CN117338706A - Minoxidil external solution and preparation method thereof - Google Patents
Minoxidil external solution and preparation method thereof Download PDFInfo
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- CN117338706A CN117338706A CN202210743494.7A CN202210743494A CN117338706A CN 117338706 A CN117338706 A CN 117338706A CN 202210743494 A CN202210743494 A CN 202210743494A CN 117338706 A CN117338706 A CN 117338706A
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- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 title claims abstract description 125
- 229960003632 minoxidil Drugs 0.000 title claims abstract description 124
- 238000002360 preparation method Methods 0.000 title abstract description 24
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 156
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 108
- 238000003756 stirring Methods 0.000 claims abstract description 64
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 49
- 238000000034 method Methods 0.000 claims abstract description 40
- 239000012046 mixed solvent Substances 0.000 claims abstract description 13
- 238000002156 mixing Methods 0.000 claims abstract description 11
- 239000002245 particle Substances 0.000 claims description 5
- 229940046530 minoxidil topical solution Drugs 0.000 claims description 4
- 239000003814 drug Substances 0.000 abstract description 42
- 238000004090 dissolution Methods 0.000 abstract description 38
- 229940079593 drug Drugs 0.000 abstract description 28
- 239000013078 crystal Substances 0.000 abstract description 18
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 description 21
- 238000005303 weighing Methods 0.000 description 16
- 238000001556 precipitation Methods 0.000 description 14
- 230000008569 process Effects 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 201000004384 Alopecia Diseases 0.000 description 9
- 238000011835 investigation Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 231100000360 alopecia Toxicity 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 5
- 229940098465 tincture Drugs 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 4
- 239000013065 commercial product Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 230000003779 hair growth Effects 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 229960004039 finasteride Drugs 0.000 description 3
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 3
- 210000004209 hair Anatomy 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 2
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 210000002768 hair cell Anatomy 0.000 description 2
- 208000024963 hair loss Diseases 0.000 description 2
- 230000003676 hair loss Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 239000012466 permeate Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 1
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 241000195940 Bryophyta Species 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 201000002996 androgenic alopecia Diseases 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
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- 238000001816 cooling Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 239000008266 hair spray Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 235000011929 mousse Nutrition 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 229940126532 prescription medicine Drugs 0.000 description 1
- 230000003693 proliferative and anti-apoptotic effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229940107889 rogaine Drugs 0.000 description 1
- 102220042174 rs141655687 Human genes 0.000 description 1
- 208000008742 seborrheic dermatitis Diseases 0.000 description 1
- 230000035946 sexual desire Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229940126673 western medicines Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a minoxidil external solution and a preparation method thereof, wherein the method comprises the following steps: (1) Mixing propylene glycol, ethanol and water, and stirring to obtain a first mixed solvent; (2) The first mixed solvent is mixed with minoxidil and stirred so as to obtain minoxidil external solution. The method well solves the problem of difficult dissolution of minoxidil bulk drug, and the obtained sample has good stability, is suitable for mass production, has low requirements on equipment, is safer and more environment-friendly, and is universally suitable for minoxidil bulk drugs with different crystal forms.
Description
Technical Field
The invention belongs to the technical field of medicines for treating alopecia, and particularly relates to minoxidil external solution and a preparation method thereof.
Background
There are various causes of alopecia: androgenic alopecia, seborrheic dermatitis, life pressure, environmental factors, etc., and the demand for hair-growth and consumption is exponentially increasing and the trend of younger. The number of Chinese alopecia is over 2.5 hundred million, over 1 time in the United states and over 7 times in Japan. Although hair-planting methods are currently available, they are not beneficial to most hair loss groups due to their "surgical" nature, high cost. With reference to the Japanese anti-drop market, which has tended to be stable in the market classification, hair planting only accounts for 5% of the market share, and washing and caring medicines reach 60% to 70%.
