Pharmaceutical composition and application thereof in preparing medicine for treating EGFRIs (epidermal growth factor receptors)-induced skin toxicity

Abstract

The invention discloses a pharmaceutical composition and application of the pharmaceutical composition in preparation of a medicine for treating EGFRIs (epidermal growth factor receptors) induced skin toxicity. The pharmaceutical composition comprises chlorogenic acid, ferulic acid, zinc salt and a matrix material. The pharmaceutical composition can be used as a gel, a film coating agent or a dressing, the permeability of the pharmaceutical composition can be remarkably enhanced, the retention amount in skin can be increased, the symptom of dry skin can be relieved due to the good moisturizing performance of the pharmaceutical composition, the curative effect of treating skin toxic reactions caused by EGFRIs is improved, and the pharmaceutical composition is easy and convenient to use, good in patient compliance and capable of better meeting clinical requirements.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a pharmaceutical composition for treating skin toxicity caused by EGFRIs, a preparation method thereof, and an application of the pharmaceutical composition in preparing a therapeutic drug for skin toxicity caused by EGFRIs. Background Art

[0002] In cancer treatment, epidermal growth factor receptor inhibitors (EGFRIs) are widely used in the clinical treatment of cancer patients with EGFR mutations, especially non-small cell lung cancer, breast cancer, colorectal cancer, etc. However, with the use of EGFRIs, patients have experienced a variety of adverse reactions, among which skin adverse reactions (including papulopustular rash, dry and itchy skin, paronychia, abnormal hair regeneration, etc.) are the most common adverse reactions, with an incidence rate of up to 79-88%. In the early stage of skin toxicity, it seriously affects the patient's daily life and mood. If the toxicity is not treated in time and effectively, it will gradually worsen with the continuous use of EGFRIs. Severe skin toxicity will force the dose of EGFRIs to be reduced or even stopped, and the interruption of treatment will aggravate the deterioration of cancer.

[0003] At present, the expert consensus on the treatment of EGFRIs adverse reactions recommends the topical use of antibiotics, steroids and emollients, or oral antibiotics, immunomodulators, etc. for adjuvant treatment, but these methods have poor clinical efficacy, recurrent attacks and long-term use bring side effects, causing secondary physical and mental damage to patients. Therefore, it is urgent to develop drug preparations that are effective in treating EGFRIs-induced skin toxicity, simple in process, and easy to industrialize for clinical use.

[0004] The applicant has found through research (application number 202510176114X) that a pharmaceutical composition composed of chlorogenic acid, ferulic acid and zinc salt has a good effect on treating the adverse reactions of EGFRIs, but the solution of the simple pharmaceutical composition is inconvenient to use, and the drug is lost or carried away by clothing before it penetrates the skin, affecting the efficacy of the drug. The pharmaceutical composition is easy to use after being prepared into a preparation, which improves patient compliance, helps to improve the ability of the pharmaceutical composition to effectively penetrate and remain in the basal layer of the skin, promotes the efficacy of the drug at the disease target, and can better meet clinical needs. The gel has a good moisturizing effect, helps the skin lock in moisture, and is conducive to alleviating the symptoms of dry and itchy skin caused by EGFRIs. The volatile solvent in the coating system improves the solubility and permeability of the pharmaceutical composition, and there is no need to add additional auxiliary materials such as cosolvents, penetration enhancers and preservatives, thereby reducing the risk of skin allergies. It can quickly form a film on the skin to protect the skin from bacterial infection, and is not easy to contaminate clothing. The electrospinning dressing uses electrospinning technology to form a "solid film" from the solution, which is easy to carry and store. The dressing immediately turns into a film when it comes into contact with water, adheres to the skin, has good moisturizing effects, and helps relieve dry skin. Summary of the invention

[0005] In view of the deficiencies of the prior art, the present invention provides a pharmaceutical composition for treating skin toxicity caused by EGFRIs, a preparation method thereof, and an application thereof in preparing a therapeutic drug for treating skin toxicity caused by EGFRIs. The pharmaceutical composition can be used as a gel, a film or a dressing to significantly enhance the permeability of the pharmaceutical composition and increase the retention amount in the skin. Its good moisturizing property can relieve the symptoms of dry skin and improve the efficacy of treating skin toxicity caused by EGFRIs. It is easy to use, has good patient compliance, and can better meet clinical needs.

[0006] The present invention uses a composition consisting of chlorogenic acid, ferulic acid and zinc salt as a basic composition and provides three different pharmaceutical compositions as preparations to obtain better skin penetration effect, skin retention effect and therapeutic effect.

[0007] The basic composition consists of chlorogenic acid, ferulic acid and zinc salt, the mass ratio of chlorogenic acid to ferulic acid is 4:1 to 1:4, preferably 2:1 to 1:3, and most preferably 1.5:1; the mass ratio of the total amount of chlorogenic acid and ferulic acid to zinc salt is 4:1 to 1:4, preferably 3:1 to 1:3, and most preferably 3:1.

[0008] The zinc salt is zinc acetate, zinc sulfate, zinc nitrate, zinc gluconate or zinc oxide, preferably zinc acetate.

[0009] The present invention adopts the following technical solution:

[0010] A pharmaceutical composition comprising chlorogenic acid, ferulic acid, zinc salt and a matrix material.

