CN113712900A - Tofacitinib citrate ointment composition and preparation method thereof - Google Patents
Tofacitinib citrate ointment composition and preparation method thereof Download PDFInfo
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- CN113712900A CN113712900A CN202010447772.5A CN202010447772A CN113712900A CN 113712900 A CN113712900 A CN 113712900A CN 202010447772 A CN202010447772 A CN 202010447772A CN 113712900 A CN113712900 A CN 113712900A
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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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
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
Abstract
The present invention relates to an external preparation comprising tofacitinib citrate as an active ingredient. In particular, the present invention relates to an external preparation containing tofacitinib citrate, which has excellent stability and very low skin irritation.
Description
Technical Field
Tofacitinib citrate ointment composition and its preparation method are provided.
The present invention relates to an external preparation comprising tofacitinib citrate as an active ingredient. In particular, the present invention relates to an external preparation containing tofacitinib citrate, which has excellent stability and very low skin irritation.
[ background of the invention ]
Tofacitinib citrate, an English name Tofacitinib citrate, is a JAK inhibitor developed by the company Perey, can effectively inhibit the activity of JAK1 and JAK3, and blocks the signal transduction of various inflammatory cytokines. FDA approved in 2012 for the treatment of adult active-life and moderate to severe active rheumatoid arthritis adult patients who respond poorly or intolerant to methotrexate treatment. The product can be used alone, or combined with other methotrexate or antirheumatic drugs. 11/06/2012, approved by the U.S. Food and Drug Administration (FDA) for marketing, under the trade name: xeljanz.
The tofacitinib citrate is prepared from tofacitinib citrate with the following chemical name: (3R,4R) -4-methyl-3- (methyl-7H-pyrrolo [2, 3-d)]Pyrimidin-4-ylamino) -beta-oxo-1-piperidinepropanitrile, 2-hydroxy-1, 2, 3-propanetricarboxylic acidAcid salt (1:1), formula C16H20N6O·C6H8O7Molecular weight 504.5, chemical formula:
description of the drawings:
FIG. 1 molecular formula C16H20N6O·C6H8O7Molecular weight 504.5, chemical formula:
alopecia (Calvities), also called alopecia, is a common hair disease, mostly occurs in about 20-30 years old, mostly occurs in males, and can be divided into congenital alopecia and acquired alopecia. Congenital baldness may be autosomal dominant inheritance with family history and close-up marriage history. The acquired alopecia includes alopecia caused by severe factors, such as alopecia areata, seborrheic alopecia and the like, wherein the seborrheic alopecia is the most common. The etiology of the disease is not completely understood, and the western medicine considers that the heredity is a relatively fixed factor and is also closely related to androgen, including the increase of sensitivity to androgen or excessive androgen; according to the traditional Chinese medicine, the disease is caused by the fact that dampness and heat invade skin, nutrition and defense disorders, vein stasis and blood generation are unfavorable, hair growth is affected, and hair roots are not fixed to cause hair sparseness and hair loss. Seborrhea is currently believed to play no significant role in the pathogenesis of the disease. The disease has high incidence rate, is mostly seen in young and strong people, and brings much trouble and pain to patients due to the influence on beauty.
There are many related products on the market today for treating alopecia, and the principle includes the following aspects:
1: controlling seborrheic alopecia and increasing the oil discharge function of scalp hair follicles;
2: promoting blood circulation, dilating pores, promoting blood circulation, removing fat, nourishing hair root, enhancing hair root cell division and metabolism, and promoting hair growth;
3: sterilizing and inhibiting bacteria, and inhibiting dandruff caused by fungi;
4: dispelling pathogenic wind, removing dampness, clearing away heat and toxic materials;
5: increasing hair tissue nutrition, maintaining normal metabolism, stimulating and promoting hair growth;
6: the function of trace elements.
