CN107157917B - A method for preparing ointment for treating psoriasis - Google Patents

A method for preparing ointment for treating psoriasis Download PDF

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CN107157917B
CN107157917B CN201610127160.1A CN201610127160A CN107157917B CN 107157917 B CN107157917 B CN 107157917B CN 201610127160 A CN201610127160 A CN 201610127160A CN 107157917 B CN107157917 B CN 107157917B
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ointment
stirring
vitamin
mixing
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CN107157917A (en
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胡一波
马媛媛
刘曲
魏冬
顾兆姝
王军平
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Shanghai Zhengda General Pharmaceutical Co ltd
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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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • A61K31/56—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • 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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention relates to a preparation method of an ointment for treating psoriasis, which comprises the steps of stirring and mixing 40 ~ 60ppm of calcipotriol, effective treatment amount of corticosteroid and 5 ~ 40% of vaseline of the formula amount based on the total weight of the ointment under specific illumination, gas density, temperature and stirring speed, adding other uniformly mixed medicinal auxiliary materials and the vaseline into the obtained mixture, and mixing and stirring to obtain the ointment for treating psoriasis with uniformly distributed active substances.

Description

A method for preparing ointment for treating psoriasis
Technical Field
The invention relates to a preparation method of a medicinal preparation, in particular to a preparation method of an ointment for treating psoriasis.
Background
Currently, 90% of psoriasis patients are treated with topical medications, 20% are treated with phototherapy, 5% are treated systemically, and 0.7% are treated with biologicals; the external medicine is mainly used for treating patients with mild-moderate psoriasis, and can also be used in combination with other therapies for treating patients with severe disease; the external medicine for treating psoriasis mainly comprises vitamin D derivatives, vitamin A acids, anthralin, cutin remover and the like; glucocorticoid, tretinoin and cutin stripper are not suitable for long-term use of patients due to more adverse reactions or higher toxicity, and have the advantages of temporary solution, permanent solution, and easy relapse after stopping administration; for anthralin, it is not easily accepted by patients due to its local irritation and easy staining; the vitamin D derivatives have the characteristics of definite curative effect, low adverse reaction and the like, and become a first-line external medicament for treating mild-moderate psoriasis, which can be safely used for a long time.
The calcipotriol serving as the vitamin D derivative is an external first-line medicament for psoriasis, can inhibit keratinocyte proliferation and induce the keratinocyte differentiation, is high in activity, generally low in content in a preparation, accounts for 0.004 ~ 0.006.006 percent of the preparation, is not easy to mix uniformly in the preparation process, and has the characteristics of light instability and high oxidation tendency, so that the preparation process of the calcipotriol semi-solid preparation is extremely difficult to operate and apply if the uniformity of a trace active substance in a matrix is ensured, and the stability of the trace active substance in the preparation process and the long-term stability of the trace active substance in the storage process are ensured.
The method has the disadvantages that when the content of the active ingredients is 0.004 ~ 0.006.006 percent of the total weight of the preparation, the difference between the content of the active ingredients and the content of the matrix in the preparation is very large, so that the number of times of repeatedly adding the matrix reaches nearly thousands of times, the defects of multiple operation steps, long production time, complex control of the production process, multiplied equipment and labor cost and the like are caused in production, the production steps are multiple, the production time is long, the reduction of the active ingredients and the generation of impurities are also caused, the reduction of the active ingredients can influence the effectiveness of the medicine for the medicine, and the generation of the impurities can influence the safety of the medicine.
