CN107157919B - Preparation method of semisolid preparation for treating psoriasis - Google Patents

Preparation method of semisolid preparation for treating psoriasis Download PDF

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CN107157919B
CN107157919B CN201610129309.XA CN201610129309A CN107157919B CN 107157919 B CN107157919 B CN 107157919B CN 201610129309 A CN201610129309 A CN 201610129309A CN 107157919 B CN107157919 B CN 107157919B
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preparation
stirring
mixing
calcitriol
amount
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CN107157919A (en
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马媛媛
刘曲
任寅
徐若娴
弓艺涓
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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • 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
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a preparation method of a semisolid preparation for treating psoriasis, which specifically comprises the steps of 1) adding a mixture of corticosteroid with effective treatment amount and calcitriol with the weight of 1 ~ 5ppm of the total weight of the semisolid preparation into a substrate with the prescription amount of 2 ~ 40%, stirring and mixing for 1 ~ 30min, 2) mixing and stirring the substrate with the rest prescription amount and other pharmaceutic adjuvants for 10 ~ 60min, and 3) combining the mixture obtained in the steps 1) and 2) at 60 ~ 90 ℃, mixing and stirring for about 20 ~ 30min to obtain the semisolid preparation for treating the psoriasis.

Description

Preparation method of semisolid preparation for treating psoriasis
Technical Field
The invention relates to a preparation method of a medicinal preparation, in particular to a preparation method of a semisolid preparation for treating psoriasis.
Background
Psoriasis, commonly known as psoriasis, is stubborn and difficult to treat, has no cure method at present, is an important research subject in the field of dermatology in the world at present, is listed as one of ten stubborn diseases by the world health organization, and is also one of important diseases for preventing and treating the dermatology in the world; at present, the external medicine for treating psoriasis mainly comprises vitamin D derivatives, glucocorticoids, tretinoins, anthralin, cutin stripper and the like, wherein the glucocorticoids, tretinoins, cutin stripper and the like are not suitable for long-term use of patients due to more adverse reactions or higher toxicity, and have the advantages of treating symptoms without treating the root cause and easily relapse after stopping the medicine; anthralin is not readily 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.
Calcitriol (Calcitriol) is white crystalline powder, sensitive to light and air, slightly soluble in methanol, ethanol and ethyl acetate, is one of the most important metabolic active products of human vitamin D3, has the effects of promoting calcium absorption by small intestine and regulating inorganic salt transport in bone, is mainly suitable for skin diseases such as osteoporosis and renal osteodystrophy of chronic renal failure patients (particularly patients needing long-term hemodialysis), spontaneous and pseudo-parathyroid insufficiency after operation, vitamin D3 dependent rickets and hypophosphatemia vitamin D resistant rickets, psoriasis and other vitamin D deficiency diseases, is fast in oral absorption of Calcitriol, reaches a high peak within 3-6 hours, t1/2 is about 3-6 hours, the concentration of urine calcium is increased after 7 hours, the pharmacological activity of a single oral dose is 3-5 days, at present, the main preparation forms of Calcitriol are soft capsules and capsules, are relatively monotonous, relatively low in the solubility of common organic solvents, the stability of the Calcitriol and the stability of the Calcitriol in soft capsules are very low, the stability of the Calcitriol and the Calcitriol is very easy to be improved in the preparation process of preparing the Calcitriol, the Calcitriol is very easy to be prepared in the stable soft capsules, the stability of the medium, the Calcitriol, the stability of the Calcitriol is very easy to be easily improved, the stability of the Calcitriol in the preparation, and the stability of the Calcitriol preparation, and the Calcitriol preparation, the stability of the stability.
To solve the above problem, the most common method is the equal increment method: grinding active ingredients, adding the ground active ingredients into a matrix with the same quantity, uniformly mixing, adding the matrix with the same quantity as the mixture, uniformly mixing, repeating the operation until all the components are completely mixed, and performing vacuum operation or nitrogen gas introduction operation in the whole mixing process, wherein the method has the following defects: when the content of the active ingredients is very low and the content of the active ingredients and the matrix in the preparation are different greatly, the number of times of repeatedly adding the matrix is greatly increased, the number of times of adding is at least eight thousand, three or hundred, the production has the problems of multiple operation steps, long production time, complex process control, multiplied equipment and labor cost and the like; the production steps are multiple, the production time is long, and the reduction of active ingredients and the generation of impurities are caused; for pharmaceutical products, the decrease of the active ingredient will affect the effectiveness of the drug, and the generation of impurities will affect the safety of the drug.
