropalmatines of reaction such as chloromethylation, cyaniding, amination, condensation hydrogenation, cyclization.
In Chinese patent CN 1562019A (publication number), put down in writing Meng Fanhao invention " tetrahydropalmatine prolonged action preparation and preparation method thereof "
[14]Wherein, related to a kind of tetrahydropalmatine prolonged action preparation and preparation method thereof, this invention adopts preparation process that the tetrahydropalmatine and the conventional slow-release auxiliary material of recipe quantity are made long-acting (slowly-releasing, controlled release) preparation.
In Chinese patent CN 1562020A (publication number), put down in writing Meng Fanhao invention " tetrahydropalmatine powder injection and preparation method thereof "
[15]Wherein, related to a kind of powder injection that contains tetrahydropalmatine and preparation method thereof.
In Chinese patent CN 1729980A (publication number), put down in writing Wang Jingang invention " a kind of dripping pills of tetrahydropalmatini sulfas and preparation method thereof "
[16]Wherein, having related to a kind of analgesic pharmaceutical composition that is used for, particularly is a kind of dripping pills of tetrahydropalmatini sulfas of feedstock production with the tetrahydropalmatine sulfate.
In Chinese patent CN 1982310A (publication number), put down in writing " preparation method of high-purity corydalis " of people such as Shen Ping Mother invention
[17]Wherein, having related to employing tells countercurrent chromatography to prepare the method for high-purity corydalis.
Summary of the invention
There are essential difference in point of penetration of the present invention and prior art, promptly be to start with from the research of Rotundine solid chemical material existence, study by the polymorphic triage techniques, on the raw material aspect of active constituents of medicine, seek, find the new crystal kind and the status flag of Rotundine solid matter, and crystal formation research combined with clinical pharmacodynamic study, provide the basic scientific research data for seeking, find, develop Rotundine solid pharmaceutical with optimal clinical curative effect.
One embodiment of the invention provide Rotundine crystal B-type and two kinds of new solid matter existence and describing modes of crystal C type.
One embodiment of the invention provide the preparation method of Rotundine crystal B-type, crystal C type two kinds of new solid matter samples.
One embodiment of the invention provide the pharmaceutical composition of Rotundine crystal-form substances as the activeconstituents preparation.Described composition comprises various pharmaceutical preparations such as tablet, capsule, pill, injection, slowly-releasing or controlled release.
Rotundine crystal-form substances of the present invention, comprise contain crystal B-type composition or crystal C type composition or by two kinds of crystal formation compositions of B, C by the arbitrary proportion mixing element or contain the crystal B-type composition and other crystal formation compositions by the arbitrary proportion mixing element or contain the crystal C type composition and other crystal formation compositions by the arbitrary proportion mixing element or contain the crystal B-type composition and crystal C type composition and other crystal formation compositions by the arbitrary proportion mixing element.
One embodiment of the invention provide Rotundine crystal formation Rotundine crystal-form substances in the preparation prevention with treat application in the medicine of the described pain that multiple reason causes, described pain comprise headache, cramp, pain of childbirth, and in the disease such as the insomnia that causes by pain and heart disorder.
One embodiment of the invention provide the Rotundine crystal-form substances preparing because the application in the medicine of Plasma Concentration in the crystal formation effect raising organism.
The crystal B-type solid sample morphological specificity of Rotundine according to an embodiment of the invention:
By the Rotundine crystal B-type solid sample that embodiment of the present invention obtain, the chemical purity of sample and crystal formation purity are all greater than 90%, and specific optical rotation is-290 °～-300 °, 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 character numerical value.Table 1 provides the powder x-ray diffraction peak value of Rotundine crystal B-type solid sample, and accompanying drawing 1 provides the x-ray diffractogram of powder spectrum of Rotundine crystal B-type solid sample.
The powder x-ray diffraction peak value of table 1 Rotundine crystal B-type solid sample
By the Rotundine crystal B-type solid matter that embodiment of the present invention obtain, the exothermic peak transformation value when using dsc analysis on the collection of illustrative plates is about about 104 ℃, and the endotherm(ic)peak transformation value is about about 143 ℃.Accompanying drawing 2 provides the DSC collection of illustrative plates of Rotundine crystal B-type solid sample.
