CN113444049A - Minoxidil-gallate crystal form for treating alopecia and preparation method thereof - Google Patents
Minoxidil-gallate crystal form for treating alopecia and preparation method thereof Download PDFInfo
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- CN113444049A CN113444049A CN202110901428.3A CN202110901428A CN113444049A CN 113444049 A CN113444049 A CN 113444049A CN 202110901428 A CN202110901428 A CN 202110901428A CN 113444049 A CN113444049 A CN 113444049A
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- 239000013078 crystal Substances 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 201000004384 Alopecia Diseases 0.000 title abstract description 8
- 231100000360 alopecia Toxicity 0.000 title abstract description 7
- LNTHITQWFMADLM-UHFFFAOYSA-N anhydrous gallic acid Natural products OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 claims abstract description 32
- 229960003632 minoxidil Drugs 0.000 claims abstract description 32
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 claims abstract description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229940074391 gallic acid Drugs 0.000 claims abstract description 16
- 235000004515 gallic acid Nutrition 0.000 claims abstract description 16
- -1 minoxidil cation Chemical class 0.000 claims abstract description 6
- 230000003993 interaction Effects 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000012153 distilled water Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 15
- 229940079593 drug Drugs 0.000 abstract description 10
- 238000010171 animal model Methods 0.000 abstract 1
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 230000002335 preservative effect Effects 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 3
- 230000003779 hair growth Effects 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 210000004209 hair Anatomy 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- ZIMGGGWCDYVHOY-UHFFFAOYSA-N 3-hydroxy-2-imino-6-(1-piperidinyl)-4-pyrimidinamine Chemical compound N=C1N(O)C(N)=CC(N2CCCCC2)=N1 ZIMGGGWCDYVHOY-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 235000014220 Rhus chinensis Nutrition 0.000 description 1
- 240000003152 Rhus chinensis Species 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000000712 assembly Effects 0.000 description 1
- 238000000429 assembly Methods 0.000 description 1
- 230000003592 biomimetic effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 210000000442 hair follicle cell Anatomy 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 230000008338 local blood flow Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- LPUQAYUQRXPFSQ-DFWYDOINSA-M monosodium L-glutamate Chemical compound [Na+].[O-]C(=O)[C@@H](N)CCC(O)=O LPUQAYUQRXPFSQ-DFWYDOINSA-M 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 239000004223 monosodium glutamate Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/50—Three nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
本发明涉及一种用于治疗脱发的米诺地尔‑没食子酸盐晶型及其制备方法。米诺地尔‑没食子酸盐晶型由1个米诺地尔阳离子、1个没食子酸阴离子和2个水分子通过离子键和氢键相互作用组合生成；晶体结构属于单斜晶系，空间群为P21/n，其轴长a=9.118~10.118Å，b=9.777~10.777Å，c=18.528~19.528Å，轴角α=γ=90°，β=90.054~91.054°。动物模型证实本发明制备的米诺地尔新晶型的治疗效果优于原药。
The present invention relates to a crystal form of minoxidil-gallate for treating alopecia and a preparation method thereof. The crystal form of minoxidil-gallate is formed by the combination of 1 minoxidil cation, 1 gallic acid anion and 2 water molecules through the interaction of ionic bonds and hydrogen bonds; the crystal structure belongs to the monoclinic system, space group is P 2 1 / n , its axis length a = 9.118~10.118Å, b = 9.777~10.777Å, c =18.528~19.528Å, the axis angles α = γ =90°, β =90.054~91.054°. The animal model proves that the therapeutic effect of the new crystal form of minoxidil prepared by the present invention is better than that of the original drug.
Description
Technical Field
The invention relates to the technical field of drug crystal forms, in particular to a minoxidil-gallate crystal form for treating alopecia and a preparation method thereof.
Background
In 2016, the Nobel prize was awarded a second time to three researchers Jean-Pierre Sauvage, Sir J. Fraser Stoddart, and Bernard L. Ferraga who contributed well in the field of supramolecular chemistry. Supramolecular chemistry is the chemistry of molecular aggregates formed based on non-covalent interactions between molecules, which are bound together by supramolecular interactions and can form new chemical entities with better physicochemical properties. Currently, supramolecular chemistry has been applied to the fields of layered supramolecular assemblies, biological and biomimetic microsystems, and the like. In the field of pharmacy, supramolecular chemistry is widely applied to the development of drug crystal forms. The supermolecule chemical technology means can combine the active components of the medicine with other molecules to generate supermolecule compounds, such as medicine salts and medicine eutectics. The idea that the poor physical properties and the undesirable treatment effects of the active ingredients of the drugs can be effectively improved through the modification of the supramolecular structure is gradually a hot spot of attention in the pharmaceutical field.