At present, only two western medicines of minoxidil and finasteride are used as ingredients with definite effects of treating alopecia and promoting hair growth, wherein the finasteride is a prescription medicine, and the minoxidil is an over-the-counter medicine. Minoxidil has relatively little side effects, except that it may have a severe period of hair loss in the later stages of use. Finasteride is effective but has the side effect of reducing sexual desire in the initial stage of use. The hair tonic product which can be seen in the market mostly contains minoxidil as an active ingredient. In countries and regions such as the united states, the european state, and japan, there are forms such as minoxidil solutions, tinctures, and aerosol foams that are marketed according to drug administration, and there are cases such as topical hair sprays and mousses that are marketed according to daily chemicals administration. The raw product is available in the united states under the trade name ROGAINE as a tablet, aerosol foam, and solution. There are two types of solutions for external use, one for male (MEN' S)EXTRA STRENGTH UNSCENTED) for female (WOMEN' S->Uncovered). The original ground product is not marketed in China, and the dosage forms marketed in China are tincture, spray, liniment and gel.
Minoxidil (Minoxidil) has been found in clinical practice to increase hair growth, stimulate hair growth to a certain extent, and treat alopecia, and has therapeutic effect on various types of alopecia. Minoxidil promotes survival of human skin papillary cells (DPC) or hair cells by activating extracellular signal-regulated kinases (ERK) and Akt and preventing cell death by increasing the ratio of BCl-2/Bax. Minoxidil may stimulate the growth of human hair by prolonging the growth phase by extending the proliferative and anti-apoptotic effects on DPC. Minoxidil, when used as a vasodilator, acts by opening potassium channels in vascular smooth muscle cells that are sensitive to adenosine triphosphate. Such vasodilation may also improve the viability of hair cells or follicles.
The minoxidil is almost insoluble, and has a certain difficulty in achieving complete dissolution in the process of preparing tincture, and the stability of minoxidil can be deteriorated with the increase of temperature. In the prior art, the process of preparing the minoxidil tincture is generally to dissolve minoxidil raw material medicine by adopting propylene glycol, and then sequentially adding ethanol and water for volume fixing. However, the dissolution time is longer, the basic dissolution time of the raw material medicine is about 5 hours, the preparation method has high requirement on minoxidil raw material medicine, and when the preparation method is combined with three available minoxidil raw material medicines on the market, only one raw material medicine (crystal form B) is dissolved in 5 hours and the other two raw material medicines (amorphous) are stirred at normal temperature for 7 hours and still are not dissolved; the technology has too great dependence on the crystal form of the raw material medicine, and cannot be widely applied to the preparation of minoxidil tincture. The preparation method of minoxidil tincture in the prior art comprises heating propylene glycol to above 50deg.C, adding minoxidil, dissolving, stirring at room temperature for about 30-40 min to dissolve, and sequentially adding ethanol and water to constant volume. However, the preparation temperature of the method is too high, and the prepared sample has poor stability.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the related art to some extent. Therefore, the invention aims to provide the minoxidil external solution and the preparation method thereof, which well solve the problem of difficult dissolution of minoxidil bulk drug, and the obtained sample has good stability, is suitable for mass production, has low requirements on equipment, is safer and more environment-friendly, and is universally applicable to minoxidil bulk drugs with different crystal forms.
In one aspect of the present invention, a method of preparing a minoxidil topical solution is provided. According to an embodiment of the invention, the method comprises:
(1) Mixing propylene glycol, ethanol and water, and stirring to obtain a first mixed solvent;
(2) The first mixed solvent is mixed with minoxidil and stirred so as to obtain minoxidil external solution.