The baldness factors are various, the factors need to be considered from multiple aspects of hair growth, the reasons of the baldness are not single, and many existing products only have the function of repairing hair follicles corresponding to a certain part of the reasons of the baldness, so that the ideal effect is difficult to achieve due to the fact that the hair loss is considered and the comprehensive factor of the baldness is not considered. This results in the main problems with the existing products: the hair follicle has unsatisfactory recovery function, and can grow hair, but the hair grows slowly, and the grown hair is thin, yellow and difficult to maintain for a long time, and the grown hair is easy to fall off once the hair follicle is not used. Tofacitinib citrate is known to be used for external application to treat alopecia diseases, such as alopecia areata. Also, it is known that abnormal dryness or itching of the skin is caused by the deterioration of the barrier function of the skin. Therefore, there is a need for external preparations containing tofacitinib citrate.
Because tofacitinib citrate is poorly soluble in water and fat-soluble solvents, formulations containing it require solubilizers that can dissolve tofacitinib citrate. Surfactants are generally used as solubilizers. However, due to its skin irritation, surfactants are not suitable for use in formulations for the treatment of skin diseases such as atopic dermatitis. The solubilizers available, other than surfactants, are very limited. Or may render the active ingredient, such as tofacitinib citrate, chemically unstable in that such solubilizers may be skin-irritating, like surfactants, and therefore unsuitable for use with solubilizers having said undesirable characteristics. Furthermore, in order to reduce the skin irritation caused by tofacitinib citrate ointment, solubilizers capable of forming stable droplet dispersions that are not miscible with the ointment base are preferred. Moreover, in the case of treating skin diseases (such as atopic dermatitis), tofacitinib citrate is preferably delivered topically since it is an immunosuppressant. Tofacitinib citrate, if administered systemically, can cause undesirable side effects (e.g., renal dysfunction) and risk leading to infection with diseases that the immune system can prevent under normal conditions. Furthermore, it is preferred that the pharmaceutical product has sufficient chemical and physical stability.
There has been a technical problem in the existing external preparations containing tofacitinib citrate, that is, tofacitinib citrate containing an ingredient or active ingredient having high skin irritation is decomposed during long-term storage. Therefore, there is still a need for an external preparation containing tofacitinib citrate having low skin irritation and excellent stability. However, propylene carbonate is skin irritant, so it is not suitable for ointments. Further, as disclosed in CN102176913B, the active ingredient tofacitinib citrate is decomposed during long-term storage.
[ summary of the invention ]
Accordingly, it is an object of the present invention to provide an external preparation containing tofacitinib citrate with very low skin irritation and excellent stability.
We have now found that external preparations containing docetaxel as a solubilizer for tofacitinib citrate have very low skin irritation and excellent stability. Accordingly, the present invention provides an external preparation comprising tofacitinib citrate as an active ingredient and cetomacrogol as a solubilizer therefor. The external preparation of the present invention not only has low skin irritation and excellent stability, but also forms stable droplets of docetaxel dissolving tofacitinib citrate because the base is not miscible with docetaxel. Such external preparations may provide topical delivery of tofacitinib citrate to a subject.
Detailed Description
In a first embodiment, the present invention provides an external preparation comprising tofacitinib citrate, cetomacrogol and a base. Preferably, the percentage of the amount of tofacitinib citrate to the docetaxel may be from 0.01% to 30% by weight, more preferably from 0.1% to 20% by weight, more preferably from 0.3% to 10.0% by weight, more preferably from 0.3% to 5.0% by weight, most preferably from 0.3% to 3% by weight.
