CN110117279B - Crystal form B of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine - Google Patents
Crystal form B of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine Download PDFInfo
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- CN110117279B CN110117279B CN201810117139.2A CN201810117139A CN110117279B CN 110117279 B CN110117279 B CN 110117279B CN 201810117139 A CN201810117139 A CN 201810117139A CN 110117279 B CN110117279 B CN 110117279B
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Abstract
The invention discloses two crystal forms of (13aS) -3-pivaloyloxy-6, 7-dimethoxy-phenanthroindolizidine, and a preparation method, a pharmaceutical composition and application thereof. Specifically, the crystal A form and the crystal B form of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine in a solid state are found; relates to a preparation method of a crystal form A and a crystal form B sample of (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine; relates to screening out the advantageous crystal form of (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine; relates to various preparations prepared and developed by using (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crystal form A and crystal form B aS active ingredients and application of the preparations and the pharmaceutical compositions thereof in cancer treatment.
Description
Technical Field
The invention relates to a solid state form of crystal A and crystal B in which (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine exists in a solid state; relates to the preparation method of the crystal A type sample and the crystal B type sample; relates to the invention of a dominant crystal form of (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine; the invention also relates to application of the (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine crystal A and crystal B aS active ingredients in preparation of medicaments for preventing and treating human glioma, human bone marrow neuroblastoma, human ovarian cancer, liver cancer and pancreatic cancer diseases.
Background
The phenanthroindolizidine alkaloid is mainly distributed in the plants of tylophora of Asclepiadaceae, has various pharmacological activities, and the antitumor effect of the phenanthroindolizidine alkaloid is of interest. The (13aS) -3,6, 7-trimethoxy phenanthroindolizidine (CAT) is separated from Tylophora atropurpurea (Tylophorovata) and Tylophora ovata (Tylophoro ovata) which belong to the genus Tylophora of the family Asclepiadaceae, and pharmacological activity screening shows that the (CAT) has obvious activity on tumor cells of various tissue sources, including human glioma U251 and BT323 cell strains, but has larger toxicity.
The main metabolite of (13aS) -3,6, 7-trimethoxy phenanthroindolizidine in the experimental animal body is (13aS) -3-hydroxy-6, 7-dimethoxy phenanthroindolizidine (PF 403). Based on the metabolite PF403, through further structural modification and biological activity research, a prodrug (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine (CAT3) is discovered according to the design concept of the prodrug, with the purposes of improving the physicochemical property, reducing the toxicity and maintaining the in-vivo anti-tumor activity of the prodrug. CAT3 was able to cross the blood-brain barrier and was metabolized to PF403, a very active prototype, resulting in a better inhibitory effect on gliomas and lower toxicity (Cancer Letters 2016,381, 391-403).
This compound is described for the first time in patent application 200980141120.0, and is also mentioned in patent application 201310467212.6. According to the prior related documents, the compound is obtained by column chromatography purification, but no description about properties such as melting point and the like is provided, and no crystal form research information is provided.
The research of the invention aims to find the existence of the crystal solid matter of the compound (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine, combine the crystal solid matter with the pharmacokinetic research by finding the existence type and state characteristics of the crystal solid matter, and provide basic scientific data for finding and discovering the medicinal crystal substance of the (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolidine with more stable structure and better clinical curative effect; meanwhile, a scientific basis is provided for applying for the patent protection of national or international intellectual property rights on the basis of (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine solid medicine raw material substances.
Disclosure of Invention
The invention starts from the research of the solid existence state of (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine, searches and discovers the existence type and the state characteristics of solid substances on the raw material level of active ingredients of the medicament through a crystal form screening technology, combines the crystal form research with the stability research and the pharmacokinetic research, and provides basic scientific research data for searching and discovering the (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolidine solid medicament which has a more stable structure and an optimal clinical curative effect.
