WO2020093956A1 - 一种含维生素k1 的外用制剂及其制备方法 - Google Patents

一种含维生素k1 的外用制剂及其制备方法 Download PDF

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WO2020093956A1
WO2020093956A1 PCT/CN2019/115217 CN2019115217W WO2020093956A1 WO 2020093956 A1 WO2020093956 A1 WO 2020093956A1 CN 2019115217 W CN2019115217 W CN 2019115217W WO 2020093956 A1 WO2020093956 A1 WO 2020093956A1
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vitamin
preparation containing
gel
cream
containing vitamin
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PCT/CN2019/115217
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French (fr)
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倪海华
蒋新国
姜锋
徐赟
潘新
庄卫红
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扬子江药业集团上海海尼药业有限公司
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Priority to US17/042,916 priority Critical patent/US11213493B2/en
Publication of WO2020093956A1 publication Critical patent/WO2020093956A1/zh

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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
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • 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
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P17/16—Emollients or protectives, e.g. against radiation

Definitions

  • the invention belongs to the technical field of pharmaceutical preparations, and relates to an external preparation containing vitamin K1 and a preparation method thereof.
  • Anti-tumor molecular targeted drugs mainly include: afatinib, erlotinib, gefitinib, cetuximab and trastuzumab antibody-drug conjugates, etc.
  • EGFR epidermal growth factor receptor
  • Proliferation, differentiation, metastasis, and adhesion, and anti-EGFR drugs cause stagnation of basal keratinocyte growth by increasing the expression of cell cycle-dependent kinase inhibitors P27, keratin-1, signal transcription, and transcription activator-3 in the basal layer And premature maturation and differentiation, accompanied by the release of neutrophils, thereby further leading to keratinocyte apoptosis and accumulation under the epidermis causing skin damage.
  • the rashes related to anti-EGFR targeted drugs are mainly manifested in the upper layer of the dermis, especially in the vicinity of the follicles, which leads to the rupture of the follicles and the mixed inflammation of the epithelial spine layer.
  • the skin toxicity of anti-EGFR drugs is mainly treated with antibiotics and steroid hormones.
  • the use of these drugs still has many problems.
  • the effect of single drug treatment is limited, usually requiring patients to use antibiotics and corticosteroids in combination;
  • the medication cycle is longer, and the symptoms of patients are improved after 2 to 3 weeks of medication. This is for large areas of skin of tumor patients.
  • Toxicity is particularly uncomfortable; in addition, due to the need for re-treatment of skin toxicity, this may bring another blow to the patient's quality of life and economic burden. Therefore, there is an urgent clinical need for a drug with rapid onset, definite curative effect, and high safety to treat the skin toxicity caused by anti-EGFR targeted drugs.
  • Vitamin K also known as coagulation vitamin, has the biological activity of chlorophyllin, and has several types such as K1, K2, K3, and K4.
  • K1 and K2 are naturally-occurring fat-soluble vitamins;
  • K3 and K4 are synthetic water-soluble vitamins.
  • the highest medicinal value is vitamin K1.
  • vitamin K1 injections are sold on the Chinese market, mainly used for bleeding diseases caused by various vitamin K deficiency.
  • the present invention aims to provide an external preparation containing vitamin K1 for the treatment of skin-related toxic reactions caused by anti-EGFR targeted drugs.
  • the external preparation includes vitamin K1 cream and vitamin K1 gel.
  • the prescription is for external use The preparation can promote the absorption of vitamin K1 through the stratum corneum, improve the efficacy, and increase the stability of vitamin K1.
  • the skin-related toxicity caused by the anti-EGFR drugs in the present invention mainly refers to the skin toxicity reaction that occurs due to the use of one or more of the following small molecule anti-EGFR inhibitors or anti-EGFR monoclonal antibody drugs.
  • the drugs mainly include: afatinib, erlotinib, gefitinib, lapatinib, vandetanib, trastuzumab, trastuzumab antibody-drug conjugate, and Toximab, panitumumab, and pertuzumab.
  • the invention provides an external preparation containing vitamin K1, which comprises the following components and their weight percentages:
  • the transdermal enhancer is urea, azone, propylene glycol, ethanol, clove oil, eucalyptus oil, menthol, A combination of one or more of camphor and borneol.
  • the dermal penetration enhancer has a urea weight percentage of 0.1-25%, an azone weight percentage of 0.1-10%, a propylene glycol weight percentage of 0.1-25%, and an ethanol weight percentage of 1-25%, clove oil single weight percent 0.1-10%, eucalyptus oil single weight percent 0.1-10%, menthol single weight percent 0.1-10%, camphor single weight percent 0.1- 10% and borneol alone use 0.1-10% by weight.
  • the dermal penetration enhancer has a urea weight percentage of 0.5-10%, an azone weight percentage of 0.5-5%, a propylene glycol weight percentage of 1-10%, and an ethanol weight percentage.
  • a urea weight percentage of 0.5-10% an azone weight percentage of 0.5-5%
  • a propylene glycol weight percentage of 1-10% an ethanol weight percentage.
  • 2-15% clove oil single weight percentage 0.5-5%
  • eucalyptus oil single weight percentage 0.5-5%
  • menthol single weight percentage 0.5-5%
  • camphor single weight percentage 0.5 -5%
  • the weight percentage of borneol alone is 0.5-5%.
  • the penetration enhancer is composed of urea, menthol and eucalyptus oil in a mass ratio of (5-6) :( 2-3) :( 1-3).
  • the invention also provides a cream preparation containing vitamin K1, which comprises the following components and their weight percentages:
  • the skin penetration enhancer is the skin penetration enhancer according to any one of claims 1 to 3.
  • the cream base is one or more of isostearic acid, stearic acid, cetyl alcohol, stearyl alcohol, glyceryl monostearate, white petrolatum, lanolin and liquid paraffin combination;
  • the emulsifier is sodium lauryl sulfate, polysorbate 60, polysorbate 80, polyethylene glycol hydroxystearate, polyethoxylated castor oil, ethylene oxide or One of propylene oxide copolymer, stearoyl polyethylene glycol-32 glyceride, lauroyl polyethylene glycol-32 glyceride, propylene glycol monocaprylate and octanoyl acetyl polyethylene glycol-8 glyceride Or a combination of two or more;
  • the humectant is one or a combination of two or more of glycerin, propylene glycol and sorbitol;
  • the pH adjuster is one or more of triethanolamine, sodium hydroxide, potassium hydroxide and hydrochloric acid A combination of;
  • the antioxidant is one of butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, tert-butylhydroquinone, sodium sulfite, sodium bisulfite, sodium metabisulfite and sodium thiosulfate Or a combination of two or more;
  • the preservative is one of hydroxyphenyl esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, chlorhexidine acetate, benzalkonium chloride, thimerosal, and quaternary ammonium salt cationic surfactants One or a combination of two or more.
  • the invention also provides a gel preparation containing vitamin K1, comprising the following components and their weight percentages:
  • the skin penetration enhancer is the skin penetration enhancer according to claims 1 to 3.
  • the gel matrix is one or more of gelatin, carbopol 943P, polyethylene glycol 300, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose Combination;
  • the thickener is one or a combination of two or more of xanthan gum, carrageenan and Brunei gum.
  • the gel matrix is composed of Carbopol 934P and polyethylene glycol 300 in mass ratio (1-3) :( 2-3).
  • the Carbopol 934P can be replaced by Carbopol 940, Carbopol 941, Carbopol 974P.
  • the thickener is one or a combination of two or more of xanthan gum, carrageenan and Brunei gum.
  • the humectant is one or a combination of two or more of glycerin, propylene glycol and sorbitol;
  • the antioxidant is butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, One or a combination of two or more of tert-butyl hydroquinone, sodium sulfite, sodium bisulfite, sodium metabisulfite and sodium thiosulfate;
  • the preservatives are parabens, chlorobutanol, benzyl alcohol , Phenethyl alcohol, chlorhexidine acetate, benzalkonium chloride, thimerosal and quaternary ammonium salt cationic surfactants or a combination of two or more.
  • the external preparation containing vitamin K1 provided by the present invention is made into a cream preparation and a gel preparation.
  • the pH or cream preparation of the vitamin K1 contains a pH value of 4.0-8.0, preferably a pH value of 5.0-7.0;
  • the pH adjusting agent is one or a combination of two or more of triethanolamine, sodium hydroxide, potassium hydroxide and hydrochloric acid.
  • vitamin K1 helps to improve the symptoms of skin itching and dry skin in the skin toxicity caused by the treatment of colon cancer patients with cetuximab.
  • vitamin K1 is a fat-soluble vitamin, insoluble in water, poorly absorbed through the skin, and has no obvious improvement effect on the symptoms of skin itching and dry skin in the skin toxicity reaction.
