CN111658602A - Preparation method of stable Kelibuo ointment - Google Patents
Preparation method of stable Kelibuo ointment Download PDFInfo
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- CN111658602A CN111658602A CN202010565860.5A CN202010565860A CN111658602A CN 111658602 A CN111658602 A CN 111658602A CN 202010565860 A CN202010565860 A CN 202010565860A CN 111658602 A CN111658602 A CN 111658602A
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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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
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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
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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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- 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
Abstract
The invention discloses a preparation method of stable clironic ointment, which comprises the following steps: preparing an oil phase: preparing an oil phase at a temperature of 70-80 ℃, said oil phase being made of one or more substrates and maintaining the temperature of the oil phase at 70-80 ℃; preparing an active phase: preparing an active phase at a temperature of 30-60 ℃, said active phase being made of one or more solvents and one or more complexing agents, and maintaining the temperature of the active phase at 30-60 ℃; the active phase is also added with Cliborol; emulsification: adding the active phase into the oil phase at 70-80 deg.C, stirring for 5-20min to complete emulsification to obtain paste; and (3) cooling: cooling the ointment to 35-45 deg.C at a rate of 0.5-2 deg.C/min to obtain ointment. Which can avoid a large change in viscosity.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a preparation method of stable Kelibuo ointment.
Background
When the skin barrier fails, it triggers the innate immune system of the stratum corneum cells, producing cytokines, causing a series of immune responses and chronic inflammatory symptoms. Th22 cytokine (interleukin-22), Th2 cytokine (interleukin-4, interleukin-5 and interleukin-13) and Th17 are overexpressed in atopic dermatitis.
Cribobromide is a potent and selective phosphodiesterase-4 (PED-4) inhibitor that acts by inhibiting phosphodiesterase-4 activity. Phosphodiesterase-4 is the major cAMP metabolizing enzyme involved in controlling inflammatory cell activity. It is highly expressed in immune cells such as dendritic cells, T cells, macrophages and monocytes.
Krebsis inhibits the production of proinflammatory mediators (TNF alpha, IL-6, IL-12) by inhibiting the hydrolysis of cAMP by PED-4, which increases its concentration. Based on the presence and role of PDE-4 in various inflammatory cells, PDE-4 inhibitors can exert anti-inflammatory effects in almost all inflammatory cells.
Kriboron was originally developed by Anacor Pharmaceuticals, available from Anacor 5 in 5 months in 2016, and approved by the U.S. FDA for topical treatment of mild to moderate atopic dermatitis in patients over 2 years of age (2%) on the market under the trade name of Eucris. The krebs chemical name is 5- (4-cyanophenoxy) -1,3-dihydro-1-hydroxy- [2,1] -benzoxaperlane; chemical name of English:
5- (4-cyanomethoxy) -1,3-dihydro-1-hydroxy- [2,1] -benzoxaborole; the molecular formula is as follows: C14H10BNO 3; molecular weight: 251.1, the chemical structural formula is shown as follows.
Kriboren is prepared as an ointment which will facilitate its penetration into the skin. Kriboren is unstable in water, which can cause chemical instability of the active ingredient. This necessarily affects the overall stability of the compositions containing krebs, including their viscosity and appearance. To reduce this phenomenon, clavulanate is dissolved in propylene glycol and then mixed with the oil phase to form a stable, homogeneous, lipid-soluble ointment. In CN 108366958 a method for the preparation of a topical pharmaceutical formulation of clavulanate is proposed. This ointment is prepared by first stirring the oil phase at elevated temperature (70-80 deg.C), then cooling the resulting mixture to 40-46 deg.C, followed by the addition of the active drug-dissolved phase and cooling the final mixture to 25 deg.C.
In the case of stable pastes before and after temperature changes during the preparation of the krebs paste, the viscosity increases from paste formation to the finished paste by 30% to 60%, and even up to 150%. It is presumed that such increase in viscosity and particle size is caused by swelling of the lamellar structure formed by the nonionic surfactant and the drug solution initially present in the oil phase in the matrix after emulsification cooling of the active phase and the oil phase. Therefore, in order to ensure that the quality of different products can be maintained at the same level, it is necessary to keep the ointment stable during the aging time until the viscosity and particle size become constant, and then obtain the finished ointment.
Disclosure of Invention
In order to overcome the defects in the prior art, the embodiment of the invention provides a preparation method of a stable kreb ointment, which can avoid the great change of viscosity.