[0011] When the matrix material is a polymer matrix and water, the pharmaceutical composition is a gel;

[0012] When the matrix material is a polymer matrix and a volatile solvent, the pharmaceutical composition is a film coating agent;

[0013] When the matrix material is a polymer matrix, the pharmaceutical composition is a dressing.

[0014] Preferably, the polymer matrix is ​​a cellulose derivative, carbomer, sodium alginate, xanthan gum, hyaluronic acid, polyvinyl alcohol, chitosan, gelatin, silk fibroin, collagen, polyethylene glycol or polylactic acid.

[0015] More preferably, in the gel, the polymer matrix is ​​a cellulose derivative, carbomer, sodium alginate, xanthan gum or hyaluronic acid; in the coating, the polymer matrix is ​​polyvinyl alcohol, carbomer, chitosan or a cellulose derivative; in the dressing, the polymer matrix is ​​hyaluronic acid, gelatin, silk fibroin, collagen, polyethylene glycol or polylactic acid.

[0016] More preferably, the cellulose derivative is sodium carboxymethyl cellulose.

[0017] Preferably, in the gelling agent, the polymer matrix is ​​sodium carboxymethyl cellulose.

[0018] Preferably, in the coating agent, the polymer matrix is ​​polyvinyl alcohol, more preferably PVA124, PVA1788 or PVA0588, and most preferably PVA124.

[0019] Preferably, in the dressing, the polymer matrix is ​​a composition of hyaluronic acid and gelatin, and more preferably, the mass ratio of hyaluronic acid to gelatin is 1:(4.8-7.2).

[0020] Preferably, in the gelling agent, the mass fraction of the matrix material is 2-6%, more preferably 4%; in the coating agent, the mass fraction of the matrix material is 2-8%, more preferably 4-6%.

[0021] More preferably, in the dressing, the mass fraction of the matrix material is 81-97%.

[0022] Preferably, the gel further comprises a solubilizer, a moisturizer and a preservative; and the coating agent further comprises a plasticizer.

[0023] Preferably, the solubilizer is PEG 400, propylene glycol or Tween-80, more preferably PEG 400.

[0024] Preferably, the mass proportion of the solubilizer in the gel is 0.75-0.85%, more preferably 0.80%.

[0025] Preferably, the humectant is glycerin.

[0026] Preferably, the mass proportion of the moisturizing agent in the gel is 5-20%, more preferably 10%.

[0027] Preferably, the preservative is sodium benzoate, ethylparaben or potassium sorbate, more preferably sodium benzoate.

[0028] Preferably, the mass proportion of the preservative in the pharmaceutical composition is 0.15-0.25%, more preferably 0.20%.

[0029] Preferably, the plasticizer is glycerol or propylene glycol, more preferably glycerol.

[0030] Preferably, the mass fraction of the plasticizer in the coating agent is 1 to 15%, more preferably 10%.

[0031] Preferably, the volatile solvent in the coating agent is ethanol.

[0032] Preferably, the mass fraction of the volatile solvent in the coating agent is 40 to 60%, more preferably 45 to 55%.

[0033] The second object of the present invention is to provide a method for preparing the gel, comprising the following steps:

[0034] The polymer matrix and water are mixed to make the polymer matrix swell, and then the remaining components are added and uniformly mixed to obtain the gel.

[0035] Preferably, the swelling or uniform mixing step is performed under stirring conditions, with a stirring speed of 1000-2000 rpm for 0.5-5 h, preferably 1400-1600 rpm for 1-2 h.

[0036] The third object of the present invention is to provide a method for preparing the coating agent, comprising the following steps:

[0037] The polymer matrix and the volatile solvent are mixed to make the polymer matrix swell, and then the remaining components are added and the volatile solvent is added again, and then they are uniformly mixed to obtain the coating agent.

[0038] Preferably, the swelling temperature is 75 to 90° C., preferably 80 to 85° C., and the swelling time is 0.5 to 3 hours, preferably 1 to 2 hours.

[0039] Preferably, the uniform mixing step is carried out under stirring conditions, with a stirring speed of 1000-2000 rpm for 0.25-2 hours, preferably 1400-1600 rpm for 1-1.5 hours.

[0040] A fourth object of the present invention is to provide a method for preparing the dressing, comprising the following steps:

[0041] The dressing is obtained by using the spinning solution through an electrostatic spinning method.

[0042] Preferably, when the polymer matrix is ​​a mixture of hyaluronic acid and gelatin, the mass concentration of hyaluronic acid in the spinning solution is 2.5-3.5%, and the mass concentration of gelatin is 12-18%.

[0043] More preferably, the mass concentration of hyaluronic acid in the spinning solution is 2.8-3.2%, and the mass concentration of gelatin is 14-16%.

[0044] Preferably, the method for preparing the dressing comprises the following steps:

[0045] (1) swelling the polymer matrix in a spinning solvent, then adding the remaining components and uniformly mixing them to obtain a spinning solution;

[0046] (2) Electrospinning the spinning solution to obtain the dressing.

[0047] Preferably, the spinning solvent is a combination of one or more of hexafluoroisopropanol, dichloromethane, chloroform, formic acid or water, preferably a mixture of hexafluoroisopropanol and water, more preferably a mixture of hexafluoroisopropanol and water in a volume ratio of 6:4 to 8:2, more preferably a mixture of hexafluoroisopropanol and water in a volume ratio of 7:3.

