CN114292305A - Pharmaceutical co-crystal of progesterone and formic acid derivative and application thereof - Google Patents
Pharmaceutical co-crystal of progesterone and formic acid derivative and application thereof Download PDFInfo
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- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 title claims abstract description 109
- 239000013078 crystal Substances 0.000 title claims abstract description 109
- 239000000186 progesterone Substances 0.000 title claims abstract description 53
- 229960003387 progesterone Drugs 0.000 title claims abstract description 53
- 150000004675 formic acid derivatives Chemical class 0.000 title claims abstract description 9
- 230000005496 eutectics Effects 0.000 claims abstract description 68
- 238000000034 method Methods 0.000 claims abstract description 15
- DVHFWKCHUQZGSF-UHFFFAOYSA-N 2,4-dihydroxy-5-nitrobenzoic acid Chemical group OC(=O)C1=CC([N+]([O-])=O)=C(O)C=C1O DVHFWKCHUQZGSF-UHFFFAOYSA-N 0.000 claims abstract description 7
- BUHKQTKKZAXSMH-UHFFFAOYSA-N 5-hydroxy-2-nitrobenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1[N+]([O-])=O BUHKQTKKZAXSMH-UHFFFAOYSA-N 0.000 claims abstract description 7
- XGWFJBFNAQHLEF-UHFFFAOYSA-N 9-anthroic acid Chemical compound C1=CC=C2C(C(=O)O)=C(C=CC=C3)C3=CC2=C1 XGWFJBFNAQHLEF-UHFFFAOYSA-N 0.000 claims abstract description 7
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Abstract
The invention discloses a pharmaceutical co-crystal of progesterone and a formic acid derivative and application thereof, wherein the formic acid derivative is selected from 2, 4-dihydroxy-5-nitrobenzoic acid, 2-nitro-5-hydroxybenzoic acid and 9-anthracenecarboxylic acid. The progesterone-2, 4-dihydroxy-5-nitrobenzoic acid eutectic, the progesterone-2-nitro-5-hydroxybenzoic acid eutectic and the progesterone-9-anthracenecarboxylic acid eutectic synthesized by the method improve the solubility of progesterone, improve the bioavailability of progesterone and reduce the irritation and adverse reaction of progesterone.
Description
Technical Field
The invention belongs to the field of biological medicines, and relates to a pharmaceutical cocrystal of progesterone and a formic acid derivative and application thereof.
Background
Progesterone (Progesterone, C)21H30O2) Also known as progesterone, 4-pregnane-3, 20 dione, is the major bioactive progestin secreted by the ovaries. The progesterone can not only induce the transformation of endometrium to secretion period and increase the receptivity of endometrium so as to be beneficial to implantation of fertilized eggs, but also act on the part of uterus so as to provide good internal environment for the maintenance of pregnancy. Clinical applications of progesterone mainly include: the pregnancy rate is improved; effectively relieve menstrual tension syndrome; the thickness of endometrium is reduced, and the menstrual cycle and the menstrual period are effectively shortened; the corpus luteum function is improved, and the success rate of the assisted reproduction technology is effectively improved; protecting nervous system and promoting its regeneration; protecting the cardiovascular system; treating respiratory diseases.
Progesterone is poor in solubility, almost insoluble in water, and only 2mg/L in solubility, and is usually administered by injection of progesterone oil injection in clinic. Its advantages are sure curative effect, low cost and the following disadvantages: the pain and stimulation of the injection part are easy to form local induration, and the absorption and recovery of the local induration and the aseptic abscess need a long time.
The development of pharmaceutical crystalline forms is one possibility to increase bioavailability and, in addition to bioavailability, may improve several other properties, such as dissolution, physical stability, mechanical properties, hygroscopicity, chemical stability, flowability and purification processing ability. Therefore, the research of new crystal forms is an important means for drug development.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a combined pharmaceutical co-crystal formed by progesterone and formic acid derivatives and application thereof, aiming at the problems that the existing progesterone is poor in solubility and the drug effect cannot be well exerted.
In order to solve the technical problems, the invention adopts the following technical scheme:
in a first aspect the invention provides a co-crystal of progesterone and a co-form selected from a formic acid derivative selected from 2, 4-dihydroxy-5-nitrobenzoic acid, 2-nitro-5-hydroxybenzoic acid, 9-anthracenecarboxylic acid.