Compared with the prior art, the method for preparing the minoxidil external solution adopts normal-temperature environment, reduces material heating steps in the production process, has low requirements on production equipment, reduces energy consumption, is beneficial to environmental protection, and has better stability of prepared samples. Meanwhile, compared with the preparation steps of sequentially adding propylene glycol, minoxidil, ethanol and water in the prior art, the preparation method has the advantages that the preparation process is simplified, the production process is simpler and more convenient, equipment does not need to be opened for multiple times in the preparation process, the possibility of ethanol volatilization is reduced, and the method is safer and more environment-friendly; the preparation method has small tolerance to minoxidil bulk drug, is suitable for preparing minoxidil bulk drug of different crystal forms available in the market at present, and has wide application range. In conclusion, the method can well prepare the sample with good stability, and is wide in application range, low in equipment requirement, simple and convenient to operate, safer and more environment-friendly.
In addition, the method for preparing minoxidil external solution according to the above embodiment of the present invention may further have the following additional technical features:
in some embodiments of the invention, the mass ratio of minoxidil, the propylene glycol, the ethanol, and the water is (4.5-5.5): (49.3-54.5): (24.4-27.0): (16.8-24.6).
In some embodiments of the invention, the mass ratio of minoxidil, the propylene glycol, the ethanol, and the water is (4.5-5.5): (51.5-52.5): (25-26): (15-16).
In some embodiments of the invention, the minoxidil, the propylene glycol, the ethanol, and the water are present in a mass ratio of 5:51.9:25.7:15.7.
in some embodiments of the invention, the minoxidil has a particle size D90 of no more than 400 μm.
In some embodiments of the invention, in step (2), the stirring temperature is from 10 ℃ to 40 ℃.
In some embodiments of the invention, in step (2), the stirring time is 2-5 hours.
In some embodiments of the invention, in step (1), the stirring temperature is from 10 ℃ to 40 ℃.
In a second aspect of the present invention, the present invention provides a minoxidil external solution. According to the embodiment of the invention, the minoxidil external solution is prepared by adopting the method described in the embodiment. Therefore, the minoxidil external solution prepared by the method has good stability.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
Embodiments of the present invention are described in detail below, examples of which are shown, wherein the same or similar reference numerals denote the same or similar elements or elements having the same or similar functions throughout. The following examples are illustrative by reference to the description, which are intended to be illustrative of the invention and are not to be construed as limiting the invention.
In one aspect of the present invention, a method of preparing a minoxidil topical solution is provided. According to an embodiment of the invention, the method comprises:
s100: mixing propylene glycol, ethanol and water, and stirring
In this step, propylene glycol, ethanol and water are mixed and stirred to obtain a first mixed solvent. The stirring rate in this step is not particularly limited as long as propylene glycol, ethanol and water can be uniformly mixed.
According to one embodiment of the invention, the stirring temperature in this step is 10-40 ℃, which if too high affects the stability of minoxidil in the subsequent steps.
S200: mixing the first mixed solvent with minoxidil, and stirring
In this step, the first mixed solvent is mixed with minoxidil and stirred so as to obtain minoxidil external solution. The stirring rate in this step is not particularly limited as long as minoxidil can be completely dissolved in the first mixed solvent.
The minoxidil is generally commercially available and is also referred to as minoxidil drug substance.
According to a further specific embodiment of the present invention, the mass ratio of minoxidil, propylene glycol, ethanol and water is (4.5-5.5): (49.3-54.5): (24.4-27.0): (16.8-24.6), preferably, the mass ratio of minoxidil, propylene glycol, ethanol and water is (4.5-5.5): (51.5-52.5): (25-26): (15-16), thereby limiting the mass ratio of the substances to the above range, further facilitating the rapid and sufficient dissolution of minoxidil raw material medicines of different crystal forms in the first mixed solvent at normal temperature, thereby preparing a sample with good stability without causing safety problems. The inventor finds that if the content of the propylene glycol is too small, the main drug (namely minoxidil) cannot be completely dissolved or the dissolution time is prolonged, and if the content of the propylene glycol is too large, the raw drug (namely minoxidil) can permeate the skin too quickly, so that the safety problem is caused; if the content of the ethanol is too low, the ethanol can not be completely dissolved or the dissolution time is prolonged, and if the content of the ethanol is too high, the raw material medicine can permeate the skin too quickly, so that the safety problem is caused; if the water content is too low, it will correspondingly result in too much propylene glycol and/or ethanol content, and if the water content is too high, it will correspondingly result in too little propylene glycol and/or ethanol content.