[0048] Preferably, the electrospinning conditions are: voltage 20-28 kV, preferably 24-26 kV, propulsion speed 0.5-1.5 mL / h, preferably 0.8-1.2 mL / h, receiving distance 12-18 cm, preferably 14-16 cm.

[0049] The fifth object of the present invention is to provide the use of the pharmaceutical composition in the preparation of therapeutic drugs for EGFRIs-induced skin toxicity.

[0050] The EGFRIs include erlotinib, imatinib, erlotinib, sorafenib, rituximab, trastuzumab, cetuximab, bevacizumab or panitumumab.

[0051] The skin toxicities of EGFRIs include papulopustular rash, dry and itchy skin, desquamation, periungual inflammation, or abnormal hair regeneration.

[0052] The beneficial effects of the pharmaceutical composition, preparation and application of the present invention are shown in the following aspects:

[0053] (1) The present invention finds that chlorogenic acid and ferulic acid have the effect of reversing the inhibitory effect of EGFRIs on the activity of human skin keratinocytes (HaCa-T cells), and can reduce the apoptosis of HaCa-T cells caused by EGFRIs. Zinc acetate can enhance the effect of chlorogenic acid and ferulic acid in reversing the inhibitory effect of EGFRIs on the activity of HaCa-T cells. The basic composition composed of chlorogenic acid, ferulic acid and zinc acetate is effective in treating skin toxic reactions such as papulopustular rash, dry and itchy skin, desquamation, periungual inflammation, and abnormal hair regeneration caused by EGFRIs, with an effective rate of up to 83.33%. A pharmaceutical composition is provided for the clinical treatment of such skin toxic reactions.

[0054] Compared with the basic composition, in the gel of the present invention, the solubility of ferulic acid in water is increased by up to 3121 times, the retention amount in the skin is increased by 8.5 times, and the retention amount of chlorogenic acid and zinc acetate in the skin is increased by 28.2 times and 21.8 times respectively, so that the drug composition can effectively penetrate and be retained in the basal layer of the skin, which is conducive to the drug exerting its therapeutic effect at the disease target, and does not affect the anti-tumor effect of EGFRIs. The moisturizer added to the gel has a good moisturizing effect, helps the skin lock in moisture, moisturizes dry skin, and is conducive to alleviating the symptoms of dry and itchy skin caused by EGFRIs.

[0055] Compared with the basic composition, the coating agent of the present invention can be well dissolved and dispersed in the coating agent system without adding a cosolvent, which not only improves the solubility of the pharmaceutical composition, but also promotes the penetration of the pharmaceutical composition in the skin. The coating agent does not need to add a preservative, reduces the risk of skin allergies, has good fluidity, can quickly form a thin film on the skin to protect the skin from bacterial infection, is not easy to contaminate clothing, is easy to use, has good patient compliance, and meets clinical needs.

[0056] Compared with the basic composition, the dressing of the present invention is prepared into an electrospinning dressing using electrospinning technology to form a "solid film", which does not require the addition of preservatives, reduces the risk of skin allergies, is safer and easier to carry and store. The electrospinning dressing immediately permeates into a film when it comes into contact with water, and fits the skin better. Adding hyaluronic acid as a material for the electrospinning dressing has a good moisturizing effect, is beneficial for relieving dry skin, has good adhesion, and is not easy to contaminate clothing, providing more options to meet patient needs. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 This is a comparison chart of the permeation of each drug in the drug composition in Example 5 and the drug composition containing PEG400.

[0058] Figure 2This is the appearance of the pharmaceutical composition gel prepared with prescription number 19 in Example 6.

[0059] Figure 3 This is the appearance diagram of the centrifugal stability of the pharmaceutical composition gel prepared with prescription number 19 in Example 6.

[0060] Figure 4 This is the appearance diagram of the heat stability of the pharmaceutical composition gel prepared with prescription number 19 in Example 6.

[0061] Figure 5 This is the appearance diagram of the cold resistance stability of the pharmaceutical composition gel prepared with prescription number 19 in Example 6.

[0062] Figure 6 This is a comparison chart of the permeability of the basic composition and the gel in Example 9.

[0063] Figure 7 This is a graph showing the alleviation of skin toxicity symptoms in model mice in Example 10.

[0064] Figure 8 This is a comparison chart of the body weights of the model mice in each group in Example 10 (n=6, X±SD, *P<0.05, **P<0.01).

[0065] Fig. 9 This is a comparison chart of the spleen index of each group of model mice in Example 10 (n=6, X±SD, *P<0.05, **P<0.01).

[0066] Fig.10 This is a comparison chart of the liver index of each group of model mice in Example 10 (n=6, X±SD, *P<0.05, **P<0.01).

[0067] Fig.11 This is a comparison chart of the thymus index of each group of model mice in Example 10 (n=6, X±SD, *P<0.05, **P<0.01).

[0068] Fig.12 This is a comparison chart of the skin water content of each group of model mice in Example 10 (n=6, X±SD, *P<0.05, **P<0.01).

[0069] Fig.13 This is a comparison chart of the skin elasticity of each group of model mice in Example 10 (n=6, X±SD, *P<0.05, **P<0.01).

[0070] Fig.14 The results of HE and Oil Red staining of the model mouse skin after treatment with the gel in Example 10 (the scale bar in the figure is 100 μm).

[0071] Fig.15 The following are the appearance of the coating agent of the composition of the present invention in Example 7 and the film formation diagram after being applied on the hand for 30s and 60s.