The Rotundine crystal B-type solid sample that obtains by embodiment of the present invention, when the KBr compressing tablet that uses infrared spectra is analyzed 3611,3320,3199,3001,2966,2942,2923,2897,2833,2801,2751,2038,1632,1610,1585,1514,1496,1457,1428,1410,1386,1360,1344,1334,1302,1279,1257,1229,1215,1190,1139,1105,1080,1052,1026,1005,991,955,911,863,811,786,775,753,708,674,644,608,571,525,509,496,453cm
-1The place has absorption peak to exist, wherein 3320,3199,3001,2966,2942,2923,2897,2833,2801,2751,2038,1632,1514,1457,1344,1302,1279,1139,1105,1052,1005,955,863,811,775,753,708,571cm
-1The peak is the characteristic absorbance peak position that presents Rotundine crystal B-type solid sample.Accompanying drawing 3 provides Rotundine crystal B-type solid sample infrared absorption spectrum.
By the Rotundine crystal B-type solid sample that embodiment of the present invention obtain, the melting point values when using the fusing point instrument to carry out sample analysis is about about 141～143 ℃.
The crystal C type solid sample morphological specificity of Rotundine according to an embodiment of the invention:
The crystal C type solid sample of the Rotundine that obtains by embodiment of the present invention, the chemical purity of sample and crystal formation purity are all greater than 90% 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, the unit cell parameters value
α=γ=90 °, β=98.39 °, accompanying drawing 4 provides the molecule relative configuration figure of Rotundine crystal C type solid sample, and accompanying drawing 5 provides the molecule stereo structure sciagraph of Rotundine crystal C type solid sample, and accompanying drawing 6 provides the molecule structure cell accumulation graph of Rotundine crystal C type solid sample.Table 2 provides the non-hydrogen atom coordinate parameters and the equivalent temperature factor values of Rotundine crystal C type solid sample molecule, table 3 provides the one-tenth key interatomic bond long value of Rotundine crystal C type solid sample molecule, and the molecule that table 4 provides Rotundine crystal C type solid sample becomes key interatomic bond angle value.
The non-hydrogen atom coordinate parameters and the equivalent temperature factor values of table 2 Rotundine crystal C type solid sample molecule
The one-tenth key interatomic bond long value of table 3 Rotundine crystal C type solid sample molecule
The molecule of table 4 Rotundine crystal C type solid sample become key interatomic bond angle value (°)
Rotundine crystal C type solid sample by embodiment of the present invention acquisition, the chemical purity of sample and crystal formation purity are all greater than 90% and do not contain crystal water or other recrystallisation solvent composition, specific optical rotation is-290 °～-300 °, when using powder x-ray diffraction analysis to adopt CuK
αDiffraction peak position 2-Theta value during the radiation experiments condition (°) or the Rotundine crystal C type solid matter that obtains by embodiment of the present invention of d, figure value when using dsc analysis
Diffraction peak relative intensity peak height value (Height%) or peak area value (Area%) have following character numerical value.Table 5 provides the powder x-ray diffraction peak value of Rotundine crystal C type solid sample, and accompanying drawing 7 provides the x-ray diffractogram of powder spectrum of Rotundine crystal C type solid sample.
The powder x-ray diffraction peak value of table 5 Rotundine crystal C type solid sample
The Rotundine crystal C type solid matter that obtains by embodiment of the present invention, when the KBr compressing tablet that uses infrared spectra is analyzed 3612,2999,2939,2858,2828,2787,2748,2042,1852,1686,1609,1583,1510,1494,1460,1426,1409,1387,1359,1342,1331,1301,1278,1258,1229,1215,1206,1190,1164,1140,1108,1082,1056,1038,1024,1003,993,955,909,889,854,806,786,772,752,705,675,645,607,569,510,496,453cm
-1The place has absorption peak to exist, wherein 2999,2939,2858,2828,2787,2748,2042,1686,1510,1460,1331,1301,1278,1206,1164,1140,1108,1056,1038,1003,955,854,806,772,752,705,569cm
-1The peak is the characteristic absorbance peak position that presents Rotundine crystal C type solid sample.Accompanying drawing 9 provides Rotundine crystal C type solid sample infrared absorption spectrum.