Patent CN201310092768.1 discloses a calcitriol emulsion and a preparation method thereof, wherein a prescription amount of vegetable oil is taken, a prescription amount of calcitriol, an emulsifier and an auxiliary emulsifier are added, the mixture is uniformly stirred at 500 ~ 1000rpm to obtain an oil phase, a prescription amount of water for injection is taken, a prescription amount of polyethylene glycol 400 is added, the mixture is uniformly stirred, the mixture is continuously added with the prescription amount of meglumine and polyethylene glycol 6000, and the mixture is stirred at 45 ~ 55 ℃ for 15 ~ 25min until the mixture is completely dissolved to obtain a solution, the oil phase is slowly added into the obtained solution along the same direction at the stirring speed of 500 ~ 1000rpm, the mixture is emulsified in an emulsifying machine for 2 ~ 4 times, filtered and filled, and sterilized at 115 ℃ for 30min to obtain the emulsion.
Patent CN201210424432.6 discloses a soft capsule containing calcitriol, the content of which consists of: calcitriol, medium-chain triglyceride, 2, 6-di-tert-butyl-4-methylphenol and tert-butyl hydroxyanisole, wherein the rubber of the soft capsule contains gelatin, glycerin, opacifier and colorant, and does not contain sorbitol; the patent is a solid preparation for preparing a dosage form, does not disclose a specific process for mixing uniformity of a pharmaceutically active substance, and cannot solve the problems of mixing uniformity, stability and generation of impurities of trace substances.
Patent CN200480013008.6 discloses a method for preparing a preparation containing a trace amount of active ingredients, which solves the problem of multiple steps in an equivalent delivery method, and the method comprises step 3) of directly introducing a container encapsulating active ingredients into a mixer to protect the active ingredients from photoreaction or oxidation, wherein the method has the disadvantages that the requirements on mixing equipment (see fig. 1 ~ of the patent CN200480013008.6 for details) are very high, complex equipment such as a stainless steel cone frustum and a sealing cover is required in the preparation process, the weighing container of raw materials has a complex structure, a grating is arranged at the tail end of the container, sealing hard plugs and porous plugs are arranged above and below the container, a connecting lock is required to be arranged to be combined with the mixer, meanwhile, the mixer is provided with a rod and a lock with a certain height to drive the weighing container encapsulating active ingredients to rotate, the mixing equipment with a complex structure is specially manufactured, the production cost and the operation cost are increased, the blending time is long, if the trace amount of active ingredients are dispersed into a large amount of a matrix, the mixing equipment needs to be manufactured by special customization, the production cost is increased, the production cost and the blending time is increased, the mixing time is high when the vitamin 7.54 h is considered as the optimal mixing temperature is 365.54 h, and the vitamin D is not stable, and the mixing time is high temperature is 365 h, and 365 h is shown in the optimal mixing time is shown in the patent specification.
In summary, the prior art has not solved the technical problem in the preparation process of vitamin D derivative semisolid preparation: when a trace amount of active substances are mixed with a large amount of matrix, the active substances are difficult to be uniformly mixed; the existing method for solving the uniformity has complex operation steps and fussy control of the production process; or the structural configuration of the mixing equipment is higher, and special production equipment needs to be customized; these methods all suffer from high production and running costs, long mixing times, instability of the active substance during mixing and storage of the formulation, and affect drug efficacy and safety.
Accordingly, there is a need for improvements in the prior art that overcome the deficiencies of the prior art.
Disclosure of Invention
In order to solve the problems, through long-term research, research personnel find that under the conditions that the illumination intensity, the air density and the mixing temperature in a specific range are 60 ~ ℃ and the first stirring speed of trace substances is 800 ~ 10000rpm, through adding the matrix twice and controlling the adding amount of the first matrix in the mixing process to be 2 6340% of the formula amount, the mixing uniformity and stability of the pharmaceutical active substance calcitriol can be ensured, the mixing time is shortened, the traditional complex equipment is abandoned, the complex operation steps are reduced, the production cost is reduced, the risk of generating impurities in the pharmaceutical production process is reduced, and the economic benefit of pharmaceutical preparation is improved.