[0072] Fig.16 The following are the appearance of the electrospun dressing of the composition of the present invention in Example 8 and the appearance of the dressing after it was permeated with water for 10s, 20s and 30s on the hand. DETAILED DESCRIPTION

[0073] The sources of animals, pig skin, drugs, reagents and instruments involved in the embodiments are as follows:

[0074] Experimental animals: SPF-grade BALB / c female mice were purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd., with experimental animal license number (SCXK (Su) 2022-0009), and were raised in the Experimental Animal Center of Jiangsu Institute of Traditional Chinese Medicine under light / dark (12h / 12h) and temperature (22±3)℃, with free access to food and water, and experimental animal use license (SYXK (Su) 2016-0018).

[0075] Experimental pig skin: Bama Xiang pig skin (Linxi County Jingde Agricultural Products Sales Co., Ltd.).

[0076] Drugs and reagents: chlorogenic acid, ferulic acid (HPLC ≥ 98%, Chengdu Pusi Biotechnology Co., Ltd.); chlorogenic acid reference substance (China National Institute for Food and Drug Control 110773-200611), ferulic acid reference substance (China National Institute for Food and Drug Control 110753-201817); erlotinib hydrochloride (Shanghai Aladdin Biochemical Technology Co., Ltd.); hyaluronic acid, zinc acetate, zinc sulfate, zinc nitrate, calcium zinc gluconate, zinc oxide (Rohn's reagent); PEG400, PEG300, Tween 8 0, dichloromethane, chloroform, formic acid, sodium hydroxide (Xilong Science); gelatin, PVA124, PVA1788, PVA0588, glycerol, propylene glycol, ethanol, carbomer, sodium alginate, xanthan gum, carboxyethyl cellulose, silk fibroin, collagen, polyethylene glycol, polylactic acid, hexafluoroisopropanol (McLean); n-octanol, sodium benzoate, ethyl paraben, potassium sorbate (Sinopharm Reagent); phosphate buffer (White Shark Biotechnology); boric acid-potassium hydroxide buffer (pH 9.0) (Yuanye Biotechnology); zinc acetate reference substance (Maidekai).

[0077] Instruments: ST16R centrifuge; MS205DU 1 / 100000 electronic balance (Mettler Toledo); OS20-Pro mechanical stirrer (SCILogex); water purifier (Millipore, TANKPE 060); electrospinning instrument (high voltage power supply (Dalian Jeman Technology Co., Ltd.), micro propulsion pump (Yanhang Power Technology Co., Ltd.)); Waters ACQITYArcSystem (Waters, USA); UV1800PC ultraviolet-visible spectrophotometer (Shanghai Phoenix Optical Instrument Co., Ltd.); TK-24BL transdermal diffusion tester (Shanghai Kaikai Technology Trading Co., Ltd.); THZ-82AHS air bath constant temperature and constant speed oscillator (Jintan Jincheng Guosheng Experimental Instrument Factory, Jiangsu).

[0078] All other sources are commercial unless otherwise specified.

[0079] Example 1: Ferulic acid solubility determination

[0080] Preparation of ferulic acid reference stock solution: Weigh an appropriate amount of ferulic acid reference, dilute to the mark with methanol in a 10 mL volumetric flask, mix well, prepare a stock solution with a mass concentration of 133.80 μg / mL, and store at 4°C for later use.

[0081] Preparation of the test sample: Weigh 3 mg of ferulic acid into a 1 mL volumetric flask, make three replicates, add pure water to the mark, sonicate to fully dissolve, centrifuge at 13,000 rpm for 10 min, and take the supernatant to obtain the test sample solution.

[0082] Investigation of linear relationship: Take the ferulic acid reference stock solution, and use methanol to prepare a series of ferulic acid reference solutions with mass concentrations of 0.67μg / mL, 1.34μg / mL, 2.68μg / mL, 5.35μg / mL, and 10.70μg / mL, respectively. Determine the ferulic acid reference solution and the test solution according to the chromatographic conditions, record the peak area, and plot the ferulic acid reference solution concentration as the abscissa (X) and the peak area (Y) as the ordinate to draw a standard curve. Use the standard curve to calculate the solubility of ferulic acid in water.

[0083] Chromatographic conditions: The chromatographic column was Agilent (4.6 mm × 250 mm, 5 μm), the mobile phase was acetonitrile and 0.1% phosphate solution, gradient elution, flow rate 1.0 mL / min, column temperature 35°C, injection volume 10 μL, detection wavelength 327 nm, and the elution gradient was shown in Table 1.

[0084] Table 1 Gradient elution table

[0085] Time (min) Acetonitrile (%) 0.1% phosphate solution (%) 0→9 13→16 87→84 9→10 16→25 84→75 10→16 25→45 75→55

[0086] Table 2 Ferulic acid solubility determination results

[0087] Ferulic acid (μg / mL) Average (μg / mL) RSD(%) 0.69 0.71 0.70 1.43 0.70

[0088] The results are shown in Table 2: The solubility of ferulic acid is 0.70 μg / mL, it is poorly soluble in water, and cannot be evenly dispersed in the gel matrix.