The invention provides the existence state, description mode and pharmacokinetic data of (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine compound prepared by a literature report method, and the stability conditions of the compound to high humidity, heating and illumination; the invention provides two crystal forms of a crystal form A and a crystal form B of a (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine compound in a solid state, and a preparation method of samples of the two crystal forms; different crystal forms are found to influence the stability of the solid medicine, thereby influencing the clinical application of the medicine; the medicine and the composition thereof prepared and developed by taking (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine with different crystal forms aS an active ingredient have the treatment effects of preventing and treating human glioma, human bone marrow neuroblastoma, human ovarian cancer, liver cancer, pancreatic cancer and other diseases; the crystal form can influence the absorption speed of the effective component of the solid medicine in the organism and change the bioavailability of the effective component of the solid medicine, thereby influencing the curative effect of the medicine in clinic.
One of the objects of the present invention is: according to the existing literature description (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine preparation method, and finally purification by column chromatography, the invention provides the state and description mode of the substance obtained by the method.
The second object of the present invention is: provides a preparation method, an existing state and a description mode of a crystal form A solid substance of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine.
The third object of the present invention is: provides a preparation method, an existing state and a description mode of a B-type solid substance of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crystal.
The fourth purpose of the invention is that: stability data for (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine prepared by literature methods aS a prodrug against high humidity, heat and light are provided.
The fifth purpose of the invention is: stability data of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crystal form A solid material aS a prodrug against high humidity, heat and light are provided.
The sixth purpose of the invention is: stability data of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crystal form B solid material aS prodrug against high humidity, heat and light are provided.
The seventh of the purposes of the present invention: provides a stable crystal form of (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine under the conditions of high humidity, heating and illumination. Experimental data after ten days of high humidity, heating and illumination show that the crystal A type and crystal B type samples have good stability to high humidity, heating and illumination, and the samples prepared by the literature method have general stability to high humidity and poor stability to illumination. The crystal A type and the crystal B type are shown to have better stability.
The invention has eight objectives: provides the pharmacokinetics data of the (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine crystal A type solid substance aS the prodrug.
The ninth object of the present invention: provides the pharmacokinetics data of the (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine crystal B solid substance aS the prodrug.
Ten of the objects of the present invention: provides the absorption data of the (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine crystal form A and crystal form B samples in organisms, and provides scientific research data for the oral administration mode of the medicine.
The eleventh object of the present invention: providing dominant crystal form data of different crystal form samples of (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine in vivo absorption and blood concentration; the prodrug content in mouse plasma and brain tissue at the same time point under the same experimental conditions is greater for form B than form a. Indicating that the crystal B form has better bioavailability.
The twelfth object of the present invention: provides the application of (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine crystal B type solid substance aS a medicine active ingredient in medicines for preventing and/or treating human glioma, human bone marrow neuroblastoma, human ovarian cancer, liver cancer and pancreatic cancer.
Thirteen objects of the present invention: provides a pharmaceutical composition containing a compound of a medicine (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine crystal form A and a compound of a crystal form B and a pharmaceutically acceptable carrier.
The fourteen objects of the invention: provides a pharmaceutical composition which takes the (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine crystal A and crystal B compounds aS active ingredients. The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the crystal form A and the crystal form B of the (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine in the pharmaceutical composition is usually 0.1 to 95% by weight.
Fifteen objects of the present invention: provides possible administration modes and preparation forms: the (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine crystal A and crystal B or the pharmaceutical composition containing the same can be administered in a unit dosage form, and the administration route can be intestinal tract or parenteral tract, such aS oral administration, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eyes, lungs, respiratory tract, skin, vagina, rectum and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine crystal A and the crystal B can be prepared into common preparations, sustained release preparations, controlled release preparations, targeted preparations and various microparticle drug delivery systems.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
In order to prepare the administration unit into a capsule, the crystal forms A and B of the active ingredient (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine can be mixed with a diluent and a cosolvent, and the mixture can be directly placed into a hard capsule or a soft capsule. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compound tablets of the present invention may also be used to prepare capsules of the compound of the present invention.