  • the external preparation containing vitamin K1 provided by the present invention adds a transdermal accelerator to solve the problem of poor transdermal absorption effect, and is targeted for the treatment of anti-epidermal growth factor receptor (EGFR) targeted drugs: afatinib, erlotib , Gefitinib, lapatinib, vandetanib, trastuzumab, trastuzumab antibody-drug conjugates, cetuximab, panitumumab, and pertuzumab Symptoms such as acne-like rash, itching, redness, dry skin, and mucositis caused by resistance have a good therapeutic effect, which can prolong the use period and adaptability of this type of anti-tumor drugs for cancer patients.
  • EGFR anti-epidermal growth factor receptor
  • the skin penetration enhancers provided by the present invention are urea, azone, propylene glycol, ethanol, clove oil, eucalyptus oil, menthol, camphor and borneol.
  • the above skin penetration enhancers are used alone, the effect of promoting skin penetration rate is limited.
  • transdermal accelerator composed of urea, menthol and eucalyptus oil at a mass ratio of (5-6) :( 2-3) :( 1-3) can significantly improve vitamin K1
  • the transdermal absorption effect can effectively treat acne-like rash, itching, redness, dry skin and mucositis caused by EGFR-related anti-tumor drugs, which can ensure the continued treatment of anti-EGFR targeted drugs.
  • a penetration enhancer composed of a mass ratio of (5-6) :( 2-3) :( 1-3) and vitamin K1 can prevent the initiation of ultraviolet rays on toxic skin inflammation.
  • the inventors also found that the external preparation containing vitamin K1 prepared by the present invention is not only a good agent for treating skin toxicity caused by anti-epidermal growth factor receptor (EGFR) targeted drugs, but also promotes The role of healing wounds.
  • the present invention uses a gel matrix composed of Carbopol 934P and polyethylene glycol 300 according to the mass ratio (1-3): (2-3).
  • Carbopol 934P is acrylic acid.
  • Copolymer of co-polymer and polyalkyl sucrose or polyalkyl pentaerythritol Carbopol molecule has a large number of carboxyl groups, and its ionization balance changes with pH value, the molecule is cross-linked; polyethylene glycol 300 molecule is linear , Has good hygroscopicity, pH change and temperature have basically no effect on polyethylene glycol 300 molecules.
  • polyethylene glycol 300 and Carbopol 934P are mixed, the arrangement of polyethylene glycol 300 and Carbopol 934P is influenced by the intermolecular van der Waals force.
  • Polyethylene glycol 300 can fill the space gap of Carbopol 934P , Making it less susceptible to changes in temperature and pH, thereby increasing the stability of Carbopol 934P; at the same time, the cross-linked molecule Carbopol 934P and linear molecule polyethylene glycol 300 are mixed and combined, due to polymerization Ethylene glycol 300 has certain hygroscopicity. After absorbing moisture, it forms a dense hydrogel protective film with Carbopol 934P of cross-linked molecules. It can be applied to the skin to prevent the growth of bacteria and promote wound healing.
  • the present invention has the following advantages:
  • the external preparation containing vitamin K1 provided by the present invention contains a dermal penetration enhancer, which can effectively increase the penetration of vitamin K1 through the stratum corneum and reach the lesion of the dermal layer to achieve the purpose of synergistic enhancement.
  • the external use of vitamin K1 The preparation is effective in treating and preventing skin toxicity caused by anti-epidermal growth factor receptor (EGFR) targeted drugs.
  • EGFR anti-epidermal growth factor receptor
  • the external preparation containing vitamin K1 provided by the present invention When the external preparation containing vitamin K1 provided by the present invention is made into a gel, it has the advantages of moisture, coolness, and no greasy feeling. It is suitable for systemic application and is more conducive to the effect of the drug.
  • 1 is a graph of the cumulative transdermal percentage of the external cream preparation containing vitamin K1, wherein: 1 is the cumulative transdermal percentage curve of the external cream preparation containing vitamin K1 prepared in Example 1; 2 is the content of the transdermal preparation prepared in Example 2 Cumulative transdermal percentage curve of vitamin K1 topical cream preparation; 5 is cumulative transdermal percentage curve of vitamin K1 topical cream preparation prepared in Example 5; 6 is vitamin K1 external topical cream preparation prepared in Example 6 Cumulative transdermal percentage curve; A is a topical cream preparation containing vitamin K1 without a transdermal accelerator.
  • Example 1-11 cream containing vitamin K1
  • Creams containing vitamin K1 were prepared according to Examples 1-11 shown in Table 1, respectively.
  • step 3 Add the mixed solution A of step 1 to the mixed solution B of step 2, constant temperature 70 ⁇ 80 °C, stir for 30min, stir to cool to 40 °C, add menthol, camphor or borneol, stir at constant temperature 40 °C for 15min, add pH adjuster Adjust the pH value to 5.0-7.0, stirring and cooling to 20 °C -30 °C, that is.
  • the gels containing vitamin K1 were prepared according to the prescriptions of Examples 12-22 shown in Table 2, respectively.
  • step 3 Add the mixed solution B of step 2 to the mixed solution A of step 1, stir and mix evenly, add a pH adjuster to adjust the pH value to 5.0-7.0, and stir evenly, that's it.
  • a cream containing vitamin K1 was prepared according to the prescriptions of Comparative Example 1 and Comparative Example 2 shown in Table 3, respectively.
  • the preparation method of the vitamin K1 cream is similar to the preparation method of Examples 1-9.
  • Comparative Example 1 The difference between Comparative Example 1 and Example 10 is that the penetration enhancer consists of urea, menthol and eucalyptus oil in a mass ratio of 4: 1: 4.
  • Comparative Example 2 The difference between Comparative Example 2 and Example 10 is that the penetration enhancer is composed of urea, menthol and eucalyptus oil in a mass ratio of 1: 1: 1.
  • a gel containing vitamin K1 was prepared according to the prescriptions of Comparative Example 3, Comparative Example 4, Comparative Example 5, or Comparative Example 6 shown in Table 4, respectively.
  • the preparation method of the vitamin K1 gel is similar to the preparation method of Examples 12-22.
  • Comparative Example 3 The difference between Comparative Example 3 and Example 21 is that the penetration enhancer is composed of urea, menthol and eucalyptus oil in a mass ratio of 4: 1: 4.
  • Comparative Example 4 The difference between Comparative Example 4 and Example 21 is that the penetration enhancer is composed of urea, menthol and eucalyptus oil in a mass ratio of 1: 1: 1.
  • Comparative Example 5 differs from Example 21 in that the gel matrix is composed of Carbopol 934P and polyethylene glycol 300 in a mass ratio of 1: 1.
  • Comparative Example 6 differs from Example 21 in that the gel matrix is composed of Carbopol 934P and sodium carboxymethyl cellulose at a mass ratio of 2: 3.
  • Test purpose the transdermal test of the vitamin K1 cream of Example 1, Example 2, Example 5 and Example 6.
  • the modified Franz diffusion cell technology was used to fix the epidermal mouse skin between the two-compartment diffusion cell.
  • the stratum corneum was facing the supply cell and the dermis was facing the receiving cell.
  • the temperature is controlled at 32 ⁇ 0.5 °C, 0.5mL, 0.5mL, 1,2,4,8,12,24h sampling 0.5mL, after shaking 12000r / Centrifuge for 10 minutes at min, take the supernatant and use HPLC to determine the concentration of vitamin K1 in the receiving solution (simultaneously add the same volume of heat preservation medium) to obtain the measured concentration C of the drug in the medium at each sampling time point, according to the formula:
  • the test is the same as the above method, and the test is stopped after 4 and 8 hours, and the skin in the diffusion pool is removed, the residual drug on the surface is washed, the filter paper is used to absorb the water, and the weight is weighed; after homogenization, dilute to the appropriate concentration, and use Extract vitamin K1 from the skin homogenate twice, dry the organic solvent with nitrogen on a constant temperature water bath, dissolve the extract with 100 ⁇ L of chromatographic mobile phase, determine the concentration of vitamin K1 by high-performance liquid chromatography, and compare the vitamin K1 in different preparations in the skin Retention in the.
  • Vitamin K1 cream can significantly improve the drug's transdermal ability after adding appropriate amount of transdermal accelerator, as shown in Figure 1.
  • the vitamin K1-containing cream preparations prepared in Example 1, Example 2, Example 5 and Example 6 accumulated 47-88% of the amount of vitamin K1 that penetrated the epidermal mouse skin within 24 hours.
  • the control preparation without the penetration enhancer accumulated 15% of vitamin K1 through the hair removal abdominal mouse skin. It shows that after adding the transdermal enhancer, the cumulative transdermal percentage of the cream preparations containing vitamin K1 prepared in Example 1, Example 2, Example 5 and Example 6 increased significantly.
  • the penetration concentration of vitamin K1 in the skin tissue was significantly increased after the addition of the penetration enhancer.
  • the drug concentration accumulated in the skin was 3.1 to 5.5 times that of the control preparation. It is suggested that the addition of various types of transdermal enhancers to vitamin K1 cream can increase vitamin K1 through the stratum corneum and enter the dermis layer to varying degrees, thereby improving the treatment of skin toxicity caused by drugs targeting epidermal growth factor receptor (EGFR) effect.