[0089] Example 2: Determination of oil-water partition coefficient

[0090] Accurately weigh 75.05 mg chlorogenic acid, 50.02 mg ferulic acid, and 41.67 mg zinc acetate, place in a 25 mL volumetric flask, dilute to scale with water-saturated n-octanol (water: n-octanol = 1:1), and dissolve them completely by ultrasonication to prepare chlorogenic acid, ferulic acid, and zinc acetate stock solutions for standby use. Accurately pipette 5.00 mL of chlorogenic acid stock solution, 5.00 mL of ferulic acid stock solution, and 5.00 mL of zinc acetate stock solution, place them in stoppered test tubes, add 5.00 mL of n-octanol-saturated phosphate buffers of different pH values ​​(pH 4.5, 5.5, and 6.5, respectively), place the stoppered test tubes in a constant temperature and constant speed oscillator, control the temperature at 32 ° C, and shake for 24 hours. Take the upper and lower liquids, centrifuge at 13000 rpm for 10 minutes, and dilute 50 times with the corresponding solution to obtain the test solution.

[0091] (1) The method for determining the contents of chlorogenic acid and ferulic acid is the same as that in Example 1.

[0092] (2) Determination of zinc acetate content

[0093] Preparation of zinc acetate reference stock solution: Accurately weigh an appropriate amount of zinc acetate reference, place in a 100 mL volumetric flask, add water to dissolve and dilute to the scale, shake well, and prepare a stock solution with a mass concentration of 228.02 μg / mL.

[0094] Zinc reagent solution: Accurately weigh 130.02 mg of zinc reagent, place in a 100 mL volumetric flask, add 2.00 mL of 1 mol / L sodium hydroxide test solution, dissolve by ultrasonication, dilute to the scale with water, shake well, and obtain the zinc reagent solution.

[0095] Linear relationship: Accurately measure 5.00mL of zinc acetate reference stock solution, place it in a 50mL volumetric flask, dilute to the mark with water, shake well, and obtain zinc acetate reference solution. Accurately measure 1.00, 1.50, 2.00, 2.50, 3.00mL of zinc acetate reference solution, place 3.00mL of test solution in a 10mL volumetric flask, accurately add 5.00mL of boric acid-potassium chloride buffer (pH 9.0) and 1.50mL of zinc reagent solution, dilute to the mark with water, and shake well. Measure the absorbance at a wavelength of 616nm, plot the concentration of zinc acetate reference solution as the abscissa (X) and the absorbance (Y) as the ordinate, draw a standard curve, and use the standard curve to calculate the mass concentration of zinc acetate in water-saturated n-octanol and water phase.

[0096] Calculate the apparent oil-water partition coefficient: P app =C0V0 / CV, C0 is the mass concentration of the index component in n-octanol, V0 is the volume of water-saturated n-octanol, C is the mass concentration of the index component measured in the aqueous phase at distribution equilibrium, and V is the volume of the aqueous phase.

[0097] Table 3 Results of determination of oil-water partition coefficients of chlorogenic acid, ferulic acid and zinc acetate in n-octanol-buffer (x±s, n=3)

[0098]

[0099]

[0100] The determination of the oil-water partition coefficient of a drug can simulate its distribution between the aqueous phase and the biological phase in the body, thereby predicting its absorption performance in the skin. <P app Drugs with a P value <100 are most likely to penetrate the stratum corneum and enter the epidermis. app Drugs with a P value less than 1 are blocked on the skin surface because they are highly water-soluble and difficult to penetrate the stratum corneum. app Drugs with a pH value greater than 100 are blocked on the skin surface due to poor water solubility and reduced transdermal ability. The results are shown in Table 3: Chlorogenic acid P app <1, Ferulic acid P app >100, zinc acetate P app <1, the three drugs are not easy to penetrate the skin, and appropriate methods are needed to increase the penetration of the three drugs through the stratum corneum of the skin and achieve drug retention in the basal layer of the epidermis.

[0101] Example 3: Selection of cosolvent type

[0102] Weigh 8 mg PEG400, 8 mg propylene glycol, and 8 mg Tween-80 into 1 mL volumetric flasks, each in triplicate, add an excess of ferulic acid (4 mg), dilute to volume with water, sonicate to fully dissolve, centrifuge at 13000 rpm for 10 min, take the supernatant and dilute 50 times with the corresponding solution to obtain the test solution. The method for determining the content of ferulic acid is the same as in Example 1.

[0103] Table 4 Determination results of ferulic acid solubility under different co-solvents (x±s, n=3)

[0104] Solvent Ferulic acid (mg / mL) PEG400 2.08±0.61 Propylene glycol 1.78±0.35 Twain-80 1.87±0.31

[0105] The results are shown in Table 4: When the dosages of PEG400, propylene glycol and Tween-80 are the same, PEG400 has the best solubilizing effect on ferulic acid.

[0106] Example 4: Selection of PEG400 dosage

[0107] Weigh 7.5 mg PEG400 (0.75%), 8 mg PEG400 (0.80%), and 8.5 mg PEG400 (0.85%) into 1 mL volumetric flasks in triplicate, add excess ferulic acid (4 mg) to the mark with water, dissolve thoroughly by ultrasound, centrifuge at 13000 rpm for 10 min, take the supernatant and dilute 50 times with the corresponding solution to obtain the test solution. The method for determining the content of ferulic acid is the same as in Example 1.