The term "tofacitinib citrate" as used herein refers to a 23-membered macrolide system lactone, also known as FK-506 or Tacrolimus (Fujimycin), as described above. Tofacitinib citrate may be in free or pharmaceutically acceptable salt form, or in the form of a solvate (e.g. hydrate or the like). The term "tofacitinib citrate" as used in the present application and claims refers to any or all forms of tofacitinib citrate, since its salt form, solvate or analogue, especially tofacitinib citrate monohydrate, has similar pharmacological activity as tofacitinib citrate in free form. The term "tofacitinib citrate" also includes tofacitinib citrate which is used in a crystalline, amorphous or semi-crystalline phase. Preferably, the external preparation of the present invention comprises tofacitinib citrate in an amount of 0.01 to 1.0% by weight, more preferably 0.02 to 0.5% by weight, most preferably 0.03 to 0.1% by weight, based on the total amount of the preparation.
Tofacitinib citrate in free form is soluble in the docetaxel at a rate of about 18.5g/100g at 25 ℃. Preferably, the external preparation of the present invention comprises 0.01 to 30% by weight, more preferably 0.1 to 20% by weight, still more preferably 0.3 to 6.0% by weight, most preferably 1.0 to 5.0% by weight of cetomacrol, based on the total amount of the preparation.
The term "external preparation" as used herein refers to a preparation for application to the skin or mucosa of a subject (e.g., skin, eye, nasal cavity, ear, anus, vagina, urethra, anus, trachea, lung, sublingual, oral cavity, etc.), and generally includes ointments, liquids, lotions, liniments, gels, aerosols, plasters, poultices or creams. In a preferred embodiment of the invention, the term "topical formulation" refers to an ointment or ophthalmic ointment as defined in the pharmacopoeia 2015 of china, general rules of preparation, which is incorporated herein by reference.
More preferably, the ointment of the present invention may be an oily ointment. The term "oily ointment" as used herein refers to any ointment wherein the active ingredient is dispersed and/or dissolved in an oily base, or a solution of the active ingredient is dispersed in an oily base, with the exception of ointments which comprise primarily an emulsion base, a water-soluble base, or a lotion base. In a more preferred embodiment, the ointment of the invention is an ointment in the form of an oil-in-oil emulsion in which droplets of docetaxel having tofacitinib citrate dissolved therein are dispersed in a matrix.
The term "emulsion" as used herein refers to a mixture of liquids in which the fine droplets are dispersed or suspended in another liquid that is immiscible with the droplets. The emulsion used herein also comprises a microemulsion in which smaller droplets are dispersed. Although the droplets and liquid are typically water or oil, they may also be oil and oil, so long as they are substantially immiscible. In general, the volume average particle diameter of the emulsion droplets is preferably in the range of about 0.01 μm to 500 μm, more preferably 0.1 μm to 50 μm, as measured by, for example, laser diffraction.
The external preparation of the present invention comprises a base in addition to tofacitinib citrate as an active ingredient and cetomacrogol as a solubilizer for tofacitinib citrate. The matrix may be any one or mixture of matrices suitable for external use formulations. The matrix itself generally does not exert a pharmacological effect. Examples of such bases include, for example, oily or hydrophobic bases, emulsion bases, hydrophilic or water-soluble bases, gel bases or conventional components, such as fatty acids or derivatives thereof, esters of polycarboxylic acids and alcohols, higher alcohols, powdered inorganic substances, gel-forming agents, water, alcohols, polyols, alkanolamines, propellants and the like. The matrix actually employed in some formulations may vary depending on the formulation, and the matrix may be readily selected by those skilled in the art according to well-known factors including the desired formulation, potency of the active ingredient, desired release rate of the active ingredient, and the like.
In more specific embodiments, the base includes, but is not limited to, for example, water, animal and vegetable oils (e.g., olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (e.g., ethanol, propanol, propylene glycol, 1, 3-butylene glycol, phenol, etc.), higher fatty acids and esters thereof, waxes, higher alcohols, polyols, hydrophilic petrolatum, purified lanolin, absorbent ointments, aqueous lanolin, hydrophilic ointments, starches, pullulan, gum arabic, tragacanth, gelatin, dextran, cellulose derivatives (e.g., methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and the like), synthetic polymers (e.g., carboxyvinyl polymers, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, and the like), propylene glycol, polyethylene glycols (e.g., polyethylene glycols 200 to 600, and the like), and combinations thereof.
