CN113116891A - Emulsifiable paste and preparation method thereof - Google Patents
Emulsifiable paste and preparation method thereof Download PDFInfo
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A—HUMAN NECESSITIES
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- 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
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- 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
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- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a preparation method of a cream and the prepared cream. The preparation method mainly comprises the step of directly dissolving tazarotene and betamethasone dipropionate in the melted oil phase, so that the problems of recrystallization and hydrolysis caused by adding an organic solvent into an oil-in-water cream substrate are avoided, the physical and chemical stability of the tazarotene and betamethasone dipropionate is further improved, the transportation and storage cost is reduced, and the evaluation and management of the medicaments are facilitated.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a preparation method of tazarotene betamethasone cream and the prepared tazarotene betamethasone cream.
Background
The tazarotene betamethasone cream is a compound preparation for treating psoriasis, contains tazarotene and betamethasone dipropionate, is a brand new compound preparation consisting of 0.05 percent of tazarotene and 0.05 percent of betamethasone dipropionate (counted by betamethasone), and is mainly used for treating psoriasis vulgaris.
Tazarotene is a third-generation vitamin A acid medicament, has special effect on plaque psoriasis vulgaris, is quickly degreased in vivo after being administered, is converted into an active component tazarotenic acid, is selectively combined with a vitamin A acid receptor, and is targeted to diseased tissues to adjust cell differentiation, anti-proliferation and anti-inflammation; betamethasone dipropionate is a fat-soluble glucocorticoid drug; the clinical research results show that the synergistic effect of the tazarotene and the betamethasone dipropionate is enhanced at the concentration, the skin atrophy caused by glucocorticoid can be relieved without inhibiting the anti-inflammatory effect, and the irritation of the tazarotene can be reduced without affecting the curative effect. In the field of clinical dermatology, the tazarotene cream and the betamethasone dipropionate cream are widely used in combination.
The tazarotene betamethasone cream is a brand new compound preparation, the two medicines are esters, are insoluble in water and easy to hydrolyze, and the prepared o/w cream is easy to recrystallize or hydrolyze, so that the problems of uneven content, increased impurities and the like are caused. Meanwhile, because the cream has poor stability, the storage temperature is usually controlled to be 20-25 ℃, which has strict requirements on the actual transportation and storage conditions of the medicine. Therefore, in order to solve the above problems, further research on a preparation method of tazarotene betamethasone cream is needed.
Disclosure of Invention
In view of the above, an object of the present invention is to provide a method for preparing a cream with a main drug that is not easily recrystallized and hydrolyzed.
The active ingredients of the tazarotene betamethasone cream are tazarotene and betamethasone dipropionate, and the two medicines are esters, are soluble in an organic solvent, are insoluble in water and are easy to hydrolyze. In the prior art, the cream for preparing the insoluble medicine generally adopts a solvent such as propylene glycol or polyethylene glycol to dissolve a main medicine, and then is added into a cream matrix to be uniformly mixed. Although the problems of medicine addition and dispersion are solved, the medicine is in a partially dissolved state and a partially suspended state in a cream matrix, and the problems of medicine recrystallization and hydrolysis are easy to occur in long-term storage, so that the content uniformity and the stability of the cream are influenced. The preparation method provided by the invention can effectively solve the problem.
In order to achieve the purpose, the invention adopts the following scheme:
the preparation method of the tazarotene betamethasone cream is characterized in that tazarotene and betamethasone dipropionate are directly dissolved in a melted oil phase.
The oil phase comprises natural fatty alcohol, liquid paraffin, glycerol polyethylene glycol-75 stearate, peregal A-20, glyceryl monostearate and vitamin E.
Specifically, the drug is dissolved with molten natural fatty alcohol and liquid paraffin, and then mixed with the rest of the molten oil phase components.