In order to prepare the (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine crystal A and crystal B into injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used aS a solvent, and a proper amount of a solubilizer, a cosolvent, a pH regulator and an osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The dosage of the (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crystal form A and crystal form B pharmaceutical composition of the present invention can be widely varied depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration, the dosage form, and the like. Generally, the suitable dosage range of the crystal form A and the crystal form B of the (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine of the present invention per day is 0.001 to 150mg/Kg of body weight, preferably 0.1 to 100mg/Kg of body weight, more preferably 1 to 60mg/Kg of body weight, and most preferably 2 to 30mg/Kg of body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine crystal form A, crystal form B or the composition can be taken alone or combined with other treatment medicines or symptomatic medicines. When the crystal form A and the crystal form B of the (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine have synergistic effect with other therapeutic drugs, the dosage of the crystal form A and the crystal form B should be adjusted according to actual conditions.
Characteristic of the technology
A solid sample morphology characteristic of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crystal form A:
1.1 the structure of the (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine crystal A type solid substance related to the invention is shown aS the following formula
The crystal form uses a characteristic peak with a relative peak Area value (Area%) of more than or equal to 5% in an X-ray powder diffraction pattern obtained by Cu-Kalpha ray measurement, and the diffraction peak position of the crystal form is 2-Theta value (°) or d value
The diffraction peak relative intensity peak Height (Height%) or peak Area (Area%) is shown in table 1:
TABLE 1 Peak value of characteristic peaks of powder X-ray diffraction of Crystal form A solid sample
1.2 crystalline solid substance of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine A according to the present invention is characterized by having a structure represented by 2965.0,2935.0,2874.1,2830.6, 2767.2,2720.5,1740.0,1619.3,1603.2,1531.2,1509.8,1469.6,1427.5,1414.8,1397.2, 1367.8,1340.6,1274.7,1256.7,1204.9,1182.0,1164.3,1136.1,1033.9,1004.9,958.7 and 938.4,921.8,899.4,842.5,820.7,785.9,762.4,636.3,609.9,577.6,509.2,455.8cm when analyzed by infrared spectroscopy-1Has characteristic absorption peaks.
1.3 the (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crystal form A solid substance of the present invention is characterized in that when a sample is analyzed by DSC, 2 endothermic peaks are present, and the peak transition values of the endothermic peaks are 194. + -.2 ℃ and 212. + -.2 ℃ respectively.
A solid sample morphological characteristic of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crystal B:
2.1 the B-type solid substance of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crystal forms is characterized in that a relative peak Area value (Area%) in an X-ray powder diffraction pattern obtained by Cu-Kalpha ray measurement is more than or equal to 5%, and the diffraction peak position is 2-Theta value (°) or d value
The diffraction peak relative intensity peak Height (Height%) or peak Area (Area%) is shown in table 2:
TABLE 2 Peak value of characteristic peaks of powder X-ray diffraction of solid sample of crystal form B
2.2A crystalline B-form solid substance of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine according to the present invention is characterized by having a molecular weight of 2957.5,2935.4,2869.7,2832.8,2765.8,1743.3,1619.1,1601.7,1531.1,1509.7,1469.7,1427.3,1413.1,1396.4,1366.6,1338.4,1274.6,1256.5,1206.8,1178.7,1164.8,1135.5,1035.9,1001.1,940.9,921.5,896.7,859.0,838.6,786.7,761.4,672.0,636.8,605.7,583.5cm when analyzed by infrared spectroscopy-1Has characteristic absorption peaks.
2.3 the (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crystal form B solid substance of the present invention is characterized in that only 1 endothermic peak is present and the peak of the endothermic peak is 212. + -. 2 ℃ when a sample is analyzed by DSC.