Further, the experimental formula of the progesterone-2, 4-dihydroxy-5-nitrobenzoic acid eutectic is C28H35NO8；
The experimental formula of the progesterone-2-nitro-5-hydroxybenzoic acid eutectic is C28H37NO8；
The experimental formula of the progesterone-9-anthracenecarboxylic acid eutectic is C57H70O6。
Further, the co-crystal has an X-ray spectrum with characteristic 2 θ values at 2 θ ± 0.2 ° respectively:
eutectic crystal of progesterone-2, 4-dihydroxy-5-nitrobenzoic acid: 10.780, 16.978;
progesterone-2-nitro-5-hydroxybenzoic acid co-crystal: 13.864, 17.403, 21.432, 25.382;
progesterone-9-anthracenecarboxylic acid co-crystal: 12.779, 16.959, 23.061.
Further, the co-crystal also has an X-ray spectrum with characteristic 2 θ values at 2 θ ± 0.2 ° below, respectively:
eutectic crystal of progesterone-2, 4-dihydroxy-5-nitrobenzoic acid: 12.822, 15.759, 26.318, 28.240;
progesterone-2-nitro-5-hydroxybenzoic acid co-crystal: 17.679, 20.116;
progesterone-9-anthracenecarboxylic acid co-crystal: 10.296, 12.199, 12.460, 15.663, 18.900, 24.701, 27.040.
Further, the co-crystal also has an X-ray spectrum with characteristic 2 θ values at 2 θ ± 0.2 ° below, respectively:
eutectic crystal of progesterone-2, 4-dihydroxy-5-nitrobenzoic acid: 16.277, 17.482, 18.339, 20.441, 23.802, 26.760;
progesterone-2-nitro-5-hydroxybenzoic acid co-crystal: 11.141, 12.133, 12.701, 16.518, 20.837, 24.839, 26.243, 26.696, 27.941;
progesterone-9-anthracenecarboxylic acid co-crystal: 10.640, 14.542, 15.400, 17.660, 19.681, 22.580, 24.282.
Further, the X-ray powder diffraction pattern of the eutectic of progesterone-2, 4-dihydroxy-5-nitrobenzoic acid is substantially as shown in fig. 1B;
an X-ray powder diffraction pattern of the co-crystal of progesterone-2-nitro-5-hydroxybenzoic acid substantially as shown in fig. 1D;
the X-ray powder diffraction pattern of the progesterone-9-anthracenecarboxylic acid co-crystal is substantially as shown in fig. 1F.
Further, the co-crystals contain endothermic peaks at about the following melting point temperatures, respectively:
eutectic crystal of progesterone-2, 4-dihydroxy-5-nitrobenzoic acid: 144.6 ℃;
progesterone-2-nitro-5-hydroxybenzoic acid co-crystal: 104.8 ℃;
progesterone-9-anthracenecarboxylic acid co-crystal: 117.5 ℃.
Further, the thermogram of the eutectic of progesterone-2, 4-dihydroxy-5-nitrobenzoic acid is substantially as shown in fig. 3A;
the thermogram of the eutectic of progesterone-2-nitro-5-hydroxybenzoic acid is substantially as shown in fig. 3B;
the thermogram of the progesterone-9-anthracenecarboxylic acid co-crystal is substantially as shown in fig. 3C.
Further, the co-crystals respectively contain the following crystal parameters:
the eutectic of progesterone-2, 4-dihydroxy-5-nitrobenzoic acid is monoclinic system, P21Space group, cell parameter of
α ═ γ ═ 90.00 °, β ═ 105.419(6 °), Z ═ 2, and unit cell volumeProduct of
The eutectic of progesterone-2-nitro-5-hydroxybenzoic acid is orthorhombic, P2 12121Space group, cell parameter of
α ═ β ═ γ ═ 90.00 °, Z ═ 4, and unit cell volume 2608.4(2)3；
The progesterone-9-anthracenecarboxylic acid eutectic is a triclinic crystal system, P1 space group and unit cell parameters are
A is 84.646(7), β is 85.564(7), γ is 86.670(8), Z is 2, unit cell volume is
In a second aspect, the present invention provides a method for preparing a co-crystal according to the first aspect of the present invention, comprising:
1) the progesterone and the copolymer are crushed to obtain a white powder sample,
2) and adding the white powder sample into an ester solvent for dissolving, and volatilizing to obtain colorless blocky crystals.
Further, the solvent is ethyl acetate.
Further, the molar ratio of progesterone to co-form is 1: 1.
Further, progesterone and the co-form were pulverized using a ball mill.
In a third aspect, the present invention provides a pharmaceutical composition comprising a co-crystal according to the first aspect of the present invention.
Further, the pharmaceutical composition also comprises a pharmaceutically acceptable carrier.
Further, the administration mode of the pharmaceutical composition comprises oral administration, injection, vaginal administration and transdermal administration.
In a fourth aspect, the invention provides the use of a co-crystal according to the first aspect of the invention or a pharmaceutical composition according to the third aspect of the invention in the manufacture of a medicament for maintaining pregnancy.