Patent CN200480013008.6 discloses a method for preparing a preparation containing a trace amount of active ingredient, which comprises the steps of 1) weighing the active ingredient in a container coated with vaseline (matrix), 2) encapsulating the active ingredient with additional vaseline (matrix), 3) introducing the container containing the active ingredient and vaseline (matrix) into a mixer, 4) dispersing the active ingredient in the mixer, which solves the problem of more steps in the equivalent delivery method, and at the same time, introducing the container encapsulating the active ingredient directly into the mixer in step 3) can protect the active ingredient from photoreaction or oxidation, but this method has two disadvantages that (i) the mixing apparatus (see fig. 1 ~ of patent CN 200480013008.6) requires a very high requirement, the preparation process requires not only a stainless cone frustum but also a sealing hood, the weighing container in step 1) is complicated, the container end is provided with a grid, the container is provided with a sealing hard plug and a porous plug for the conversion of the different operation steps, and the lock catch is provided for the simultaneous mixing of the same amount of active ingredient in the mixer 3), the mixing apparatus requires a high mixing time, even mixing operation of the mixing apparatus, even mixing apparatus requires a long time, even mixing operation of the mixing apparatus, the mixing apparatus requires a special mixing apparatus, even mixing apparatus, the mixing apparatus requires a long time, the mixing apparatus requires a special mixing apparatus, the mixing apparatus 3) requires a special mixing apparatus, the mixing apparatus requires a high cost is increased, the mixing apparatus is required, the mixing apparatus is increased, the mixing apparatus is required is increased, the mixing apparatus is required is increased, the mixing apparatus is reduced by the mixing apparatus is increased by the mixing apparatus, the mixing apparatus is increased.
Although, there are several patents currently in use to address: when a trace amount of active substances are mixed with a large amount of matrix, the active substances are difficult to be uniformly mixed; however, these methods for solving the uniformity have complicated operation steps, complicated control of the production process, high structural configuration of the mixing equipment, need of customizing special production equipment, and overlong mixing time; or the mixing times of the matrix are extremely large, and the problems that the active substance is unstable in the mixing process and the preparation storage process and the effectiveness and the safety of the medicament are influenced exist.
Disclosure of Invention
The present inventors have made extensive studies to develop a solution to the above-mentioned problems.
The inventor of the invention discovers that under the conditions of specific range of illumination intensity, air density and mixing temperature of 60 ~ 90 ℃ and the first stirring speed of trace active substances of 800 ~ 10000rpm, the preparation method simplifies fussy operation steps, reduces the requirement of the preparation process on equipment, reduces production cost and shortens homogenization time while ensuring the distribution uniformity and stability of the pharmaceutical active substance calcipotriol by controlling the first addition amount of vaseline to be 2 ~ 40% of the prescription amount in the mixing process and adding vaseline twice.
The invention provides a preparation method of an ointment for treating psoriasis, which comprises the following steps:
1) mixing calcipotriol 40 ~ 60ppm of the total weight of the ointment, corticosteroid with a therapeutically effective amount, and vaseline 5 ~ 40% of the prescription amount with stirring at 60 ~ 90 deg.C and 800 ~ 10000rpm for not less than 1 min;
2) weighing vaseline 60 ~ 95% of the prescription amount, adding light liquid paraffin 1 ~ 10% of the total weight of the ointment, stirring at 20 ~ 100rpm and 100rpm in a gas environment with the light intensity not more than 100lux and the nitrogen-oxygen molar ratio not less than 3.7 at 60 ~ 90 ℃, and stirring for not less than 10 min;
3) adding the mixture obtained in step 2) into the mixture prepared in step 1), stirring at 20 ~ 100rpm under the gas environment of 60 ~ 90 deg.C, illumination intensity not more than 100lux and nitrogen-oxygen molar ratio not less than 3.7, and stirring for not less than 10min to obtain uniformly mixed ointment.
Further, the preparation method comprises the following steps of 1) carrying out the preparation method under the environment that the illumination intensity does not exceed 60 lux; preferably, the preparation method comprises the step 1) that the air density is not more than 1.29kg/m3Of (2)The operation is carried out in a body environment and an environment with the illumination intensity not more than 60 lux; more preferably, the preparation method comprises the step 1) of carrying out in a gas environment with the illumination intensity not more than 60lux and the nitrogen-oxygen introducing molar ratio not less than 20.
Further, the corticosteroid is selected from one or more of betamethasone, budesonide, clobetasol, clobetasone and desoximetasone.
Further, components useful for external use are added (either already added or not) during all of the stirring process.
Further, the components for external use comprise an antioxidant.