[0108] Table 5 Solubility determination results of ferulic acid containing different concentrations of PEG400 (x±s, n=3)

[0109] sample Ferulic acid (mg / mL) 0.75% PEG400 1.96±0.63 0.80% PEG400 2.08±0.61 0.85% PEG400 2.18±0.55

[0110] The results are shown in Table 5: the mass concentration of ferulic acid in the pharmaceutical composition solution is 0.20% (2 mg / mL). When the mass concentration of PEG400 is 0.80%, the solubility of ferulic acid is greater than 2 mg / mL. The preferred mass concentration of PEG400 is 0.80%.

[0111] Example 5: Effect of PEG400 on the penetration and retention of drug compositions in the skin

[0112] Take Bama Xiang pig skin and lay it on the upper end of the receiving pool, then add 20% ethanol phosphate solution to the receiving pool, so that the receiving pool liquid contacts the pig skin, and there should be no bubbles, add 1.00mL of the drug composition solution (0.30% chlorogenic acid, 0.20% ferulic acid, 0.17% zinc acetate) and 1.00mL of the drug composition solution containing PEG400 (0.30% chlorogenic acid, 0.20% ferulic acid, 0.17% zinc acetate, 0.8% PEG400) to the supply pool, and cover the upper part of the supply pool with plastic wrap to prevent data errors caused by evaporation of the drug solution. Put it into the transdermal instrument, set the temperature to 32°C, the speed to 350rpm, and take samples at 2, 4, 6, 8, 10, 12, and 24h as the test solution for the transdermal experiment. The Bama Xiang pig skin was taken out after 24 hours of percutaneous treatment, cut into pieces, added with 5.00 mL of methanol, and ultrasonicated for 60 minutes to fully dissolve the drug in the methanol. This solution was used as the test solution for the retention experiment.

[0113] The methods for determining the contents of chlorogenic acid, ferulic acid and zinc acetate are the same as those in Example 1 and Example 2, respectively.

[0114] Table 6 PEG400 on the effect of drug composition on skin retention results (x ± s, n = 3)

[0115]

[0116] The results are as follows Figure 1 As shown: The cumulative permeation amounts of chlorogenic acid, ferulic acid, and zinc acetate in the PEG400 drug composition were (200.29±1.70) μg / cm 2 、(162.30±0.63)μg / cm 2 、(121.23±1.78)μg / cm 2 The cumulative permeation amounts of chlorogenic acid, ferulic acid, and zinc acetate in the PEG400 drug composition for 24 h were (128.59±2.44) μg / cm 2 、(87.63±0.94)μg / cm 2 、(73.78±1.89)μg / cm 2 , indicating that PEG400 can significantly improve the transdermal ability of chlorogenic acid, ferulic acid and zinc acetate. As shown in Table 6: the skin retention of chlorogenic acid, ferulic acid and zinc acetate in the pharmaceutical composition containing PEG400 increased by 18 times, 5.5 times and 12 times, respectively, indicating that PEG400 can improve the retention of chlorogenic acid, ferulic acid and zinc acetate in the basal layer of the skin, which is beneficial for the drug to exert its therapeutic effect at the disease target.

[0117] Example 6: Preparation of gel

[0118] (1) Selection of matrix type: 1% carbomer 940, 10% hyaluronic acid, and 4% sodium carboxymethyl cellulose (CMC-Na) were taken according to the final concentration (mass fraction), and an appropriate amount of pure water was added. The mixture was stirred at 1500 rpm for 1.5 h at room temperature, and the basic composition (0.30% chlorogenic acid, 0.20% ferulic acid, and 0.17% zinc acetate) and 0.8% PEG400 were added respectively. Sodium hydroxide was added to adjust the pH value of the carbomer gel to 6 while stirring. Pure water was added to 100 g, and the mixture was stirred at 1500 rpm for 1 h at room temperature. The mixture was mixed and obtained.

[0119] According to the provisions of Part III of the 2020 edition of the Chinese Pharmacopoeia, gels should be uniform and fine and maintain a gel state, so the following evaluation is carried out:

[0120] Drug content determination: Take 1g of each gel, put it into a 50mL volumetric flask, dilute it to the mark with methanol, make it fully dissolved, centrifuge at 13000rpm for 10min, and obtain the test solution. The content determination method of chlorogenic acid, ferulic acid and zinc acetate is the same as that of Example 1-2.

[0121] pH value determination: Take 1g of each gel, put it into a 10mL volumetric flask, dilute to the mark with water, dissolve it by ultrasonic, and measure the pH value with a pH meter.

[0122] Determination of moisture retention rate: Weigh three portions of each gel in parallel (M0), spread them on a petri dish, put them in an oven at 55°C to dry until the mass no longer decreases, then take them out and cool them to determine the mass (M i ). Moisture retention rate = M i / M0×100%.

[0123] Viscosity measurement: Use NDJ-9S rotational viscometer, select the appropriate rotor and speed, place the rotor in different gels, immerse the gel liquid surface in the rotor groove, measure three times and take the average value.

[0124] Centrifugal stability: Take 1g of each gel, place it in a centrifuge tube, centrifuge at 3000rpm for 30min, and observe the gel stratification and color change.

[0125] Heat stability: Take 1g of each gel, place it in a centrifuge tube, seal it, and place it in a 55℃ constant temperature box for 6 hours to observe the gel stratification and color change.

[0126] Cold resistance stability: Take 1g of each gel, place it in a centrifuge tube, seal it, and place it in a -20℃ refrigerator for 24 hours to observe the gel stratification and color change.