In order to achieve the above purpose, the embodiments of the present application disclose a method for preparing a stable krebs ointment, which comprises the following steps:
preparing an oil phase: preparing an oil phase at a temperature of 70-80 ℃, said oil phase being made of one or more substrates and maintaining the temperature of the oil phase at 70-80 ℃;
preparing an active phase: preparing an active phase at a temperature of 30-60 ℃, said active phase being made of one or more solvents and one or more complexing agents, and maintaining the temperature of the active phase at 30-60 ℃; the active phase is also added with Cliborol;
emulsification: adding the active phase into the oil phase at 70-80 deg.C, stirring for 5-20min to complete emulsification to obtain paste;
and (3) cooling: cooling the ointment to 35-45 deg.C at a rate of 0.5-2 deg.C/min to obtain ointment.
Preferably, an antioxidant is also added into the oil phase.
Preferably, the oil phase also comprises at least one surfactant, and the surfactant can be fatty alcohol ester, glycerin mono-stearate, glycerin di-stearate, tween 60, tween 80, span 60, span 80, and polyoxyethylated fatty acid ester.
Preferably, the base may be one or more of white petrolatum, solid paraffin, liquid paraffin, lanolin, beeswax, and spermaceti wax.
Preferably, the solvent may be one or more of propylene glycol, ethanol, isopropanol, butanol, benzyl alcohol, phenoxyethanol, and glycerol.
Preferably, the complexing agent can be one or more of sodium edetate, calcium sodium edetate, disodium edetate and tetrasodium edetate.
Preferably, the average droplet size of the ointment is 10-20 μm.
The invention has the following beneficial effects: the stability of the ointment is improved, the large viscosity change of the ointment is avoided, and the phenomenon that the ointment has the particle size of oil drops which are not tightly and uniformly dispersed is prevented;
the viscosity of the manufactured ointment can be better controlled, the ointment can be well absorbed, the product quality is ensured, and the manufacturing process is positively influenced in economics.
In order to make the aforementioned and other objects, features and advantages of the invention comprehensible, preferred embodiments accompanied with figures are described in detail below.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a complete flow curve of viscosity versus shear rate for samples of examples 1 and 3 of the present invention;
FIG. 2 is a microscopic view of sample A in example 1 of the present invention;
FIG. 3 is a microscopic view of sample B in example 1 of the present invention;
FIG. 4 is a microscopic view of sample C in example 2 of the present invention;
FIG. 5 is a microscopic view of sample D in example 2 of the present invention;
FIG. 6 is a plot of viscosity versus days for sample A and sample B of example 1 of the present invention;
FIG. 7 is a plot of viscosity versus days for samples C and D of example 3 of the present invention;
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In the description of the present invention, it should be noted that the terms "upper", "lower", "bottom", "inner", "outer", and the like indicate orientations or positional relationships based on those shown in the drawings, and are only for convenience of description and simplicity of description, but do not indicate or imply that the referred device or element must have a specific orientation, be constructed in a specific orientation, and be operated, and thus, should not be construed as limiting the present invention. Furthermore, the terms "first", "second", etc. are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first," "second," etc. may explicitly or implicitly include one or more of that feature.
To achieve the preparation of the oil phase: preparing an oil phase at a temperature of 70-80 ℃, said oil phase being made of one or more substrates and maintaining the temperature of the oil phase at 70-80 ℃.
The oil phase contains 70-80% of white vaseline, 3-7% of solid paraffin, 5-10% of glycerin monostearate and glycerin distearate, and 0.05-0.15% of dibutyl hydroxy toluene.
Preparing an active phase: preparing an active phase at a temperature of 30-60 ℃, said active phase being made of one or more solvents and one or more complexing agents, and maintaining the temperature of the active phase at 30-60 ℃; the active phase is also added with the Cliborol.
The active phase contains 1-3% of krebs, 7-17% of propylene glycol and 0.003-0.004% of calcium disodium edetate.
Emulsification: adding the active phase into the oil phase at 70-80 deg.C, stirring for 5-20min to complete emulsification to obtain paste;
and (3) cooling: cooling the ointment to 35-45 deg.C at a rate of 0.5-2 deg.C/min to obtain ointment. To achieve the above object, the present invention provides a method for preparing a stable krebs ointment, comprising the steps of:
furthermore, an antioxidant is added into the oil phase.
Further, the oil phase also comprises at least one surfactant, and the surfactant can be fatty alcohol ester, glycerol monostearate, glycerol distearate, tween 60, tween 80, span 60, span 80 and polyoxyethylated fatty acid ester.