Further, the antioxidant is selected from one or more of vitamin E alcohol (ester), tea polyphenol, sesamol, vitamin A, vitamin C, vitamin E, vitamin P, plant polyphenol, plant active selenium, ephenol, oryzanol, gossypol, cantharene, plum polyphenol, stevioside, lycopene, olivetol, beta-carotene, flavonoids, bamboo leaf flavonoid, astaxanthin, tea pigment, allicin, sesamin or carotenoid.
Further, the antioxidant content is not less than 0.0005%.
Further, the content of corticosteroid is 0.0005 ~ 1% of the total weight of the ointment.
The preparation method of the ointment for treating psoriasis provided by the invention has the following advantages:
1) the operation steps are simple, and the industrial production is easy to control;
2) simple and universal stirring equipment is adopted, so that the production cost is reduced;
3) the preparation time is shortened and the risk of degradation of the active pharmaceutical substances is reduced while the mixing uniformity of the active pharmaceutical substances is ensured.
Detailed Description
"range" as disclosed herein is in the form of lower and upper limits; may be one or more lower limits, and one or more upper limits, respectively; the given range is defined by the selection of a lower limit and an upper limit; the selected lower and upper limits define the boundaries of the particular range; all ranges that can be defined in this manner are inclusive and combinable, i.e., any lower limit can be combined with any upper limit to form a range; for example, ranges of 60-120 and 80-110 are listed for particular parameters, with the understanding that ranges of 60-110 and 80-120 are also contemplated; furthermore, if the minimum range values 1 and 2 are listed, and if the maximum range values 3, 4, and 5 are listed, the following ranges are all contemplated: 1-3, 1-4, 1-5, 2-3, 2-4, and 2-5.
In the present invention, the ranges of the contents of the components of the composition and the preferred ranges thereof may be combined with each other to form a new technical solution, unless otherwise specified.
In the present invention, unless otherwise specified, "combinations thereof" mean multicomponent mixtures of the elements described, for example two, three, four and up to the maximum possible.
In the present invention, all "parts" and percentages (%) refer to weight percentages unless otherwise indicated.
In the present invention, the sum of the percentages of the components in all compositions is 100%, unless otherwise specified.
In the present invention, unless otherwise stated, the numerical range "a-b" represents a shorthand representation of any combination of real numbers between a and b, where a and b are both real numbers; for example, a numerical range of "0 to 5" indicates that all real numbers between "0 to 5" have been listed herein, and "0 to 5" is only a shorthand representation of the combination of these numbers.
In the present invention, unless otherwise indicated, the integer numerical range "a-b" represents a shorthand representation of any combination of integers between a and b, where a and b are both integers; for example, an integer numerical range of "1-N" means 1, 2 … … N, where N is an integer.
The term "a" or "an" as used herein means "at least one" if not otherwise specified.
All percentages (including weight percentages) stated herein are based on the total weight of the composition, unless otherwise specified.
Herein, unless otherwise specified, the proportions or weights of the components are referred to as dry weights.
In the present invention, all embodiments and preferred embodiments mentioned herein may be combined with each other to form a new technical solution, if not specifically stated.
In the present invention, all the technical features mentioned herein and preferred features may be combined with each other to form a new technical solution, if not specifically stated.
In the present invention, all the steps mentioned herein may be performed sequentially or randomly, if not specifically stated, but preferably sequentially; for example, the method comprises steps (a) and (b), meaning that the method may comprise steps (a) and (b) performed sequentially, and may also comprise steps (b) and (a) performed sequentially; for example, reference to the process further comprising step (c) means that step (c) may be added to the process in any order, for example, the process may comprise steps (a), (b) and (c), may also comprise steps (a), (c) and (b), may also comprise steps (c), (a) and (b), etc.
In the present invention, unless otherwise specified, the term "comprising" as used herein means either open or closed; for example, the term "comprising" may mean that additional elements not listed may also be included, or that only listed elements may be included.