According to a further specific embodiment of the present invention, the mass ratio of minoxidil, propylene glycol, ethanol and water is 5:51.9:25.7:15.7, thereby being further beneficial to the quick and sufficient dissolution of minoxidil bulk drugs with different crystal forms in the first mixed solvent at normal temperature, so as to prepare a sample with good stability, and the safety problem cannot be caused.
According to another specific embodiment of the present invention, the particle size D90 of minoxidil is not more than 400 μm, so that it is further advantageous that minoxidil raw material medicines of different crystal forms can be rapidly and sufficiently dissolved in the first mixed solvent at normal temperature, and no precipitation phenomenon occurs after cooling to room temperature, thereby preparing a sample with good stability.
According to a further embodiment of the invention, the stirring temperature in this step is between 10℃and 40℃and if the temperature is too low, dissolution of minoxidil is not favored and if the temperature is too high, stability of minoxidil is affected.
According to another embodiment of the invention, the stirring time of the step is 2-5 hours, so that minoxidil is completely dissolved in the stirring time range, the crystallization condition of the obtained minoxidil external solution during taking is improved, and compared with the prior art, the stirring time of the step is shorter, a large amount of manpower and material resources are saved, and the mass production is facilitated.
Compared with the prior art, the method for preparing the minoxidil external solution adopts normal-temperature environment, reduces material heating steps in the production process, has low requirements on production equipment, reduces energy consumption, is beneficial to environmental protection, and has better stability of prepared samples. Meanwhile, compared with the preparation steps of sequentially adding propylene glycol, minoxidil, ethanol and water in the prior art, the preparation method has the advantages that the preparation process is simplified, the production process is simpler and more convenient, equipment does not need to be opened for multiple times in the preparation process, the possibility of ethanol volatilization is reduced, and the method is safer and more environment-friendly; the preparation method has small tolerance to minoxidil bulk drug, is suitable for preparing minoxidil bulk drug of different crystal forms available in the market at present, and has wide application range. In conclusion, the method can well prepare the sample with good stability, and is wide in application range, low in equipment requirement, simple and convenient to operate, safer and more environment-friendly.
In a second aspect of the present invention, the present invention provides a minoxidil external solution. According to the embodiment of the invention, the minoxidil external solution is prepared by adopting the method described in the embodiment. Therefore, the minoxidil external solution prepared by the method has good stability.
The following detailed description of embodiments of the invention is provided for the purpose of illustration only and is not to be construed as limiting the invention. In addition, all reagents employed in the examples below are commercially available or may be synthesized according to methods herein or known, and are readily available to those skilled in the art for reaction conditions not listed, if not explicitly stated.
Investigation of the addition sequence of the raw materials:
example 1
The preparation method comprises the steps of weighing propylene glycol, ethanol and water according to a prescription, uniformly mixing, adding minoxidil raw material medicine (amorphous) and stirring for dissolution, wherein the temperature of the whole dissolution process is controlled to be constant at 30 ℃, and the minoxidil raw material medicine is completely dissolved within 30 min. The mass ratio of minoxidil to propylene glycol to ethanol to water is 5:51.9:25.7:15.7.
comparative example 1:
weighing propylene glycol with a prescription amount, adding minoxidil raw material medicine (amorphous) into the propylene glycol, stirring and dissolving, adding ethanol and water with the prescription amount, and controlling the temperature at 30 ℃ in the whole dissolving process. The minoxidil raw material medicine is stirred for 7 hours, and obvious dissolution phenomenon is not seen yet. The other contents are the same as in example 1.