In a fifth aspect, the present invention provides the use of a co-crystal according to the first aspect of the present invention or a pharmaceutical composition according to the third aspect of the present invention in the manufacture of a medicament for the prevention and/or treatment of gynaecological disorders.
Further, the gynecological diseases include spontaneous premature birth, corpus luteum insufficiency, secondary amenorrhea, premenstrual syndrome.
According to a sixth aspect of the present invention, there is provided a use of the co-crystal according to the first aspect of the present invention or the pharmaceutical composition according to the third aspect of the present invention for the preparation of a medicament for the prevention and/or treatment of cardiovascular diseases and nervous system diseases.
In a seventh aspect, the invention provides a method of treating a disease, the method comprising administering to the subject an effective amount (e.g. a therapeutically effective amount) of a co-crystal according to the invention or a composition thereof. The diseases include but are not limited to gynecological diseases, cardiovascular and cerebrovascular diseases and nervous system diseases.
In some embodiments, the methods described herein further comprise administering to the subject an additional agent. In some embodiments, the methods described herein further comprise contacting the biological sample with an additional agent. In some embodiments, the methods described herein further comprise contacting the tissue with an additional agent. In some embodiments, the methods described herein further comprise contacting the cell with an additional agent.
In the present invention, the relative amounts of the active ingredient, pharmaceutically acceptable carrier and/or any additional ingredients in the pharmaceutical composition will vary depending on the identity, size and/or condition of the subject being treated and further depending on the route of administration of the composition. The composition may comprise from 0.1% to 100% (w/w) of the active ingredient.
In the present invention, "pharmaceutically acceptable" refers to compounds, molecular entities, compositions, materials and/or dosage forms that do not produce a negative reaction, allergic reaction or other untoward reaction when properly administered to an animal or human. For human administration, the formulations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.
In the present invention, "carrier" refers to a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent, such as progesterone, from one organ or portion of the body to another organ or portion of the body.
By "pharmaceutically acceptable excipient" is meant a substance that aids in the administration and/or absorption of an active agent to a subject and that can be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological salt solutions (such as phosphate buffered saline solution), emulsions (such as, for example, water-in-oil or oil-in-water emulsions), lactated ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, salt solutions (such as ringer's solution), alcohols, oils, gelatin, sugars (such as lactose, amylose, or starch), fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, colorants, and the like. These preparations can be sterilized and, if desired, mixed with adjuvants which do not deleteriously react with the compounds of the invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants and/or aromatic substances, etc.
In the present invention, the pharmaceutical composition or medicament may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. Oral administration or injection administration is preferred. The pharmaceutical compositions of the present invention may contain any of the usual non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles. In some cases, pharmaceutically acceptable acids, bases or buffers may be used to adjust the pH of the formulation to improve the stability of the formulated compound or its dosage form in which it is administered. The term parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intracolic, intralesional, and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention may be administered to a subject by any route as long as the target tissue is reached.
The term "crystalline" or "crystalline form" refers to a solid form that exhibits substantially three-dimensional ordering. In some embodiments, the crystalline form of the solid is a solid form that is not substantially amorphous. In some embodiments, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising one or more sharp defined peaks. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause a crystalline form to dominate. Various polymorphs of a compound may be prepared by crystallization under different conditions.
The term "co-crystal" refers to a crystal structure comprising at least two different components (e.g., progesterone and a co-form), wherein each component is independently an atom, ion, or molecule. In some embodiments, none of the components are solvents. In some embodiments, at least one component is a solvent. The co-crystal of progesterone and the co-form is different from the salt formed by progesterone and the co-form. In salts, progesterone is complexed with the coformer in such a way that protons are easily transferred from the coformer (e.g., intact proton transfer) to the progesterone at room temperature. However, in this co-crystal, progesterone is complexed with the co-former in such a way that protons are not readily transferred from the co-former to the progesterone at room temperature. In some embodiments, in the co-crystal, no protons are transferred from the conformality to the progestin. In some embodiments, in the co-crystal, a portion of the protons are transferred from the conformality to the progestin. Co-crystals can be used to improve the properties of progesterone (e.g., solubility, stability, ease of formulation, or bioavailability).
The terms "treat" and "treating" include any effect, e.g., reduction, modulation, amelioration, or elimination, that results in the amelioration of the condition, disease, disorder, etc., or alleviation of the symptoms thereof. The treatment may be to cure, ameliorate, or at least partially alleviate the disease. In certain embodiments, the treatment is a cure for the disease.
In the present invention, an "effective amount" or "therapeutically effective amount" refers to an amount of a compound (e.g., a compound of the present invention) sufficient to produce a beneficial or desired effect. An effective amount may be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or route of administration. As used herein, the term "treating" includes any effect, e.g., reduction, modulation, amelioration, or elimination, that results in the amelioration of a condition, disease, disorder, etc., or alleviation of a symptom thereof.