3. (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine solid sample morphology characteristics obtained according to literature preparation method (Chinese patent application No. 200980141120.0):
3.1 the present invention relates to (13aS) -3-novel compounds reported in the literatureValeryloxy-6, 7-dimethoxyphenanthroindolizidine is a yellow solid substance, a characteristic peak with a relative peak Area value (Area%) of not less than 5% in an X-ray powder diffraction pattern obtained by Cu-Kalpha ray measurement is used, and the diffraction peak position is 2-Theta value (°) or d value
The diffraction peak relative intensity peak Height (Height%) or peak Area (Area%) is shown in table 3:
TABLE 3 peak of characteristic peak of powder X-ray diffraction of solid sample obtained from literature
3.2 the present invention relates to a literature reported solid substance of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine characterized by its presence in 3668.8,2963.1,2936.6, 2872.4,2830.5,2786.8,2719.5,1746.4,1618.3,1601.7,1530.2,1510.0,1464.2,1426.9, 1413.5,1396.3,1364.3,1275.0,1260.0,1204.8,1182.1,1165.1,1131.6,1113.8,1031.2, 1006.6,958.7,937.5,919.9,898.6,840.0,786.7,759.9,635.6,608.2,598.0,579.0cm when analyzed using infrared spectroscopy-1Has characteristic absorption peaks.
3.3 the present invention relates to a literature reported yellow solid substance of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine, characterized by an endothermic peak shift at 204. + -. 2 ℃ when the sample is analyzed using DSC.
4. Stability of different crystalline forms of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine samples:
the invention relates to different crystal forms of (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine, and the stability of the crystal forms for ten days is examined according to a pharmacopoeia method. The results show that the crystal a and B type samples are very stable under high humidity and heating conditions with a destruction rate below 0.05%. The samples obtained according to the literature method, which were 0.71% destroyed under high humidity conditions, showed a certain high humidity instability compared to the crystal a and crystal B type samples. Under the illumination condition, the stability of three different samples is greatly different. Wherein, the crystal B type sample is relatively stable under illumination, and only 1.54 percent of the crystal B type sample is damaged; the crystal A sample was then 3.89% destroyed under light; the samples prepared according to the literature methods were the least stable and 20.38% destroyed under light. The stability of the crystal A type and the crystal B type samples under illumination is far better than that of the samples obtained by the literature method. In general, (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine of crystal A and crystal B was very stable, whereas (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine obtained by the literature method was poor in stability (see Table 4).
TABLE 4 stability Studies of various samples (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine
Destruction ratio [ (purity after 1-10 days)/initial purity) ] × 100%; a: chinese patent application No. 200980141120.0.
Pharmacodynamic characteristics of different crystal form components of (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine:
5.1 the (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine with good stability plays a role in preventing and treating cardiovascular and cerebrovascular system diseases, nervous system diseases, osteoporosis, metabolic diseases, inflammation and other diseases in a living body through oral administration, and is characterized in that two crystal form solid substances detect the existence of PF403 in blood after oral administration of mice, and the result shows that the two crystal form substances of (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolidine can be absorbed into the blood to play a role in preventing and treating human glioma, human bone marrow neuroblastoma, human ovarian cancer, liver cancer, pancreatic cancer, inflammation and other diseases in whole body and play a role in clinical treatment.
5.2 the invention relates to (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine with better stability, which has absorption difference in organisms, and is characterized in that the bioavailability of (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine in different crystal forms is remarkably different after oral administration under the same experimental conditions, wherein the AUC (0-t) of the PF403 of the CAT3 crystal form B in mouse plasma is about 9 times that of the crystal form A, and the AUC of the PF403 crystal form B in brain tissue is about 10 times that of the crystal form A, and the result shows that the crystal form B of the (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolidine can easily pass through a blood brain barrier, so that the bioavailability is better.
6. The invention relates to a preparation method of a (13aS) -3-pivaloyloxy-6, 7-dimethoxy-phenanthroindolizidine crystal A sample, which is characterized in that the (13aS) -3-pivaloyloxy-6, 7-dimethoxy-phenanthroindolidine sample is dissolved in ethyl acetate at the temperature of 15-80 ℃, and a crystal A solid substance of the (13aS) -3-pivaloyloxy-6, 7-dimethoxy-phenanthroindolidine is obtained under the conditions of ambient temperature of 4-40 ℃ and ambient relative humidity of 10-80% under normal pressure or reduced pressure.