By the Rotundine crystal C type solid matter that embodiment of the present invention obtain, the melting point values when using the fusing point instrument to carry out sample analysis is about about 141～143 ℃.
The preparation method of the crystal formation of Rotundine according to an embodiment of the invention
The preparation method of Rotundine crystal B-type sample, be to use the Rotundine solid sample as the preparation raw material, employing physical mechanics lattice damage and molecular transposition rotating crystal method prepare crystal B-type solid matter or prepare Rotundine crystal B-type chemistry solid matter by pressure condition, the temperature condition that changes physics.
The preparation method of Rotundine crystal B-type sample is to use chloroform earlier, acetone, ethyl acetate, propyl carbinol, Virahol, n-propyl alcohol, acetonitrile, tetrahydrofuran (THF), benzene, toluene, methylene dichloride, normal hexane, hexanaphthene, dioxane, DMF, DMSO, sherwood oil, pyridine or water single solvent dissolve the Rotundine sample fully or use methyl alcohol, ethanol, 95% ethanol, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, n-propyl alcohol, acetonitrile, tetrahydrofuran (THF), benzene, toluene, methylene dichloride, normal hexane, hexanaphthene, dioxane, DMF, DMSO, sherwood oil, any two or more in pyridine or the water different sorts solvent mix the back through different proportionings and under 4 ℃～60 ℃ temperature the Rotundine sample are dissolved fully and adopt cold and hot spray method to prepare the chemical solid matter of Rotundine crystal B-type fast again.
Because being used to prepare the single organic solvent of crystal B-type Rotundine sample has 19 kinds, can be used to prepare two kinds of crystal B-type Rotundine sample or above solvent combination has hundreds of, every kind of organic solvent boiling point value difference, to Rotundine 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 under using different solvents condition preparation crystal B-type Rotundine sample.These variate-values all can there is some difference property and constant interval scope, these variate-values are easy to determine for those of ordinary skill in the art.
The preparation method of Rotundine crystal C type sample is the single solvent that uses earlier chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, n-propyl alcohol, acetonitrile, tetrahydrofuran (THF), benzene, toluene, methylene dichloride, normal hexane, hexanaphthene, dioxane, DMF, DMSO, sherwood oil, pyridine or water is dissolving the Rotundine sample under 15 ℃～80 ℃ temperature and recrystallization preparation technology under 4 ℃～80 ℃ of envrionment temperatures, ambient moisture 10%～75%, normal pressure or vacuum experiment condition obtains the crystal C type solid matter of Rotundine fully.
The preparation method of Rotundine crystal C type sample is to use methyl alcohol earlier, ethanol, 95% ethanol, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, n-propyl alcohol, acetonitrile, tetrahydrofuran (THF), benzene, toluene, methylene dichloride, normal hexane, hexanaphthene, dioxane, DMF, DMSO, sherwood oil, any two or more in pyridine or the water different sorts solvent dissolve the Rotundine sample under 15 ℃～80 ℃ temperature after different proportionings are mixed and fully through 4 ℃～80 ℃ of envrionment temperatures, ambient moisture 10%～75%, recrystallization preparation technology under normal pressure or the vacuum experiment condition obtains the crystal C type solid matter of Rotundine.
The preparation method of Rotundine crystal C type sample is to use the various solid crystal form samples of Rotundine as the preparation raw material, adopts thermostatic heating method to change the brilliant crystal C type solid matter for preparing Rotundine after the time through 60min under 105 ℃ of conditions.
Because can be used for preparing the single organic solvent of crystal C type Rotundine sample has 19 kinds, two or more solvent combination hundreds of is arranged, every kind of organic solvent boiling point value difference, to Rotundine sample dissolution degree difference, variate-values such as the envrionment temperature of its experiment, humidity, time all there is some difference property and constant interval scope when causing under using different solvents condition preparation crystal C type Rotundine sample.These variate-values all can there is some difference property and constant interval scope, these variate-values are easy to determine for those of ordinary skill in the art.