In the present invention, specific numerical values and specific substances in the examples herein may be combined with other features of the parts described herein, if not specifically stated; for example, if the specification refers to a reaction temperature of 10-100 ℃ and the examples refer to a reaction temperature of 20 ℃, then it is believed that the range of 10-20 ℃ or the range of 20-100 ℃ has been specifically disclosed herein and may describe some of the other features that may be combined to form new embodiments.
The invention provides a preparation method of an ointment for treating psoriasis, which comprises the following steps:
1) mixing calcipotriol 40 ~ 60ppm of the total weight of the ointment, corticosteroid with a therapeutically effective amount, and vaseline 5 ~ 40% of the prescription amount with stirring at 60 ~ 90 deg.C and 800 ~ 10000rpm for not less than 1 min;
2) weighing vaseline 60 ~ 95% of the prescription amount, adding light liquid paraffin 1 ~ 10% of the total weight of the ointment, stirring at 60 ~ 90 deg.C and 20 ~ 100rpm for at least 10 min;
3) adding the mixture obtained in step 2) into the mixture prepared in step 1), stirring at 20 ~ 100rpm under the gas environment of 60 ~ 90 deg.C, illumination intensity not more than 100lux and nitrogen-oxygen molar ratio not less than 3.7, and stirring for not less than 10min to obtain uniformly mixed ointment.
In a preferred embodiment, the preparation method comprises the steps of 1) carrying out the preparation method under the environment that the illumination intensity does not exceed 60 lux; preferably, the preparation method comprises the step 1) that the air density is not more than 1.29kg/m3The gas environment and the illumination intensity do not exceed 60 lux; more preferably, the preparation method comprises the step 1) of carrying out in a gas environment with the illumination intensity not more than 60lux and the nitrogen-oxygen introducing molar ratio not less than 20.
In a preferred embodiment, the corticosteroid is selected from one or more of betamethasone, budesonide, clobetasol, clobetasone and desoximetasone.
In a preferred embodiment, the components useful for external application are added (either already added or not) during all of the stirring process.
In a preferred embodiment, the component for external use comprises an antioxidant.
In a preferred embodiment, the antioxidant is selected from one or more of vitamin E alcohol (ester), tea polyphenol, sesamol, vitamin A, vitamin C, vitamin E, vitamin P, plant polyphenol, phytoactive selenium, ephenol, oryzanol, gossypol, cantharene, plum polyphenol, stevioside, lycopene, olivetol, beta-carotene, flavonoids, bamboo leaf flavonoid, astaxanthin, tea pigment, allicin, sesamin or carotenoids.
In a preferred embodiment, the antioxidant content is not less than 0.0005%.
In a preferred embodiment, the corticosteroid is present in an amount of 0.0005 ~ 1% by weight of the total ointment.
Unless otherwise specified, the experimental method of the present invention in which the specific conditions are not specified can be performed by a method conventional in the art, for example, refer to the pharmacopoeia of the people's republic of china (the pharmacopoeia of chinese medical science and technology, 2015 edition) or conditions recommended by suppliers.
Unless otherwise specified, various raw materials, equipment and the like of the invention are common and commercially available; or prepared according to conventional methods in the art.
Unless defined or stated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
Example 1 a method for preparing 40ppm of calcipotriol compound ointment was performed as follows:
1) mixing calcipotriol 0.004% of the total weight of the ointment (3 kg, the same below) and betamethasone 0.0005% of the total weight of the ointment under the gas protection conditions of 60 ℃, the illumination intensity of 1 lux and the nitrogen-oxygen molar ratio of 100, then adding vaseline 5% of the prescription amount, stirring and mixing at 6000rpm for 10 min;
2) 95% of the prescribed amount of petrolatum was weighed out, to which was added 2% by weight of light liquid paraffin based on the total weight of the ointment and 0.0005% by weight of vitamin E alcohol based on the total weight of the ointment (CAS No.: 10191-41-0), stirring and mixing for 10min at 60 ℃ and 100 rpm;
3) adding the mixture prepared in the step 1) into the mixture prepared in the step 2), and stirring for 30min at 100rpm under the conditions of 60 ℃ and gas protection with the illumination intensity of 1 lux and the nitrogen-oxygen molar ratio of 100 to obtain the uniformly mixed calcipotriol compound ointment;
4) and (3) measuring the mixing uniformity of the mixture by using an HPLC method at 6 different positions of the mixer in the step 3), wherein the content (in the marked amount) of the calcipotriol is 95 ~ 105%, and RSD =2.7% (according to the requirement of FDA on the content uniformity RSD < 4.2%).