Comparative example 2:
weighing the prescription amount of propylene glycol and ethanol, uniformly mixing, adding minoxidil raw material medicine (amorphous) and stirring for dissolution, and then adding the prescription amount of water, wherein the temperature of the whole dissolution process is controlled at constant temperature of 30 ℃, and the raw material medicine is not completely dissolved within 30min and can be completely dissolved within 70 min. The other contents are the same as in example 1.
The quality of minoxidil external solutions prepared in example 1 and comparative examples 1 and 2, respectively, was tested, and the test results are shown in table 1.
TABLE 1
As can be seen from table 1, the addition sequence of example 1 makes dissolution of minoxidil drug substance fastest at the same temperature, and the prepared minoxidil external solution was qualified for all the relevant contents, and after 24 hours of standing, the amount of impurities in minoxidil external solution of example 1 was smaller.
Investigation of stirring temperature at normal temperature
Further examining the influence of temperature on dissolution and solution stability in normal temperature environment (10-30 ℃), and examining the temperature at 10 ℃, 20 ℃ and 30 ℃.
Example 2:
weighing the prescription amount of propylene glycol, ethanol and water, uniformly stirring, and keeping the temperature to 10 ℃; adding minoxidil (amorphous) for dissolving, and stirring at 300rpm for 2.5h to dissolve completely; stirring is continued for 2 hours, and no precipitation phenomenon exists after the mixture is cooled to room temperature. The mass ratio of minoxidil to propylene glycol to ethanol to water is 5:51.9:25.7:15.7.
example 3:
weighing the prescription amount of propylene glycol, ethanol and water, uniformly stirring, and keeping the temperature to 20 ℃; adding minoxidil (amorphous) for dissolving, stirring at 300rpm for 50min to dissolve completely; stirring is continued for 2 hours, and no precipitation phenomenon exists after the mixture is cooled to room temperature. The mass ratio of minoxidil to propylene glycol to ethanol to water is 5:51.9:25.7:15.7.
example 4:
weighing the prescription amount of propylene glycol, ethanol and water, uniformly stirring, and keeping the temperature to 30 ℃; adding minoxidil (amorphous) for dissolving, and stirring at 300rpm for 30min to dissolve completely; stirring is continued for 2 hours, and no precipitation phenomenon exists after the mixture is cooled to room temperature. The mass ratio of minoxidil to propylene glycol to ethanol to water is 5:51.9:25.7:15.7.
the quality of the minoxidil external solutions prepared in examples 2 to 4 was measured, the test results are shown in table 2, and the influence factors of the minoxidil external solutions prepared in examples 2 to 4 were measured, respectively, and the test results are shown in table 3.
TABLE 2
TABLE 3 Table 3
As can be seen from tables 2 and 3, the external minoxidil solutions prepared in examples 2 to 4 all meet the requirements on solution properties, pH values, related contents and influence factors in the process of lofting, and the impurities are not obviously increased.
Investigation of stirring time
Example 5
Weighing propylene glycol, ethanol and water with the prescription amount, uniformly mixing, adding minoxidil raw material medicines (amorphous) and stirring for dissolution, wherein the mass ratio of minoxidil to the propylene glycol to the ethanol to the water is 5:51.9:25.7:15.7, the temperature of the whole dissolution process is controlled to be constant at 30 ℃, the minoxidil raw material medicine is completely dissolved within 30min, and stirring is continued for 0.5h, 1h, 1.5h, 2h and 2.5h. And dipping a small amount of liquid medicine on the glass rod after stirring at each time point, standing the glass rod open to check the precipitation phenomenon of the glass rod, and respectively taking two samples from the upper layer, the middle layer and the lower layer of the solution after stirring at the time points of 1.5h, 2h and 2.5h to detect the mixing uniformity, wherein the detection results are shown in table 4.
TABLE 4 Table 4
As can be seen from Table 4, the longer the stirring time, the less likely the solution adhered to the glass rod is to be devitrified. When stirring for 1.5h, the solution is fully mixed, the content uniformity meets the requirements, but the crystallization phenomenon of the crude drug can slightly occur, and when stirring is carried out for 2-2.5h, no obvious precipitation exists. Compared with the precipitation phenomenon of commercial products, the product is obviously improved and is more stable in use.