Other than in the examples, and where otherwise indicated, all numbers expressing quantities of ingredients used in the specification and claims are to be understood as being modified in all instances by the term "about" or "approximately", such that, unless otherwise indicated, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure, at the very least, and are not intended to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.
In the present invention, the diffraction peaks shown in FIG. 1 do not represent an exhaustive list of diffraction peaks exhibited by the crystalline forms. The 2 θ values of the X-ray powder diffraction patterns are slightly variable with machine and with variations in sample preparation and lot-to-lot variations, and the values quoted are not considered absolute values. It should also be understood that the relative intensities of the peaks may vary with orientation effects, and thus the intensities shown in the PXRD traces included in the present disclosure are exemplary and not intended for absolute comparison.
The invention has the advantages and beneficial effects that:
the invention synthesizes the pharmaceutical eutectic of the progesterone and the formic acid derivatives, namely 2, 4-dihydroxy-5-nitrobenzoic acid, 2-nitro-5-hydroxybenzoic acid and 9-anthracenecarboxylic acid, for the first time, improves the solubility of the progesterone, improves the bioavailability of the progesterone and reduces the irritation and adverse reaction of the progesterone.
Drawings
Figure 1 is an X-powder diffraction pattern of a progesterone-carboxylic acid derivative co-crystal; wherein 1A and 1B are progesterone-2, 4-dihydroxy-5-nitrobenzoic acid eutectic; 1C and 1D are progesterone-2-nitro-5-hydroxybenzoic acid co-crystal; 1E and 1F are progesterone-9-anthracenecarboxylic acid co-crystals;
FIG. 2 is a chart of the infrared absorption spectrum of a progesterone-carboxylic acid derivative co-crystal; wherein 2A is progesterone-2, 4-dihydroxy-5-nitrobenzoic acid eutectic; 2B is progesterone-2-nitro-5-hydroxybenzoic acid eutectic; 2C is progesterone-9-anthracenecarboxylic acid eutectic;
FIG. 3 is a TG/DSC scan of a progesterone-carboxylic acid derivative co-crystal; wherein 3A is progesterone-2, 4-dihydroxy-5-nitrobenzoic acid eutectic; 3B is progesterone-2-nitro-5-hydroxybenzoic acid eutectic; 3C is progesterone-9-anthracenecarboxylic acid eutectic;
fig. 4 is a progesterone-carboxylic acid derivative co-crystal1H-NMR nuclear magnetic resonance spectrum; wherein 4A is progesterone-2, 4-dihydroxy-5-nitrobenzoic acid eutectic; 4B is progesterone-2-nitro-5-hydroxybenzoic acid eutectic; 4C is progesterone-9-anthracenecarboxylic acid eutectic;
fig. 5 is a molecular structural diagram of a progesterone-carboxylic acid derivative co-crystal; wherein 5A is progesterone-2, 4-dihydroxy-5-nitrobenzoic acid eutectic; 5B is progesterone-2-nitro-5-hydroxybenzoic acid eutectic; 5C is progesterone-9-anthracenecarboxylic acid eutectic;
fig. 6 is a stability test chart of a progesterone-carboxylic acid derivative co-crystal; wherein 6A is progesterone-2, 4-dihydroxy-5-nitrobenzoic acid eutectic; 6B is progesterone-2-nitro-5-hydroxybenzoic acid eutectic; 6C is progesterone-9-anthracenecarboxylic acid eutectic;
fig. 7 is a solubility experimental plot of a progesterone-carboxylic acid derivative co-crystal; wherein 7A is a progesterone-2, 4-dihydroxy-5-nitrobenzoic acid eutectic; 7B is progesterone-2-nitro-5-hydroxybenzoic acid eutectic; 7C is progesterone-9-anthracenecarboxylic acid eutectic;
fig. 8 is a bioavailability graph of a progesterone-carboxylic acid derivative co-crystal; wherein 8A is progesterone-2, 4-dihydroxy-5-nitrobenzoic acid eutectic; 8B is progesterone-2-nitro-5-hydroxybenzoic acid eutectic; 8C is progesterone-9-anthracenecarboxylic acid eutectic.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings and examples. The following examples are intended to illustrate the invention only and are not intended to limit the scope of the invention. The experimental procedures, in which specific conditions are not specified in the examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers.