  • EGFR epidermal growth factor receptor
  • Test Example 2 Transdermal test of external preparation containing vitamin K1
  • Test purpose ordinary vitamin K1 cream, vitamin K1-containing cream prepared in Example 1, Example 8, Example 9, Example 10, and Example 11 of the present invention; Example 12, Example 16 of the present invention , Example 19, Example 20, Example 21 and Example 22 prepared vitamin K1-containing gel; the present invention prepared by Comparative Example 1 and Comparative Example 2 prepared by the vitamin K1-containing cream and the present invention Comparative Example 3 and The vitamin K1-containing gel prepared in Comparative Example 4.
  • Vitamin K1-containing creams prepared in Example 1, Example 8, Example 9, Example 10, and Example 11 of the present invention; Example 12, Example 16, Example 19, Example 20, and Example of the present invention Vitamin K1-containing gel prepared in Example 21 and Example 22; vitamin K1-containing cream prepared in Comparative Example 1 and Comparative Example 2 of the present invention and vitamin K1-containing gel prepared in Comparative Example 3 and Comparative Example 4 of the present invention Adhesive, in vitro transdermal diffusion test. After 12h, the content of vitamin K1 in the receiving pool was measured. The drug concentration in the sample solution was detected by HPLC method.
  • Chromatography conditions Chromatography column: Diamonsil C18 (4.6mm ⁇ 250mm, 5 ⁇ m); column temperature: 30 °C; mobile phase: absolute ethanol-water (90:10); flow rate 1.0mL / min; detection wavelength 254nm; injection volume : 20 ⁇ L.
  • the peak area normalization method was used to determine the drug concentration, and the permeability of vitamin K1 was calculated.
  • Test results The cumulative transdermal percentage results of each vitamin K1 external preparation are shown in Table 5.
  • Example 1 72.50
  • Example 8 50.05
  • Example 9 80.23
  • Example 10 87.45
  • Example 11 84.16
  • Example 12 80.42
  • Example 16 61.43
  • Example 19 60.24
  • Example 20 86.74
  • Example 21 88.40
  • Example 22 85.28 Comparative Example 1 71.83 Comparative Example 2 70.02 Comparative Example 3 72.34 Comparative Example 4 73.56
  • Vitamin K1-containing creams prepared in Example 1, Example 8, Example 9, Example 10, and Example 11 of the present invention and Example 12, Example 16, Example 19, and Example 20 of the present invention The cumulative transdermal percentages of the gels containing vitamin K1 prepared in Example 21 and Example 22 are higher than those of ordinary vitamin K1 emulsions, wherein the transdermal agents urea, menthol and eucalyptus oil are in a mass ratio of 5.5: 2.5: 2
  • the prepared vitamin K1 cream (Example 10) had the best transdermal effect in each cream, and the cumulative transdermal percentage of the vitamin K1 gel (Example 21) in each gel was transdermal The effect is the best.
  • the cumulative transdermal percentage (88.40%) of the gel containing vitamin K1 prepared in Example 21 is slightly higher than that of the ointment containing vitamin K1 prepared in Example 10 (87.45%). It shows that the penetration enhancers urea, menthol and eucalyptus oil are added according to the mass ratio (5-6) :( 2-3) :( 1-3), and the effect of promoting skin penetration is remarkable.
  • Test Example 3 The efficacy test of external cream preparation containing vitamin K1
  • Test purpose The human body pharmacodynamic test was carried out with the vitamin K1 cream of Example 10.
  • Test method 6 patients with metastatic advanced colorectal cancer were enrolled. The clinical bi-weekly regimen was treated with rectal cancer chemotherapy (FOLFOX / FOLFIRI) + cetuximab. Six patients were randomly divided into two groups, one The group was treated with vitamin K1 cream in Example 10, and the other group was treated with ordinary vitamin K1 cream (see Dong Xue, "Clinical Efficacy Study of Vitamin K1 Emulsion on Cetuximab-induced Skin Toxicity" in Vitamin K1 Emulsion The preparation method obtained) as a control. Apply twice in the morning and evening, and use continuously for 7 days.
  • the patient's upper body torso When not in use, the patient's upper body torso has severe acne-like rash, itching, and redness caused by the use of cetuximab. After 7 days of treatment with the vitamin K1 cream of Example 10 of the present invention, the patient's upper body torso rash occurred The degree is significantly less than the ordinary vitamin K1 emulsion in the control group, the degree of redness and swelling is reduced, and the itching sensation disappears, showing a significant effect.
  • Test Example 4 Anti-ultraviolet effect of external preparation containing vitamin K1
  • Test purpose To examine the vitamin K1 containing gels prepared in Example 12, Example 13, Example 14, Example 20, Example 21 and Example 22; the vitamins prepared in Comparative Example 3 and Comparative Example 4 The anti-ultraviolet effect of K1 gel.
  • Hacat cells and ESF cells were seeded in 6-well plates at 2 ⁇ 10 5 cells / well. When cultured to a degree of cell fusion above 80%, they were prepared for UVB irradiation. Cells were divided into 8 groups, and 3 secondary wells were repeated, namely blank control group (no UVB treatment, medium without vitamin K1 external preparation), UVB irradiation group (UVB treatment, medium without vitamin K1 external preparation), UVB + Vitamin K1 external preparation (UVB treatment, medium added with different concentrations of the vitamin K1-containing gel prepared in Example 12, Example 13, Example 14, Example 20, Example 21 and Example 22; Comparative Example 3 And the vitamin K1 gel prepared in Comparative Example 4. Each vitamin K1 containing gel is calculated according to the concentration of vitamin K1, and the added concentrations are: 5 ⁇ g / ml, 25 ⁇ g / ml, 50 ⁇ g / ml.
  • the UVB radiation source has a wavelength of 280-320nm and a peak of 312nm.
  • the irradiation dose of Hacat cells treated with UVB was 20mJ / cm 2
  • the irradiation dose of ESF cells treated was 60mJ / cm 2 .
  • complete medium and vitamin K1 preparations were added for 24 hours, and the supernatant of the cell culture was collected for IL-1 content detection.
  • the IL-1 ⁇ content in the culture supernatant of Hacat cells after UVB treatment was detected using human IL-1 ⁇ / IL-1F1 DuoSet ELISA kit (RD System, USA), and the IL-6 content was detected using human IL-6 DuoSet ELISA kit (R & D System, United States), TNF-a content detection using humanTNF-a DuoSet ELISA kit (R & D System, United States), the method is the same as the instructions. At the same time, the protein content was detected to correct the results. The protein content was determined using BCA protein concentration determination kit (Biyuntian, China).
  • test results are shown in Table 6 for the determination of IL-1 ⁇ , IL-6 and TNF-a.
  • the vitamin K1 gels prepared in Comparative Example 3 and Comparative Example 4 also have a certain anti-ultraviolet radiation effect, and the anti-ultraviolet radiation effect is better as the concentration of vitamin K1 increases, even higher than the implementation
  • the prescription of the glue, the vitamin K1 containing gel prepared in Example 20, Example 21 and Example 22 is better than Example 13 and Example 14, and Example 12 is equivalent to it, of which, Comparative Example 3 and Ratio 4
  • the difference of the prepared vitamin K1 gel is that the penetration enhancer is urea, menthol and eucalyptus oil, and the mass ratio is (5-6) :( 2-3) :( 1-3).
  • Vitamin K1 cream prepared by adding the penetration enhancer urea, menthol and eucalyptus oil in mass ratio of (5-6) :( 2-3) :( 1-3) and Vitamin K1 gel can inhibit inflammation caused by ultraviolet radiation and protect epithelial cells.
  • Test Example 5 Wound healing test with external preparation containing vitamin K1
  • Test purpose Vitamin K1-containing gels prepared in Example 12, Example 13, Example 14, Example 20, Example 21 and Example 22 and Vitamin K1 prepared in Comparative Example 5 and Comparative Example 6 A gel to promote wound healing test.
  • the blank control group does not use any drugs, apply three times a day in the morning, middle and night, observe the wound healing on the first day, the third day, the seventh day and the fifteenth day, and evaluate the wound healing by the wound healing rate.
  • the vitamin K1 creams prepared in Example 12, Example 13 and Example 14 had wound healing rates between 65% and 80% on the 15th day.
  • the creams prepared in Example 13 and Example 14 contained The vitamin K1 cream is equivalent to the blank control group, indicating that it has no effect of promoting wound healing.
  • the cream containing vitamin K1 prepared in Example 12 is higher than that of the blank control, but it is comparable to Comparative Example 5 and Comparative Example, indicating that the gel matrix is Carbopol 934P and sodium carboxymethylcellulose also have a certain role in promoting wound healing.
  • Example 21 The vitamin K1-containing gels prepared in Example 20, Example 21, and Example 22 had a healing rate of more than 80% on the tenth day and a healing rate of more than 90% on the fifteenth day, especially Example 21
  • the prepared gel containing vitamin K1 has a healing rate as high as 98.48%, indicating that the vitamin K1 containing gel prepared by the present invention has a significant effect of promoting wound healing.