Example 2 a method of preparing 60ppm of calcipotriol compound ointment was performed as follows:
1) mixing calcipotriol 0.006% of the total weight of the ointment (5 kg, same below) and clobetasol 1% of the total weight of the ointment under the protection of gas with the light intensity of 10 lux and the nitrogen-oxygen molar ratio of 50 at 90 ℃, then adding vaseline 8% of the prescription amount, stirring and mixing at 1000rpm for 3 min;
2) 92% of the prescribed amount of vaseline was weighed, and light liquid paraffin 20% by weight of the total ointment and 0.002% by weight of tocopherol alcohol (CAS No.: 10191-41-0), stirring at 90 ℃ and 100rpm for 20 min;
3) adding the mixture obtained in the step 1) into the mixture prepared in the step 2), and stirring for 20min at a speed of 20rpm under the conditions of 90 ℃ and gas protection with the illumination intensity of 10 lux and the nitrogen-oxygen molar ratio of 50 to obtain the uniformly mixed calcipotriol compound ointment;
4) and (3) measuring the mixing uniformity of the mixture by using an HPLC method at 6 different positions of the mixer in the step 3), wherein the content (in the marked amount) of the calcipotriol is 95 ~ 105%, and RSD =3.0% (according to the requirement of FDA on the content uniformity RSD < 4.2%).
Example 3 a method of preparing 50ppm of calcipotriol compound ointment was performed as follows:
1) under the protection of gas with the light intensity of 0.1 lux and the nitrogen-oxygen molar ratio of 20 at 75 ℃, 0.005% of calcipotriol of the total weight of the ointment (4.5 kg, the same below), 0.05% of betamethasone of the total weight of the ointment and 0.002% of vitamin E alcohol of the total weight of the ointment (CAS number: 10191-41-0), then 12 percent of the prescription amount of the vaseline is added, and the mixture is stirred and mixed for 5min at 2000 rpm;
2) weighing 88% of vaseline according to the prescription, adding light liquid paraffin 3% of ointment total weight, and stirring at 75 deg.C and 20rpm for 40 min;
3) adding the mixture obtained in the step 1) into the mixture prepared in the step 2), and stirring at 40rpm for 20min under the conditions of 75 ℃ and gas protection with the illumination intensity of 0.1 lux and the nitrogen-oxygen molar ratio of 50 to obtain the uniformly mixed calcipotriol compound ointment;
4) and (3) measuring the mixing uniformity of the mixture by using an HPLC method at 6 different positions of the mixer in the step 3), so that the content (in the indicated amount) of the calcipotriol is 95 ~ 105%, and the RSD =2.8% (according to the requirement of FDA on the content uniformity RSD < 4.2%).
Example 4 a method of preparing 55ppm of calcipotriol compound ointment was performed as follows:
1) at 85 deg.C, the illumination intensity is 30 lux and the air density is 0.29kg/m3Under the condition, 40 percent of vaseline prescription amount is added into a mixture of calcipotriol accounting for 0.0055 percent of the total weight of the ointment (5.5 kg, the same below) and clobetasol accounting for 0.03 percent of the total weight of the ointment, and the mixture is mixed for 1min at 10000 rpm;
2) 60% of the prescribed amount of vaseline was weighed, and 6% of light liquid paraffin by total weight of ointment and 0.0009% of vitamin E alcohol by total weight of ointment (CAS No.: 10191-41-0), stirring at 85 ℃ and 30rpm for 60 min;
3) adding the mixture obtained in the step 1) into the mixture prepared in the step 2), and stirring for 30min at the temperature of 85 ℃ and under the condition of gas protection with the illumination intensity of 30 lux and the nitrogen-oxygen molar ratio of 100 at the speed of 30rpm to obtain the uniformly mixed calcipotriol compound ointment;
4) taking 6 different parts of the mixer in the step 3), taking the mixture, and measuring the mixing uniformity by an HPLC method to obtain calcipotriol (accounting for the labeled amount) of between 95 ~ 105 percent and RSD =2.3 percent (according with the requirement of FDA on the content uniformity RSD < 4.2 percent).
