CN113214065B - Gossypol crystal III substance, preparation method, composition and application thereof - Google Patents
Gossypol crystal III substance, preparation method, composition and application thereof Download PDFInfo
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- CN113214065B CN113214065B CN202010080016.3A CN202010080016A CN113214065B CN 113214065 B CN113214065 B CN 113214065B CN 202010080016 A CN202010080016 A CN 202010080016A CN 113214065 B CN113214065 B CN 113214065B
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- gossypol
- crystal
- solid substance
- crystalline form
- iii
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- QBKSWRVVCFFDOT-UHFFFAOYSA-N gossypol Chemical compound CC(C)C1=C(O)C(O)=C(C=O)C2=C(O)C(C=3C(O)=C4C(C=O)=C(O)C(O)=C(C4=CC=3C)C(C)C)=C(C)C=C21 QBKSWRVVCFFDOT-UHFFFAOYSA-N 0.000 title claims abstract description 264
- QHOPXUFELLHKAS-UHFFFAOYSA-N Thespesin Natural products CC(C)c1c(O)c(O)c2C(O)Oc3c(c(C)cc1c23)-c1c2OC(O)c3c(O)c(O)c(C(C)C)c(cc1C)c23 QHOPXUFELLHKAS-UHFFFAOYSA-N 0.000 title claims abstract description 132
- 229930000755 gossypol Natural products 0.000 title claims abstract description 132
- 229950005277 gossypol Drugs 0.000 title claims abstract description 132
- 239000013078 crystal Substances 0.000 title claims abstract description 95
- 239000000126 substance Substances 0.000 title claims abstract description 77
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 239000000203 mixture Substances 0.000 title claims abstract description 13
- -1 preparation method Substances 0.000 title description 6
- 239000007787 solid Substances 0.000 claims abstract description 69
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- 206010013908 Dysfunctional uterine bleeding Diseases 0.000 claims abstract description 9
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- NIOHNDKHQHVLKA-UHFFFAOYSA-N acetic acid;7-(8-formyl-1,6,7-trihydroxy-3-methyl-5-propan-2-ylnaphthalen-2-yl)-2,3,8-trihydroxy-6-methyl-4-propan-2-ylnaphthalene-1-carbaldehyde Chemical compound CC(O)=O.CC(C)C1=C(O)C(O)=C(C=O)C2=C(O)C(C=3C(O)=C4C(C=O)=C(O)C(O)=C(C4=CC=3C)C(C)C)=C(C)C=C21 NIOHNDKHQHVLKA-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- 239000000463 material Substances 0.000 claims description 10
- 238000000498 ball milling Methods 0.000 claims description 8
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 8
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- 239000011343 solid material Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
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- 239000000843 powder Substances 0.000 claims description 5
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- MSBVBOUOMVTWKE-UHFFFAOYSA-N 2-naphthalen-2-ylnaphthalene Chemical compound C1=CC=CC2=CC(C3=CC4=CC=CC=C4C=C3)=CC=C21 MSBVBOUOMVTWKE-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
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- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- 241000220479 Acacia Species 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
- C07C47/56—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups
- C07C47/57—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups polycyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/16—Masculine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention discloses a gossypol crystal III type solid substance, a preparation method thereof, a composition and application thereof, and belongs to the technical field of medicines. Specifically, the invention discloses that gossypol exists in a crystal III type solid substance state form in a solid state; a preparation method of a crystal III type solid substance sample; the application of the gossypol crystal III solid substance as the active pharmaceutical ingredient in preparing various contraceptive, anti-tumor, antiviral, anti-inflammatory, antimalarial and antioxidant medicines and medicines for treating gynaecological diseases such as endometriosis, uterine fibroids, dysfunctional uterine bleeding, dysmenorrhea and the like.
Description
Technical Field
The invention relates to a crystal III type solid substance state form of gossypol existing in a solid state; relates to a preparation method of the crystal III; relates to a pharmaceutical composition containing gossypol crystal III or mixed crystal forms containing any non-zero proportion of the crystal III; the invention also relates to application of the gossypol crystal form substance as an effective component of the medicine in preparing various contraceptive, anti-tumor, antiviral, anti-inflammatory, antimalarial and antioxidant medicines and treating gynaecological diseases such as endometriosis, uterine fibroids, dysfunctional uterine bleeding, dysmenorrhea and the like; belongs to the technical field of medicines.