High temperature stirring temperature investigation
Example 6
Weighing propylene glycol, ethanol and water with the prescribed amounts, uniformly mixing, adding minoxidil raw material medicines (amorphous) and stirring for dissolution, controlling the temperature in the whole dissolution process at a constant temperature of 40 ℃, and stirring for 15min for complete dissolution; stirring is continued for 2 hours, and no precipitation phenomenon exists after the mixture is cooled to room temperature. The other matters were the same as in example 4.
Comparative example 3
Weighing propylene glycol, ethanol and water with the prescribed amounts, uniformly mixing, adding minoxidil raw material medicines (amorphous) and stirring for dissolution, controlling the temperature in the whole dissolution process at constant temperature of 50 ℃, and stirring for 5min for complete dissolution; stirring is continued for 2 hours, and no precipitation phenomenon exists after the mixture is cooled to room temperature. The other matters were the same as in example 4.
The properties of minoxidil external solutions prepared in examples 4, 6 and comparative example 3 were tested, respectively, and the test results are shown in table 5.
TABLE 5
As can be seen from table 5, the stirring temperature has an accelerating effect on the dissolution of API in terms of the preparation process, the higher the temperature, the faster the dissolution; the preparation method has no obvious influence on the freshly prepared solution, and the relevant solution meets the requirements and is far smaller than the specified limit, but in the long-term storage process, the stability of the sample prepared at 50 ℃ is poor, and the relevant substances are obviously increased when the sample is stored for 1 month, so that the optimal temperature for preparing the product is 10-40 ℃.
Investigation of different crystal forms of bulk drugs
Under the condition of process determination, the crude drugs in different crystal forms and respective dissolution time are examined.
Example 7:
weighing the prescription amount of propylene glycol, ethanol and water, uniformly stirring, and keeping the solvent temperature at 14 ℃; adding minoxidil crude drug of another crystal form (crystal form B, whose crystal patterns show diffraction peaks at 15.63 °, 16.45 °, 19.59 °, 22.58 °, 23.17 °, 24.84 ° and 29.83 °), stirring at 300rpm for 2h to dissolve, stirring for 2h, and packaging. The mass ratio of minoxidil to propylene glycol to ethanol to water is 5:51.90:25.72:15.65.
comparative example 4:
weighing the prescription amount of propylene glycol and the solvent temperature is 14 ℃; adding minoxidil crude drug of another crystal form (crystal form B, whose crystal patterns show diffraction peaks at 15.63 °, 16.45 °, 19.59 °, 22.58 °, 23.17 °, 24.84 ° and 29.83 °), stirring at 300rpm for 4h to dissolve, sequentially adding prescribed amount of ethanol and water, stirring for 2h, and packaging. The mass ratio of minoxidil to propylene glycol to ethanol to water is 5:51.90:25.72:15.65.
TABLE 6
As can be seen from Table 6, the above crude drug of the crystal form B and the amorphous minoxidil crude drug were prepared according to the preparation method of the present invention, the total stirring time was 4 hours, and the relevant contents of the obtained minoxidil external solution were all qualified, but the dissolution time was too long according to the prior art, which was not suitable for production.
Investigation of particle size of crude drug
Example 8:
weighing the prescription amount of propylene glycol, ethanol and water, uniformly stirring, and keeping the temperature to 10 ℃; adding minoxidil (amorphous) for dissolution, stirring at 300rpm for 2.5h for complete dissolution, and stirring for 2h, wherein the minoxidil has no precipitation phenomenon after standing at room temperature. The mass ratio of minoxidil to propylene glycol to ethanol to water is 5:51.9:25.7:15.7.