Specifically, the base of the ointment includes higher fatty acids and esters thereof (e.g., adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipate, myristate, palmitate, diethyl sebacate, hexyl laurate, cetyl isooctanoate, lanolin and lanolin derivatives), waxes (e.g., spermaceti, beeswax, ozokerite), higher alcohols (e.g., cetyl alcohol, stearyl alcohol, cetearyl alcohol), hydrocarbons (e.g., hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin), animal and vegetable oils, and combinations thereof. Especially preferred is a combination of beeswax and petrolatum. In addition to the above-mentioned bases, the ointment of the present invention may optionally contain paraffin such as liquid paraffin, lanolin, animal and vegetable oils, natural wax, hydrogenated soybean phospholipids (lecithin), higher alcohols. Preferably, the ointment bases of the present invention are immiscible in the docetaxel.
The base of the plaster includes, for example, polymers such as acrylate copolymers, silicone resins, polyisobutylene resins, styrene-isoprene-styrene block copolymers, styrene-butadiene-styrene block copolymers. The plaster also contains, for example, a tackifier (such as a rosin, rosin ester, or petroleum resin), a plasticizer (such as polybutene, olive oil, liquid paraffin, or liquid isoprene), or a filler (such as titanium oxide, zinc oxide, or silica).
Bases for poultices include, for example, glycerin, water, polyacrylates, sodium polyacrylate, methyl vinyl ether-maleic anhydride copolymers, carboxyvinyl polymers, gum arabic, alginic acid, methylcellulose, hydroxypropylcellulose, gelatin. The cataplasm may also contain, for example, a humectant (such as propylene glycol or sorbitol); fillers (such as kaolin, titanium oxide or talc); or an absorbent (such as crotamiton or diisopropyl adipate). Bases for creams include, for example, hydrocarbons, such as white petrolatum, waxes, liquid paraffin or squalane; higher alcohols such as cetyl alcohol, stearyl alcohol or behenyl alcohol; fatty acid esters such as medium chain triglycerides, isopropyl myristate or diisopropyl adipate; polymers such as carboxyvinyl polymer, hydroxypropyl cellulose, polyvinylpyrrolidone or sodium hyaluronate; or polyhydric alcohols such as glycerol, propylene glycol, 1, 3-butylene glycol. The cream may further comprise, for example, a surfactant (such as polyoxyethylene glycol fatty acid ester or polyoxyethylene glycol fatty acid ester glycol alkyl ether), a pH adjuster (such as diisopropanolamine or sodium hydroxide), a stabilizer (such as sodium hydrogen phosphate, sodium chloride or sodium sulfite), a preservative (such as methyl paraben or propyl paraben), or an absorbent (such as crotamiton or menthol).
Beeswax is a member of the natural waxes, including white beeswax. Preferably, the beeswax is column purified beeswax, wherein impurities such as pigments, peroxides, etc. are removed. Preferably, the ointments of the invention may comprise beeswax in an amount of 1.0% to 10% by weight of the total amount of the ointment, more preferably 2% to 9% by weight, still more preferably 4% to 8% by weight, most preferably 5% to 7% by weight.
The vaseline includes general vaseline such as white vaseline or yellow vaseline, preferably column-purified vaseline, in which impurities such as pigments, peroxides, etc. are removed. Preferably, the ointments of the invention may comprise petrolatum in an amount of 60% to 99% by weight, more preferably 70% to 95% by weight, most preferably 80% to 90% by weight of the total amount of the ointment.