EXAMPLE preparation of drug Co-crystals and functional testing
Materials (I) and (II)
Progesterone: zhejiang Xianju pharmaceutical Co Ltd (purity > 99%)
2, 4-dihydroxy-5-nitrobenzoic acid, 2-nitro-5-hydroxybenzoic acid, 9-anthracenecarboxylic acid: shanghai Mielin Biochemical technology Co., Ltd. (purity > 99%)
Ethyl acetate: beijing chemical plant (analytical pure)
Second, Experimental methods
1. Preparation of samples
943.4mg (3.0mmol) of progesterone is weighed, and is respectively added with 597.4mg (3.0mmol) of 2, 4-dihydroxy-5-nitrobenzoic acid, 549.4mg (3.0mmol) of 2-nitro-5-hydroxybenzoic acid, 666.7mg (3.0mmol) of 9-anthracenecarboxylic acid, 3.0mmol of m-aminobenzoic acid and 3.0mmol of terephthalic acid into a ball mill (planetary ball mill, Nanjing Ching scientific and technological development Co., Ltd.) without solvent, and ball milling is carried out at 28Hz for 40min, thus obtaining a white powder sample.
2. Cultivation of single crystals
Taking 100mg of the powder sample, adding 15ml of ethyl acetate to dissolve the powder sample, slowly volatilizing the solvent, and obtaining colorless massive crystals after about 1 week.
3. Powder X-ray diffraction (PXRD):
bruker D8 PHASER, Bruker, Germany, Bruk, Inc. And (3) testing conditions are as follows: normal temperature, light source Cu
Voltage 30kV, current 10mA, test step 0.014 °, scan speed 0.1s/step, scan range 3-60 ° 2 θ.
4. Fourier transform infrared spectroscopy (FT-IR):
5. Simultaneous thermal analysis (TG-DSC):
STA 449F3+ ASC, German Steed instruments manufacturing Ltd. Analysis conditions were as follows: an aluminum crucible, a nitrogen atmosphere (20 mL/min of protective gas and 60mL/min of purge gas), a temperature range of room temperature to 400 ℃, and a heating rate of 10 ℃/min.
6. Nuclear magnetic hydrogen spectrum (1H-NMR)：
AVANCE III 400MHz, Bruker analysis, Germany. And (3) testing conditions are as follows: solvent d6DMSO, 16 scans.
7. Single crystal X-ray diffraction (SXRD):
gemini A Ultra, Agilent, USA. And (3) testing conditions are as follows: the light source is
Data was collected in a ω/2 θ scan. Reduction and absorption correction of data: CrysAlis PRO software. Space group: and determining according to the extinction rule of the system, and verifying by the fine modification result. Crystal structure analysis: the SHELXS-97 program, the direct method, corrects the result by a full matrix least square method, the coordinates of hydrogen atoms on carbon are added according to theoretical calculation, and the coordinates of hydrogen atoms on other atoms are added according to calculation of an electron density map.
8. Evaluation of stability:
a drug stability test kit (model DAA-1, Shanghai-Hengchun scientific instruments, Inc.) was used. And (3) testing conditions are as follows: the sample was placed in a drug stability laboratory box under high temperature (60 ℃), high humidity (90. + -. 5%), and light (4500. + -. 500lx) conditions for 10 days, and sampled on day 5 and day 10 for PXRD analysis, respectively.
9. Water solubility study:
a dissolution apparatus (RC806D, Technology Ltd. Tianjin Tiandada). The experimental conditions are as follows: deionized water (degassed standby), volume: 1000mL, temperature: 37 ℃, rotation speed: at 100rpm, grinding different eutectic crystals of progesterone, respectively taking 20mg of the fine powder, placing in a dissolution instrument, sampling 10mL for 5min, 15min, 30min, 60min, 120min, 240min, 300min and 360min, supplementing 10mL of solution, filtering with 0.45 μm membrane, and measuring content by high performance liquid chromatography.
10. Pharmacokinetic studies:
1) animal(s) production
Healthy female SD rats (7-9 weeks old, weight 220 + -30 g, 5 per group) were purchased from Peking Wintolite laboratory animals technology, Inc.
2) Animal administration method
All animals were kept on a 12 hr/12 hr light/dark cycle, 5 animals per cage, with free diet. The progesterone eutectic is prepared into a solution with PBS (phosphate buffered saline, containing 0.1% DMSO), the dosage of the progesterone eutectic is 5.0mg/kg, and the progesterone eutectic is administered through intramuscular injection.
3) Method for preparing biological sample
Samples of 50 μ L jugular venous blood were collected in batches at defined times (15, 30min and 1, 1.5, 2, 3, 5, 7, 12, 24, 48h) into heparinized tubes. The blood was then centrifuged for 15 min. Plasma samples were stored at-20 ℃. mu.L rat plasma, 5. mu.L methanol and 200. mu.L internal standard solution (buspirone, 5ng/mL) were added to 1mL methanol: acetonitrile (1:1, v/v). The plasma samples were vortexed for 1min, centrifuged at 4000rpm for 15min, and the plasma samples were vortexed with methanol: the supernatant was diluted 20 times with water (1:1, v/v, 0.1% trifluoroacetic acid) and injected.