The present invention provides a process for the preparation of a semi-solid formulation for the treatment of psoriasis, said process comprising the steps of:
1) mixing therapeutically effective amount of corticosteroid, ossification triol 0.0001, 0.0001 ~ 0.0005 wt% of semisolid preparation, and matrix 2, 2 ~ 40 wt% of prescription under stirring at 60, 60 ~ 90 deg.C and stirring rate 800 ~ 10000 rpm;
2) taking the rest of the substrate except the substrate used in the step 1), and mixing and stirring at 20 ~ 100rpm for 10 ~ 60min at the temperature of 60 ~ 90 ℃;
3) adding the mixture prepared in the step 1) into the mixture prepared in the step 2) at the temperature of 60 ~ 90 ℃ and stirring at 20 ~ 100rpm for 20 ~ 30min to obtain the semi-solid preparation for treating psoriasis.
In a preferred embodiment, the mixing temperature in step 1) above is 75 ~ 85 deg.C, the stirring time in step 1) above is 1 ~ 30min, and the matrix content in step 1) above is 5 ~ 20% of the prescribed amount.
In a preferred embodiment, the semi-solid formulation is an ointment, cream or gel.
In a preferred embodiment, the substrate is selected from: vaseline, liquid paraffin (or light liquid paraffin), or their mixture.
In a preferred embodiment, the corticosteroid is present in an amount of 0.0005 ~ 0.1.1% by weight of the total weight of the semisolid formulation.
In a preferred embodiment, 0.0005 ~ 0.002.002% by weight of antioxidant based on the total weight of the semisolid formulation is added (or not added) during all of the above stirring processes.
In a preferred embodiment, the above antioxidant is selected from: tocopherol, other natural antioxidants that perform similar functions to tocopherol, or a mixture of both.
In a preferred embodiment, other components useful for topical application are added (either with or without addition) during all of the above-described agitation.
In a preferred embodiment, the corticosteroid is selected from: one or more of betamethasone, budesonide, clobetasol, clobetasone and desoximetasone.
In a preferred embodiment, the preparation method is carried out in an environment with the illumination intensity not exceeding 60 lux; preferably, the preparation method is to use the air density not more than 1.29kg/m3The gas environment and the illumination intensity do not exceed 60 lux; most preferably, the preparation method is carried out in a gas environment with the nitrogen-oxygen molar ratio not less than 3.7 and an environment with the illumination intensity not more than 60 lux.
In a preferred embodiment, other components useful for topical application are added (either with or without addition) during all of the described agitation.
In a preferred embodiment, the components of the external preparation are selected from: one or more of tea polyphenol, sesamol, vitamin A, vitamin C, vitamin E, vitamin P, plant polyphenol, plant active selenium, ephenol, oryzanol, gossypol, cantharene, plum fruit polyphenol, stevioside, lycopene, olivetol, beta-carotene, flavonoids, bamboo leaf flavone, astaxanthin, tea pigment, allicin, sesamin or carotenoid.
The preparation method of the semisolid preparation for treating psoriasis provided by the invention has the following advantages:
1) the complicated operation steps are simplified, and the industrial production is easy to control;
2) traditional complex equipment is abandoned, the production cost is reduced, and the economic benefit is improved;
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 reaction temperature is mentioned herein as 10-100 ℃ and the reaction temperature is mentioned in the examples as 20 ℃, it is considered that the range of 10-20 ℃ or the range of 20-100 ℃ has been specifically disclosed herein, and that this range can be combined with other features of the description to form a new technical solution.
The present invention provides a process for the preparation of a semi-solid formulation for the treatment of psoriasis, said process comprising the steps of:
1) mixing therapeutically effective amount of corticosteroid, ossification triol 0.0001. 0.0001 ~ 0.0005% in total weight of semisolid preparation, and matrix 2 ~ 40% in prescription amount under stirring at 60 ~ 90 deg.C, stirring speed of 800 ~ 10000rpm, and stirring time of 1 ~ 30 min;
2) weighing liquid paraffin (or light liquid paraffin) 2 ~ 30% of the total weight of the matrix used in the step 1) and the semisolid preparation in the prescription amount except the matrix used in the step 1), and mixing and stirring at 20 ~ 100rpm for 10 ~ 60min at the temperature of 60 ~ 90 ℃;
3) adding the mixture prepared in the step 1) into the mixture prepared in the step 2) at the temperature of 60 ~ 90 ℃ and stirring at 20 ~ 100rpm for 20 ~ 30min to obtain the semi-solid preparation for treating psoriasis.