The external preparation of the present invention may contain conventional additives such as emulsifiers, wetting agents, stabilizers, dispersants, plasticizers, pH adjusters, absorbents, gelling agents, preservatives, fillers, preservatives, antibacterial agents, pigments, flavors, fresheners, thickeners, antioxidants, whitening agents, ultraviolet absorbers. Surfactants (e.g., Tween (registered trademark) 20, 80, etc.) may also be added in minute amounts (e.g., less than 1% by weight of the total amount of the formulation). The actual additives added in the formulation and their purpose can be easily understood by those skilled in the art. It is also understood that certain compounds may exhibit two or more properties.
Preferably, the humectant includes, but is not limited to, for example, glycerin, propylene glycol, dipropylene glycol, sodium hyaluronate, cholesterol, pullulan, and the like.
Preferably, the stabilizer or co-stabilizer includes, but is not limited to, for example, edetic acid (EDTA), citric acid
Sodium, L-arginine, tocopherol, silicone, polyoxyethylene sorbitan fatty acid ester, and the like.
Preferably, the freshening agent includes, but is not limited to, for example, camphor, menthol, botanical extract flavors, and the like.
Preferably, thickeners include, but are not limited to, for example, gum arabic, guar gum, carrageenan, carboxyvinyl polymers, cellulose, polyacrylates, and the like.
In another embodiment, the present invention relates to a process for preparing a tofacitinib citrate-containing external preparation, said process comprising the step of dissolving tofacitinib citrate in docetaxel. In a more specific embodiment, the method for preparing the tofacitinib citrate-containing external preparation comprises the following steps:
(1) dissolving tofacitinib citrate in the docetaxel; and
(2) mixing the solution of tofacitinib citrate in cetostearyl alcohol with the matrix.
Each additive or a mixture of any additives is added independently to the substrate, the polycetol, the solution of tofacitinib citrate in polycetol or the mixture of the solution and the substrate before or during step (1) or before, during or after step (2).
The above step (1) is preferably carried out at 60 ℃ to 80 ℃ with any conventional stirrer such as a magnetic stirrer, a homogenizer, a vacuum emulsification stirrer, a vacuum emulsifier and the like. At temperatures below 60 c there may be a risk that tofacitinib citrate will not dissolve rapidly in the docetaxel. Above 80 ℃, there may also be a risk of tofacitinib citrate decomposition or of docetaxel evaporation. These conditions are therefore not preferred. The above step (2) is preferably carried out by dispersing at 60 ℃ to 80 ℃, for example at about 70 ℃ for a suitable time using any of the conventional mixers, gradually cooling while stirring, and terminating the stirring when the mixture reaches 20 to 40 ℃ (e.g., 30 to 40 ℃, preferably about 35 ℃). The ointments of the invention may be prepared, for example, by employing any conventional method for preparing ointments, for example, as described in the examples below. For example, the ointment of the present invention may be prepared as follows: heating an oil-containing substrate to melt, mixing and semi-cooling the substrate; dissolving tofacitinib citrate in a small amount of docetaxel; dispersing the docetaxel having tofacitinib citrate dissolved therein into the matrix; mixing until a homogeneous dispersion is obtained (liquefaction process).
The thus obtained external preparation of the present invention has low skin or mucosal irritation and high stability. The skin or mucosal irritation may be determined, for example, by any known animal test or model of skin or mucosal test, such as the skin irritation test described in the examples below. The stability may be determined, for example, by any known stability test, such as the stability test described in the examples below.
[ examples ] A method for producing a compound
Example 1
Prescription:
the preparation method comprises the following steps:
weighing beewax and white vaseline according to the prescription amount, adding into an emulsification tank, heating and melting at 70 ℃, and keeping the temperature at 65 +/-5 ℃ for later use;
weighing a prescription amount of docetaxel (docetaxel/glyceryl triacetate) and placing the docetaxel in a liquid preparation container, adding the prescription amount of tofacitinib citrate and stirring until the docetaxel is completely dissolved;
adding the raw material solution into an emulsifying tank, flushing a solution preparation container by using part of light liquid paraffin, adding the rest light liquid paraffin into the emulsifying tank, and uniformly stirring;
starting a milk homogenizing machine, homogenizing milk for 60-90 min at the rotating speed of 3500rpm, slowly cooling, and continuously stirring until the temperature is reduced to 30 +/-2 ℃;
and (4) filling and sealing the tail by using a composite hose, wherein the filling temperature is controlled to be 30 +/-5 ℃.