Example 5 a method of preparing 42ppm of calcipotriol compound ointment was performed as follows:
1) under the conditions of 65 ℃, light intensity of 0.1 lux and gas protection with nitrogen-oxygen molar ratio of 200, under the conditions of 0.0042 percent of calcipotriol of the total weight of the ointment (6 kg, the same below), 0.04 percent of betamethasone of the total weight of the ointment and 0.0015 percent of vitamin E alcohol of the total weight of the ointment (CAS number: 10191-41-0), adding 30% of vaseline according to the prescription amount, stirring and mixing for 4min at 5000 rpm;
2) 70% of the prescribed amount of vaseline was weighed, and 5% of light liquid paraffin by weight and 0.0015% of vitamin E alcohol by weight (CAS No.: 10191-41-0), stirring at 85 ℃ and 50rpm for 10 min;
3) adding the mixture obtained in the step 1) into the mixture prepared in the step 2), and stirring at 50rpm for 20min under the protection of gas with the light intensity of 0.1 lux and the nitrogen-oxygen molar ratio of 120 at 85 ℃ to obtain uniformly mixed ointment for treating psoriasis;
4) and (3) measuring the mixing uniformity of the mixture by using an HPLC method at 6 different positions of the mixer in the step 3), wherein the content (in the marked amount) of the calcipotriol is 95 ~ 105%, and RSD =2.9% (according to the requirement of FDA on the content uniformity RSD < 4.2%).
Example 6 a method of preparing 53ppm of calcipotriol compound ointment was performed as follows:
1) adding 20% of vaseline prescription amount into 0.0053% of calcipotriol and 0.7% of betamethasone based on the total weight of ointment (5 kg, the same below) under gas protection of 70 deg.C, illumination intensity of 60lux and nitrogen-oxygen molar ratio of 100, and stirring at 800rpm for 20 min;
2) 80% of the prescribed amount of petrolatum was weighed out, to which 16% by weight of light liquid paraffin and 0.0007% by weight of vitamin E alcohol (CAS No.: 10191-41-0), stirring at 85 ℃ and 35rpm for 60 min;
3) adding the mixture obtained in the step 1) into the mixture prepared in the step 2), and stirring at 35rpm for 20min under the protection of gas with the light intensity of 60lux and the nitrogen-oxygen molar ratio of 3.7 at 85 ℃ to obtain uniformly mixed ointment for treating psoriasis;
4) and (3) measuring the mixing uniformity of the mixture by using an HPLC method at 6 different positions of the mixer in the step 3), wherein the content (in the marked amount) of the calcipotriol is 95 ~ 105%, and RSD =3.1% (according to the requirement of FDA on the content uniformity RSD < 4.2%).
Example 7 a process for preparing 49ppm of calcipotriol compound ointment was carried out as follows:
1) at 85 deg.C, the illumination intensity is 0.1 lux and the air density is 1.29kg/m3Under the condition of the gas atmosphere of (1),adding 16% of vaseline prescription amount into calcipotriol 0.0049% of the total weight of ointment (4 kg, the same below) and betamethasone 0.7% of the total weight of ointment, stirring and mixing at 3000rpm for 10 min;
2) 84% of the prescribed amount of petrolatum was weighed out, to which 1% by weight of light liquid paraffin and 0.0007% by weight of vitamin E alcohol (CAS No.: 10191-41-0), stirring at 85 ℃ and 60rpm for 40 min;
3) adding the mixture obtained in the step 1) into the mixture prepared in the step 2), and stirring at 60rpm for 30min under the conditions of 85 ℃ and gas protection with the illumination intensity of 0.1 lux and the nitrogen-oxygen molar ratio of 50 to obtain the uniformly mixed calcipotriol compound ointment;
4) and (3) measuring the mixing uniformity of the mixture by using an HPLC method at 6 different positions of the mixer in the step 3), wherein the content (in the marked amount) of the calcipotriol is 95 ~ 105%, and RSD =2.6% (according to the requirement of FDA on the content uniformity RSD < 4.2%).