The inventor finds in research that if the medicine is dissolved by using any one of the oil phase components alone, the medicine cannot be completely dissolved even being heated for 3 hours at 85-95 ℃; if the drug is dissolved after all the oil phase is melted, the mixture is heated and stirred at 85-95 ℃ for about 1.5 h. Dissolution at high temperatures for long periods of time increases the risk of drug stability. The inventor finds that the medicine is dissolved by the melted natural fatty alcohol and the liquid paraffin firstly, and then is added into the other melted oil phase components for mixing, so that the medicine dissolving temperature can be reduced, the medicine heating and dissolving time can be obviously shortened, and the medicine stability in the process can be improved. Meanwhile, the liquid paraffin and the natural fatty alcohol are mixed and melted, so that the viscosity of the medicine-containing liquid can be obviously reduced, the medicine loss caused by the fact that the viscous liquid is adhered to the wall and the pipeline of the container in the material transfer process is reduced, and the content of the main medicine in the finished product is guaranteed. The insoluble drug is successfully dissolved in the oil phase to prepare the oil-in-water type emulsifiable paste, so that the drug presents a good dissolved state in an emulsifiable paste matrix, the phenomenon of recrystallization or crystallization which is easy to occur in the long-term storage process of the suspension drug is avoided, meanwhile, the main drug is dissolved in the oil phase, the occurrence of hydrolysis can be reduced, and the emulsifiable paste has more stable quality.
Further, the preparation method comprises the following steps:
1) preparing an oil phase, and dissolving tazarotene and betamethasone dipropionate in the melted oil phase;
2) preparing a water phase, homogenizing and emulsifying the water phase and the oil phase obtained in the step 1), and homogenizing again;
3) cooling the preparation after homogenizing in the step 2) to obtain a cream intermediate.
Further, the steps also comprise the steps of inspecting the cream intermediate product, encapsulating after the cream intermediate product is inspected to be qualified, directly encapsulating the cream by adopting an aluminum pipe, inspecting the finished product obtained by encapsulation, and warehousing, storing and managing after the cream intermediate product is inspected to be qualified.
Further, the step 1) is specifically that tazarotene and betamethasone dipropionate are dissolved in molten natural fatty alcohol and liquid paraffin, and then mixed with a molten mixed oil phase of glycerol polyethylene glycol-75 stearate, peregal A-20, glyceryl monostearate and vitamin E.
Further, the dissolving temperature is 75-85 ℃, and the total dissolving time is 20-50 min.
Specifically, in order to prevent the formation of unnecessary impurities during the production, the dissolution temperature and time are adjusted to achieve the best production effect.
Further, the water phase in the step 2) is prepared from purified water, glycerol, disodium hydrogen phosphate dodecahydrate, sodium dihydrogen phosphate monohydrate, potassium sorbate, disodium edetate and sodium bisulfite.
Further, the emulsifier in the step 2) is glycerol polyethylene glycol-75 stearate and peregal A-20, and the mass ratio of the glycerol polyethylene glycol-75 stearate to the peregal A-20 is 1: 1.5-2.
Specifically, the glycerol polyethylene glycol-75 stearate is a nonionic O/W type emulsifier, has excellent thermal stability and pH tolerance, and has an HLB value of 10; the peregal A-20 is a non-ionic O/W type emulsifier, has the HLB value of 15, and has the advantages of high stability, good water solubility, electrolyte resistance and small foam. The two emulsifiers are used together, so that the compatibility is good, the salt resistance is strong, the emulsifying effect is good, and the cream body of the emulsifiable paste is soft and exquisite and comfortable to apply.
Further, the sodium dihydrogen phosphate monohydrate and the disodium hydrogen phosphate dodecahydrate are buffer pairs, and the mass ratio of the sodium dihydrogen phosphate monohydrate to the disodium hydrogen phosphate dodecahydrate is 3.1: 0.5.