  • the vitamin K1 gels prepared in Comparative Examples 5 and 6 also have a certain effect of promoting wound healing, but the vitamin K1-containing gels prepared in Comparative Examples 5 and 6
  • the effect of the agent to promote wound healing was inferior to the vitamin K1-containing gel prepared in Examples 20, 21 and 22 on Days 1, 3, 7, 10 and 15 days.
  • the possible reason is that the mass ratio of carbopol 934P and polyethylene glycol 300 in the gel matrix of the vitamin K1 gel prepared in Comparative Example 5 and Comparative Example 6 is not in (1-3) :( 2-3) Within the range, a dense gel layer film cannot be formed.
  • Test Purpose To examine the vitamin K1 containing cream prepared in Example 10; the vitamin K1 containing gel prepared in Example 21; the vitamin K1 cream prepared in Comparative Examples 1 and 2; Comparative Examples 3 and The stability of the vitamin K1 gel prepared in Comparative Example 4.
  • Content determination method take vitamin K1 cream and vitamin K1 gel under two conditions separately, dissolve in water to obtain mixed solution, and accurately measure solution 2.0 at 0, 0.5, 1, 2, 4 and 6h respectively mL, placed in a 10mL volumetric flask, dilute the mobile phase to the mark, shake well, pass 0.22 ⁇ m microporous filter membrane, and then respectively detect by high performance liquid chromatography, injection volume 20 ⁇ L, wavelength 254nm, determine each test Peak area of the liquid. Substitute the peak area value into the regression equation to calculate the content of each test solution. Based on the content of the measured value relative to 0h, calculate the relative percentage content at each time point.
  • the content of the vitamin K1 cream prepared in Example 10 and the vitamin K1 gel prepared in Example 21 at 6h is as high as 80.2% and 86.0%, comparative example 5
  • the content of the vitamin K1 gel prepared in Comparative Example 6 is also as high as 82.2% and 82.1%.
  • the content of Vitamin K1 in Example 10 and the vitamin K1 cream prepared in Comparative Example 1 and Comparative Example 2; Comparative Example 3 and Comparative Example 4 The prepared vitamin K1 gel has no difference.
  • the stability of the vitamin K1 gel prepared in Example 21 is better than that of the vitamin K1 cream prepared in Example 10 because of the inclusion of a gel base, and the preparation of Comparative Examples 5 and 6
  • the stability of the vitamin K1 gel is slightly better than the vitamin K1 cream prepared in Comparative Example 1 and Comparative Example 2, and the vitamin K1 gel prepared in Comparative Example 3 and Comparative Example 4 is also good because it contains gel
  • the gel matrix, and the gel matrix is composed of Carbopol 934P and polyethylene glycol 300 according to the mass ratio (1-3) :( 2-3), which can better maintain the stability of the vitamin K1 preparation.
  • the added gel matrix is composed of Carbopol 934P and polyethylene glycol 300 in mass ratio (1-3) :( 2-3), which can increase the stability of the external preparation containing vitamin K1 provided by the present invention to a certain extent.
  • antioxidants provided by the present invention butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, tert-butylhydroquinone, sodium sulfite, sodium bisulfite, sodium metabisulfite and sodium thiosulfate
  • the stability of external preparations containing vitamin K1 has a greater impact, especially the fat-soluble antioxidant tert-butyl hydroquinone and the water-soluble antioxidant sodium bisulfite have a more advantageous antioxidant effect. After the two antioxidants, the stability of vitamin K1 is better.

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Abstract

提供一种含维生素K1的外用制剂及其制备方法。含维生素K1的外用制剂，可用于表皮生长因子受体(EGFR)相关的抗肿瘤药物引起的中重度皮肤毒性，可以有效的治疗EGFR相关的抗肿瘤药物引起的痤疮样皮疹、瘙痒、红肿、皮肤干燥和黏膜炎等症状，可以保证抗EGFR靶向药物的继续治疗。而且该外用制剂可增加维生素K1透过角质层，到达真皮层病灶部位，可以快速减轻表皮生长因子受体相关的抗肿瘤药物引起的中重度皮肤病。另外，含维生素K1的外用制剂制成乳膏剂或凝胶剂，具有水润、清凉、无油腻感的优点，适合全身涂布，更有利于药物疗效的发挥。