4) Biological sample analysis method
(1) LC-MS/MS instrument model: AB Sciex 5500; LC-MS/MS quantitative analysis software: 1.6.3; an ionization mode: electrospray positive ions; the scanning mode is as follows: multiple Reaction Monitoring (MRM); analyte MRM: EE-DNS, 530.4/171.0; internal standard MRM: buspirone, 386.2/122.2; (2) liquid phase conditions: shimadzu LC-30AD, ACE Excel 5C4(50mm × 2.1mm), sample size 10 μ L; mobile phase: a5 mM ammonium acetate (0.05% trifluoroacetic acid) and B acetonitrile (0.1% trifluoroacetic acid) at a flow rate of 0.8mL/min, and the gradients of mobile phases A and B are shown in the following table.
TABLE 1 gradient of mobile phases A and B
Third, experimental results
2, 4-dihydroxy-5-nitrobenzoic acid, 2-nitro-5-hydroxybenzoic acid, 9-anthracenecarboxylic acid and progesterone form a eutectic; under the same conditions, m-aminobenzoic acid and terephthalic acid cannot form eutectic with progesterone.
The powder X-ray diffraction (PXRD) results of the co-crystals are shown in fig. 1 and table 2, where the peak intensity is highest at about 16.978 for the co-crystal of progesterone-2, 4-dihydroxy-5-nitrobenzoic acid at 2 θ; the peak intensity was highest for the progesterone-2-nitro-5-hydroxybenzoic acid co-crystal at about 25.382 ° 2 θ; the peak intensity was highest for the progesterone-9-anthracenecarboxylic acid co-crystal at about 16.959 ° 2 θ.
TABLE 2X-ray powder diffraction results for drug cocrystal samples
The results of fourier transform infrared spectroscopy (FT-IR) of the co-crystals are shown in fig. 2 and table 3, and the drug co-crystals of progesterone have infrared absorption peaks at the positions shown in table 3.
TABLE 3 major infrared absorption peaks of drug cocrystals
The results of the simultaneous thermal analysis (TG-DSC) of the co-crystals are shown in FIG. 3, and the Differential Scanning Calorimeter (DSC) shows that the melting point of the co-crystals of progesterone-2, 4-dihydroxy-5-nitrobenzoic acid is 144.6 ℃ in the test temperature range; the melting point of the eutectic of the progesterone-2-nitro-5-hydroxybenzoic acid is 104.8 ℃; the melting point of the progesterone-9-anthracenecarboxylic acid eutectic is 117.5 ℃; thermogravimetric analysis (TGA) shows: decomposition of the conformer with progesterone was observed for all co-crystals over the temperature range tested.
The results of the eutectic nuclear magnetic hydrogen spectrum (1H-NMR) are shown in fig. 4, and the shifts of the eutectic nuclear magnetic resonance hydrogen spectrum are as follows:
eutectic crystal of progesterone-2, 4-dihydroxy-5-nitrobenzoic acid:1H-NMR(500MHz,d6-DMSO)δ＝11.70(s,1H),8.44(s,1H),6.40(s,2H),5.63(s,1H),2.57-2.55(t,1H),2.42-2.33(m,2H),2.26-2.22(m,2H),2.18-2.14(m,6H),1.80-1.64(d,1H),1.60-1.52(m,5H),1.43-1.35(m,2H),1.20-1.14(m,5H),0.99-0.91(m,2H),0.67(S,3H)。
progesterone-2-nitro-5-hydroxybenzoic acid co-crystal:1H-NMR(500MHz,d6-DMSO)δ＝11.20(s,1H),7.99(s,1H),7.01(s,2H),5.63(s,1H),2.57-2.55(t,1H),2.42-2.33(m,2H),2.26-2.22(m,2H),2.18-2.14(m,6H),1.80-1.64(d,1H),1.60-1.52(m,5H),1.43-1.35(m,2H),1.20-1.14(m,5H),0.99-0.91(m,2H),0.67(S,3H)。
progesterone-9-anthracenecarboxylic acid co-crystal:1H-NMR(500MHz,d6-DMSO)δ＝13.80(s,1H),8.73(s,1H),8.14(d,1H),8.03(d,1H),7.57(d,2H),5.63(s,1H),2.57-2.55(t,1H),2.42-2.33(m,2H),2.26-2.22(m,2H),2.18-2.14(m,6H),1.80-1.64(d,1H),1.60-1.52(m,5H),1.43-1.35(m,2H),1.22(m,1H),1.14(m,3H),1.07(m,1H),0.99-0.91(m,2H),0.67(S,3H)。
the results of single crystal X-ray diffraction (SXRD) of the co-crystals are shown in fig. 5 and table 4, with a molecular ratio of progesterone to the co-form of the progesterone-2, 4-dihydroxy-5-nitrobenzoic acid co-crystals, progesterone-2-nitro-5-hydroxybenzoic acid co-crystals of 1: 1; the molecular ratio of the progesterone to the co-formed substance in the progesterone-9-anthracenecarboxylic acid co-crystal is 1: 2.