Example 9:
weighing the prescription amount of propylene glycol, ethanol and water, uniformly stirring, and keeping the temperature to 10 ℃; minoxidil (amorphous) is added for dissolution, the minoxidil has a particle size D90= 19.015 μm, and the minoxidil is stirred at 300rpm for 1 hour for complete dissolution, and the stirring is continued for 2 hours, and no precipitation phenomenon exists after the minoxidil is cooled to room temperature. The mass ratio of minoxidil to propylene glycol to ethanol to water is 5:51.9:25.7:15.7.
Example 10:
weighing the prescription amount of propylene glycol, ethanol and water, uniformly stirring, and keeping the temperature to 10 ℃; adding minoxidil (amorphous) for dissolution, stirring at 300rpm for 3h to dissolve completely, stirring for 2h, and standing at room temperature without precipitation. The mass ratio of minoxidil to propylene glycol to ethanol to water is 5:51.9:25.7:15.7.
it can be seen that the dissolution time of example 10 is longer compared to examples 7 and 8.
Prescription dose investigation
Example 11:
weighing the prescription amount of propylene glycol, ethanol and water, and uniformly stirring at normal temperature; minoxidil (amorphous) was added for dissolution, and stirred at 300rpm for 5 hours, the solution was clear and transparent and had no precipitation phenomenon after leaving to stand at room temperature. The mass ratio of minoxidil to propylene glycol to ethanol to water is 5:49.3:24.4:24.6.
example 12:
weighing the prescription amount of propylene glycol, ethanol and water, and uniformly stirring at normal temperature; minoxidil (amorphous) was added for dissolution, and stirred at 300rpm for 5 hours, the solution was clear and transparent and had no precipitation phenomenon after leaving to stand at room temperature. The mass ratio of minoxidil to propylene glycol to ethanol to water is 5:54.5:27.0:16.8.
TABLE 7
As can be seen from Table 7, the samples prepared by the above prescription have no obvious difference in dissolution time, and the prepared minoxidil external solution has acceptable properties, pH value and related content.
For the formulation product obtained in example 1 and commercially availableProduct MEN' SEXTRA STRENGTH UNSCENTED A transdermal test was performed to obtain a release rate per unit area (ng/cm 2 The test result data of/h) are shown in Table 7. Wherein 1-6 are 6 groups of parallel experiments.
TABLE 8
As can be seen from table 8, the ratio of the average value of the cumulative release rate per unit area at each time point of the formulation product of example 1 was between 70% and 130% compared to the commercial product, indicating that the product was comparable to the commercial product, and the standard deviation of the relative standard was smaller than the commercial product, indicating that the product was more stable than the commercial product.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (9)
1. A method of preparing minoxidil in an external solution, comprising:
(1) Mixing propylene glycol, ethanol and water, and stirring to obtain a first mixed solvent;
(2) The first mixed solvent is mixed with minoxidil and stirred so as to obtain minoxidil external solution.
2. The method according to claim 1, wherein the mass ratio of minoxidil, propylene glycol, ethanol, and water is (4.5-5.5): (49.3-54.5): (24.4-27.0): (16.8-24.6).
3. The method according to claim 1, wherein the mass ratio of minoxidil, propylene glycol, ethanol, and water is (4.5-5.5): (51.5-52.5): (25-26): (15-16).
4. The method according to claim 1, wherein the mass ratio of minoxidil, propylene glycol, ethanol, and water is 5:51.9:25.7:15.7.
5. the method of any one of claims 1-4, wherein the minoxidil has a particle size D90 of no greater than 400 μιη.
6. The method according to claim 5, wherein in the step (2), the stirring temperature is 10 to 40 ℃.
7. The method according to claim 6, wherein in the step (2), the stirring time is 2 to 5 hours.
8. The method according to any one of claims 1 to 4, wherein in step (1), the stirring temperature is 10 ℃ to 40 ℃.
9. A minoxidil topical solution, characterized in that the minoxidil topical solution is prepared by the method of any one of claims 1 to 7.
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