Description

一种含维生素K1的外用制剂及其制备方法 技术领域
本发明属于药物制剂技术领域，涉及一种含维生素K1的外用制剂及其制备方法。
背景技术
肿瘤已成为人类健康的最大杀手，人类一直不遗余力的寻找肿瘤治疗的最佳方法。近年来，随着人们对肿瘤发生机制和基因分子分型认识的不断深入，靶向药物的研究逐渐成为肿瘤治疗领域的主要突破点，并受到医学界的普遍重视，越来越多的抗肿瘤分子靶向药物被应用于临床而发挥良好的疗效。抗肿瘤分子靶向药物主要有：阿法替尼、厄洛替尼、吉非替尼、西妥昔单抗和曲妥珠单抗抗体-药物共轭物等，靶向药物在多项肿瘤治疗领域均有突破性进展，大大改善了患者的生存预期。在众多靶向药物中，针对表皮生长因子受体(EGFR)相关的抑制剂或单抗目前应用最为广泛，但是，抗EGFR靶向药物都有一类主要的不良反应：中重度的皮肤毒性。
目前，关于抗EGFR靶向药物引起皮疹的机制尚未完全明确，通常认为对滤泡以及滤泡间细胞表皮生长信号传导通路的干扰是其关键性原因。另有研究认为，EGFR在表皮角化细胞、皮脂腺、外分泌腺体、毛囊滤泡以及上皮脂肪层均有表达，这些细胞主要存在于皮肤的基底层；抑制EGFR后可影响胶质细胞形成细胞的增殖、分化、转移以及黏附，而抗EGFR药物通过增加在基底层的细胞周期依赖性激酶抑制剂P27、角蛋白-1、信号转录和转录激活因子-3的表达，引起基底角质细胞生长的停滞以及过早成熟分化，同时伴有中性粒细胞的释放，由此进一步导致角质细胞凋亡并积聚在表皮下引起皮肤的损伤。这样便可解释抗EGFR靶向药物相关的皮疹主要表现在真皮上层，尤其在滤泡附近，由此导致卵泡破裂和上皮棘层出现混合型炎症反应。皮肤毒性的发生虽很少危及生命，但可严重影响患者的生活质量，甚至因此而中止治疗。
临床上针对抗EGFR药物产生的皮肤毒性，均以抗生素和类固醇激素治疗为主，这些药物的使用仍具有诸多问题。首先，单一药物治疗的效果有限，通常需 要患者联合使用抗生素和皮质类固醇药物；其次，用药周期较长，患者在用药2～3周后症状才有所改善，这对于肿瘤患者较大面积的皮肤毒性尤其不适；再者，由于需要对皮肤毒性的再次治疗，由此可能给患者无论是生活质量还是经济负担都带来再一次的打击。因此临床上迫切需要一种起效迅速、疗效确切、安全性高的药物来治疗抗EGFR靶向药物产生的皮肤毒性。
维生素K又称凝血维生素，具有叶绿醌生物活性，有K1、K2、K3、K4等几种类型。K1、K2是天然存在的脂溶性维生素；K3、K4为人工合成的水溶性维生素。其中，药用价值最高的当属维生素K1，目前我国市场上销售的仅有维生素K1注射剂，主要用于各种维生素K缺乏引起的出血性疾病。
董雪等发表了题目为“维生素K1乳剂对西妥昔单抗所致皮肤毒性反应的临床疗效研究”的论文，该论文探讨了0.1％维生素K1乳剂对结直肠癌患者应用西妥昔单抗所致皮肤毒性反应的影响，结果发现0.1％维生素K1有助于改善结肠癌患者应用西妥昔单抗治疗所致皮肤毒性反应中的皮肤瘙痒和皮肤干燥的症状。但该维生素K1乳剂总体有效率较低，原因主要是维生素K1不易透过角质层，难以到达皮疹发生的靶部位真皮层，一定程度上限制了维生素K1在临床上的进一步应用。
然而，研究和开发一种吸收率高，对抗EGFR药物产生的皮肤毒性治疗效果好和稳定性的维生素K1的外用制剂仍是目前亟需解决的难题。
发明内容
本发明旨在提供一种含维生素K1的外用制剂，用于治疗因抗EGFR靶向药物引起的皮肤相关毒性反应，所述的外用制剂包括维生素K1乳膏剂和维生素K1凝胶剂，该处方外用制剂，可促维生素K1透过角质层吸收，提高疗效，增加维生素K1的稳定性。
本发明所述的抗EGFR药物引起的皮肤相关毒性主要是指因使用下述一种或多种小分子抗EGFR抑制剂或抗EGFR单抗药物而发生的皮肤毒性反应。该类药物主要有：阿法替尼、厄洛替尼、吉非替尼、拉帕替尼、凡德他尼，曲妥珠单抗、曲妥珠单抗抗体-药物共轭物、西妥昔单抗、帕尼单抗和帕妥珠单抗等。
为了达到上述目的，本发明采用以下技术方案：
本发明提供了一种含维生素K1的外用制剂，包括以下成分及其重量百分比：
0.01-5％维生素K1、0.1-25％透皮促进剂和70-99％外用制剂基质，所述透皮促进剂为尿素、氮酮、丙二醇、乙醇、丁香油、桉叶油、薄荷脑、樟脑和冰片中的一种或多种的组合。
优选地，所述透皮促进剂的尿素单用重量百分比为0.1-25％、氮酮单用重量百分比为0.1-10％、丙二醇单用重量百分比为0.1-25％、乙醇单用重量百分比为1-25％、丁香油单用重量百分比为0.1-10％、桉叶油单用重量百分比为0.1-10％、薄荷脑单用重量百分比为0.1-10％、樟脑单用重量百分比为0.1-10％和冰片单用重量百分比为0.1-10％。
更优选地，所述透皮促进剂的尿素单用重量百分比为0.5-10％、氮酮单用重量百分比为0.5-5％、丙二醇单用重量百分比为1-10％、乙醇单用重量百分比为2-15％、丁香油单用重量百分比为0.5-5％、桉叶油单用重量百分比为0.5-5％、薄荷脑单用重量百分比为0.5-5％、樟脑单用重量百分比为0.5-5％和冰片单用重量百分比为0.5-5％。
更优选地，所述透皮促进剂为尿素、薄荷脑和桉叶油的按质量比为(5-6):(2-3):(1-3)组成。
本发明还提供了一种含维生素K1的乳膏制剂，包括以下成分及其重量百分比：
0.01-5％维生素K1、0.1-25％透皮促进剂、1-25％乳膏基质、0.2-10％乳化剂、2-20％保湿剂、0.05-2％抗氧剂、0.01-1％防腐剂和10-72％水，所述透皮促进剂为权利要求1～3任一所述的透皮促进剂。
优选地，所述乳膏基质为异硬脂酸、硬脂酸、十六醇、十八醇、单硬脂酸甘油酯、白凡士林、羊毛脂和液体石蜡中的一种或两种以上的组合；
优选地，所述乳化剂为十二烷基硫酸钠、聚山梨醇酯60、聚山梨醇酯80、聚乙二醇羟基硬脂酸酯、聚乙氧基化蓖麻油、环氧乙烷或环氧丙烷共聚物、硬脂酰聚乙二醇-32甘油酯、月桂酰聚乙二醇-32甘油酯、丙二醇单辛酸酯和辛酰乙酰聚乙二醇-8甘油酯中的一种或两种以上的组合；
优选地，所述保湿剂为甘油、丙二醇和山梨醇中的一种或两种以上的组合；所述的pH调节剂为三乙醇胺、氢氧化钠、氢氧化钾和盐酸一种或两种以上的组 合；所述抗氧剂为丁基羟基茴香醚、二丁羟基甲苯、没食子酸丙酯、叔丁基对苯二酚、亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠和硫代硫酸钠的一种或两种以上的组合；所述防腐剂为羟苯酯类、三氯叔丁醇、苯甲醇、苯乙醇、醋酸洗必泰、苯扎氯胺、硫柳汞和季铵盐阳离子表面活性剂的一种或两种以上的组合。
本发明还提供了一种含维生素K1的凝胶制剂，包括以下成分及其重量百分比：
0.01-5％维生素K1、0.1-25％透皮促进剂、0.5-10％凝胶基质、0.1-10％增稠剂、2-20％保湿剂、0.05-2％抗氧剂、0.01-1％防腐剂和40-80％水，所述透皮促进剂为权利要求1～3所述的透皮促进剂。
优选地，所述凝胶基质为明胶、卡波普943P、聚乙二醇300、甲基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素中的一种或两种以上的组合；所述增稠剂为黄原胶、卡拉胶和文莱胶中的一种或两种以上的组合。
优选地，所述凝胶基质由卡波普934P和聚乙二醇300按质量比(1-3):(2-3)组成。
优选地，所述卡波普934P可以由卡波普940、卡波普941、卡波普974P替代。
优选地，所述增稠剂为黄原胶、卡拉胶和文莱胶的中的一种或两种以上的组合。
优选地，所述的保湿剂为甘油、丙二醇和山梨醇中的中的一种或两种以上的组合；所述抗氧剂为丁基羟基茴香醚、二丁羟基甲苯、没食子酸丙酯、叔丁基对苯二酚、亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠和硫代硫酸钠的一种或两种以上的组合；所述防腐剂为羟苯酯类、三氯叔丁醇、苯甲醇、苯乙醇、醋酸洗必泰、苯扎氯胺、硫柳汞和季铵盐阳离子表面活性剂的一种或两种以上的组合。
本发明提供的含维生素K1的外用制剂制成乳膏制剂和凝胶制剂，所述含维生素K1的乳膏制剂或凝胶制剂pH值为4.0-8.0，优选为pH值为5.0-7.0；所述的pH调节剂为三乙醇胺、氢氧化钠、氢氧化钾和盐酸的一种或两种以上的组合。
目前，现有技术发现维生素K1有助于改善结肠癌患者应用西妥昔单抗治疗所致皮肤毒性反应中的皮肤瘙痒和皮肤干燥的症状。但是维生素K1是一种脂溶性维生素，不溶于水，透皮吸收差，对皮肤毒性反应中的皮肤瘙痒和皮肤干燥的 症状改善效果不明显。本发明提供的含维生素K1的外用制剂中添加了透皮促进剂解决了透皮吸收效果差的问题，对治疗抗表皮生长因子受体(EGFR)靶向药物：阿法替尼、厄洛替尼、吉非替尼、拉帕替尼、凡德他尼，曲妥珠单抗、曲妥珠单抗抗体-药物共轭物、西妥昔单抗、帕尼单抗和帕妥珠单抗等引起的痤疮样皮疹、瘙痒、红肿、皮肤干燥和黏膜炎等症状具有很好的治疗效果，可以延长肿瘤病人对该类抗肿瘤药物的使用期限和使用适应性。