TABLE 4 Crystal Structure of drug cocrystals
The stability evaluation results of the eutectic are shown in fig. 6, and the powder X-ray diffraction of the eutectic of progesterone-2, 4-dihydroxy-5-nitrobenzoic acid, progesterone-2-nitro-5-hydroxybenzoic acid and progesterone-9-anthracenecarboxylic acid under the conditions of high temperature, high humidity and illumination does not change significantly, which indicates that the eutectic is stable.
The result of the study on the water solubility of the co-crystal is shown in fig. 7, and the water solubility of the co-crystal of the drug, progesterone-2, 4-dihydroxy-5-nitrobenzoic acid co-crystal, progesterone-2-nitro-5-hydroxybenzoic acid co-crystal and progesterone-9-anthracenecarboxylic acid is remarkably increased.
The result of the pharmacokinetic study of the cocrystal is shown in FIG. 8, where the peak time of progesterone is 1h, the peak time of cocrystal is 1.5h, and the cocrystal C of progesterone-2, 4-dihydroxy-5-nitrobenzoic acidmax1.5 times of progesterone; progesterone-2-nitro-5-hydroxybenzoic acid eutectic Cmax1.7 times of progesterone; progesterone-9-anthracenecarboxylic acid eutectic CmaxIs 1.8 times of progesterone, and has better bioavailability.
The above description of the embodiments is only intended to illustrate the method of the invention and its core idea. It should be noted that, for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications will also fall into the protection scope of the claims of the present invention.
Claims (10)
1. Co-crystal of progesterone and a co-form, characterized in that said co-form is selected from formic acid derivatives selected from 2, 4-dihydroxy-5-nitrobenzoic acid, 2-nitro-5-hydroxybenzoic acid, 9-anthracenecarboxylic acid;
preferably, the experimental formula of the progesterone-2, 4-dihydroxy-5-nitrobenzoic acid eutectic is C28H35NO8；
The experimental formula of the progesterone-2-nitro-5-hydroxybenzoic acid eutectic is C28H37NO8；
The experimental formula of the progesterone-9-anthracenecarboxylic acid eutectic is C57H70O6。
2. The co-crystal of claim 1, wherein the co-crystal has an X-ray spectrum with characteristic 2 Θ values at 2 Θ ± 0.2 ° respectively:
eutectic crystal of progesterone-2, 4-dihydroxy-5-nitrobenzoic acid: 10.780, 16.978;
progesterone-2-nitro-5-hydroxybenzoic acid co-crystal: 13.864, 17.403, 21.432, 25.382;
progesterone-9-anthracenecarboxylic acid co-crystal: 12.779, 16.959, 23.061;
preferably, the co-crystal also has an X-ray spectrum with characteristic 2 θ values at 2 θ ± 0.2 ° below, respectively:
eutectic crystal of progesterone-2, 4-dihydroxy-5-nitrobenzoic acid: 12.822, 15.759, 26.318, 28.240;
progesterone-2-nitro-5-hydroxybenzoic acid co-crystal: 17.679, 20.116;
progesterone-9-anthracenecarboxylic acid co-crystal: 10.296, 12.199, 12.460, 15.663, 18.900, 24.701, 27.040;
preferably, the co-crystal also has an X-ray spectrum with characteristic 2 θ values at 2 θ ± 0.2 ° below, respectively:
eutectic crystal of progesterone-2, 4-dihydroxy-5-nitrobenzoic acid: 16.277, 17.482, 18.339, 20.441, 23.802, 26.760;
progesterone-2-nitro-5-hydroxybenzoic acid co-crystal: 11.141, 12.133, 12.701, 16.518, 20.837, 24.839, 26.243, 26.696, 27.941; progesterone-9-anthracenecarboxylic acid co-crystal: 10.640, 14.542, 15.400, 17.660, 19.681, 22.580, 24.282;
preferably, the X-ray powder diffraction pattern of the eutectic of progesterone-2, 4-dihydroxy-5-nitrobenzoic acid is substantially as shown in fig. 1B;
an X-ray powder diffraction pattern of the co-crystal of progesterone-2-nitro-5-hydroxybenzoic acid substantially as shown in fig. 1D;
the X-ray powder diffraction pattern of the progesterone-9-anthracenecarboxylic acid co-crystal is substantially as shown in fig. 1F.