Further, the base may be one or more of white petrolatum, solid paraffin, liquid paraffin, lanolin, beeswax, and spermaceti wax.
Further, the solvent may be one or more of propylene glycol, ethanol, isopropanol, butanol, benzyl alcohol, phenoxyethanol, and glycerol.
Further, the complexing agent can be one or more of edetate sodium, edetate calcium sodium, edetate disodium and edetate tetrasodium.
Further, the average droplet size of the ointment is 10-20 μm.
Example 1 preparation of an ointment containing 2% Keliboro obtained by Process I
a) Preparation of two phases:
1. preparation of the oil phase
Under continuous stirring, 70% white vaseline, 3% solid paraffin and 10% mono-and diglycerol fatty acid esters were added while heating to 70 ℃ and maintaining the temperature, and the oil phase was melted and stirred uniformly.
While maintaining stirring and at this temperature, 0.05% of the antioxidant dibutylhydroxytoluene was added to the oil phase.
The oil phase was kept at 75 ℃ with stirring (homogenizer 2000rpm) and incubated until the active phase was added.
2. Preparation of the active phase
Under continuous stirring, 2% of kreb and 0.003% of calcium disodium edetate are added into 14.947% of propylene glycol while heating to 40 ℃, and the mixture is kept warm and dissolved and stirred uniformly.
It will be appreciated that the dissolution was effected by the addition of Klebsiella, while maintaining the temperature at 40 ℃.
b) Emulsification:
the active phase was added to the molten oil phase and stirred for 5 minutes.
Stopping heating, cooling, homogenizing at 35 deg.C, and vacuum defoaming for 0.5 hr to vacuum degree of-0.07 MPa.
When the temperature of the ointment is reduced to 30 ℃, the Cliboro ointment is obtained.
The above process was carried out on a laboratory scale on a 1kg batch of the composition (sample a) and on a pilot scale on a 100kg batch of the composition (sample B).
It will be appreciated that the emulsification temperature can be reduced to 50 ℃ without compromising viscosity stability.
Example 2 preparation of an ointment containing 2% Keliboro obtained by Process I
a) Preparation of two phases:
1. preparation of the oil phase
Under continuous stirring, 80% white vaseline, 7% solid paraffin and 5% mono-and diglycerol fatty acid esters were added while heating to 80 ℃, and the temperature was maintained, and the oil phase was melted and stirred uniformly. While stirring and at this temperature, 0.15% of the antioxidant dibutylhydroxytoluene was added.
The oil phase was kept at 75 ℃ with stirring (homogenizer 2000rpm) and incubated until the active phase was added.
2. Preparation of the active phase
Under continuous stirring, adding raw material medicine 2% of kresoxim and 0.004% of calcium disodium edetate into 5.846% of propylene glycol, simultaneously heating to 50 ℃, preserving heat, dissolving and stirring uniformly.
It will be appreciated that the dissolution was effected by the addition of Klebsiella while maintaining the temperature at 50 ℃.
b) An emulsification step:
the active phase was added to the molten oil phase and stirred for 15 minutes.
Stopping heating, cooling, homogenizing at 45 deg.C, and vacuum defoaming for 0.5 hr to reach vacuum degree of-0.07 MPa.
When the temperature of the paste is reduced to 30 ℃, the Cliboro ointment is obtained.
Example 3: preparation of an ointment containing 2% Kelibuo by Process II
The same composition as the ointment ingredients prepared in example 1 were prepared on a laboratory scale (1kg batch, sample C) and a pilot scale (100kg, sample D) according to a similar method to that carried out in example 1, with the difference that:
the emulsion is cooled for an uncontrolled length and rate of time by standing at room temperature (laboratory scale) or by using water jacket cooling without any temperature control.
A significant difference from the processes of example i and example 2 is that the composition does not undergo a controlled cooling step with an average cooling rate below 2 ℃/5 min.
Example 4: comparative stability Studies of compositions obtained by method I or method II
The viscosity change of the batches prepared according to examples 1 (method I) and 3 (method II) was evaluated using a rheometer equipped with a 20mm diameter flat plate frosting, and referring to fig. 1, for viscosity measurements under high and low shear rate conditions of the resulting composition, it can be seen that samples a and B of example 1 are lower than samples C and D of example 3.
The particle size variation of the batches prepared according to example 1 (method I) and example 3 (method II) was evaluated using a biomicroscopic examination at 200 magnification.