In a preferred embodiment, the mixing temperature in step 1) is 75 ~ 85 ℃, and the matrix content in step 1) is 5 ~ 20% of the prescribed amount.
In a preferred embodiment, the semisolid preparation is an ointment, a cream or a gel.
In a preferred embodiment, the base is vaseline.
In a preferred embodiment, the corticosteroid is present in an amount of 0.0005 ~ 0.1.1% by weight of the total weight of the semisolid formulation.
In a preferred embodiment, 0.0005 ~ 0.002.002% by weight of antioxidant based on the total weight of the semisolid formulation is added (or not added) during all of the above stirring processes.
In a preferred embodiment, the antioxidant is selected from: tocopherol, other natural antioxidants that perform similar functions to tocopherol, or a mixture of both.
In a preferred embodiment, other components useful for external application are added (either with or without addition) during all of the above-described agitation.
In a preferred embodiment, the corticosteroid is selected from the group consisting of: one or more of betamethasone, budesonide, clobetasol, clobetasone and desoximetasone.
In a preferred embodiment, the preparation method is carried out in an environment with the illumination intensity not more than 60 lux; preferably, the preparation method is to use the air density not more than 1.29kg/m3The gas environment and the illumination intensity do not exceed 60 lux; most preferably, the preparation method is carried out in a gas environment with the nitrogen-oxygen molar ratio not less than 3.7 and an environment with the illumination intensity not more than 60 lux.
In a preferred embodiment, other components useful for external application are added (either with or without addition) during all of the described agitation.
In a preferred embodiment, the components of the external medicine are selected from: one or more of tea polyphenol, sesamol, vitamin A, vitamin C, vitamin E, vitamin P, plant polyphenol, plant active selenium, ephenol, oryzanol, gossypol, cantharene, plum fruit polyphenol, stevioside, lycopene, olivetol, beta-carotene, flavonoids, bamboo leaf flavone, astaxanthin, tea pigment, allicin, sesamin or carotenoid.
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 present invention are commercially available; or prepared according to the conventional method in the field; 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: preparation of an ointment containing 1ppm calcitriol
1) Adding betamethasone 0.0005% of total weight of ointment and light liquid paraffin 2% of total weight of ointment into calcitriol 0.0001% of total weight of ointment (3 kg, the same below), and mixing at 90 deg.C and 4000rpm for 3 min; sampling, performing microscopic examination by using an optical microscope under a 400-time visual field, and stopping stirring after no crystallization is performed in the microscopic examination;
2) the prescribed amount of petrolatum was weighed out and 0.0005% by weight of vitamin E alcohol (CAS No.: 10191-41-0), stirring for 30min at the temperature of 90 ℃ and the rpm of 20;
3) adding the mixture obtained in the step 1) into the mixture prepared in the step 2), and stirring at 90 ℃ and 20rpm for 30min to obtain uniformly mixed ointment containing calcitriol;
4) in 6 different parts of the mixer in the step 3), the mixture is taken and the mixing uniformity is measured by an HPLC method, and the calcitriol content (in the marked amount) is 95 ~ 105%, and the RSD =3.7% (according to the requirement of FDA on the content uniformity RSD < 4.2%) is obtained.
Example 2: preparation of an ointment containing 4ppm calcitriol
1) Adding clobetasol and vaseline accounting for 30% of the prescription amount, 1% of the total weight of the ointment, into calcitriol accounting for 0.0004% of the total weight of the ointment (4 kg, the same below), mixing at 6000rpm for 15min under the conditions that the illumination intensity is 0.1lux, the nitrogen-oxygen introducing molar ratio is 40 and the temperature is 60 ℃, sampling, performing microscopic examination by using an optical microscope under a field of view of 400 times, and stopping stirring after no crystal is generated in the microscopic examination;
2) 70% of the prescribed amount of vaseline was weighed, and light liquid paraffin 8% by weight of the total ointment and vitamin E alcohol 0.001% by weight of the total ointment were added thereto (CAS No.: 10191-41-0), stirring for 10min at 100rpm in a gas environment with the illumination intensity of 0.1lux and the nitrogen-oxygen molar ratio of 40 at 60 ℃;
3) adding the mixture obtained in the step 1) into the mixture prepared in the step 2), and stirring for 30min at 100rpm under the gas environment with the light intensity of 0.1lux and the nitrogen-oxygen molar ratio of 40 at the temperature of 60 ℃ to obtain uniformly mixed ointment containing calcitriol;
4) in 6 different parts of the mixer in the step 3), the mixture is taken and the mixing uniformity is measured by an HPLC method, and the calcitriol content (in the marked amount) is 95 ~ 105%, and the RSD =3.6% (according to the requirement of FDA on the content uniformity RSD < 4.2%) is obtained.