本发明提供的透皮促进剂为尿素、氮酮、丙二醇、乙醇、丁香油、桉叶油、薄荷脑、樟脑和冰片，单独使用上述透皮促进剂时，其促透皮率效果有限，经发明人大量摸索试验发现，将尿素、薄荷脑和桉叶油的按质量比(5-6):(2-3):(1-3)组成的透皮促进剂可明显有效的提高维生素K1的透皮吸收效果，可以有效的治疗EGFR相关的抗肿瘤药物引起的痤疮样皮疹、瘙痒、红肿、皮肤干燥和黏膜炎等症状，可以保证抗EGFR靶向药物的继续治疗。
进一步地，发明人还发现，按质量比(5-6):(2-3):(1-3)组成的透皮促进剂与维生素K1联合使用可以防止紫外线对毒性皮肤炎症的引发作用。
另外，发明人还发现，本发明制备的含维生素K1的外用制剂制成凝胶剂，不仅具有良好的治疗抗表皮生长因子受体(EGFR)靶向药物引起的皮肤毒性的优点，还具有促进愈合伤口的作用。经过试验和分析，可能原因为本发明采用由卡波普934P和聚乙二醇300按质量比(1-3):(2-3)组成的凝胶基质中，卡波普934P为丙烯酸交联聚合物与聚烷基蔗糖或聚烷基季戊四醇的共聚物，卡波普分子存在大量的羧基，其电离平衡随pH值而变化，分子呈交联型；聚乙二醇300分子呈线型，具有良好的吸湿性，pH值变化和温度对聚乙二醇300分子基本无影响。当聚乙二醇300与卡波普934P混合后，两者受分子间范德华力影响聚乙二醇300和卡波普934P的排列结合，聚乙二醇300可以填补卡波普934P的空间空隙，使其不易受温度和pH值变化而变化，从而增加卡波普934P的稳定性；同时交联型分子的卡波普934P与线型分子的聚乙二醇300混合排列结合后，因聚乙二醇300具有一定吸湿性，吸湿后与交联型分子的卡波普934P形成一层致密性水凝胶保护膜，涂抹在皮肤上可以防止细菌滋生、促进伤口愈合。
与现有技术相比，本发明具有以下优点：
(1)本发明提供的含维生素K1的外用制剂中含有透皮促进剂，可以有效 的增加维生素K1透过角质层，到达真皮层病灶部位，达到协同增效的目的，该含维生素K1的外用制剂在治疗和预防抗表皮生长因子受体(EGFR)靶向药物引起的皮肤毒性的效果显著。
(2)本发明提供的含维生素K1的外用制剂制成凝胶剂时，具有水润、清凉、无油腻感的优点，适合全身涂布，更有利于药物疗效的发挥。
附图说明
图1为含维生素K1外用乳膏制剂的累积透皮百分率图，其中：1为实施例1制得的含维生素K1外用乳膏制剂的累积透皮百分率曲线；2为实施例2制得的含维生素K1外用乳膏制剂的累积透皮百分率曲线；5为实施例5制得的含维生素K1外用乳膏制剂的累积透皮百分率曲线；6为实施例6制得的含维生素K1外用乳膏制剂的累积透皮百分率曲线；A为无透皮促进剂的含维生素K1外用乳膏制剂。
具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下实施例。
实施例1-11、含维生素K1的乳膏剂
分别按表1所示的实施例1-11制备含维生素K1的乳膏剂。
表1.维生素K1乳膏剂的处方(w/w％)
Figure PCTCN2019115217-appb-000001
Figure PCTCN2019115217-appb-000002
含维生素K1复合乳膏剂的制备：
①油相的制备：将乳膏基质加热至70～80℃融化，搅拌使混合均匀，再加入维生素K1、抗氧剂、防腐剂和脂溶性透皮促进剂，溶解混匀，得混合溶液A；
②水相的制备：将乳化剂、抗氧剂和水溶性透皮促进剂混合，加入水中，加热至70～80℃，搅拌，溶解混匀，得混合溶液B；
③将步骤①的混合溶液A加入步骤②的混合溶液B中，恒温70～80℃，搅拌30min，搅拌冷却至40℃，加入薄荷脑、樟脑或冰片，恒温40℃搅拌15min，加入pH调节剂调节pH值为5.0-7.0，搅拌冷却至20℃-30℃，即得。
实施例12-22、含维生素K1的凝胶剂
分别按表2所示的实施例12-22处方制备含维生素K1的凝胶剂。
表2.维生素K1凝胶剂的处方(w/w％)
Figure PCTCN2019115217-appb-000003
含维生素K1凝胶剂的制备：
①将凝胶基质和增稠剂加入蒸馏水中，静置8-12h后，加入水溶性透皮促进剂和抗氧剂，混匀，得混合溶液A；
②将维生素K1和脂溶性透皮促进剂加入乙醇中，搅拌溶解、混匀，得混 合溶液B；
③将步骤②的混合溶液B加入步骤①的混合溶液A中，搅拌并混合均匀后，加入pH调节剂调节pH值为5.0-7.0，搅拌均匀，即得。
对比例1-2、含维生素K1的乳膏剂
分别按表3所示的对比例1和对比例2处方制备含维生素K1的乳膏剂。
表3.维生素K1乳膏剂的处方(w/w％)
成分 对比例1 对比例2
维生素K1 3 3
尿素 8 6
桉叶油 2 6
薄荷脑 8 6
硬脂酸 5 5
十六醇 1 1
单硬脂酸甘油酯 5 5
液体石蜡 10 10
叔丁基对苯二酚 2 2
聚山梨醇酯60 1 1
丙二醇 10 10
三乙醇胺 0.1 0.1
苯甲醇 0.5 0.5
尼泊金甲酯 0.2 0.2
蒸馏水 44.2 44.2
所述维生素K1乳膏剂的制备方法与实施例1-9的制备方法类似。
对比例1与实施例10的区别在于：透皮促进剂由尿素、薄荷脑和桉叶油按质量比例4:1:4组成。
对比例2与实施例10的区别在于：透皮促进剂为尿素、薄荷脑和桉叶油按质量比例1:1:1组成。
对比例3-6、含维生素K1的凝胶剂
分别按表4所示的对比例3、对比例4、对比例5或对比例6处方制备含维生素K1的凝胶剂。
表4.维生素K1凝胶剂的处方(w/w％)
成分 对比例3 对比例4 对比例5 对比例6
维生素K1 3 3 3 3
卡波普934P 4 4 4 4
聚乙二醇300 6 6 4 -
羧甲基纤维素钠 - - - 6
尿素 8 - 11 11
薄荷脑 8 20 5 5
桉叶油 2 - 4 4
乙醇 1 1 1 1
甘油 4 4 4 4
焦亚硫酸钠 1 1 1 1
尼泊金乙酯 0.1 0.1 0.1 0.1
蒸馏水 54.9 52.9 52.9 52.9
所述维生素K1凝胶剂的制备方法与实施例12-22的制备方法类似。
对比例3与实施例21的区别在于：透皮促进剂由尿素、薄荷脑和桉叶油按质量比4:1:4组成。
对比例4与实施例21的区别在于：透皮促进剂为尿素、薄荷脑和桉叶油按质量比1:1:1组成。
对比例5与实施例21的区别在于：凝胶基质由卡波普934P和聚乙二醇300按质量比1:1组成。
对比例6与实施例21的区别在于：凝胶基质为卡波普934P和羧甲基纤维素钠按质量比2:3组成。
试验例一、含维生素K1乳膏剂的透皮试验
1.试验目的：实施例1、实施例2、实施例5和实施例6的维生素K1乳膏剂的透皮试验。
2.试验方法：
透皮试验采用改良的Franz扩散池技术，将脱毛的腹部鼠皮固定在两室扩散池之间，角质层面向供给池，真皮面向接受池，分别取乳膏剂1g置于皮肤上，接收池为18mL的PBS(pH＝7.4)溶出介质，调节转子转速至75r/min，温度控制在32±0.5℃，分别于0.5，1，2，4，8，12，24h取样0.5mL，摇匀后12000r/min离心10min，取上清液用HPLC测定接受液中维生素K1浓度(同时补加同体积保温介质)，得各取样时间点介质中药物的测定浓度C测，按公式：
Figure PCTCN2019115217-appb-000004
计算校正浓度。以校正浓度计算累积透皮百分率F(t)，以F(t)对时间作图，绘制透皮吸收曲线。将不含透皮促进剂的维生素K1乳膏剂作为对照制剂。
同上述方法试验，分别于试验4、8h后停止试验，取下扩散池中的皮肤，洗净表面残余药物后用滤纸吸干水分，称重；匀浆后稀释至合适浓度，用二氯甲烷分两次萃取皮肤匀浆中的维生素K1，恒温水浴上通氮气吹干有机溶剂，用100μL色谱流动相溶解萃取物，用高效液相色谱法测定维生素K1浓度，比较不同制剂中维生素K1在皮肤中的滞留量。
3.试验结果：
维生素K1乳膏剂中加入适量透皮促进剂后能够显著提高药物透皮能力，如图1。
从图1可知，实施例1、实施例2、实施例5和实施例6制得的含维生素K1乳膏制剂在24小时内，累积透过脱毛腹部鼠皮的维生素K1量为47～88％，而无透皮促进剂的对照制剂的累积透过脱毛腹部鼠皮的维生素K1量为15％。说明加了透皮促进剂后，实施例1、实施例2、实施例5和实施例6制得的含维生素K1乳膏制剂的累积透皮百分率显著增高。
此外，经组织浓度测定，加入透皮促进剂后明显提高维生素K1在皮肤组织 中的残留浓度，在8小时观察时间点，皮肤中蓄积的药物浓度分别是对照制剂的3.1～5.5倍。提示维生素K1乳膏剂中添加各类透皮促进剂后能够不同程度上增加维生素K1透过角质层，进入真皮层，从而提高对抗表皮生长因子受体(EGFR)靶向药物引起的皮肤毒性的治疗效果。
试验例二、含维生素K1外用制剂的透皮试验