Crystal formation composition, dosage and the pharmaceutical preparations composition of Rotundine according to an embodiment of the invention
Further aspect of the present invention also relates to the pharmaceutical composition of Rotundine crystal-form substances as active ingredient.This pharmaceutical composition can be according to method preparation well known in the art.Can be by the pharmaceutically acceptable solid of Rotundine crystal-form substances and one or more or liquid excipient and/or assistant agent being combined, make any formulation that is suitable for human or animal's use.The content of Rotundine crystal-form substances in its pharmaceutical composition is generally 0.1-95 weight %.
The Rotundine crystal-form substances or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be enteron aisle or non-enteron aisle, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The Rotundine crystal-form substances can be made ordinary preparation, also make is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For the Rotundine crystal-form substances is made tablet, can be extensive use of various vehicle well known in the art, comprise thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, lime carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and Citric Acid, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Tablet further can also be made coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
For capsule is made in the administration unit, effective constituent Rotundine crystal-form substances can be mixed with thinner, glidant, mixture is directly placed hard capsule or soft capsule.Also effective constituent Rotundine crystal-form substances particle or micropill be can be made with thinner, tamanori, disintegrating agent earlier, hard capsule or soft capsule placed again.Each thinner, tamanori, wetting agent, disintegrating agent, the glidant kind that are used to prepare Rotundine crystal-form substances tablet also can be used for preparing the capsule of Rotundine crystal-form substances.
For the Rotundine crystal-form substances is made injection, can water, ethanol, Virahol, propylene glycol or their mixture as solvent and add an amount of this area solubilizing agent commonly used, solubility promoter, pH and adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be poloxamer, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjustment agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepare lyophilized injectable powder, also can add N.F,USP MANNITOL, glucose etc. as propping agent.
In addition, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives or other additive.
The pharmaceutical composition that uses crystal formation Rotundine sample to manufacture as active constituents of medicine, can use the activeconstituents of crystal C type Rotundine as medicine, every day, dosage was 180mg, can be prepared into 3 times/each 1 60mg conventional tablet every day respectively, every day 2 times/each 1 90mg conventional tablet or every day 1 time/each 1 180mg slow control formula tablet type.
The pharmaceutical composition that uses crystal formation Rotundine sample to manufacture as active constituents of medicine, can use the activeconstituents of mixed crystal Rotundine sample as medicine, wherein crystal C type accounts for more than 50% of Rotundine composition total amount, every day, dosage was 90mg, can be prepared into 3 times/each 1 30mg conventional tablet every day, every day 2 times/each 1 45mg conventional tablet or every day 1 time/each 1 90mg slow control formula tablet type.
The crystal formation Rotundine pharmaceutical composition that the present invention relates to has many factor affecting on the dosage of effective constituent, for example: be used to prevent different with the purposes for the treatment of and cause the difference of dosage every day; Ill character is different with ill severity and cause the different of dosage every day; The difference of patient's sex, age, body surface area, route of administration, administration number of times, therapeutic purpose are different and cause the difference of dosage every day; In addition, absorption that exists between crystal form samples and Plasma Concentration are not equal, and also causing the present invention is 0.01～150mg/kg body weight in suitable dose scope every day of using crystal formation Rotundine composition, is preferably 1～100mg/kg body weight.Should formulate different crystal formation Rotundine effective constituent total dose schemes according to the prevention of reality and treatment different situations demand during use, and can be divided into repeatedly or the single administration mode is finished.
For reaching the medication purpose, strengthen result of treatment, medicine of the present invention or pharmaceutical composition can be with any known medication administrations.
Rotundine crystal-form substances or composition can be taken separately, or merge use with other treatment medicine or symptomatic drugs.When Rotundine crystal-form substances and other medicine existence synergy, should adjust its dosage according to practical situation.
The pharmacodynamic profile of different crystal forms Rotundine according to an embodiment of the invention:
Absorption and Plasma Concentration difference that one embodiment of the invention provide Rotundine crystal formation solid matter to exist in vivo, Rotundine crystal B-type and crystal C type composition have significant absorption in vivo than the crystal type A composition and Plasma Concentration advantage, biological activity size order are crystal C type＞crystal B-type＞crystal type A, has shown that promptly Rotundine crystal C type and crystal B-type are more suitable for the solid administering mode and are easy to absorb distribution at gi tract.Therefore the present invention also provides the Rotundine crystal-form substances preparing because the application in the medicine of Plasma Concentration in the crystal formation effect raising organism.