Example 3: preparation of an ointment containing 4ppm calcitriol
1) 0.0004% calcitriol, 0.0005% betamethasone, and 0.002% tocopheryl alcohol (CAS No.: 10191-41-0), then 10 percent of vaseline is added into the mixture, and the mixture is mixed for 8min at 2000rpm under the conditions of 75 ℃, the illumination intensity is 90lux and the gas with the mol ratio of nitrogen to oxygen being 9;
2) 90% of the prescribed amount of vaseline was weighed, and 2% by weight of light liquid paraffin and 0.002% by weight of tocopherol alcohol (CAS No.: 10191-41-0), stirring for 10min at the temperature of 75 ℃ and the rpm of 40;
3) adding the mixture obtained in the step 1) into the mixture prepared in the step 2), and stirring at the temperature of 75 ℃ and the rpm of 100 for 30min to obtain uniformly mixed ointment containing calcitriol;
4) and (3) measuring the mixing uniformity of the mixture by using an HPLC method at 6 different parts of the mixer in the step 3), and obtaining the calcitriol content (in the marked amount) of 95 ~ 105% and RSD =3.2% (according to the requirement of FDA on the content uniformity RSD < 4.2%).
Example 4: preparation of an ointment containing 5ppm calcitriol
1) Adding clobetasol and vaseline accounting for 43% of the prescription amount, accounting for 0.03% of the total weight of the ointment, into calcitriol accounting for 0.0005% of the total weight of the ointment (50 kg, the same below), mixing at 3000rpm for 25min under the conditions of a gas environment with the illumination intensity of 1lux and the nitrogen-oxygen molar ratio of 100 and the temperature of 85 ℃, sampling, performing microscopic examination by using an optical microscope under a field of view of 400 times, and stopping stirring after no crystal is formed in the microscopic examination;
2) 57% of the prescription amount of vaseline was weighed, and 7% of light liquid paraffin by the total weight of the ointment and 0.001% of vitamin E alcohol by the total weight of the ointment (CAS No.: 10191-41-0), stirring for 10min at the temperature of 85 ℃ and the rpm of 30;
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 gas environment with the light intensity of 1lux and the nitrogen-oxygen molar ratio of 100 at the speed of 30rpm to obtain uniformly mixed ointment containing calcitriol;
4) and (3) measuring the mixing uniformity of the mixture by using an HPLC method at 6 different parts of the mixer in the step 3), wherein the content (in the marked amount) of the calcitriol is 95 ~ 105%, and RSD =2.1% (according to the requirement of FDA on the content uniformity RSD < 4.2%).
Example 5: preparation of an ointment containing 3ppm calcitriol
1) Adding betamethasone 0.04% of total weight of ointment and light liquid paraffin 18% of total weight of ointment into calcitriol 0.0003% of total weight of ointment (6 kg, the same below), and irradiating at light intensity of 10lux and air density of 0.29kg/m3In an atmospheric environment and at the temperature of 90 ℃, mixing for 15min at 800rpm, sampling, performing microscopic examination by using an optical microscope under a field of view of 400 times, and stopping stirring after no crystallization is generated in the microscopic examination;
2) the prescribed amount of petrolatum was weighed out, to which 0.0009% by weight of the total weight of the ointment of vitamin E alcohol (CAS No.: 10191-41-0), stirring for 60min at 180rpm in a gas environment with the illumination intensity of 0.1lux and the nitrogen-oxygen molar ratio of 100 at 45 ℃;
3) adding the mixture obtained in the step 1) into the mixture prepared in the step 2), wherein the illumination intensity is 10lux, and the air density is 0.29kg/m3Stirring at 85 deg.C and 60rpm for 20min to obtain ointment containing calcitriol;
4) and (3) measuring the mixing uniformity of the mixture by using an HPLC method at 6 different parts of the mixer in the step 3), wherein the content (in the marked amount) of the calcitriol is 95 ~ 105%, and RSD =2.2% (according to the requirement of FDA on the content uniformity RSD < 4.2%).