[0127] The results showed that the gel formed with CMC-Na as the matrix had better drug stability than the gel formed with carbomer, and had more moderate fluidity than the gel formed with hyaluronic acid.

[0128] (2) Selection of matrix mass concentration:

[0129] Take 2%, 4%, and 6% CMC-Na according to the final concentration (mass fraction), add appropriate amount of pure water, stir at 1500rpm at room temperature for 1.5h to make it completely swell, add 0.30% chlorogenic acid, 0.20% ferulic acid, 0.17% zinc acetate and 0.8% PEG400, add water to 100g, continue stirring at 1500rpm at room temperature for 1h, mix well, and obtain.

[0130] The evaluation index is the same as above (1).

[0131] The results showed that the gel formed by 4% CMC-Na had more moderate fluidity than the gel formed by 2% CMC-Na and was easier to spread than the gel formed by 6% CMC-Na.

[0132] (3) Selection of the amount of moisturizer glycerin:

[0133] Take 4% CMC-Na according to the final concentration (mass fraction), make four parallel portions, add appropriate amount of pure water, stir at 1500rpm at room temperature for 1.5h to fully swell it, add 0.30% chlorogenic acid, 0.20% ferulic acid, 0.17% zinc acetate and 0.8% PEG400, add 5%, 10%, 15%, 20% glycerol respectively, add water to 100g, stir at 1500rpm at room temperature for 1h, mix well, and obtain.

[0134] The evaluation index is the same as above (1).

[0135] The results showed that the CMC-Na gel with 10% glycerol was easier to spread than the CMC-Na gel with 15% or 20% glycerol, and had better moisturizing properties than the CMC-Na gel with 5% glycerol.

[0136] (4) Selection of preservatives:

[0137] Take 4% CMC-Na according to the final concentration (mass fraction), make three parallel copies, add appropriate amount of pure water, stir at 1500rpm at room temperature for 1.5h to fully swell it, add 0.30% chlorogenic acid, 0.20% ferulic acid, 0.17% zinc acetate, 0.8% PEG400, 10% glycerol, add 0.2% sodium benzoate, 0.1% ethyl paraben, 0.2% potassium sorbate respectively, add water to 100g, continue stirring at 1500rpm at room temperature for 1h, mix well, and obtain.

[0138] The evaluation index is the same as above (1).

[0139] The results showed that the centrifugal stability and heat stability of CMC-Na gel were better when sodium benzoate was added than when ethyl paraben and potassium sorbate were added. Therefore, sodium benzoate was the preferred preservative for CMC-Na gel.

[0140] (5) Gel preparation process parameters:

[0141] Take 4% CMC-Na according to the final concentration (mass fraction), add appropriate amount of pure water, stir at S1 speed for t1 under T1 to make it fully swell, add 0.30% chlorogenic acid, 0.20% ferulic acid, 0.17% zinc acetate, 0.8% PEG400, 10% glycerol, 0.2% sodium benzoate, add pure water to 100g, continue stirring at S2 speed for t2 under T2, mix well, and obtain.

[0142] The process parameters of each recipe are shown in Table 7:

[0143] Table 7 Process parameters of each recipe

[0144] Prescription Number <![CDATA[T1 / ℃]]> <![CDATA[S1 / rpm]]> <![CDATA[t1 / h]]> <![CDATA[T2 / ℃]]> <![CDATA[S2 / rpm]]> <![CDATA[t2 / h]]> 1 25 1000 1 25 1500 1 2 45 1000 1.5 25 1500 1 3 35 1000 2 25 1500 1 4 45 1500 1 25 1500 1 5 35 1500 1.5 25 1500 1 6 25 1500 2 25 1500 1 7 35 2000 1 25 1500 1 8 25 2000 1.5 25 1500 1 9 45 2000 2 25 1500 1 10 25 1500 1.5 25 1000 0.5 11 25 1500 1.5 45 1000 1 12 25 1500 1.5 35 1000 1.5 13 25 1500 1.5 45 1500 1.5 14 25 1500 1.5 35 1500 1 15 25 1500 1.5 25 1500 1.5 16 25 1500 1.5 35 2000 0.5 17 25 1500 1.5 25 2000 1 18 25 1500 1.5 45 2000 1.5 19 25 1500 1.5 25 1500 1

[0145] Three pharmaceutical composition gels were prepared according to prescription No. 19 and labeled as 1, 2, and 3, respectively. Their stability was tested according to Example 6 (1). The appearance, centrifugal stability appearance, heat stability appearance, and cold stability appearance were as follows: Figures 2 to 5 shown.

[0146] Example 7: Preparation of film coating agent

[0147] According to the final concentration (mass fraction), a certain amount of polymer matrix, plasticizer and solvent are mixed and swelled / dissolved, and then the polymer matrix is ​​fully swollen in a water bath t3, and then removed and cooled for use. In addition, 0.30% chlorogenic acid, 0.20% ferulic acid, and 0.17% zinc acetate are added to the above polymer matrix to dissolve, and ethanol is added to 100g, and stirred at a speed of S4 for t4, and mixed to obtain.