Rotundine crystal B-type composition and existing medicinal crystal type A composition have determined that new crystal B-type solid matter has significant absorption and Plasma Concentration advantage in vivo by biological experiment after relatively, and oral administration Rotundine medicine can reach maximum plasma concentration after 0.5 hour, Plasma Concentration can reach 24 hours, crystal B-type Plasma Concentration＞crystal type A has shown that promptly the Rotundine crystal B-type is more suitable for solid and is easy to absorb distribution through gastrointestinal administration, the new crystal B-type solid matter of Rotundine has changed original solid pharmaceutical effective constituent absorption rate in vivo, strengthen Plasma Concentration in the organism and reached raising medicine advantage preventive and therapeutic effect in clinical disease treatment.
Rotundine crystal C type composition and existing medicinal crystal type A material have determined that new crystal C type solid matter has significant absorption and Plasma Concentration advantage in vivo by biological experiment after relatively, and the oral administration Rotundine can reach maximum plasma concentration after 0.5 hour, Plasma Concentration can be kept 24 hours, crystal C type Plasma Concentration＞crystal type A also can be kept the higher Plasma Concentration long period and shown that promptly the Rotundine crystal C type is more suitable for solid and is easy to absorb to distribute through gastrointestinal administration, Rotundine crystal C type solid matter has changed original solid pharmaceutical effective constituent absorption rate in vivo, strengthen Plasma Concentration in the organism and reached raising medicine advantage preventive and therapeutic effect in clinical disease treatment.
Description of drawings
The x-ray diffractogram of powder spectrum of accompanying drawing 1 Rotundine crystal B-type solid sample
Accompanying drawing 2 Rotundine crystal B-type solid sample DSC collection of illustrative plates.
Accompanying drawing 3 Rotundine crystal B-type solid sample infrared absorption spectruies.
The molecule relative configuration figure of accompanying drawing 4 Rotundine crystal C type solid samples,
The molecule stereo structure sciagraph of accompanying drawing 5 Rotundine crystal C type solid samples,
The molecule structure cell accumulation graph of accompanying drawing 6 Rotundine crystal C type solid samples.
The x-ray diffractogram of powder spectrum of accompanying drawing 7 Rotundine crystal C type solid samples.
Accompanying drawing 8 Rotundine crystal C type solid sample DSC collection of illustrative plates.
Accompanying drawing 9 Rotundine crystal C type solid sample infrared absorption spectruies.
After the accompanying drawing 10 Rotundine crystal form samples oral absorption at the intravital determination of plasma concentration of rat.
Accompanying drawing 11 Rotundine crystal form samples Plasma Concentration matched curves.
Embodiment
For technical scheme of the present invention better is described, provide following illustrative embodiment, but the present invention is not limited to this.
The preparation method 1 of brilliant B Rotundine sample:
The preparation method of crystal B-type Rotundine sample uses the crystal type A solid sample as the preparation raw material, adopts physical mechanics lattice damage and molecular transposition rotating crystal method to prepare crystal B-type solid matter.
The preparation method 2 of brilliant B Rotundine sample:
The preparation method of crystal B-type Rotundine sample uses tetrahydrofuran solvent under 15～30 ℃ of normal temperature states the Rotundine sample to be dissolved fully earlier, adopts the cold spray method to prepare crystal B-type Rotundine solid matter fast again.
The preparation method 1 of crystal C type Rotundine sample:
The preparation method of crystal C type Rotundine sample, the Rotundine sample is dissolved fully under 15～30 ℃ of normal temperature states with the propyl carbinol solvent earlier, utilizing Rotary Evaporators again is under 40 ℃ the vacuum condition solvent to be steamed fast to prepare the crystal C type Rotundine solid matter that obtains in temperature.
The preparation method 2 of crystal C type Rotundine sample:
The preparation method of crystal C type Rotundine sample is dissolved the Rotundine sample under 15～30 ℃ of normal temperature states fully with pyridine solvent earlier, is placed on temperature again and is the crystal C type Rotundine solid matter that under 22 ℃ the condition of normal pressure solvent is volatilized gradually to prepare.