7. The invention relates to a preparation method of a (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine crystal B sample, which is characterized in that the (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolidine sample is dissolved in absolute ethyl alcohol at the temperature of 15-100 ℃, and the solvent is removed under the conditions of the environmental temperature of 4-40 ℃, the environmental relative humidity of 10-80% and normal pressure or reduced pressure experiment to obtain the (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolidine crystal B solid substance.
8. The invention relates to a pharmaceutical composition, which is characterized in that (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine crystal form A and crystal form B are used aS active ingredients.
9. The pharmaceutical composition is characterized by being various powder, injection, tincture, emulsifiable paste or suspension pharmaceutical preparations.
10. The invention relates to application of a mixed crystal component of (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine in preparing medicaments for treating human glioma, human bone marrow neuroblastoma, human ovarian cancer, liver cancer and pancreatic cancer, wherein the mixed crystal component contains crystal A and crystal B or contains crystal B (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolidine in any proportion.
Drawings
FIG. 1 is a powder X-ray diffraction pattern of a crystal form A sample of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine
FIG. 2 is an infrared absorption spectrum of a crystal form A sample of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine
FIG. 3 DSC thermogram of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crystal form A sample
FIG. 4 is a powder X-ray diffraction pattern of a B-type sample of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crystal
FIG. 5 is an infrared absorption spectrum of a B-type crystal sample of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine
FIG. 6 DSC thermogram of B-type sample of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crystal form
FIG. 7 powder X-ray diffraction pattern of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine sample obtained according to literature report
FIG. 8 is a chart showing an infrared absorption spectrum of a sample of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine obtained according to a report in the literature
FIG. 9 DSC thermogram of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine sample obtained according to literature report
FIG. 10 is a graph showing PF403 plasma profiles after oral administration of CAT3-A (10mg/kg) in mice
FIG. 11 is a graph showing PF403 plasma profiles after oral administration of CAT3-B (10mg/kg) in mice
FIG. 12 is a graph showing the drug effect of PF403 brain tissue after oral administration of CAT3-A (10mg/kg) to mice
FIG. 13 is a graph showing the PF403 brain tissue drug-loading curve of mice after oral administration of CAT3-B (10mg/kg)
Detailed Description
The following examples are given to better illustrate the technical aspects of the present invention, but the present invention is not limited thereto.
Example 1: the preparation method of the (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine crystal A sample comprises the following steps:
1g of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crude product is heated and dissolved in 20ml of ethyl acetate at 80 ℃, filtered while hot, and the obtained clear filtrate is kept stand for 24h under the conditions of ambient temperature of 20 ℃, ambient humidity of 30% and normal pressure to obtain 780mg of crystal form A (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolidine.
Example 2: the preparation method of the (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine crystal B sample comprises the following steps:
1g of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crude product is heated and dissolved in 25ml of absolute ethanol at 100 ℃, the solution is filtered while the solution is hot, and the obtained filtrate is stirred for 6 hours under the conditions of ambient temperature of 20 ℃ and ambient humidity of 30% to obtain 880mg of crystal B type (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine.
Example 3: pharmacokinetics research of plasma and brain tissues of mice orally taking (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine (CAT3) with different crystal forms
In order to obtain a dominant crystal form so aS to select a proper crystal form substance for pharmacodynamic study, systematic pharmacokinetic study is carried out on (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crystal form A and crystal form B samples obtained in the embodiment of the invention.
3.1 test methods
3.1.1 sample Collection
Dividing 66 mice (male ICR mice, the weight of 22-24 g, purchased from Beijing Wintolite laboratory animal technology Co., Ltd.) into 2 groups at random, respectively orally administering CAT3-A (crystal A type CAT3, 0.5% CMC ground and ultrasonic, the concentration of 10mg/kg/10ml), CAT3-B (crystal B type CAT3, 0.5% CMC ground and ultrasonic, the concentration of 10mg/kg/10ml), taking carotid artery blood at each time point of 5min, 10min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h and 24h after administration, collecting the blood in an EP tube with heparin anticoagulation, placing the blood on ice, centrifuging 7000r/min x 5min, and separating plasma for later use; meanwhile, the brain tissue was completely removed, placed on ice, weighed, and then ground into a homogenate at a volume of 1:3(g/v) in physiological saline.