Example 6: preparation of an ointment containing 3ppm calcitriol
1) Adding betamethasone 0.5% of total weight of ointment and 20% of prescription amount of matrix (80% of vaseline and 20% of liquid paraffin) into calcitriol 0.0003% of total weight of ointment (3 kg, the same below), mixing at 10000rpm for 1min under the conditions of illumination intensity of 10lux and gas with nitrogen-oxygen molar ratio of 20 and 85 ℃, sampling under an optical microscope under 400 times visual field, stopping stirring after no crystallization is detected by the microscope;
2) 80% of the prescribed amount of the base (80% by weight of vaseline and 20% by weight of liquid paraffin) was weighed out, to which 0.0009% of vitamin E alcohol (CAS No.: 10191-41-0) and tea polyphenol (mixed at any ratio), stirring at 85 deg.C and 30rpm for 20 min;
3) adding the mixture obtained in the step 1) into the mixture prepared in the step 2), and stirring at 85 ℃ and 40rpm for 20min to obtain uniformly mixed ointment containing calcitriol;
4) in 6 different parts of the mixer in the step 3), the mixture is taken and the mixing uniformity is measured by an HPLC method, and the calcitriol content (in the marked amount) is 95 ~ 105%, and the RSD =1.7% (according to the requirement of FDA on the content uniformity RSD < 4.2%) is obtained.
Example 7: preparation of an ointment containing 2ppm of calcitriol
1) Adding betamethasone 0.7% of the total weight of the ointment and vaseline 8% of the prescription amount into calcitriol 0.0002% of the total weight of the ointment (5 kg, the same below); mixing at 10000rpm in atmospheric environment with illumination intensity of 60lux, 70 deg.C and nitrogen-oxygen molar ratio of 6 for 5min, sampling under 400 times visual field, microscopic examination with optical microscope, and stopping stirring after microscopic examination has no crystal;
2) 92% of the prescribed amount of vaseline was weighed out, and 30% by weight of light liquid paraffin and 0.0007% by weight of vitamin E alcohol (CAS No.: 10191-41-0), stirring for 50min at the temperature of 60 ℃ and the rpm of 100;
3) adding the mixture obtained in the step 1) into the mixture prepared in the step 2), and stirring at the temperature of 60 ℃ and the rpm of 200 for 30min to obtain uniformly mixed ointment containing calcitriol;
4) and (3) measuring the mixing uniformity of the mixture by using an HPLC method at 6 different parts of the mixer in the step 3), wherein the content (in the marked amount) of the calcitriol is 95 ~ 105%, and the RSD =2.4% (according to the requirement of FDA on the content uniformity RSD < 4.2%).
Example 8: preparation of an ointment containing 5ppm calcitriol
1) 0.0005% by weight of calcitriol based on the total weight of the ointment (6 kg, same below) and 0.001% by weight of tocopheryl alcohol based on the total weight of the ointment (CAS No.: 10191-41-0) is added with 0.02% of beta of the total weight of the ointmentThe prescription amount of the methasone and the vaseline is 10%, the illumination intensity is 10lux, and the air density is 1.29kg/m3Mixing at 4000rpm at 90 deg.C for 5 min;
2) 90% of the prescribed amount of vaseline was weighed out, and 2% of liquid paraffin by total weight of ointment and 0.002% of vitamin E alcohol by total weight of ointment (CAS No.: 10191-41-0), stirring for 10min at the temperature of 75 ℃ and the rpm of 20;
3) adding the mixture obtained in the step 1) into the mixture prepared in the step 2), wherein the illumination intensity is 10lux, and the air density is 1.29kg/m3Stirring at 75 deg.C and 40rpm for 40min to obtain ointment containing calcitriol;
4) and (3) measuring the mixing uniformity of the mixture by using an HPLC method at 6 different parts of the mixer in the step 3), and obtaining the calcitriol content (in the marked amount) of 95 ~ 105% and RSD =3.4% (according to the requirement of FDA on the content uniformity RSD < 4.2%).