Example 8: comparison of the present invention with the closest Prior Art
Comparing example 1 ~ 7 of the present invention with the closest prior art CN200480013008.6 sample preparation, the results are as follows:
index (I) Inventive example 1 ~ 7 CN200480013008.6
Stirring equipment Low equipment requirement, common stirring equipment Complex equipment such as a frustum conical container, a sealing cover and the like is required, and the device needs to be independently processed and customized
Time of homogenization Not more than 95min 210~240min
Amount of paraffin wax used 2~8% 40~50%
Process flow The process flow is simplified as shown in any of examples 1 ~ 7 Complicated steps, see page 5, paragraph 1 ~ 8 of the specification of patent CN200480013008.6
Example 9 a process for preparing 56ppm ointment of calcipotriol was carried out as follows:
1) under the gas protection conditions of 85 ℃, 10 lux of illumination intensity and 50 mol ratio of nitrogen to oxygen, 0.0056% of calcipotriol based on the total weight of the ointment (5 kg, the same below), 0.02% of corticosteroid mixture based on the total weight of the ointment, 0.0007% of vitamin E alcohol based on the total weight of the ointment (CAS number: 10191-41-0) and 16 percent of vaseline prescription amount are stirred and mixed, and the stirring speed is 10000 rpm;
2) stirring for 1min, taking the mixture, performing microscopic examination with an optical microscope under a field of view of 400 times, and stopping stirring if no crystal appears; if the crystalline substance exists, continuing stirring; stirring for no more than 10 min;
3) weighing 84% of vaseline according to the prescription amount, adding light liquid paraffin 8% of ointment total weight and tocopherol 0.002% according to the prescription amount, and stirring at 85 deg.C and 40rpm for 30 min;
4) adding the mixture obtained in the step 3) into the mixture prepared in the step 1), and stirring at 50rpm for 30min under the conditions of 60 ℃ and gas protection with the illumination intensity of 10 lux and the nitrogen-oxygen molar ratio of 50 to obtain uniformly mixed ointment;
5) and (3) measuring the mixing uniformity of the mixture by using an HPLC method at 6 different positions of the mixer in the step 4), wherein the content (in the marked amount) of the calcipotriol is 95 ~ 105%, and RSD =2.2% (according to the requirement of FDA on the content uniformity RSD < 4.2%).
Example 10 a method of preparing 56ppm of calcipotriol compound ointment was performed as follows:
1) at 70 deg.C, the illumination intensity is 60lux and the air density is 0.1kg/m3Under the gas environment of (1), adding 20 percent of vaseline prescription amount into 0.0056 percent of calcipotriol in the total weight of the ointment (4 kg, the same below) and 0.7 percent of betamethasone in the total weight of the ointment, stirring and mixing for 3min at 3000rpm, sampling, performing microscopic examination by using an optical microscope under a 400-time visual field, and stopping stirring after no crystal is detected by the microscopic examination;
2) weighing 80% of vaseline according to the prescription, adding light liquid paraffin 9% of ointment total weight, and stirring at 85 deg.C and 50rpm for 30 min;
3) adding the mixture obtained in step 1) into the mixture prepared in step 2), at 85 deg.C, with illumination intensity of 60lux and air density of 0.1kg/m3Stirring at 50rpm for 30min to obtain uniformly mixed ointment for treating psoriasis;
4) and (3) measuring the mixing uniformity of the mixture by using an HPLC method at 6 different positions of the mixer in the step 3), wherein the content (in the marked amount) of the calcipotriol is 95 ~ 105%, and RSD =4.0% (according to the requirement of FDA on the content uniformity RSD < 4.2%).