In addition, docetaxel (comparative example 1-1), triacetin (comparative example 1-2) were used as substitutes for docetaxel to provide another ointment (comparative control).
Stability test
The ointments of examples and comparative examples were stored at 3 ℃ or 36 ℃ for 10 days. Then, the change in appearance was observed and the amount of tautomer (decomposition product of tofacitinib citrate) and other related substances was determined.
Table 1 stability test results
The results show that the ointment of the present invention comprising docetaxel is more stable to tofacitinib citrate than the control containing docetaxel and triacetin.
Skin irritation test Primary Rabbit skin irritation test
The backs of rabbits (Japanese white rabbits, male, 2.0kg or more in body weight) were dehaired with an electric clipper the day before application. 0.5g of the preparation of example 1 or 0.5g of the same preparation with the active ingredient removed are applied using an animal test plaster with a lining cloth (2.5X 2.5cm) closed with parafilm. To avoid the patch falling off, the collar was placed for 24 hours. Each group contained 5 animals.
After 24 hours of application, the collar and patch were removed and the application site was cleaned with absorbent cotton. Erythema and scabbing or edema formation were scored according to the skin reaction evaluation criteria of the Draize method 24, 48 and 72 hours after application.
TABLE 2 skin reaction evaluation criteria (Draize)
The sum of the scores for erythema/scarring and edema formation at the application site 24 hours and 72 hours after application was divided by 4 to determine each stimulation index. The average of the indices was calculated to determine the primary stimulation index (p.i.i.). P.i.i. was administered according to the irritation grade of Draize to grade the degree of irritation to evaluate irritation to rabbit skin.
TABLE 3 irritation grading (Draize)
In each case, no erythema/scabbing and edema formation was observed in example 1 and comparative examples 1-2 throughout the observation period. P.i.i. is 0 in both cases, so they are rated as "non-irritating"; comparative example 1-1 the primary irritation index was 1.6 and was classified as "mild irritation".
EXAMPLE 2 Anhydrous gel (Water soluble gel)
1.02g of tofacitinib citrate hydrate was dissolved in 3g of cetostearyl alcohol under heating, and polyethylene glycol 400(85.98g) and polyethylene glycol 4000(10g) were added thereto. The mixture was further heated to mix and then cooled to provide an anhydrous gel. (Here and hereinafter,% means% by weight)
In addition, glyceryl triacetate (control 2) was used as a substitute for cetomacrogol to provide another ointment (control).
Stability test
The ointments of examples and comparative examples were stored at 3 ℃ or 36 ℃ for 10 days. Then, the change in appearance was observed and the amount of tautomer (decomposition product of tofacitinib citrate) and other related substances was determined.
Table 4 stability test results
The results show that the ointment of the present invention comprising docetaxel is more stable to tofacitinib citrate than the control containing docetaxel and triacetin.
Example 3 hydrogel
0.15g of methyl paraben and 0.1g of propyl paraben were dissolved in purified water with heating, and 10g of glycerin, 0.5g of citric acid (or acetic acid (example 3-2) or phosphoric acid (example 3-3)) and 980(0.5g) were dissolved after cooling to 40 ℃ or less. 1.02g of tofacitinib citrate hydrate was dissolved in 20g of cetostearyl alcohol under heating, added to the solution and dispersed with a stirrer. Aqueous sodium hydroxide solution was added dropwise with stirring, and the pH was adjusted to pH4 to 7 to form a gel. Purified water was added to adjust the total amount to 100g to provide a hydrogel. Also, a lotion can be prepared by using 0.1g to 0.2g of carbopol 980.