3. The co-crystal of claim 1, wherein the co-crystal comprises endotherms at about the following melting point temperatures:
eutectic crystal of progesterone-2, 4-dihydroxy-5-nitrobenzoic acid: 144.6 ℃;
progesterone-2-nitro-5-hydroxybenzoic acid co-crystal: 104.8 ℃;
progesterone-9-anthracenecarboxylic acid co-crystal: 117.5 ℃;
preferably, the thermogram of the eutectic of progesterone-2, 4-dihydroxy-5-nitrobenzoic acid is substantially as shown in fig. 3A;
the thermogram of the eutectic of progesterone-2-nitro-5-hydroxybenzoic acid is substantially as shown in fig. 3B;
the thermogram of the progesterone-9-anthracenecarboxylic acid co-crystal is substantially as shown in fig. 3C.
4. The co-crystal according to claim 1, characterized in that it comprises the following crystallographic parameters, respectively:
the eutectic of progesterone-2, 4-dihydroxy-5-nitrobenzoic acid is monoclinic system, P21Space group, cell parameter of
α ═ γ ═ 90.00 °, β ═ 105.419(6) °, Z ═ 2, and the unit cell volume is
The eutectic of progesterone-2-nitro-5-hydroxybenzoic acid is orthorhombic, P212121Space group, cell parameter of
α ═ β ═ γ ═ 90.00 °, Z ═ 4, and unit cell volume 2608.4(2)3；
The progesterone-9-anthracenecarboxylic acid eutectic is a triclinic crystal system, P1 space group and unit cell parameters are
A is 84.646(7), β is 85.564(7), γ is 86.670(8), Z is 2, unit cell volume is
5. A process for the preparation of the co-crystal according to any one of claims 1 to 4, comprising:
1) the progesterone and the copolymer are crushed to obtain a white powder sample,
2) adding a white powder sample into an ester solvent for dissolving, and volatilizing to obtain a colorless blocky crystal;
preferably, the solvent is ethyl acetate;
preferably, the molar ratio of progesterone to co-form is 1: 1;
preferably, the progesterone and the co-form are milled using a ball mill.
6. A pharmaceutical composition comprising a co-crystal according to any one of claims 1 to 4.
Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier;
preferably, the administration mode of the pharmaceutical composition comprises oral administration, injection, vaginal administration and transdermal administration.
7. Use of a co-crystal according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 6 in the manufacture of a medicament for maintaining pregnancy.
8. Use of the co-crystal according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 6 for the preparation of a medicament for the prevention and/or treatment of gynaecological disorders.
9. Use according to claim 8, characterized in that the gynaecological disorders comprise spontaneous preterm birth, luteal insufficiency, secondary amenorrhea, premenstrual syndrome.
10. Use of the co-crystal according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 6 for the preparation of a medicament for the prevention and/or treatment of cardiovascular diseases, neurological diseases.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20140235595A1 (en) * | 2012-09-05 | 2014-08-21 | Aptuit, Inc. | Cocrystals of progesterone |
| CN111303230A (en) * | 2020-03-09 | 2020-06-19 | 中国食品药品检定研究院 | A kind of progesterone co-crystal and its preparation method and use |
| CN113292621A (en) * | 2021-05-19 | 2021-08-24 | 国家卫生健康委科学技术研究所 | Pharmaceutical crystal form of progesterone and application thereof |
| CN113683654A (en) * | 2021-09-29 | 2021-11-23 | 国家卫生健康委科学技术研究所 | Preparation and application of progesterone eutectic |
| CN113817012A (en) * | 2021-09-16 | 2021-12-21 | 国家卫生健康委科学技术研究所 | Progesterone eutectic crystal and preparation method and application thereof |
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2022
- 2022-01-25 CN CN202210085842.6A patent/CN114292305A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140235595A1 (en) * | 2012-09-05 | 2014-08-21 | Aptuit, Inc. | Cocrystals of progesterone |
| CN111303230A (en) * | 2020-03-09 | 2020-06-19 | 中国食品药品检定研究院 | A kind of progesterone co-crystal and its preparation method and use |
| CN113292621A (en) * | 2021-05-19 | 2021-08-24 | 国家卫生健康委科学技术研究所 | Pharmaceutical crystal form of progesterone and application thereof |
| CN113817012A (en) * | 2021-09-16 | 2021-12-21 | 国家卫生健康委科学技术研究所 | Progesterone eutectic crystal and preparation method and application thereof |
| CN113683654A (en) * | 2021-09-29 | 2021-11-23 | 国家卫生健康委科学技术研究所 | Preparation and application of progesterone eutectic |
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