1.试验目的：普通维生素K1乳膏剂、本发明实施例1、实施例8、实施例9、实施例10和实施例11制备得到的含维生素K1乳膏剂；本发明实施例12、实施例16、实施例19、实施例20、实施例21和实施例22制备得到的含维生素K1凝胶剂；本发明对比例1和对比例2制备得到的含维生素K1乳膏剂和本发明对比例3和对比例4制备得到的含维生素K1凝胶剂。
2.试验方法：
2.1体外药物经皮吸收实验
在改进的Franz非套层扩散池内进行体外透皮吸收实验。将脱毛腹部鼠皮固定在两室扩散池之间，角质层面向供给池，真皮面向接受池，并将1g的含有透皮促进剂的乳膏或凝胶均匀地涂抹在鼠皮的角质层上面，处理20分钟后，擦去相应含透皮促进剂的乳膏或凝胶。设定恒温槽中水温为32±0.1℃，向接受池中加入7mL相应的接受液，接受液即生理盐水，放入已经预热30分钟的体外渗透扩散装置恒温槽中，设定接受池搅拌速度为100r/min。
向供给池中加入1g的含5％的普通维生素K1乳膏剂(参照董雪，《维生素K1乳剂对西妥昔单抗所致皮肤毒性反应的临床疗效研究》中维生素K1乳剂的制备方法得到)、本发明实施例1、实施例8、实施例9、实施例10和实施例11制备得到的含维生素K1乳膏剂；本发明实施例12、实施例16、实施例19、实施例20、实施例21和实施例22制备得到的含维生素K1凝胶剂；本发明对比例1和对比例2制备得到的含维生素K1乳膏剂和本发明对比例3和对比例4制备得到的含维生素K1凝胶剂，进行体外透皮扩散试验。在12h后测定接收池维生素K1的含量。样品液中的药物浓度采用HPLC方法检测。
色谱条件：色谱柱：Diamonsil C18(4.6mm×250mm，5μm)；柱温：30℃；流动相：无水乙醇-水(90:10)；流速1.0mL/min；检测波长254nm；进样量：20μL。采用峰面积归一法测定药物浓度，计算维生素K1的透过率。
3.试验结果：各维生素K1外用制剂的累积透皮百分率结果如表5。
表5.不同维生素K1外用制剂中维生素K1的累积透皮百分率％
样品 累积透皮百分率(％)
普通维生素K1乳膏剂 12.34
实施例1 72.50
实施例8 50.05
实施例9 80.23
实施例10 87.45
实施例11 84.16
实施例12 80.42
实施例16 61.43
实施例19 60.24
实施例20 86.74
实施例21 88.40
实施例22 85.28
对比例1 71.83
对比例2 70.02
对比例3 72.34
对比例4 73.56
(1)本发明实施例1、实施例8、实施例9、实施例10和实施例11制备得到的含维生素K1乳膏剂和本发明实施例12、实施例16、实施例19、实施例20、实施例21和实施例22制备得到的含维生素K1凝胶剂的累积透皮百分率都高于 普通维生素K1乳剂，其中透皮剂尿素、薄荷脑和桉叶油按质量比例5.5:2.5:2制得的含维生素K1乳膏剂(实施例10)在各乳膏剂中的透皮效果最好，含维生素K1凝胶剂(实施例21)的累积透皮百分率在各凝胶剂中的透皮效果最好，实施例21制备得到的含维生素K1凝胶剂的累积透皮百分率(88.40％)略高于实施例10制备得到的含维生素K1软膏剂(87.45％)。说明透皮促进剂尿素、薄荷脑和桉叶油按质量比(5-6):(2-3):(1-3)加入，促透皮吸收效果显著。
(2)对比例1和对比例2的含维生素K1乳膏剂、对比例3和对比例4的含维生素K1凝胶剂的累积透皮百分率比普通维生素K1乳膏剂高，但与实例1和实施例8制备得到的含维生素K1乳膏剂相比的累积透皮百分率相当，甚至对比例1-4制得的含维生素K1外用制剂的累积透皮百分率高于实施例制得的含维生素K1外用制剂，如实施例8的透皮率50.05％，实施例19的透皮率60.24％，而对比例4为73.56％，说明选用透皮促进剂尿素、薄荷脑和桉叶油的促透皮吸收效果优于使用其他透皮促进剂及其组合。
试验例三、含维生素K1外用乳膏制剂的药效试验
1.试验目的：以实施例10的含维生素K1乳膏剂进行人体药效学试验。
2.试验方法：收录6例转移性晚期结直肠癌患者，临床双周方案使用直肠癌化疗方案(FOLFOX/FOLFIRI)+西妥昔单抗进行治疗，随机将6名患者分为两组，一组使用维生素K1乳膏实施例10进行治疗，另一组以普通维生素K1乳膏剂(参照董雪，《维生素K1乳剂对西妥昔单抗所致皮肤毒性反应的临床疗效研究》中维生素K1乳剂的制备方法得到)作对照。早晚各两次进行涂抹，连续使用7天。
3.试验结果：
未使用时，患者上身躯干有严重的使用西妥昔单抗后引起的痤疮样皮疹、瘙痒、红肿，而使用本发明实施例10的含维生素K1乳膏治疗7天后，患者的上身躯干皮疹发生程度明显少于对照组的普通维生素K1乳剂，红肿程度降低，瘙痒感消失，显示出明显的疗效。
试验例四、含维生素K1外用制剂的防紫外线作用
1.试验目的：考察实施例12、实施例13、实施例14、实施例20、实施例21和实施例22制得的含维生素K1凝胶剂；对比例3和对比例4制得的维生素K1凝胶剂的防紫外线作用。
2.试验方法：
将Hacat细胞和ESF细胞以2×10 5cells/well接种于6孔板中，培养至细胞融合度80％以上时准备进行UVB辐照处理。细胞分为8组，重复3个副孔，即空白对照组(无UVB处理，培养基无维生素K1外用制剂添加)、UVB辐照组(UVB处理，培养基无维生素K1外用制剂添加)、UVB+维生素K1外用制剂(UVB处理，培养基添加不同浓度的实施例12、实施例13、实施例14、实施例20、实施例21和实施例22制得的含维生素K1凝胶剂；对比例3和对比例4制得的维生素K1凝胶剂。各含维生素K1凝胶剂按维生素K1浓度计算，加入浓度分别为：5μg/ml，25μg/ml，50μg/ml。
细胞接种24h后，吸去培养基，加入PBS清洗细胞一次，除去PBS，放入紫外辐照箱中进行UVB处理。UVB辐照源波长280-320nm，波峰为312nm。UVB处理Hacat细胞辐照剂量为20mJ/cm 2，处理ESF细胞辐照剂量为60mJ/cm 2。辐照处理完成后加入完全培养基和各维生素K1制剂培养24h，收集细胞培养的上清液用于IL-1含量检测。
Hacat细胞经过UVB处理后培养上清液中的IL-1α含量使用人IL-1α/IL-1F1DuoSet ELISA试剂盒(RD System，美国)进行检测，IL-6含量检测使用human IL-6DuoSet ELISA试剂盒(R&D System，美国)进行，TNF-a含量检测使用humanTNF-a DuoSet ELISA试剂盒(R&D System，美国)进行，方法同说明书。同时检测蛋白含量对结果进行校正，蛋白含量测定使用BCA蛋白浓度测定试剂盒(碧云天，中国)进行检测。
3.试验结果：
检测结果见表6中IL-1α、IL-6和TNF-a的含量测定。
表6.IL-1α、IL-6和TNF-a的含量测定(％)
Figure PCTCN2019115217-appb-000005
由表6可知：
(1)紫外辐照处理可引起Hacat细胞前炎症因子IL-1α、IL-6及TNF-a表达增加，从而导致另一些炎症因子的活化，炎症因子活化后会加重人体皮肤在收到化学试剂和抗肿瘤的化疗药物代谢引起的炎症反应，不利于炎症伤口愈合，从实验数据我们得知正常Hacat细胞使用辐照处理Hacat细胞后，IL-1α表达显著增加，而添加实施例12、实施例13、实施例14、实施例20、实施例21和实施例22制得的含维生素K1凝胶剂，Hacat细胞IL-1α、IL-6及TNF-a表达明显有所降低，并且随着浓度增高效果更明显。
(2)对比例3和对比例4制得的维生素K1凝胶剂也具有一定的防紫外辐照作用，且随维生素K1浓度升高防紫外辐照作用效果也更好，甚至还高于实施例13和实施例14制得的含维生素K1凝胶剂。
(3)根据实施例12、实施例13、实施例14、实施例20、实施例21和实施例22制得的含维生素K1凝胶剂；对比例3和对比例4制得的维生素K1凝胶剂的处方，实施例20、实施例21和实施例22制得的含维生素K1凝胶剂效果好于实施例13和实施例14，实施例12效果与其相当，其中，对比例3和对比例4 制得的维生素K1凝胶剂的区别在于透皮促进剂为尿素、薄荷脑和桉叶油的按质量比为(5-6):(2-3):(1-3)加入，该结果表明本发明制备得到的将透皮促进剂尿素、薄荷脑和桉叶油按质量比为(5-6):(2-3):(1-3)加入的含维生素K1乳膏剂和含维生素K1凝胶剂可抑制由紫外辐照引起的炎症反应，并对上皮细胞起保护作用。
试验例五、含维生素K1外用制剂的促进伤口愈合试验
1.试验目的：实施例12、实施例13、实施例14、实施例20、实施例21和实施例22制得的含维生素K1凝胶剂和对比例5和对比例6制得的维生素K1凝胶剂的促进伤口愈合测验。
2.试验方法：
SD雄性大鼠180只，每只重220±20g，随机分9组，每组20只，分别标号，在背部脊柱一侧，剪去毛，用手术刀划开长2cm，深度0.2cm的刀口，分别用实施例12、实施例13、实施例14、实施例20、实施例21和实施例22制得的含维生素K1凝胶剂和对比例5和对比例6制得的维生素K1凝胶剂，空白对照组不使用任何药物，每天早中晚涂抹三次，在第1天、第3天、第7天和第15天观察伤口愈合情况，以创面愈合率评价创面愈合情况。