Minoxidil is an antihypertensive drug collected by Chinese pharmacopoeia and used as a potassium ion channel opener, and can promote local blood circulation and stimulate the proliferation and differentiation of hair follicle cells, so that minoxidil is widely applied to clinic as a first-line drug for treating alopecia. Gallic acid is the earliest organic acid produced in the world and is also one of the active ingredients of Chinese gall. In the theory of traditional Chinese medicine, gallnut monosodium glutamate can treat heat sores of head sores, so that gallic acid serving as an active ingredient can be used for treating skin diseases and has antibacterial and antiviral effects. The gallic acid structure contains three adjacent phenolic hydroxyl groups, and intramolecular and intermolecular hydrogen bonds with different structure types can be formed, so that more possibilities are provided for the gallic acid to form supramolecular compounds with other molecules. The existing minoxidil product has the defects of poor curative effect, strong side effect and the like. The supermolecule chemistry is taken as theoretical guidance, the minoxidil and the gallic acid are self-assembled to prepare the minoxidil crystal form drug, and a foundation is provided for developing a novel minoxidil external preparation.
Disclosure of Invention
The invention aims to provide a minoxidil-gallate crystal form for treating alopecia and a preparation method thereof.
The minoxidil is used as a medicine active component, the chemical name of the minoxidil is 6- (1-piperidyl) -2, 4-pyrimidinediamine-3-oxide, and the molecular formula of the minoxidil is C9H15N5O, the structure is shown in figure a. Selecting gallic acid as salt forming reagent with chemical name of 3,4, 5-trihydroxybenzoic acid and molecular formula C7H6O5The structure is shown in figure b.
The minoxidil-gallate crystal form has the following characteristics.
The minoxidil-gallate crystal form basic structural unit is formed by passing 1 minoxidil cation, 1 gallic acid anion and 2 water moleculesIon bond and hydrogen bond interaction, the crystal structure belongs to monoclinic system, and the space group isP21/nAxial length ofa = 9.118~10.118 Å，b = 9.777~10.777 Å，c=18.528~ 19.528A, axial angleα = γ = 90°，β = 90.054~91.054°。
The preparation method of the minoxidil-gallate crystal form is a heating-room temperature volatilization crystallization method, and the steps are as follows.
(1) Dissolving minoxidil and gallic acid at a molar ratio of 1:1 in a certain amount of solvent selected from distilled water, methanol, ethanol, and water,N,NOne or more than one of dimethylformamide, and the concentration of the minoxidil in the final reaction system is 1-6 mg/mL.
(2) Stirring the reaction solution under a heating condition for 0.5-2 hours at the reaction temperature of 30-70 ℃, and filtering the reaction solution by using medium-speed filter paper after reaction.
(3) Standing the solution at room temperature for 6-48 hours to separate out light yellow blocky crystals, namely the minoxidil-gallate crystal form.
The minoxidil-gallate crystal form prepared by the invention has better treatment effect than minoxidil raw drug and has the potential of treating alopecia.
The instrument for detecting the minoxidil-gallate crystal form structure is as follows.
The single crystal structure was measured using a Bruker APEX II type X-ray single crystal diffractometer.
Drawings
Figure 1 is a structural diagram of a minoxidil-gallate crystal form.
Fig. 2 is a graph showing the effects of minoxidil bulk drug and minoxidil-gallate crystal form on promoting hair growth on the back of mice.
Detailed Description
The invention is further described below with reference to specific examples, but is not limited thereto.
Example 1.
(1) Weighing 20.0 mg of minoxidil and 18.9 mg of gallic acid, mixing and dissolving in 20 mL of distilled water, placing in a 100 mL round bottom flask after mixing, and installing a reflux device.
(2) The reaction was stirred in a water bath at 70 ℃ for 0.5 h and the solid completely dissolved.
(3) Filtering the reaction solution by using medium-speed filter paper, placing the filtrate in a 50 mL beaker, covering the cup mouth with a preservative film, pricking 6 small mouths by using a 10 mL syringe, standing for crystallization, and separating out a light yellow blocky crystal after about 6 hours to obtain the minoxidil-gallate crystal form.
Example 2.
(1) 420.3 mg of minoxidil and 339.6 mg of gallic acid were weighed and placed in a 200 mL round-bottomed flask, 60 mL of distilled water and 10 mL of ethanol were added, and a reflux apparatus was installed.
(2) The reaction was stirred in a water bath at 50 ℃ for 1 hour and the solid completely dissolved.
(3) Filtering the reaction solution by using medium-speed filter paper, placing the filtrate in a 100 mL beaker, covering the opening of the beaker with a preservative film, pricking 7 small openings by using a 10 mL syringe, and standing for crystallization. The light yellow blocky crystal is separated out after about 24 hours, and is a minoxidil-gallate crystal form.
Example 3.
(1) 415.5 mg of minoxidil and 342.9 mg of gallic acid were weighed and placed in a 500 mL round-bottomed flask, 150 mL of distilled water and 30 mL of methanol were added, and a reflux apparatus was installed.
(2) The reaction was stirred in a water bath at 40 ℃ for 1 hour and the solid completely dissolved.
(3) Filtering the reaction solution by using medium-speed filter paper, placing the filtrate in a 250 mL beaker, covering the opening of the beaker with a preservative film, pricking 3 small openings by using a 10 mL syringe, and standing for crystallization. The light yellow blocky crystal is separated out after about 48 hours, and is a minoxidil-gallate crystal form.