Background
The molecular structural formula of gossypol (chemical name ：1,1',6,6',7,7'-hexahydroxy-5,5'-dIIIsopropyl-3,3'-dimethyl-[2,2'-binaphthalene]-8,8'-dicarbaldehyde, English name: gossypol) is as follows:
Searching CCDC library, obtaining theoretical powder X-ray diffraction pattern of gossypol by CIF file of gossypol monocrystal, and naming it as crystal I type, and only crystal I type of gossypol is reported so far.
A method for preparing high-purity gossypol acetate in the process of refining cotton oil is disclosed in Chinese patent CN107573237A (publication No.), which relates to a method for preparing high-purity gossypol acetate by acidifying cotton oil soapstock, standing and layering to obtain upper-layer gossypol acid oil, adding glacial acetic acid for crystallization, filtering and drying to obtain a pure product crude product of gossypol acetate, and recrystallizing to obtain high-purity gossypol acetate. The applicant has proved by repeating this experiment that the solid obtained is gossypol acetate.
A paper published in journal of pharmacy, 1986, vol.21, page 551, on "comparison of certain properties of different solvent recrystallized gossypol" was retrieved from the literature and described 3 solvates of gossypol. Searching CCDC (Cambridge Crystallographic DATA CENTRE) database, by 2019, more than eighty kinds of gossypol solvate crystal structure reports are reported, which suggests that the compound is extremely easy to form a solvate with an organic solvent.
In summary, no report of the gossypol crystal form III solid substance related to the patent is seen so far, and no similar or conflicting research contents are seen in aspects of substance form, combination proportion, preparation method, application and the like.
Disclosure of Invention
The invention aims to start from the research on the existence state of the crystal form solid substance of the gossypol, search and find the existence type and the state characteristic of the crystal form solid substance on the raw material level of the active ingredients of the medicine through the crystal form screening technology and the crystal form stability evaluation technology, combine the crystal form substance with the pharmacodynamics research, and provide basic scientific data for searching, finding and developing the dominant medicinal crystal form solid substance of the gossypol with the optimal clinical curative effect; meanwhile, a scientific basis is provided for applying national or international intellectual property patent protection on the basis of the solid medical raw material substance of the gossypol.
The invention provides a novel existence state and characterization mode of crystal III solid substances of gossypol.
The second technical problem to be solved by the invention is: provides a preparation method of gossypol crystal III type solid substance.
The third technical problem to be solved by the invention is: solid medicaments and compositions thereof are provided that contain pure forms of gossypol crystalline form III, or mixed forms of crystalline form III in any non-zero proportion.
The invention aims to solve the fourth technical problem: a pharmaceutical composition using a solid substance of form III of gossypol crystals as a pharmaceutically active ingredient is provided, which has a dose per administration in the range of 5-3000 mg. The medicine composition comprises tablets, capsules, pills, injection, slow release or controlled release preparation medicines
The invention solves the technical problems: the gossypol crystal III solid substance has better solubility.
The invention solves the technical problems: the gossypol crystal III solid substance can improve the blood concentration of organisms due to the crystal substance in the process of treating diseases, thereby playing a role in effective treatment.
The invention solves the technical problems: the gossypol crystal III solid substance is used as the effective component of the medicine, and can be used for preparing various contraceptive, anti-tumor, antiviral, anti-inflammatory, antimalarial and antioxidant medicines and treating gynecological diseases such as endometriosis, hysteromyoma, dysfunctional uterine bleeding, dysmenorrhea, etc.
In order to solve the technical problems, the invention adopts the following technical scheme:
1. morphology characterization of crystalline form III sample of gossypol:
1.1A solid substance of form III of gossypol crystals according to the present invention is characterized by containing no crystallization solvent or crystallization water component, and having a diffraction peak position of 2-Theta (DEG) or d-value when the experimental conditions of CuK α irradiation are employed by powder X-ray diffraction analysis The diffraction peak relative intensity peak Height value (Height%) or peak Area value (Area%) is shown below (table 1, fig. 1).