In addition, glyceryl triacetate (control 3) was used as a substitute for cetomacrogol to provide another ointment (control).
Stability test
The ointments of examples and comparative examples were stored at 3 ℃ or 36 ℃ for 10 days. Then, the change in appearance was observed and the amount of tautomer (decomposition product of tofacitinib citrate) and other related substances was determined.
Table 5 stability test results
The results show that the ointment of the present invention comprising docetaxel is more stable to tofacitinib citrate than the control containing docetaxel and triacetin.
Example 4 ointment cream: cream (o/w)
10g of polycetol, 3g of cetyl alcohol, 3g of stearyl alcohol and Tween80(0.5g) were mixed at 70 ℃ and 1.02g of tofacitinic citrate hydrate was added thereto and dissolved by heating. To the solution were added 0.15g of methyl paraben and 0.1g of propyl paraben dissolved in appropriate amounts of purified water (62.23 g, purified water was added to adjust the total amount to 100 g) and mixed with a stirrer. The solution was cooled under stirring to provide a cream.
In addition, glyceryl triacetate (control 4) was used as a substitute for cetomacrogol to provide another ointment (control reference).
Stability test
The ointments of examples and comparative examples were stored at 3 ℃ or 36 ℃ for 10 days. Then, the change in appearance was observed and the amount of tautomer (decomposition product of tofacitinib citrate) and other related substances was determined.
Table 6 stability test results
The results show that the ointment of the present invention comprising docetaxel is more stable to tofacitinib citrate than the control containing docetaxel and triacetin.
Claims (8)
1. An external preparation comprises tofacitinib citrate, cetomacrol and matrix.
2. The external preparation according to claim 1, wherein the percentage of tofacitinib citrate relative to the amount of docetaxel is 0.01 to 30% by weight.
3. The external preparation of claim 1 or 2, which is in the form of an ointment.
4. The external preparation of claim 3, which comprises a mixture of beeswax and vaseline as an ointment base.
5. The external preparation according to claim 4, wherein the beeswax is column purified beeswax.
6. The external preparation of claim 4, wherein the petrolatum is column-purified petrolatum.
7. The external preparation according to any one of claims 3 to 6, wherein the docetaxel droplets dissolving tofacitinib citrate are dispersed in the base.
8. A process for preparing a tofacitinib citrate-containing external preparation, comprising the step of dissolving tofacitinib citrate with a docetaxel.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1285186A (en) * | 1999-05-27 | 2001-02-28 | 强生消费者公司 | Novel preparation for local use |
| CN102176913A (en) * | 2008-10-08 | 2011-09-07 | 高田制药株式会社 | Tacrolimus preparation for external applications |
| CN107753419A (en) * | 2017-10-18 | 2018-03-06 | 江苏知原药业有限公司 | Tacrolimus external preparation |
| CN108283620A (en) * | 2018-03-13 | 2018-07-17 | 兆科药业（广州）有限公司 | A kind of local medicine composition of inhibitors of phosphodiesterase-4 and preparation method thereof |
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2020
- 2020-05-25 CN CN202010447772.5A patent/CN113712900A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1285186A (en) * | 1999-05-27 | 2001-02-28 | 强生消费者公司 | Novel preparation for local use |
| US20020102295A1 (en) * | 1999-05-27 | 2002-08-01 | Susan Niemiec | Compositions for application to the skin or hair |
| CN102176913A (en) * | 2008-10-08 | 2011-09-07 | 高田制药株式会社 | Tacrolimus preparation for external applications |
| CN107753419A (en) * | 2017-10-18 | 2018-03-06 | 江苏知原药业有限公司 | Tacrolimus external preparation |
| CN108283620A (en) * | 2018-03-13 | 2018-07-17 | 兆科药业（广州）有限公司 | A kind of local medicine composition of inhibitors of phosphodiesterase-4 and preparation method thereof |
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