Experimental results show that the preparation method provided by the invention has the advantages of simplified equipment requirements, simplified operation steps, greatly reduced vaseline adding times, short homogenization time, less raw material consumption and improved economic benefits of pharmaceutical products.
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the scope of the invention, which is defined by the claims appended hereto, and any other technical entity or method that is encompassed by the claims as broadly defined herein, or equivalent variations thereof, is contemplated as being encompassed by the claims.
All documents mentioned in this application are incorporated by reference into this application as if each were individually incorporated by reference; furthermore, it should be understood that various changes and modifications can be made by those skilled in the art after reading the above disclosure, and equivalents also fall within the scope of the invention as defined by the appended claims.

Claims (8)

1. A method for preparing an ointment for treating psoriasis, comprising the steps of:
1) stirring and mixing calcipotriol 40-60 ppm of the total weight of the ointment, corticosteroid with a therapeutically effective amount and vaseline 5-40% of the prescription amount, wherein the mixing temperature is 60-90 ℃, the stirring speed is 800-10000 rpm, and the stirring time is not less than 1 min;
2) weighing vaseline accounting for 60-95% of the prescription amount, adding light liquid paraffin accounting for 1-20% of the total weight of the ointment, and stirring at 60-90 ℃ and 20-100 rpm for not less than 10 min;
3) adding the mixture obtained in the step 2) into the mixture prepared in the step 1), and stirring at 20-100 rpm for not less than 10min at 60-90 ℃ in a gas environment with the illumination intensity not more than 100lux and the nitrogen-oxygen molar ratio not less than 3.7 to obtain uniformly mixed ointment;
the preparation method comprises the steps of 1) preparing the mixture with the nitrogen-oxygen molar ratio not less than 20 and the air density not more than 1.29kg/m3The gas atmosphere and the illumination intensity of the illumination.
2. The method of claim 1, wherein the corticosteroid is selected from one or more of betamethasone, budesonide, clobetasol, clobetasone, and desoximetasone.
3. The method of claim 1, wherein components useful for external application are added during all of the stirring.
4. The method of claim 3, wherein the component for external use comprises an antioxidant.
5. The method according to claim 4, wherein the antioxidant is one or more selected from the group consisting of vitamin E alcohol (ester), tea polyphenol, sesamol, vitamin A, vitamin C, vitamin E, vitamin P, phytoactive selenium, ephenol, oryzanol, gossypol, cantharene, prunus salicin, stevioside, lycopene, olivetol, beta-carotene, bamboo leaf flavonoid, astaxanthin, tea pigment, allicin, sesamin and carotenoids.
6. The method according to claim 4, wherein the antioxidant is selected from plant polyphenols or flavonoids.
7. The method of claim 4, wherein the antioxidant is present in an amount of not less than 0.0005%.
8. The method of any one of claims 1-7, wherein the corticosteroid is present in an amount of 0.0005% to 1% by weight of the total ointment.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2016935A1 (en) * 2007-07-09 2009-01-21 Intendis GmbH Pharmaceutical composition for topical application of poorly soluble compounds

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EP2455083B1 (en) * 1999-04-23 2013-09-18 Leo Pharma A/S Pharmaceutical composition for dermal use comprising calcipotriol and betamethasone for treating psoriasis
FR2909284B1 (en) * 2006-11-30 2012-09-21 Galderma Sa NOVEL VASELIN-FREE OINTMENTAL COMPOSITIONS COMPRISING VITAMIN D DERIVATIVE AND POSSIBLY STEROID ANTI-INFLAMMATORY
CN103110648A (en) * 2013-01-25 2013-05-22 江苏圣宝罗药业有限公司 Calcipotriol betamethasone ointment and preparation method thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2016935A1 (en) * 2007-07-09 2009-01-21 Intendis GmbH Pharmaceutical composition for topical application of poorly soluble compounds

Non-Patent Citations (1)

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Title
"Efficacy of once-daily treatment regimens with calcipotriol ⁄betamethasone dipropionate ointment and calcipotriol ointment in psoriasis vulgaris";K.KRAGBALLE et al.;《British Journal of Dermatology》;20031215;第150卷;第1167-1173页 *

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