TABLE 1 powder X-ray diffraction peak values for gossypol crystalline form III substance samples
1.2 The gossypol crystalline form III solid matter according to the present invention, when analyzed by attenuated total reflection Fourier infrared spectroscopy, has an infrared spectrum characteristic peak at 3498、2960、2929、2875、1710、1615、1573、1500、1440、1419、1381、1336、1297、1244、1183、1123、1054、1025、994、966、913、841、797、770、722、699、671、655cm-1, wherein the allowable deviation of the infrared spectrum characteristic peak is + -2 cm -1 (FIG. 3).
1.3 The gossypol crystalline form III solid substance according to the present invention, when analyzed by differential scanning calorimetry, shows 1 endothermic peak at 163.+ -. 5 ℃ in its DSC spectrum at a temperature in the range of 30 to 200 ℃ and a temperature rising rate of 10 ℃ per minute. (FIG. 4)
1.4 The gossypol mixed crystal form solid substance according to the invention contains a gossypol crystal form III substance component in an arbitrary non-zero proportion.
2. The preparation method of the gossypol crystal III type substance sample and the mixed crystal is characterized in that:
2.1 the preparation method of the gossypol crystal III solid matter is characterized in that the gossypol acetate and agate balls are weighed according to a certain ball-to-material ratio, ball milling is carried out for proper time, the gossypol crystal III solid matter is prepared, wherein the ball-to-material ratio is 1:1-20:1, proper rotating speed is 200-1000 revolutions per minute, proper time is 3-20 hours, ball milling is carried out for 10 minutes in each forward direction, stopping for 5 minutes, ball milling is carried out for 10 minutes in the reverse direction, and the process is repeated.
2.2 The gossypol mixed crystal form solid substance of the invention is prepared by mixing the gossypol crystal form III component prepared by the method with other gossypol crystal form solid substances according to any non-zero proportion and conventional method.
3. Pharmaceutical formulation compositions containing gossypol crystalline form ingredients, dosing profile and pharmaceutical use:
3.1 pharmaceutical compositions according to the invention comprise gossypol crystalline form III and a pharmaceutically acceptable carrier.
3.2 The pharmaceutical composition of the invention comprises a gossypol mixed crystal form solid substance and a pharmaceutically acceptable carrier.
3.3 The pharmaceutical composition of the invention has the daily dosage of gossypol in the range of 5-3000 mg.
3.4 The pharmaceutical composition according to the invention is characterized in that the pharmaceutical composition is in the form of various tablets, capsules, pills, powder injection, sustained release preparations or controlled release preparations.
3.5 The invention relates to the application of gossypol crystal III solid substance in preparing various contraceptive, anti-tumor, antiviral, anti-inflammatory, antimalarial and antioxidant medicines and medicines for treating gynaecological diseases such as endometriosis, uterine fibroids, dysfunctional uterine bleeding, dysmenorrhea and the like.
3.6 The invention relates to the application of the gossypol mixed crystal solid substance containing any non-zero proportion in preparing various contraceptives, anti-tumor, anti-virus, anti-inflammatory, anti-malarial and anti-oxidation medicines and medicines for treating endometriosis, uterine fibroids, dysfunctional uterine bleeding, dysmenorrhea and other gynecological diseases.
The invention relates to a pharmaceutical composition which takes the gossypol crystal III component and the gossypol mixed crystal solid substance as active components. The pharmaceutical compositions may be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be made by combining the gossypol crystalline form III ingredient of the invention, the gossypol mixed crystalline form solid matter of the invention, with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the gossypol crystalline form III component of the present invention, the gossypol mixed crystalline form solid substance of the present invention in the pharmaceutical composition thereof is usually 0.1 to 95% by weight.
The gossypol crystalline form III component of the present invention, the gossypol mixed crystalline form solid substance of the present invention or a pharmaceutical composition containing the same may be administered in unit dosage form by the enteral or parenteral route such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
The administration form of the present invention is preferably a solid dosage form. The solid dosage forms can be tablets (including common tablets, enteric coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules and enteric coated capsules), granules, powder, micropills, dripping pills, suppositories, films, patches, aerosol (powder) and spray.