Referring to figures 2 and 3, the ointment emulsions prepared according to the method of the invention had an average droplet size of 10-20 μm in sample a (laboratory scale) and sample B (pilot scale) prepared according to method I with a controlled cooling step.
In contrast, referring to fig. 4 and 5, sample C (lab scale) and sample D (pilot scale) prepared according to method II with an uncontrolled cooling step had emulsion average droplet sizes that were large (greater than 20 μm) and non-uniform.
The respective krebs ointment of example 1 and example 3 were packaged on the market, subjected to an influence factor test at a high temperature of 40 ℃, sampled once on days 0, 5, 10 and 30, and the change in viscosity of the krebs ointment was measured.
Referring to fig. 6, the ointment prepared according to the method of the present invention showed no more than 10% change in viscosity in 30 days, more precisely no more than 5%, between sample a (laboratory scale) and sample B (pilot scale) prepared according to method I with a controlled cooling step.
In contrast, referring to fig. 7, the 30 day viscosities of sample C (lab scale) and sample D (pilot scale) prepared according to method II with an uncontrolled cooling step varied by 30% (on the lab scale) and up to 50% (on the 100kg pilot scale), respectively.
Examples 1 and 2 demonstrate that, in contrast to the comparative method (method II), the method of the invention (method I) allows the manufacture of ointments with a stable viscosity, without significant changes over the time.
Therefore, the method of the invention can improve the stability of the ointment, avoid large viscosity change of the ointment and prevent the ointment from having oil drop particle size which is not tightly and uniformly dispersed. The viscosity of the manufactured ointment can be better controlled, the ointment can be well absorbed, the product quality is ensured, and the manufacturing process is positively influenced in economics.
The principle and the implementation mode of the invention are explained by applying specific embodiments in the invention, and the description of the embodiments is only used for helping to understand the method and the core idea of the invention; meanwhile, for a person skilled in the art, according to the idea of the present invention, there may be variations in the specific embodiments and the application scope, and in summary, the content of the present specification should not be construed as a limitation to the present invention.
Claims (7)
1. A method of preparing a stable krebs ointment, comprising:
preparing an oil phase: preparing an oil phase at a temperature of 70-80 ℃, said oil phase being made of one or more substrates and maintaining the temperature of the oil phase at 70-80 ℃;
preparing an active phase: preparing an active phase at a temperature of 30-60 ℃, said active phase being made of one or more solvents and one or more complexing agents, and maintaining the temperature of the active phase at 30-60 ℃; the active phase is also added with Cliborol;
emulsification: adding the active phase into the oil phase at 70-80 deg.C, stirring for 5-20min to complete emulsification to obtain paste;
and (3) cooling: cooling the ointment to 35-45 deg.C at a rate of 0.5-2 deg.C/min to obtain ointment.
2. The method of claim 1, wherein an antioxidant is added to the oil phase.
3. The method of claim 1, wherein the oil phase further comprises at least one surfactant selected from the group consisting of fatty alcohol esters, glycerol monostearate, glycerol distearate, tween 60, tween 80, span 60, span 80, and polyoxyethylated fatty acid esters.
4. The method of claim 1, wherein the base is one or more of white petrolatum, paraffin wax, liquid paraffin, lanolin, beeswax and spermaceti wax.
5. The method of claim 1, wherein the solvent is one or more of propylene glycol, ethanol, isopropanol, butanol, benzyl alcohol, phenoxyethanol, and glycerol.
6. The method of claim 1, wherein the complexing agent is one or more of edetate sodium, edetate calcium sodium, edetate disodium, and edetate tetrasodium.
7. The method of claim 1, wherein the paste has a mean droplet size of 10-20 μm.
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| CN114767623A (en) * | 2022-04-20 | 2022-07-22 | 北京阳光诺和药物研究股份有限公司 | Keliboro ointment and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110464702A (en) * | 2018-05-09 | 2019-11-19 | 上海键合医药科技有限公司 | A kind of ointment and preparation method thereof of gram of vertical boron sieve |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110464702A (en) * | 2018-05-09 | 2019-11-19 | 上海键合医药科技有限公司 | A kind of ointment and preparation method thereof of gram of vertical boron sieve |
Non-Patent Citations (1)
| Title |
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| 陈丽梅等: "冷却速率对新生皂类乳膏基质流变学特性和物理稳定性的影响", 《江西中医药大学学报》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114767623A (en) * | 2022-04-20 | 2022-07-22 | 北京阳光诺和药物研究股份有限公司 | Keliboro ointment and preparation method thereof |
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