3.试验结果：创面愈合率情况见表7。
表7.创面愈率(％)
Figure PCTCN2019115217-appb-000006
由表7中数据可知：
(1)实施例12、实施例13和实施例14制得的含维生素K1乳膏剂在第15 天时伤口愈合率均在65％-80％之间，实施例13和实施例14制得的含维生素K1乳膏剂与空白对照组相当，说明其无促进伤口愈合的作用，实施例12制得的含维生素K1乳膏剂高于空白对照，但与对比例5和对比例相当，说明凝胶基质由卡波普934P和羧甲基纤维素钠组成也具有一定的促伤口愈合作用。
(2)实施例20、实施例21和实施例22制得的含维生素K1凝胶剂，在第十天愈合率达到80％以上，第15天愈合率打90％以上，尤其是实施例21制得的含维生素K1凝胶剂愈合率高达98.48％说明本发明制备的含维生素K1凝胶剂具有显著地促进伤口愈合的效果。
(3)相比空白对照组，对比例5和对比例6制得的维生素K1凝胶剂也具有一定的促进伤口愈合作用，但对比例5和对比例6制备得到的的含维生素K1凝胶剂促进伤口愈合效果在第1天、3天、7天、10天和15天都比实施例20、实施例21和实施例22制得的含维生素K1凝胶剂差。可能原因为对比例5和对比例6制得的维生素K1凝胶剂中的凝胶基质的卡波普934P和聚乙二醇300的质量比不在(1-3):(2-3)的范围内，无法形成致密的凝胶层薄膜。
试验例六、含维生素K1外用制剂的稳定性
1.试验目的：考察实施例10制得的含维生素K1乳膏剂；实施例21制得的含维生素K1凝胶剂；对比例1和对比例2制得的维生素K1乳膏剂；对比例3和对比例4制得的维生素K1凝胶剂的稳定性。
2.试验方法：
外观观察：在光照和避光条件下，用目测法分别观察实施例10制得的含维生素K1乳膏剂；实施例21制得的含维生素K1凝胶剂；对比例1和对比例2制得的维生素K1乳膏剂；对比例3和对比例4制得的维生素K1凝胶共8组样品溶液在0、0.5、1、2、4和6h的外观性状(色泽)，并测定维生素K1的含量。
含量测定方法：分别取两种条件下的含维生素K1乳膏剂和含维生素K1凝胶剂，溶于水中，得混合溶液，在0、0.5、1、2、4和6h分别精密量取溶液2.0mL，置于10mL的容量瓶中，加流动相稀释至刻度，摇匀，过0.22μm微孔滤膜，再 分别用高效液相色谱法检测，进样量20μL，波长254nm，测定各供试液的峰面积。将峰面积值代入回归方程，计算各供试品溶液的含量。以测得值相对0h的含量，计算每个时间点的相对百分含量。
3.试验结果：
光稳定性试验中，避光组样品外观颜色和质地均无明显变化，光照组变化情况如表8，避光和光照条件下维生素K1的含量测定结果见表9。
表8.各维生素K1外用制剂的光照稳定性
Figure PCTCN2019115217-appb-000007
表9.避光与光照条件下维生素K1的含量
Figure PCTCN2019115217-appb-000008
Figure PCTCN2019115217-appb-000009
(1)表8的记录显示，对比例1和对比例2制得的维生素K1乳膏剂；对比例3和对比例4制得的维生素K1凝胶剂经过光照1h后开始变黄，2h、4h和6h后的色泽持续变暗，由刚开始的有光泽变成暗沉；对比例5和对比例6制得的维生素K1凝胶剂与实施例10制得的维生素K1乳膏剂和实施例21制得的维生素K1凝胶剂外观受光照情况相同。
(2)表9的数据显示避光条件下，各含维生素K1外用制剂种维生素K1的含量基本不变，但光照后，0-6h内随着光照时间的延长，对比例1和对比例2制得的维生素K1乳膏剂；对比例3和对比例4制得的维生素K1凝胶剂和实施例10制得的维生素K1乳膏剂和实施例21制得的维生素K1凝胶剂中维生素K1的一直在下降，6h时实施例17制得的维生素K1凝胶剂的维生素K1的含量最高86.0％(表9)。
(3)表9中的数据更值得注意的是，6h时实施例10制得的维生素K1乳膏剂和实施例21制得的维生素K1凝胶剂含量高达为80.2％和86.0％，对比例5和对比例6制得的维生素K1凝胶剂含量也高达82.2％和82.1％，实施例10的维生素K1含量和对比例1和对比例2制得的维生素K1乳膏剂；对比例3和对比例4制得的维生素K1凝胶剂无差异性。
(4)根据结果，实施例21制得的维生素K1凝胶剂比实施例10制得的维生素K1乳膏剂的稳定性好的原因在于含有凝胶基质，对比例5和对比例6制得 的维生素K1凝胶剂的稳定性稍优于对比例1和对比例2制得的维生素K1乳膏剂、对比例3和对比例4制得的维生素K1凝胶剂好的原因也在于在于其中含有凝胶基质，并且凝胶基质由卡波普934P和聚乙二醇300按质量比(1-3):(2-3)组成可更好维持维生素K1制剂的稳定性，由此可知，处方中加入凝胶基质由卡波普934P和聚乙二醇300按质量比(1-3):(2-3)组成，可在一定程度上增加本发明提供的含维生素K1外用制剂的稳定性。
另外，本发明提供的抗氧剂：丁基羟基茴香醚、二丁羟基甲苯、没食子酸丙酯、叔丁基对苯二酚、亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠和硫代硫酸钠对本发明含维生素K1外用制剂的稳定性具有较大的影响，尤其是脂溶性抗氧剂叔丁基对苯二酚和水溶性抗氧剂亚硫酸氢钠的抗氧化作用更具优势，配方中加入这两种抗氧剂后，维生素K1的稳定性效果更好。
上述实施例仅例示性说明本发明的原理及其功效，而非用于限制本发明。任何熟悉此技术的人士皆可在不违背本发明的精神及范畴下，对上述实施例进行修饰或改变。因此，举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变，仍应由本发明的权利要求所涵盖。

Claims (8)

  1. 一种含维生素K1的外用制剂，其特征在于，包括以下成分及其重量百分比：
    0.01-5％维生素K1、0.1-25％透皮促进剂和70～99％外用制剂基质，所述透皮促进剂为尿素、薄荷脑和桉叶油按质量比为(5-6):(2-3):(1-3)组成。
  2. 一种含维生素K1的乳膏制剂，其特征在于，包括以下成分及其重量百分比：
    0.01-5％维生素K1、0.1-25％透皮促进剂、1-25％乳膏基质、0.2-10％乳化剂、2-20％保湿剂、0.05-2％抗氧剂、0.01％-1％防腐剂和10％-72％水，所述透皮促进剂为权利要求1所述的透皮促进剂。
  3. 根据权利要求2所述的含维生素K1的乳膏制剂，其特征在于，所述乳膏基质为异硬脂酸、硬脂酸、十六醇、十八醇、单硬脂酸甘油酯、白凡士林、羊毛脂和液体石蜡中的一种或两种以上的组合；所述乳化剂为十二烷基硫酸钠、聚山梨醇酯60、聚山梨醇酯80、聚乙二醇羟基硬脂酸酯、聚乙氧基化蓖麻油、环氧乙烷或环氧丙烷共聚物、硬脂酰聚乙二醇-32甘油酯、月桂酰聚乙二醇-32甘油酯、丙二醇单辛酸酯和辛酰乙酰聚乙二醇-8甘油酯中的一种或两种以上的组合；所述保湿剂为甘油、丙二醇和山梨醇中的一种或两种以上的组合；所述抗氧剂为丁基羟基茴香醚、二丁羟基甲苯、没食子酸丙酯、叔丁基对苯二酚、亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠和硫代硫酸钠的一种或两种以上的组合；所述防腐剂为羟苯酯类、三氯叔丁醇、苯甲醇、苯乙醇、醋酸洗必泰、苯扎氯胺和硫柳汞的一种或两种以上的组合。
  4. 一种含维生素K1的凝胶制剂，其特征在于，包括以下成分及其重量百分比：
    0.01-5％维生素K1、0.1-25％透皮促进剂、0.5-10％凝胶基质、0.1-10％增稠剂、2-20％保湿剂、0.05-2％抗氧剂、0.01％-1％防腐剂和40％-80％水，所述透皮促进剂为权利要求1所述的透皮促进剂。
  5. 根据权利要求4所述的含维生素K1的凝胶制剂，其特征在于，所述凝胶基质为明胶、卡波普943P、聚乙二醇300、甲基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素中的一种或两种以上的组合；所述增稠剂为黄原胶、卡拉胶和文莱胶中的一种或两种以上的组合。
  6. 根据权利要求5所述的含维生素K1的凝胶制剂，其特征在于，所述凝胶 基质由卡波普943P和聚乙二醇300按质量比(1-3):(2-3)组成。
  7. 根据权利要求4所述的含维生素K1的凝胶制剂，其特征在于，所述保湿剂为甘油、丙二醇和山梨醇中的一种或两种以上的组合。
  8. 根据权利要求4所述的含维生素K1的凝胶制剂，其特征在于，所述抗氧剂为丁基羟基茴香醚、二丁羟基甲苯、没食子酸丙酯、叔丁基对苯二酚、亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠和硫代硫酸钠的一种或两种以上的组合；所述防腐剂为羟苯酯类、三氯叔丁醇、苯甲醇、苯乙醇、醋酸洗必泰、苯扎氯胺和硫柳汞的一种或两种以上的组合。
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