The gossypol crystal III component and the gossypol mixed crystal solid substance can be prepared into common preparations, sustained release preparations, controlled release preparations, targeted preparations and various microparticle drug delivery systems.
For the purpose of tableting the gossypol crystalline form III ingredient of the present invention, the gossypol crystalline form III solid substance of the present invention, various excipients known in the art may be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent can be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrating agent can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer and multilayer tablets.
In order to prepare the administration unit into a capsule, the active ingredient of the gossypol crystal III component of the invention and the solid substance of the gossypol mixed crystal form of the invention can be mixed with a diluent and a glidant, and the mixture can be directly placed into a hard capsule or a soft capsule. The active ingredient of the gossypol crystal III component and the gossypol mixed crystal solid substance of the invention can be prepared into particles or pellets by mixing with a diluent, a binder and a disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants and glidants used for preparing the gossypol crystal III component of the invention and the gossypol mixed crystal solid substance tablet of the invention can also be used for preparing the gossypol crystal III component of the invention and the gossypol mixed crystal solid substance capsule of the invention.
In addition, colorants, preservatives, fragrances, flavoring agents, or other additives may also be added to the pharmaceutical formulation, if desired.
4. Use of a solid material comprising gossypol crystalline form III:
The invention discloses application of gossypol crystal III solid substance in preparing and/or preparing various contraceptive, anti-tumor, antiviral, anti-inflammatory, antimalarial and antioxidant medicines and treating endometriosis, uterine fibroid, dysfunctional uterine bleeding and dysmenorrhea.
For the purpose of administration, the drug or the pharmaceutical composition of the present invention can be administered by any known administration method to enhance the therapeutic effect.
The dosage of the composition of the crystalline form III of gossypol of the present invention, the solid pharmaceutical composition of the mixed crystalline form of gossypol of the present invention may vary widely 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 and the dosage form, etc. The above-mentioned dosages may be administered in one dosage unit or in several dosage units, depending on the clinical experience of the physician and the dosage regimen involved in the application of other therapeutic means.
The gossypol crystalline form III component of the present invention, the gossypol mixed crystalline form solid substance or composition of the present invention may be taken alone or in combination with other therapeutic or symptomatic agents. When the gossypol crystal III component and the gossypol mixed crystal solid substance of the invention have synergistic effect with other therapeutic drugs, the dosage of the solid substance is adjusted according to the actual situation.
The technical scheme of the invention has the following beneficial technical effects
The gossypol crystal III solid substance has obvious advantages in the aspects of solubility, stability, safety and the like compared with the gossypol in the prior art.
The solubility of the gossypol crystal III solid substance in 0.2% SDS aqueous solution is obviously superior to that of the known gossypol crystal I and gossypol acetate, the dissolution rate of the crystal III is obviously improved compared with that of the gossypol crystal I and the gossypol acetate, and the solubility of the solid substance in 0.2% SDS aqueous solution is about 3 times or more of that of the gossypol crystal I and the gossypol acetate, so that the solid substance has obvious solubility advantage characteristics.
The gossypol crystal III solid substance is stable under high temperature and high humidity conditions, does not generate crystal transformation phenomenon, and has stability advantage.
The gossypol crystal III solid substance does not contain any crystallization solvent, has substantial characteristics and remarkable progress compared with the disclosed solvate crystal form, and has obvious advantage characteristics in the aspect of patent medicine safety.
Drawings
FIG. 1 powder X-ray diffraction pattern of gossypol crystalline form III substance sample
FIG. 2X-ray diffraction pattern of gossypol crystal form I theoretical powder
FIG. 3 is an infrared absorption spectrum of a sample of gossypol crystalline form III substance
FIG. 4 DSC spectra of gossypol crystalline form III substance samples
FIG. 5 is a graph comparing the solubility of a sample of gossypol crystalline form III material with a sample of crystalline form I material.