3.1.2 Standard Curve preparation
Mu.l of mouse blank plasma is taken, 180 mu.l of acetonitrile containing internal standard CAT (10ng/ml, 10 mu.l) is added, 10 mu.l of CAT3 and PF403 methanol solutions (0.5, 1, 5,10, 50, 100, 500, 1000, 2000ng/ml) with different concentrations are added, the mixture is mixed evenly, the mixture is centrifuged at high speed for 2 times at 13000r/min multiplied by 5min, and 10 mu.l of supernatant is taken for UPLC-MS/MS analysis.
A mouse blank brain homogenate is taken and added with 180 mul acetonitrile containing internal standard CAT (10ng/ml, 10 mul), 10 mul of CAT3 and PF403 methanol solutions (0.5, 1, 5,10, 50, 100, 500, 1000, 2000ng/ml) with different concentrations are added, evenly mixed and centrifuged at 13000r/min multiplied by 5min for 2 times at a high speed, and 10 mul supernatant is taken for UPLC-MS/MS analysis.
3.1.3 sample treatment
100 mul of plasma or brain homogenate sample is taken, 200 mul of acetonitrile containing internal standard is added into the plasma or brain homogenate sample, 13000r/min multiplied by 5min high-speed centrifugation is carried out for 2 times, and 10 mul of supernatant fluid is taken for UPLC-MS/MS analysis.
3.1.4UPLC-MS/MS assay
A chromatographic column: zorbax C18column (2.1 mm. times.100 mm,3.5 μm), column temperature: 25 ℃, mobile phase: methanol (0.1% FA): water (0.1% FA) was eluted at a gradient of 10:90, flow rate: 0.2mL/min, MRM detection: m/z 434.5 → 365.4(CAT 3); m/z 350.2 → 281.2(PF 403); m/z 364.4 → 295.1 (CAT); m/z 526.2 → 350.2(GLU-PF 403).
3.2 test results
3.2.1 plasma and brain tissue sample Standard Curve
According to LC-MS/MS spectra of each sample, the concentrations of CAT3 and PF403 are respectively used as abscissa, the peak area and the peak area ratio of the internal standard are used as ordinate, linear analysis is carried out, the linear relation of the standard curve of the plasma sample and the brain tissue sample in the concentration range of 0.05-50ng/ml is good, r is2>0.99。
3.2.2 measurement of plasma and brain tissue drug concentrations in mice after oral administration of CAT3
After the mice take CAT3-A and CAT3-B orally for 5min, metabolites PF403 can be detected in blood plasma, the peak reaching time of the CAT3-A metabolites PF403 is 10-15 min, and the peak reaching concentration is 4.52-5.79 ng/ml; the peak reaching time of the CAT-B metabolite PF403 is 15min to 4h, the peak reaching concentration is 25.1 to 82.8ng/ml, and the blood concentration of the PF403 is slightly higher than or close to the limit of quantification 24h after administration. The proto-drug plasma levels after administration to each group of animals were near or below the lowest quantitation limit and the results are shown in tables 5-6 and figures 10-11.
After the mice take CAT3-A and CAT3-B orally for 5min, the metabolites PF403 can be detected in brain tissues, the peak reaching time is 15-30 min and 15 min-4 h respectively, the peak reaching concentrations are 8.96-11.92 ng/g and 16.84-91.20 ng/g respectively, and the PF403 brain tissue drug concentration is close to or lower than the limit of quantitation 24h after administration. The concentration of the proto-drug after administration to each group of animals was near or below the lowest quantitation limit and the results are shown in tables 7-8 and FIGS. 12-13.