Example 9: preparation of an ointment containing 2ppm of calcitriol
1) Adding betamethasone 1% of the total weight of the ointment and vaseline 35% of the prescription amount into calcitriol 0.0002% of the total weight of the ointment (6 kg, the same below); mixing at 4000rpm in gas environment with nitrogen-oxygen ratio of 3.7 at 60 deg.C for 30min, sampling under 400 times visual field, examining with optical microscope, and stopping stirring after no crystal is detected;
2) 65% of the prescribed amount of vaseline was weighed, and 6% of light liquid paraffin by weight of the total ointment and 0.0009% of vitamin E alcohol by weight of the total ointment (CAS No.: 10191-41-0) and beta-carotene (the mixing ratio is any ratio), stirring for 30min at the temperature of 60 ℃ and the rpm of 100;
3) adding the mixture obtained in the step 1) into the mixture prepared in the step 2), and stirring at 100rpm for 30min at 60 ℃ to obtain uniformly mixed ointment containing calcitriol;
4) in 6 different parts of the mixer in the step 3), the mixture is taken and the mixing uniformity is measured by an HPLC method, and the calcitriol content (in the marked amount) is 95 ~ 105%, and the RSD =3.6% (according to the requirement of FDA on the content uniformity RSD < 4.2%) is obtained.
The semisolid preparation for treating psoriasis prepared by the conventional method needs complex preparation such as a frustum conical container, a sealing cover and the like, the devices need to be specially customized in production, the process is complex, the flow is complex, and the stirring time is as long as more than 3.5 hours; the active substance is degraded, which is very bad for the effectiveness and stability of the medicine, and affects the application of industrial production and increases the production cost.
The semisolid preparation for treating psoriasis prepared by the method of example 1 ~ 9 is obtained by market by adopting common equipment in the pharmaceutical field instead of complex equipment such as a frustum conical container and a sealing cover in the production process, is simple to operate, greatly reduces the adding times of the matrix, ensures the mixing uniformity of the active substances, reduces the mixing time, can be used for treating skin diseases such as psoriasis and the like, and improves the economic benefit of industrial production.
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 (10)

1. A process for the preparation of a semi-solid formulation for the treatment of psoriasis, characterized in that it consists of the following steps:
1) stirring and mixing corticosteroid with effective treatment amount, ossification triol accounting for 0.0001-0.0005% of the total weight of the semisolid preparation and matrix accounting for 2-40% of the prescription amount, wherein the mixing temperature is 60-90 ℃, and the stirring speed is 800-10000 rpm;
2) taking the matrix of the rest prescription except the matrix used in the step 1), and mixing and stirring at 20-100 rpm for 10-60 min at the temperature of 60-90 ℃;
3) adding the mixture prepared in the step 1) into the mixture prepared in the step 2) at the temperature of 60-90 ℃, and mixing and stirring at 20-100 rpm for 20-30 min to obtain a semisolid preparation for treating psoriasis;
the preparation method is characterized in that the nitrogen-oxygen molar ratio is not less than 3.7, and the air density is not more than 1.29kg/m3The gas atmosphere and the illumination intensity of the illumination.
2. The method according to claim 1, wherein the mixing temperature in step 1) is 75 to 85 ℃, the stirring time in step 1) is 1 to 30min, and the content of the base material in step 1) is 5 to 20% of the amount of the prescription.
3. The method of claim 1, wherein the semi-solid formulation is an ointment, cream or gel.
4. The method of claim 1, wherein the corticosteroid is present in an amount of 0.0005 to 1% by weight of the total weight of the semisolid formulation.
5. The method of claim 1, wherein the antioxidant is added in an amount of 0.0005 to 0.002% by weight based on the total weight of the semisolid formulation during all the stirring.
6. The method of claim 5, wherein the antioxidant is selected from the group consisting of: tocopherol, other natural antioxidants that perform similar functions to tocopherol, or a mixture of both.
7. The process according to any one of claims 1 to 6, wherein the corticosteroid is selected from: one or more of betamethasone, budesonide, clobetasol, clobetasone and desoximetasone.
8. The process of claim 1 wherein other ingredients useful for topical application are added during all of said agitation.
9. The method of claim 8, wherein the components of the topical formulation are selected from the group consisting of: one or more of tea polyphenol, sesamol, vitamin A, vitamin C, vitamin E, vitamin P, plant active selenium, gingerol, oryzanol, gossypol, cantharene, plum fruit polyphenol, stevioside, lycopene, olivetol, beta-carotene, bamboo leaf flavone, astaxanthin, tea pigment, allicin, sesamin or carotenoid.
10. The method of claim 8, wherein the components of the topical formulation are selected from the group consisting of: plant polyphenol, or flavonoid.
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Citations (1)

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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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HU230045B1 (en) * 1999-04-23 2015-06-29 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) Pharmaceutical composition for dermal use
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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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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"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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