FIG. 6 stability profile of gossypol crystalline form III substance sample under high temperature and high humidity conditions
Detailed Description
The following examples are given for better illustration of the technical solution of the present invention, but the present invention is not limited thereto.
Example 1
Taking gossypol acetate as a raw material, weighing the gossypol acetate and agate balls according to a certain ball-to-material ratio, setting the rotating speed to be 200-1000 r/min, performing forward ball milling for 10min each time, performing reverse ball milling for 10min each time, performing interval for 5min each time, repeating the steps for 3-20h each time, and preparing to obtain a gossypol solid sample, wherein the graph is basically consistent with that of figure 1 through powder X-ray diffraction analysis, and shows that the obtained solid sample is gossypol crystal III type solid substance.
TABLE 2 preparation condition parameters of gossypol Crystal form III substance samples
Example 2
Stability characteristics of gossypol crystalline form III solid matter:
High temperature test: the crystalline form samples were placed in open clean dishes, left at 60 ℃ for 10 days, and sampled on day 0, day 5, and day 10. The samples obtained from the sampling points are subjected to powder X-ray diffraction analysis, and diffraction patterns of the samples are consistent with those of fig. 1, which shows that the gossypol crystal III type solid substance is stable under a high-temperature influence factor test.
High humidity test: the crystalline form samples were placed in open clean dishes, left at 25 ℃ for 10 days at 90% ± 5% relative humidity, and sampled on day 0, day 5, and day 10. The samples obtained from the sampling points are subjected to powder X-ray diffraction analysis, and diffraction patterns of the samples are consistent with those of fig. 1, which shows that the gossypol crystal III type solid substance is stable under a high-humidity influence factor test.
The stability test result shows that the gossypol crystal III has the advantage of high-temperature and high-humidity stability.
Example 3
Gossypol crystalline form III solid matter solubility characteristics:
taking 0.2% SDS aqueous solution as solvent, examining the solubility difference of the gossypol in the form III and the form I, and the result shows that the solubility of the form III is obviously better than that of the form I, as shown in figure 5.
Since the dissolution rate of the gossypol indissoluble drugs is not obvious in water or aqueous solutions with different pH values, experiments are carried out by using an aqueous solution containing 0.2% of SDS cosolvent, and the solvent system has good differentiation of the dissolution rates of two crystal forms of the gossypol. The dissolution rate was measured by referring to the method for measuring the dissolution rate (general oral solid preparation dissolution test technical guidelines (first draft), 2012.10 pharmaceutical panel center). Calculating the dissolved mass of the sample by using the chromatographic peak area data of the sample by using a high performance liquid phase method, and respectively drawing solubility curves by taking time as an abscissa and the dissolution content as an ordinate, wherein the data are shown in the following table:
TABLE 3 dissolution profile data for gossypol crystalline form I, crystalline form III and gossypol acetate in 0.2% SDS aqueous solution
From experimental data, the gossypol crystal III substance of the patent has the advantage of solubility in 0.2% SDS aqueous solution, and is particularly better in dissolution rate and solubility, and the solubility of the gossypol crystal III substance is about 3 times or more than that of gossypol crystal I and gossypol acetate.
Example 4
Preparation method of combination pharmaceutical formulation 1 (tablet):
A preparation method of a combined medicine tablet is characterized in that a pure product of a gossypol crystal III substance or a mixed crystal solid substance containing a crystal III with any proportion is used as a raw material medicine of the combined medicine, a plurality of excipients are used as auxiliary material components for preparing the combined medicine tablet, a tablet sample with the drug content of 5-500 mg of each tablet is prepared according to a certain proportion, and the formula proportion of the tablet is shown in a table 3:
Table 4 formulation for preparing gossypol combination pharmaceutical tablet
The method for preparing the gossypol crystal III substance pure product or mixed crystal bulk drug containing any proportion of crystal III into the tablet preparation comprises the following steps: mixing several excipients and raw materials, adding 1% sodium hydroxymethyl cellulose solution, making into soft material, sieving, granulating, oven drying, sieving, granulating, adding magnesium stearate and pulvis Talci, mixing, and tabletting.