TABLE 5 oral CAT3-A (10mg/kg) in mice, PF403 plasma was changed with time
TABLE 6 oral CAT3-B (10mg/kg) in mice, PF403 plasma was changed with time
TABLE 7 oral administration of CAT3-A (10mg/kg) in mice, PF403 brain tissue concentration changes with time
TABLE 8 oral administration of CAT3-B (10mg/kg) in mice, PF403 brain tissue concentration changes with time
3.2.3 plasma and brain tissue pharmacokinetic parameters
After mice are orally administered with CAT3-A and CAT3-B, plasma and brain tissue pharmacokinetics are analyzed by WinNonLin software, and the AUC (0-t) of PF403 in the plasma after oral administration of CAT3-A is 17.27 +/-5.53 h ng/ml respectively through fitting of a non-atrioventricular model; AUC (0-t) of PF403 in brain tissue was 29.22 ± 6.04h ng/g. AUC (0-t) of PF403 in plasma after oral administration of CAT3-B was 158.71 ± 59.37h ng/ml, respectively; the AUC (0-t) of PF403 in brain tissue was 209.78 + -42.26 h ng/g, and the results are shown in tables 9-12.
TABLE 9 PF403 plasma pharmacokinetic parameters after oral administration of CAT3-A (10mg/kg) in mice
TABLE 10 PF403 plasma pharmacokinetic parameters after oral administration of CAT3-B (10mg/kg) in mice
TABLE 11 pharmacokinetic parameters of PF403 brain tissue after oral administration of CAT3-A (10mg/kg) in mice
TABLE 12 pharmacokinetic parameters of PF403 brain tissue after oral administration of CAT3-B (10mg/kg) in mice
3.3, conclusion
After mice orally take CAT3-A and CAT3-B, Cmax and AUC (0-t) of PF403 in CAT3-B plasma and brain tissue are obviously higher than CAT3-A, and the bioavailability is better. The CAT3 crystal form B is the dominant crystal form and is suitable for further pharmacodynamic study.
Example 4: (13aS) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine crystal B (CAT3-B) in-vitro antitumor activity determination
4.1 Experimental procedures
1) Culturing the normal growth tumor cells at 1X 104cells/ml were plated in 96-well plates (100. mu.l per well),
at 37 ℃ 5% CO2The culture was carried out in an incubator for 24 hours.
2) The test compounds were added separately at 5% CO2And culturing in a complete humidity incubator for 5 days.
3) The culture medium was discarded, and 100. mu.l of 0.04% MTT was added to each well, followed by culturing under the same conditions for 4 hours.
4) The culture medium was discarded, DMSO (150. mu.l/well) was added, and after mixing, the measurement wavelength was 570nm, the reference wave
The length of the compound is 450nm, the absorbance of the light is recorded colorimetrically, and the inhibition rate of the compound on the growth of tumor cells is calculated (see table 13).
Growth inhibition of Epsilon-13 crystal B (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine (CAT3-B) on in vitro cultured tumor cells (72h)
Mia-PaCa2 human pancreatic cancer cells; SHSY-5Y human bone marrow neuroblastoma cells; SKOV3 human ovarian cancer cells; TJ905 human glioma cells
4.2, conclusion
The sample CAT3-B, which is a prodrug of PF403, still had growth inhibitory effect on tumor cells in vitro, but was weaker than its prototype PF 403.
Example 5: determination of in vivo antitumor Activity of CAT3-B
5.1 Experimental methods
5.1.1 Experimental animals and groups
ICR mice, SPF grade, female, weight 18-20 g. Purchased from: after inoculating G422 mouse glioblastoma (tumor solution: sterile physiological saline 1:3) to the armpit, the following day was randomly divided, weighed and administered. The test samples were randomly divided into a blank control group, a positive control group (cyclophosphamide) and an administration group (CAT 3-B10 mg/kg and 5mg/kg oral administration groups, PF 40310 mg/kg, 5mg/kg, 2.5mg/kg intraperitoneal injection administration groups).
5.1.2 pharmaceutical formulation and mode of administration
Cyclophosphamide for injection was dissolved in sterile physiological saline (concentration 10mg/ml, 0.2ml per 20g mouse intraperitoneal injection) immediately before use, and administered once intraperitoneal injection on the first day after inoculation. Test compound CAT3-B is dissolved in double distilled water (concentration 5mg/ml, 2.5mg/ml, each 20g mouse is intragastrically 0.4ml) after solubilizing with Tween 80, and is intragastrically administered every other day; PF403 is dissolved in sterile normal saline (25% of polyethylene glycol final concentration) after being dissolved with polyethylene glycol 400, and is injected into the abdominal cavity; the test compound and PF403 were prepared as they were, and stored in the dark.