Specifically, because tazarotene and betamethasone dipropionate are both ester drugs and are easy to hydrolyze, the pH value of the product is maintained in a relatively stable range by using a buffer pair, and the risk of degradation of the product in the long-term storage process can be reduced. The inventor conducts screening and a large number of experiments on the buffer pair used in the water phase, and finds that when sodium dihydrogen phosphate monohydrate and disodium hydrogen phosphate dodecahydrate are selected as the buffer pair and the mass ratio is 3.1:0.5, the pH of the cream is 6, and the main drug is most stable under the pH condition.
Further, the pH of the cream was 6.
Further, the emulsifying and homogenizing speed in the step 2) is 1000-3000 rpm.
In particular, the speed of homogenization affects the appearance, the shape and size of the emulsion droplets, the viscosity of the cream, etc. When the homogenizing speed is lower, the cream has rough appearance, incomplete emulsion drop shape, and too viscous paste which is not easy to smear; the homogenization speed is too high, the emulsion drops are too fine, the ointment is thin, and a large number of fine bubbles are easily generated, so that the stability of the product is influenced. The inventor selects a proper homogenizing speed through a large amount of experiments so as to meet the product quality requirement.
Further, the formulation of step 3) is cooled to 40-45 ℃.
The invention also aims to provide tazarotene betamethasone cream prepared by the preparation method. Experiments prove that the tazarotene betamethasone cream has a wider tolerance range on temperature, the storage temperature variation range of the cream is-15-40 ℃, and the physical and chemical stability and uniformity are good.
Specifically, the emulsifier used in the product is glycerol polyethylene glycol-75 stearate and peregal A-20, and the mass ratio of the glycerol polyethylene glycol-75 stearate to the peregal A-20 is 1: 1.5-2.
The glycerol polyethylene glycol-75 stearate is a nonionic O/W type emulsifier, has excellent thermal stability and pH tolerance, and has an HLB value of 10; the peregal A-20 is a non-ionic O/W type emulsifier, has the HLB value of 15, and has the advantages of high stability, good water solubility, electrolyte resistance and small foam. The two emulsifiers are used together, so that the compatibility is good, the salt resistance is strong, the emulsifying effect is good, and the cream body of the emulsifiable paste is soft and exquisite and comfortable to apply.
Further, the cream takes sodium dihydrogen phosphate monohydrate and disodium hydrogen phosphate dodecahydrate as a buffer pair, and the mass ratio of the sodium dihydrogen phosphate monohydrate to the disodium hydrogen phosphate dodecahydrate is 3.1: 0.5.
In particular, since the cream is a thermodynamically unstable multiphase system, most creams have a narrow storage temperature range, typically 20-25 ℃, which imposes severe requirements on the transport and storage conditions of the drug. The inventor unexpectedly finds that when the product selects the sodium dihydrogen phosphate monohydrate and the disodium hydrogen phosphate dodecahydrate as the buffer pair and the mass ratio is 3.1:0.5, the physical stability of the cream is excellent, the cream can bear the storage condition at the temperature of-15-40 ℃, the storage and transportation requirements of the product are greatly reduced, and the cost is saved. The phenomenon is probably because the selected buffer salt is sodium salt, which has weak influence on the emulsifying capacity of the emulsifier of the product, and simultaneously, a proper amount of electrolyte is introduced into the formula, so that the surface charge of the emulsion drop can be increased, and the stability of the emulsion drop is favorably improved.
The invention has the beneficial effects that:
the preparation method of the tazarotene betamethasone cream overcomes the problem of poor physical and chemical stability of the cream easily caused by the prior preparation technology, and avoids the medicine quality problem caused by crystallization and hydrolysis due to instability; the tolerance range of the prepared tazarotene betamethasone cream to temperature change is improved, the physical and chemical stability of the tazarotene betamethasone cream is further improved, the temperature control requirement and cost of transportation and storage are reduced, and the evaluation and management of medicaments are facilitated.
Detailed Description
The examples are given for the purpose of better illustration of the invention, but the invention is not limited to the examples. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.