Preparation method 2 (capsule) of the combined pharmaceutical preparation:
A preparation method of a combination drug capsule is characterized in that a pure product of a gossypol crystal III substance or a mixed crystal solid substance containing a crystal III with any proportion is used as a raw material drug of the combination drug, several excipients are used as auxiliary material components for preparing the combination drug capsule, a capsule sample with the drug content of 5-500 mg of each tablet is prepared according to a certain proportion, and the formula proportion of the capsule is shown in a table 4:
table 5 raw material medicine and auxiliary material formulation of gossypol combined medicine capsule preparation
The method for preparing the gossypol crystal III substance pure product or mixed crystal bulk drug containing any proportion of crystal III into the tablet preparation comprises the following steps: mixing several excipients with the raw materials, adding 1% sodium hydroxymethyl cellulose solution, making into wet granule, oven drying, sieving, grading, adding magnesium stearate, mixing, and making into capsule; or directly mixing the crude drug of gossypol crystal III type substance with several excipient adjuvants without granulating, sieving, and directly encapsulating.
Example 5
Dose 1 (tablet) of gossypol crystalline form combination drug:
The developed pharmaceutical composition is prepared by using a crystalline form gossypol sample as a pharmaceutical active ingredient, and is characterized in that crystalline form III gossypol is used as the pharmaceutical active ingredient, the daily administration dosage is 5-3000mg, and 1-6 tablets each time can be prepared into common tablet types containing 5, 50, 100, 200, 300 and 500mg of the active ingredient.
Dose 2 (capsule) of gossypol crystalline form combination drug:
The developed pharmaceutical composition is prepared by using a crystalline form gossypol sample as a pharmaceutical active ingredient, and is characterized in that crystalline form III gossypol is used as the pharmaceutical active ingredient, the daily administration dosage is 5-3000mg, and 1-6 capsules containing 5, 50, 100, 200, 300 and 500mg of the active ingredient can be prepared respectively.
Problems to be described: the gossypol crystalline form pharmaceutical composition of the present invention has many factors influence on the administration dosage of the active ingredient, such as: the age and body surface area of patients are different, and the dosage of each administration is different due to the different administration routes, administration times and treatment purposes; the presence of absorption and plasma concentrations that differ between the crystalline form samples also results in the invention being used in a suitable dosage range of 0.01-300mg/kg body weight, preferably 10-100mg/kg body weight, per time of the crystalline form component of gossypol. When in use, the total dosage scheme of the active ingredients of the different gossypol crystal III substances is formulated according to the actual requirements of different treatment conditions, and the administration can be completed in a mode of multiple times or one time.
Claims (12)
1. A gossypol crystal form III solid material which does not contain a crystallization solvent or a crystallization water component and which has a diffraction peak position of 2-Theta (DEG) or d-value when subjected to CuK α irradiation test conditions by powder X-ray diffraction analysisThe diffraction peak relative intensity peak Height value (Height%) or peak Area value (Area%) has the following expression:
2. The gossypol crystalline form III solid substance of claim 1, wherein an infrared spectrum characteristic peak exists at 3498、2960、2929、2875、1710、1615、1573、1500、1440、1419、1381、1336、1297、1244、1183、1123、1054、1025、994、966、913、841、797、770、722、699、671、655cm-1 when analyzed using attenuated total reflection fourier infrared spectroscopy, wherein the allowable deviation of the infrared spectrum characteristic peak is ±2cm "1.
3. The gossypol crystalline form III solid substance according to claim 1, characterized by the presence of 1 endothermic peak in its DSC profile at 163 ℃ ± 5 ℃ when analyzed using differential scanning calorimetry in the range of 30-200 ℃ and at a rate of rise of 10 ℃ per minute.
4. The method for preparing the gossypol crystal III solid substance according to any one of claims 1-3, characterized in that the gossypol acetate and agate balls are weighed according to a certain ball-to-material ratio, a grinding mode of forward ball milling for 10min, stopping for 5min and then reverse ball milling for 10min is adopted, the rotating speed is set to be 200-1000 revolutions per minute, and the gossypol crystal III solid substance is prepared after ball milling for 3-20h, wherein the ball-to-material ratio is 1:1-20:1.