5.1.3 animal treatment
Body weights were recorded every other day and body weight change curves were plotted, and on day 15 post-inoculation, animals were sacrificed by cervical dislocation, tumors were removed, photographed, tumor weights were recorded and tumor inhibition rates were calculated (see table 14).
TABLE 14(13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crystal form B (CAT3-B) screening for in vivo antitumor Effect on G422 mouse glioblastoma
+: the prodrug CAT3-B is orally taken and is taken on days 2,4, 6,7, 9,11 and 13 after inoculation, and the administration is carried out for 7 times; the injection dosage of the prototype drug PF403 is the total dosage, 10mg/kg on days 2 and 5, 15mg/kg on days 7, 10 and 12 and 20mg/kg on days 13 and 14 of the high-dosage group are administered for 7 times; the administration time of the medium dose group is the same as that of the high dose group, and the administration amount is reduced by half; the low dose group was administered at the same time as the high dose group, and the dose was half of that of the medium dose group.
# p < 0.05; # p is less than 0.01; # p is less than 0.001; p < 0.05; p < 0.01; p < 0.001, compared to the negative control group.
5.2, conclusion
The in vivo inhibitory activity of CAT3-B on G422 mouse glioblastoma is close to that of the prototype compound PF403, the dose-effect relationship is good, the weight reduction degree of the tested animal is greatly reduced compared with that of the prototype compound, no toxic or side effect such as ascites is observed, and the toxicity is obviously reduced.
Claims (7)
1.(13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crystal form B solid matter having the following structure, characterized in that, when Cu-Kalpha radiation experimental conditions are employed using powder X-ray diffraction analysis, a characteristic peak having a relative peak Area value (Area%) of not less than 5%, and a diffraction peak position of 2-Theta value (°) or d value
The diffraction peak relative intensity peak Height (Height%) or peak Area (Area%) is shown in the following table:
2. crystalline form B solid substance of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine according to claim 1, analyzed by IR spectroscopy at 2957.5,2935.4,2869.7,2832.8,2765.8,1743.3,1619.1,1601.7,1531.1,1509.7,1469.7,1427.3,1413.1,1396.4,1366.6,1338.4,1274.6,1256.5,1206.8,1178.7,1164.8,1135.5,1035.9,1001.1,940.9,921.5,896.7,859.0,838.6,786.7,761.4,672.0,636.8,605.7,583.5cm-1Has characteristic absorption peak, wherein the allowable deviation of the characteristic peak of the infrared spectrum is +/-2 cm-1。
3. The crystalline solid substance of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine B aS claimed in claim 1, wherein there are 1 endothermic peak whose peak shift is 212 ± 2 ℃ when a sample is analyzed by DSC.
4. The method for preparing (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crystal B solid substance according to claim 1, characterized by dissolving a (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolidine sample in absolute ethanol at a temperature of 15 to 100 ℃, and removing the solvent at an ambient temperature of 4 to 40 ℃, an ambient relative humidity of 10 to 80%, and under normal pressure or reduced pressure experimental conditions to obtain (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolidine crystal B solid substance.
5. A pharmaceutical composition comprising the crystalline form B solid substance of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine according to claim 1 aS a pharmaceutically active ingredient or a pharmaceutically acceptable salt thereof.
6. The use of the (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine crystal B solid substance aS defined in claim 1 in the preparation of medicaments for preventing and/or treating human glioma, human bone marrow neuroblastoma, human ovarian cancer, liver cancer and pancreatic cancer.
7. The use of the pharmaceutical composition of claim 5 in the preparation of a medicament for the prevention and/or treatment of human glioma, human bone marrow neuroblastoma, human ovarian cancer, liver cancer, pancreatic cancer.
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