Example 4.
(1) 620.4 mg of minoxidil and 512.7 mg of gallic acid are weighed into a 250 mL round bottom flask, and 120 mL of water, 20 mL of methanol and 10 mL of gallic acid are addedN,NDimethylformamide, reflux unit installed.
(2) The reaction was stirred in a water bath at 60 ℃ for 2 hours and the solid completely dissolved.
(3) Filtering the reaction solution by using medium-speed filter paper, placing the filtrate in a 200 mL beaker, covering the opening of the beaker with a preservative film, pricking 5 small openings by using a 10 mL syringe, and standing for crystallization. The light yellow blocky crystal is separated out after about 48 hours, and is a minoxidil-gallate crystal form.
Example 5.
(1) 40.2 mg of minoxidil and 34.3 mg of gallic acid were weighed and placed in a 50 mL round-bottomed flask, 20 mL of distilled water was added, and a reflux apparatus was installed.
(2) The reaction was stirred in a water bath at 30 ℃ for 0.5 h and the solid completely dissolved.
(3) Filtering the reaction solution by using medium-speed filter paper, placing the filtrate in a 50 mL beaker, covering the cup mouth with a preservative film, pricking 7 small mouths with a 10 mL syringe, standing for crystallization, and separating out a light yellow blocky crystal after about 12 hours to obtain the minoxidil-gallate crystal form.
Effect example 1.
The minoxidil-gallate crystal form obtained in the example is subjected to X-ray single crystal diffraction characterization, and the test is carried out on an APEX II type X-ray single crystal diffractometer of Bruker company in Germany by adopting Mo rays monochromatized by a graphite monochromator. The structure is solved by a direct method by adopting a SHELL XT-2013 program, and the refinement is carried out by a full matrix least square method by adopting a SHELL XL-2018 program. The hydrogen atoms attached to the oxygen atoms were found in difference fourier plots, a saddle conformation refinement, and other hydrogen atom coordinates were calculated as C-H = 0.93 a (aromatic ring) and 0.97 a (methylene). The crystallographic parameters of the minoxidil-gallate crystal form are shown in the table, and the crystal structure is shown in figure 1.
Effect example 2.
2 male Kunming mice and 2 female Kunming mice were selected, anesthetized with ether, shaved on their backs, and depilated with wax. Respectively preparing 8 mmol/L minoxidil technical and the same concentration minoxidil-gallate crystal form physiological saline solution. The back skin of the mouse is evenly divided into a left area, a middle area and a right area, wherein the left area, the middle area and the right area are respectively and locally coated with 8 mmol/L minoxidil normal saline solution, 8 mmol/L normal saline solution and 8 mmol/L minoxidil-gallate crystal form normal saline solution for 2 times a day for 2 weeks. The hair growth on the back of the mice was recorded by daily photographs and representative results are shown in figure 2. According to the results, the back skin hairs of the minoxidil-gallate crystal form treatment group grow more and more densely than the hairs of the minoxidil treatment group and the normal saline treatment group, so that the effect of promoting the hair growth of mice by using the prepared minoxidil-gallate crystal form is better than that of a minoxidil raw drug, and the prepared minoxidil salt crystal form has a better treatment effect than that of the minoxidil raw drug. Compared with the existing minoxidil preparation, the preparation prepared by taking the minoxidil-gallate crystal form as the active ingredient can play a role in treatment at a lower concentration, the use of irritant organic solvents is reduced by reducing the concentration of minoxidil in the preparation, the problem that the existing minoxidil preparation irritates the skin is solved, and a new thought is provided for the development of hair loss resistant pharmaceutical preparations.
Claims (2)
1. A minoxidil-gallate crystal form, characterized in that: the minoxidil-gallate crystal form basic structural unit is generated by combining 1 minoxidil cation, 1 gallic acid anion and 2 water molecules through ionic bond and hydrogen bond interaction; the crystal structure of the minoxidil-gallate crystal form belongs to a monoclinic system, and the space group isP21/nAxial length ofa = 9.118~10.118 Å，b = 9.777~10.777 Å，c=18.528~ 19.528A, axial angleα = γ = 90°，β= 90.054~91.054°。
2. The method of preparing the crystalline form of minoxidil-gallate of claim 1, comprising the steps of:
(1) dissolving minoxidil and gallic acid at a molar ratio of 1:1 in a certain amount of solvent selected from distilled water, methanol, ethanol, and water,N,NIn dimethylformamideThe concentration of the minoxidil in the final reaction system is 1-6 mg/mL;
(2) stirring the reaction solution for 0.5-2 hours under a heating condition, wherein the reaction temperature is 30-70 ℃, and filtering the reaction solution by using medium-speed filter paper after reaction;
(3) standing the solution at room temperature for 6-48 hours to separate out light yellow blocky crystals, namely the minoxidil-gallate crystal form.
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| NATE SCHULTHEISS ET AL: "Attempted construction of minoxidil: carboxylic acid cocrystals; 7 salts and 1 cocrystal resulted", 《CRYSTENGCOMM》 * |
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Application publication date: 20210928 |