Crystal B-type Rotundine solid pharmaceutical absorbs feature and Plasma Concentration feature in the rat body:
Laboratory animal: the Wistar rat, male, body weight: 194.2 ± 9.2g.Purchase laboratory animal institute in the Chinese Academy of Medical Sciences.
Experimental technique: Rotundine crystal type A, crystal B-type.Prepare into about the 17mg/ml suspension with suitable solution (physiological saline).The conventional raising condition of rat is raised, and freely drinks water, and behind the fasting 12h, irritates stomach by 200mg/kg and gives medicine.After the administration 0.083,0.25,0.5,1,1.5,2,2.5,3,4,6,8,10,12,24 (h).Eye socket is got the about 0.3～0.5ml of blood, the centrifugal 15min of 5000rpm.Get 150 μ l blood plasma, add ethyl acetate 1ml, vortex oscillation 3min, the centrifugal 5min of 13400rpm gets organic layer 800 μ l, and nitrogen volatilizes.With 75 μ l dissolve with methanol residues, behind the vortex oscillation 0.5min, the centrifugal 1min of 13400rpm; Get supernatant 20 μ l and carry out the HPLC detection.
The HPLC condition: detection system is Aligent 1100 highly effective liquid phase chromatographic systems, and chromatographic column is AligentXDB-C18 (150 * 4.6mm, 5 μ m), moving phase is methyl alcohol: water=70: 30, sample size are 20 μ l, and flow velocity is 1ml/min, the detection wavelength is 281nm, and column temperature is 30 ℃.
Experimental result shows: Rotundine crystal formation chemistry solid matter can be absorbed by rat, Rotundine crystal B-type composition and existing medicinal crystal type A composition have determined that new crystal B-type solid matter has significant absorption and Plasma Concentration advantage in vivo by biological experiment after relatively, crystal B-type Plasma Concentration＞crystal type A has shown that promptly the Rotundine crystal B-type is more suitable for the solid administering mode and is easy to absorb distribution at gi tract, and Rotundine new crystal solid matter has changed original solid pharmaceutical effective constituent absorption rate in vivo, strengthen Plasma Concentration in the organism and reached raising medicine advantage preventive and therapeutic effect in clinical disease treatment.
Rat serum concentration data after table 6 Rotundine crystal type A and the administration of crystal B-type oral administration
Crystal C type Rotundine solid pharmaceutical absorbs feature and Plasma Concentration feature in the rat body:
Laboratory animal: the Wistar rat, male, body weight: 194.2 ± 9.2g.Purchase laboratory animal institute in the Chinese Academy of Medical Sciences.
Experimental technique: Rotundine crystal type A, crystal B-type, crystal C type.Prepare into about the 17mg/ml suspension with suitable solution (physiological saline).The conventional raising condition of rat is raised, and freely drinks water, and behind the fasting 12h, irritates stomach by 200mg/kg and gives medicine.After the administration 0.083,0.25,0.5,1,1.5,2,2.5,3,4,6,8,10,12,24 (h).Eye socket is got the about 0.3～0.5ml of blood, the centrifugal 15min of 5000rpm.Get 150 μ l blood plasma, add ethyl acetate 1ml, vortex oscillation 3min, the centrifugal 5min of 13400rpm gets organic layer 800 μ l, and nitrogen volatilizes.With 75 μ l dissolve with methanol residues, behind the vortex oscillation 0.5min, the centrifugal 1min of 13400rpm; Get supernatant 20 μ l and carry out the HPLC detection.
The HPLC condition: detection system is Aligent 1100 highly effective liquid phase chromatographic systems, and chromatographic column is AligentXDB-C
18(150 * 4.6mm, 5 μ m), moving phase is methyl alcohol: water=70: 30, sample size are 20 μ l, and flow velocity is 1ml/min, and the detection wavelength is 281nm, and column temperature is 30 ℃.