Example 1 preparation of tazarotene betamethasone cream
Main drugs: 0.05g of tazarotene and 0.05g of betamethasone dipropionate.
Oil phase: 4g of natural fatty alcohol (C16), 4g of liquid paraffin, 1g of glycerol polyethylene glycol-75 stearate, 1.75g of peregal A-201.75 g, 1.75g of glycerin monostearate and 1.5g of vitamin E.
Water phase: 77.24g of purified water, 8g of glycerol, 0.05g of disodium hydrogen phosphate dodecahydrate, 0.31g of sodium dihydrogen phosphate monohydrate, 0.2g of potassium sorbate, 0.05g of disodium edetate and 0.05g of sodium bisulfite.
Emulsifier: glycerol polyethylene glycol-75 stearate, peregal A-20.
1) Dissolving main drugs tazarotene and betamethasone dipropionate in a formula ratio in molten natural fatty alcohol and liquid paraffin, mixing and melting glycerol polyethylene glycol-75 stearate, peregal A-20, glyceryl monostearate and vitamin E, and mixing with the natural fatty alcohol and the liquid paraffin in which the main drugs are dissolved;
2) mixing purified water, glycerol, disodium hydrogen phosphate dodecahydrate, sodium dihydrogen phosphate monohydrate, potassium sorbate, disodium edetate and sodium bisulfite to prepare a water phase, mixing with an oil phase, emulsifying and homogenizing at the homogenizing speed of 1200rpm, and further homogenizing after emulsification at the homogenizing speed of 2500 rpm;
3) cooling the homogenized cream to 40 deg.C, and bottling with aluminum tube to obtain the final product.
Example 2 preparation of tazarotene betamethasone cream
Main drugs: 0.05g of tazarotene and 0.05g of betamethasone dipropionate.
Oil phase: 5g of natural fatty alcohol (C16), 3g of liquid paraffin, 1g of glycerol polyethylene glycol-75 stearate, 1.75g of peregal A-202 g, 1.75g of glycerin monostearate and 1.5g of vitamin E.
Water phase: 76.99g of purified water, 8g of glycerol, 0.05g of disodium hydrogen phosphate dodecahydrate, 0.31g of sodium dihydrogen phosphate monohydrate, 0.2g of potassium sorbate, 0.05g of disodium edetate and 0.05g of sodium bisulfite.
Emulsifier: glycerol polyethylene glycol-75 stearate, peregal A-20.
1) Dissolving main drugs tazarotene and betamethasone dipropionate in a formula ratio in molten natural fatty alcohol and liquid paraffin, mixing and melting glycerol polyethylene glycol-75 stearate, peregal A-20, glyceryl monostearate and vitamin E, and mixing with the natural fatty alcohol and the liquid paraffin in which the main drugs are dissolved;
2) mixing purified water, glycerol, disodium hydrogen phosphate dodecahydrate, sodium dihydrogen phosphate monohydrate, potassium sorbate, disodium edetate and sodium bisulfite to prepare a water phase, mixing with an oil phase, emulsifying and homogenizing at a homogenizing speed of 1500rpm, and further homogenizing after emulsifying at a homogenizing speed of 3000 rpm;
3) cooling the homogenized cream to 43 deg.C, and bottling with aluminum tube to obtain the final product.
Example 3 preparation of tazarotene betamethasone cream
Main drugs: 0.05g of tazarotene and 0.05g of betamethasone dipropionate.
Oil phase: 5g of natural fatty alcohol (C16), 3g of liquid paraffin, 1g of glycerol polyethylene glycol-75 stearate, 1.75g of peregal A-202 g, 1.75g of glycerin monostearate and 1.5g of vitamin E.
Water phase: 76.81g of purified water, 8g of glycerol, 0.31g of disodium hydrogen phosphate dodecahydrate, 0.23g of sodium dihydrogen phosphate monohydrate, 0.2g of potassium sorbate, 0.05g of disodium edetate and 0.05g of sodium bisulfite.