5. A mixed crystalline form solid material of gossypol, characterized by comprising a gossypol crystalline form III solid material of claim 1 in any non-zero proportion.
6. A pharmaceutical composition comprising an effective amount of the solid material of form III of gossypol according to any one of claims 1-3 and a pharmaceutically acceptable carrier.
7. A pharmaceutical composition comprising an effective amount of the gossypol mixed crystalline solid material of claim 5 and a pharmaceutically acceptable carrier.
8. Pharmaceutical composition according to any of claims 6 or 7, characterized in that the daily dose of gossypol is in the range of 5-3000 mg.
9. Pharmaceutical composition according to any of claims 6 or 7, characterized in that the dosage form of the pharmaceutical composition is a tablet, capsule, pill, powder injection, slow release formulation or controlled release formulation.
10. Use of the solid substance of gossypol crystalline form III according to any one of claims 1-3 for the preparation of various contraceptive, antitumor, antiviral, anti-inflammatory, antimalarial, antioxidant drugs and drugs for the treatment of endometriosis, uterine fibroids, dysfunctional uterine bleeding, dysmenorrhea gynaecological diseases.
11. The use of the gossypol mixed crystal solid substance as claimed in claim 5 for preparing various contraceptive, anti-tumor, antiviral, anti-inflammatory, antimalarial and antioxidant medicines and medicines for treating endometriosis, uterine fibroids, dysfunctional uterine bleeding and dysmenorrhea.
12. Use of a pharmaceutical composition according to any one of claims 6-7 for the preparation of various contraceptive, antitumor, antiviral, anti-inflammatory, antimalarial, antioxidant drugs and drugs for the treatment of gynaecological diseases such as endometriosis, uterine fibroids, dysfunctional uterine bleeding, dysmenorrhea.
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| CN101434522A (en) * | 2008-12-15 | 2009-05-20 | 湖北同一石油化工有限公司 | Method for preparing high-purity gossypol from cottonseed dephenolizing solution |
| WO2011017145A2 (en) * | 2009-08-07 | 2011-02-10 | The Regents Of The University Of Michigan | Biomarkers for gossypol chemotherapy and methods of treating disease |
| CN102898486A (en) * | 2012-09-21 | 2013-01-30 | 晨光生物科技集团股份有限公司 | Comprehensive method for preparation of raffinose and gossypol from cottonseed meal |
| CN105693488A (en) * | 2016-03-18 | 2016-06-22 | 江南大学 | Clean production process for high purity gossypol |
| CN107298641A (en) * | 2017-06-07 | 2017-10-27 | 新疆维吾尔自治区中药民族药研究所 | The preparation method of gossypol and the preparation method of gossypol acetate |
| CN108276263A (en) * | 2018-04-09 | 2018-07-13 | 中国科学院新疆理化技术研究所 | A method of preparing free gossypol by raw material of gossypol acetate |
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2020
- 2020-02-04 CN CN202010080016.3A patent/CN113214065B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101434522A (en) * | 2008-12-15 | 2009-05-20 | 湖北同一石油化工有限公司 | Method for preparing high-purity gossypol from cottonseed dephenolizing solution |
| WO2011017145A2 (en) * | 2009-08-07 | 2011-02-10 | The Regents Of The University Of Michigan | Biomarkers for gossypol chemotherapy and methods of treating disease |
| CN102898486A (en) * | 2012-09-21 | 2013-01-30 | 晨光生物科技集团股份有限公司 | Comprehensive method for preparation of raffinose and gossypol from cottonseed meal |
| CN105693488A (en) * | 2016-03-18 | 2016-06-22 | 江南大学 | Clean production process for high purity gossypol |
| CN107298641A (en) * | 2017-06-07 | 2017-10-27 | 新疆维吾尔自治区中药民族药研究所 | The preparation method of gossypol and the preparation method of gossypol acetate |
| CN108276263A (en) * | 2018-04-09 | 2018-07-13 | 中国科学院新疆理化技术研究所 | A method of preparing free gossypol by raw material of gossypol acetate |
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