Experimental result shows: absorption and Plasma Concentration difference that Rotundine crystal formation chemistry solid matter exists in vivo, Rotundine crystal C type composition and existing medicinal crystal type A composition by biological experiment relatively after, determined that new crystal C type solid matter has significant absorption and Plasma Concentration advantage in vivo, Plasma Concentration crystal C type＞crystal type A has shown that promptly the Rotundine crystal C type is more suitable for the solid administering mode and is easy to absorb distribution at gi tract, and Rotundine new crystal solid matter has changed original solid pharmaceutical effective constituent absorption rate in vivo, strengthen Plasma Concentration in the organism and reached raising medicine advantage preventive and therapeutic effect in clinical disease treatment.
Rat serum concentration data after table 7 Rotundine crystal type A and the administration of crystal C type oral administration.
Subordinate list 7 has provided the rat serum concentration data after Rotundine crystal type A and the administration of crystal C type oral administration.Accompanying drawing 10 provides after the Rotundine crystal form samples oral absorption in the intravital determination of plasma concentration result of rat.Accompanying drawing 11 provides the matched curve of Rotundine crystal form samples Plasma Concentration.
The preparation method 1 of the C crystal formation medicinal composition solid dosage-tablet of Rotundine:
With the crystal C type solid matter of Rotundine drug regimen method for preparing tablet thereof as effective constituent, the crystal C type solid sample that has been to use Rotundine as active constituents of medicine, use the adjunct ingredient of several vehicle as preparation medicinal composition tablet, proportioning is made every tablet samples that contains the crystal C type solid pharmaceutical composition 10～200mg of Rotundine according to a certain percentage, and table 8 provides the formula rate of conventional tablet.
The bulk drug and the accessory formula of the crystal C type solid medicinal composition tablet of table 8 Rotundine
With the crystal C type solid matter of the Rotundine of some amount and the method that the vehicle auxiliary material is prepared into the various dose tablet is with several vehicle auxiliary materials and bulk drug uniform mixing, add 1% sodium cellulose glycolate solution and make soft material in right amount, the granulation of sieving, the wet grain oven dry and the whole grain that sieves add Magnesium Stearate and talcum powder and mix the back compressing tablet promptly.
The C crystal formation medicinal composition solid dosage-capsular preparation method 2 of Rotundine:
With the crystal C type solid sample of Rotundine drug regimen capsule preparations preparation method as effective constituent, the crystal C type solid sample that is to use Rotundine as active constituents of medicine, use the adjunct ingredient of several vehicle as preparation medicinal composition tablet, proportioning is made the capsule preparations of the crystal C type pharmaceutical cpd 10～150mg that contains Rotundine in every capsules according to a certain percentage, and table 9 provides the formula rate of conventional capsule preparation:
The bulk drug and the accessory formula of the C crystal formation solid medicinal composition capsule preparations of table 9 Rotundine
With the crystal C type solid matter of the Rotundine of some amount and the method that the vehicle auxiliary material is prepared into capsule preparations be: the crystal C type solid material medicine of several vehicle auxiliary materials and Rotundine is 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 crystal C type solid material medicine and several vehicle auxiliary material of Rotundine mixed, after sieving, directly incapsulate and make.
Reference
1, Chinese Pharmacopoeia, two ones, 2005 editions, Rotundine tablet (339 pages), rotundine hydrochloride tablet (536 pages), rotundine sulfate injection liquid (339 pages).
2、P.Luger?et.al，Acta?Crystallogr.Sect.C，1998，54(2)：1977-1980.
3, Chinese patent, patent No. ZL 02130672.9.
4, Chinese patent, publication number CN 1125572A.
5, Chinese patent, publication number CN 1778300A.
6, Chinese patent, publication number CN 1634056A.
7, Chinese patent, publication number CN 1704058A.
8, Chinese patent, publication number CN 1704059A.
9, Chinese patent, publication number CN 1706383A.
10, Chinese patent, publication number CN 1726914A.
11, Chinese patent, publication number CN 1490007A.
12, Chinese patent, publication number CN 86108482A.
13, Chinese patent, publication number CN 1068113A.
14, Chinese patent, publication number CN 1562019A.
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16, Chinese patent, publication number CN 1729980A.
17, Chinese patent, publication number CN 1982310A.