Emulsifier: glycerol polyethylene glycol-75 stearate, peregal A-20.
1) Dissolving main drugs tazarotene and betamethasone dipropionate in a formula ratio in molten natural fatty alcohol and liquid paraffin, mixing and melting glycerol polyethylene glycol-75 stearate, peregal A-20, glyceryl monostearate and vitamin E, and mixing with the natural fatty alcohol and the liquid paraffin in which the main drugs are dissolved;
2) mixing purified water, glycerol, disodium hydrogen phosphate dodecahydrate, sodium dihydrogen phosphate monohydrate, potassium sorbate, disodium edetate and sodium bisulfite to prepare a water phase, mixing with an oil phase, emulsifying and homogenizing at a homogenizing speed of 1500rpm, and further homogenizing after emulsifying at a homogenizing speed of 3000 rpm;
3) cooling the homogenized cream to 43 deg.C, and bottling with aluminum tube to obtain the final product.
Example 4 preparation of tazarotene betamethasone cream
Main drugs: 0.05g of tazarotene and 0.05g of betamethasone dipropionate.
Organic solvent: propylene glycol 5g
Oil phase: 4g of natural fatty alcohol (C16), 4g of liquid paraffin, 1g of glycerol polyethylene glycol-75 stearate, 1.75g of peregal A-201.75 g, 1.75g of glycerin monostearate and 1.5g of vitamin E.
Water phase: 72.24g of purified water, 8g of glycerol, 0.05g of disodium hydrogen phosphate dodecahydrate, 0.31g of sodium dihydrogen phosphate monohydrate, 0.2g of potassium sorbate, 0.05g of disodium edetate and 0.05g of sodium bisulfite.
Emulsifier: glycerol polyethylene glycol-75 stearate, peregal A-20.
1) Mixing and melting natural fatty alcohol, liquid paraffin, glycerol polyethylene glycol-75 stearate, peregal A-20, glyceryl monostearate and vitamin E according to the formula ratio;
2) mixing purified water, glycerol, sodium citrate, citric acid, potassium sorbate, edetate disodium, and sodium bisulfite to obtain water phase, mixing with oil phase, emulsifying at homogenizing speed of 1200rpm, and emulsifying at homogenizing speed of 2500 rpm. After homogenization, the emulsion begins to cool.
3) Dissolving main medicines of tazarotene and betamethasone dipropionate in propylene glycol, adding the medicine-containing propylene glycol solution into the emulsion when the temperature of the emulsion is reduced to about 50-55 ℃, homogenizing at 1200rpm, and uniformly mixing. Then, the temperature is continuously reduced.
4) Cooling the cream of 3) to 45 deg.C, and bottling with aluminum tube to obtain the final product.
Example 5 stability testing of tazarotene betamethasone cream
The cream products prepared in examples 1-4 were subjected to freeze-thaw cycles (-15 ℃ C. for 2 days → 40 ℃ C. for 2 days) for 5 times, appearance of the cream was compared, microscopic observation of the smears was performed, and at the same time, the cream was subjected to high-speed centrifugation (5000rpm, 30min) to observe whether oil-water separation occurred. The results are shown in Table 1.
Table 1 examples 1-4 physical stability of creams after freeze-thaw cycling
The physical stability of the creams of example 1 and example 2 was good as indicated by freeze-thaw cycling tests. While the amount of the buffer salt used in example 3 is larger than that used in examples 1 and 2, the main drug in example 4 was dissolved in an organic solvent and then added to a cream base, and as a result, both examples 3 and 4 failed the challenge.
The samples of example 1 and example 2 were placed in a firm manner, and subjected to accelerated 6-month stability at 30 ℃ and long-term retention at room temperature (0 to 40 ℃) for 24-month examination, and the results are shown in tables 2 and 3 below.
Table 2 accelerated 6 month stability study of example 1 and example 2
TABLE 3 Long-term sample retention at room temperature (0-40 ℃ C.) for example 1 and example 2
And (4) conclusion: the product is subjected to stability inspection at 30 deg.C for 6 months and long-term sample retention at room temperature (0-40 deg.C) for 24 months, and has stable content, impurities, pH value, content uniformity and viscosity of main drug, and no crystallization.
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (10)
1. A preparation method of tazarotene betamethasone cream is characterized in that tazarotene and betamethasone dipropionate are directly dissolved in a melted oil phase.
2. The method of claim 1, comprising the steps of:
1) preparing an oil phase, and dissolving tazarotene and betamethasone dipropionate in the melted oil phase;
2) preparing a water phase, emulsifying and homogenizing with the oil phase obtained in the step 1) and then homogenizing;
3) cooling the preparation after homogenizing in the step 2) to obtain a cream intermediate.
3. The preparation method according to claim 2, wherein the step 1) is specifically to dissolve tazarotene and betamethasone dipropionate in molten natural fatty alcohol and liquid paraffin, and then mix with molten mixed oil phase of glycerol polyethylene glycol-75 stearate, peregal A-20, glyceryl monostearate and vitamin E.
4. The method according to claim 3, wherein the dissolution temperature is 75 to 85 ℃ and the total dissolution time is 20 to 50 min.
5. The method of claim 2, wherein the aqueous phase of step 2) is prepared from purified water, glycerin, disodium hydrogen phosphate dodecahydrate, sodium dihydrogen phosphate monohydrate, potassium sorbate, disodium edetate, and sodium bisulfite.
6. The preparation method according to claim 2, wherein the emulsifier in step 2) is glycerol polyethylene glycol-75 stearate and peregal A-20, and the mass ratio of the glycerol polyethylene glycol-75 stearate to the peregal A-20 is 1: 1.5-2.
7. The method according to claim 2, wherein the emulsifying and homogenizing speed in step 2) is 1000-3000 rpm.
8. The method according to claim 5, wherein the monobasic sodium phosphate monohydrate and the dibasic sodium phosphate dodecahydrate are a buffer pair, and the mass ratio of the monobasic sodium phosphate monohydrate to the dibasic sodium phosphate dodecahydrate is 3.1: 0.5.
9. The method of claim 2, wherein the emulsion of step 3) is cooled to a temperature of 40-45 ℃.
10. The tazarotene betamethasone cream prepared by the method for preparing the tazarotene betamethasone cream according to any one of claims 1 to 9, wherein the storage temperature of the cream ranges from-15 ℃ to 40 ℃.
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| WO2012053007A1 (en) * | 2010-10-21 | 2012-04-26 | Cadila Healthcare Limited | Topical pharmaceutical compositions containing nanodroplets for the treatment psoriasis |
| CN102988987A (en) * | 2012-12-13 | 2013-03-27 | 西安力邦制药有限公司 | Pharmaceutical composition for treating hyperproliferative skin disease and preparation of pharmaceutical composition |
| CN107468637A (en) * | 2016-06-08 | 2017-12-15 | 厦门恩成制药有限公司 | Compound tazarotene urea external preparation and preparation method thereof |
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2019
- 2019-12-30 CN CN201911395318.3A patent/CN113116891A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040192662A1 (en) * | 1997-02-20 | 2004-09-30 | Allergan, Inc. | Tazarotene and corticosteriod treatment for psoriasis |
| WO2012053007A1 (en) * | 2010-10-21 | 2012-04-26 | Cadila Healthcare Limited | Topical pharmaceutical compositions containing nanodroplets for the treatment psoriasis |
| CN102988987A (en) * | 2012-12-13 | 2013-03-27 | 西安力邦制药有限公司 | Pharmaceutical composition for treating hyperproliferative skin disease and preparation of pharmaceutical composition |
| CN107468637A (en) * | 2016-06-08 | 2017-12-15 | 厦门恩成制药有限公司 | Compound tazarotene urea external preparation and preparation method thereof |
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