Claims (15)
1. a Rotundine crystal B-type solid matter is characterized in that, when the chemical purity of sample and crystal formation purity all greater than 90%, when specific optical rotation is-290 °～-300 °, use 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 character numerical value:
2. according to the Rotundine crystal B-type solid matter of claim 1, it is characterized in that, exist 1 exothermic peak transformation value when using dsc analysis on the collection of illustrative plates about reaching 1 endotherm(ic)peak transformation value about 104 ℃ about about 143 ℃.
3. according to each Rotundine crystal B-type solid matter of claim 1-2, it is characterized in that, when using infrared spectra to analyze 3611,3320,3199,3001,2966,2942,2923,2897,2833,2801,2751,2038,1632,1610,1585,1514,1496,1457,1428,1410,1386,1360,1344,1334,1302,1279,1257,1229,1215,1190,1139,1105,1080,1052,1026,1005,991,955,911,863,811,786,775,753,708,674,644,608,571,525,509,496,453cm
-1The place has absorption peak to exist, wherein 3320,3199,3001,2966,2942,2923,2897,2833,2801,2751,2038,1632,1514,1457,1344,1302,1279,1139,1105,1052,1005,955,863,811,775,753,708,571cm
-1The peak is the absorption peak position that presents the Rotundine crystal B-type solid matter feature.
4. according to each Rotundine crystal B-type solid matter of claim 1-3, it is characterized in that its melting point values is about about 141～143 ℃ when using the fusing point instrument to carry out sample analysis.
5. the mixed crystal of a Rotundine is characterized in that, contains Rotundine crystal B-type composition.
6. according to the mixed crystal of the Rotundine of claim 5, it is characterized in that, is the arbitrary proportion crystal formation mixture of Rotundine crystal B-type and Rotundine crystal C type.
7. according to the mixed crystal of the Rotundine of claim 5, it is characterized in that, is the arbitrary proportion crystal formation mixture of Rotundine crystal B-type and Rotundine crystal type A.
8. according to the mixed crystal of the Rotundine of claim 5, it is characterized in that, is the arbitrary proportion crystal formation mixture of Rotundine crystal B-type, Rotundine crystal C type, Rotundine crystal type A.
9. according to the preparation method of the Rotundine crystal B-type sample of claim 1-4, it is characterized in that, use the Rotundine solid sample as the preparation raw material, employing physical mechanics lattice damage and molecular transposition rotating crystal method prepare crystal B-type solid matter or prepare Rotundine crystal B-type chemistry solid matter by pressure condition, the temperature condition that changes physics.
10. according to the preparation method of the Rotundine crystal B-type sample of claim 1-4, it is characterized in that, use chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, n-propyl alcohol, acetonitrile, tetrahydrofuran (THF), benzene, toluene, methylene dichloride, normal hexane, hexanaphthene, dioxane, DMF, DMSO, sherwood oil, pyridine or water single solvent dissolve the Rotundine sample fully or use methyl alcohol, ethanol, 95% ethanol, chloroform, acetone, ethyl acetate, propyl carbinol, Virahol, n-propyl alcohol, acetonitrile, tetrahydrofuran (THF), benzene, toluene, methylene dichloride, normal hexane, hexanaphthene, dioxane, DMF, DMSO, sherwood oil, any two or more in pyridine or the water different sorts solvent mix the back through different proportionings and under 4 ℃～60 ℃ temperature the Rotundine sample are dissolved fully and adopt cold and hot spray method to prepare the chemical solid matter of Rotundine crystal B-type fast again.
11. a pharmaceutical composition, its contain treat significant quantity claim 1-8 each the Rotundine crystal-form substances and one or more plant pharmaceutically acceptable carrier.
12., it is characterized in that described composition is selected from tablet, capsule, pill, injection, sustained release preparation or controlled release preparation according to claim 11 compound.
13. sharp each the Rotundine crystal-form substances of 1-8 that requires prevents and/or treats application in the medicine of pain and related complication in preparation.
14. use according to claim 13, it is characterized in that described pain comprises headache, cramp, pain of childbirth; Described related complication comprises insomnia, the heart disorder that pain causes.
15. the sharp purposes of 1-8 Rotundine crystal-form substances in preparing the medicine that improves Plasma Concentration in the organism owing to the crystal formation effect that require.
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