[0148] The process parameters of each recipe are shown in Table 8:

[0149] Table 8 Process parameters of each recipe

[0150] Prescription Number Polymer Matrix Plasticizers Solvents <![CDATA[T3 / ℃]]> <![CDATA[t3 / h]]> <![CDATA[S4 / rpm]]> <![CDATA[t4 / h]]> 1 4% PVA-124 10% Glycerin 55% ethanol 85 2 1600 1 4 4% PVA-1788 6% Glycerin Distilled water 85 12 1600 0.5 5 4% PVA-0588 6% Glycerin Distilled water 85 12 1600 0.5 6 2% PVA-124 6% Glycerin 55% ethanol 85 2 1600 1 7 6% PVA-124 6% Glycerin 55% ethanol 85 2 1600 1 8 8% PVA-124 6% Glycerin 55% ethanol 85 2 1600 1 9 4% PVA-124 10% Glycerin 55% ethanol 85 2 1600 1 10 4% PVA-124 5% Glycerol 55% ethanol 85 2 1600 1 11 4% PVA-124 15% Glycerin 55% ethanol 85 2 1600 1 12 4% PVA-124 10% Glycerin 40% ethanol 85 2 1600 1 13 4% PVA-124 10% Glycerin 45% ethanol 85 2 1600 1 14 4% PVA-124 10% Glycerin 50% ethanol 85 2 1600 1 15 4% PVA-124 10% Glycerin 60% ethanol 85 2 1600 1 16 4% PVA-124 10% Glycerin 50% ethanol 75 2 1600 1 17 4% PVA-124 10% Glycerin 50% ethanol 80 2 1600 1 18 4% PVA-124 10% Glycerin 50% ethanol 90 2 1600 1 19 4% PVA-124 10% Glycerin 50% ethanol 85 0.5 1600 1 20 4% PVA-124 10% Glycerin 50% ethanol 85 1 1600 1 21 4% PVA-124 10% Glycerin 50% ethanol 85 3 1600 1 22 4% PVA-124 10% Glycerin 50% ethanol 85 2 1000 1 23 4% PVA-124 10% Glycerin 50% ethanol 85 2 1500 1 24 4% PVA-124 10% Glycerin 50% ethanol 85 2 2000 1 25 4% PVA-124 10% Glycerin 50% ethanol 85 2 1400 1 26 4% PVA-124 10% Glycerin 50% ethanol 85 2 1600 1 27 4% PVA-124 10% Glycerin 50% ethanol 85 2 1600 0.25 28 4% PVA-124 10% Glycerin 50% ethanol 85 2 1600 0.5 29 4% PVA-124 10% Glycerin 50% ethanol 85 2 1600 1.5 30 4% PVA-124 10% Glycerin 50% ethanol 85 2 1600 2

[0151] Prescription 2: 4% carbomer, 6% glycerol and appropriate amount of distilled water are swollen. Also, 0.30% chlorogenic acid, 0.20% ferulic acid and 0.17% zinc acetate are dissolved in an appropriate amount of 50% ethanol solution, and an appropriate amount of 50% ethanol is added to make the ethanol concentration in the system 50% (total mass is 10g). The two solutions are mixed, and the pH is adjusted to 4.5 with anhydrous sodium sulfite. Stirring is continued for 0.5h to mix the film-forming material and the drug solution.

[0152] Prescription 3: 1% chitosan, 0.5% carbomer, 6% glycerol and appropriate amount of distilled water are swollen. Also, 0.30% chlorogenic acid, 0.20% ferulic acid and 0.17% zinc acetate are dissolved in appropriate amount of 50% ethanol solution, and 50% ethanol is added to 10g, and stirring is continued for 0.5h to mix the film-forming material and drug solution.

[0153] The results showed that the above-mentioned pharmaceutical composition coating formulations can all be made into coatings. Fig.15 This is the appearance of the coating agent of prescription 26 composition and the film formation pictures after 30s and 60s of application on the hand. It can be seen that the coating agent has fluidity, is easy to apply, and can form a film quickly.

[0154] Example 8: Preparation of dressing

[0155] The following percentages are all final concentrations (mass fractions).

[0156] Prescription 1: Add 3% hyaluronic acid and 15% gelatin to 10mL of a mixed solution of hexafluoroisopropanol and water (7:3) to swell, then add 0.30% chlorogenic acid, 0.20% ferulic acid, and 0.17% zinc acetate to the above solution, mix well, and obtain a uniform electrospinning solution; use an electrospinning instrument to prepare an electrospinning dressing under the conditions of a voltage of 25kV, a propulsion speed of 0.8mL / h, and a receiving distance of 15cm.

[0157] Prescription 2: Use 10mL of 60% formic acid as solvent to prepare a 1% polyethylene glycol solution, stir magnetically at room temperature for 24 hours; then add 16% type I collagen peptide COP and 0.30% chlorogenic acid, 0.20% ferulic acid, and 0.17% zinc acetate, stir magnetically at room temperature to obtain COP / PEG spinning solution. Obtain uniform electrospinning solution; prepare electrospinning dressing under the conditions of voltage 25kV, propulsion speed 0.8mL / h, and receiving distance 15cm.

[0158] Prescription 3: PVP40%, chlorogenic acid 0.30%, ferulic acid 0.20%, and zinc acetate 0.17% were added to 6 mL of anhydrous ethanol, magnetically stirred at room temperature for 8 hours until completely dissolved, and then ultrasonically degassed for 20 minutes to prepare a homogeneous spinning solution of the PVP shell containing the drug composition. In addition, an appropriate amount of PLA was weighed and dissolved in an appropriate amount of chloroform-acetone (volume ratio 3:1) to prepare a 6% mixed solution, magnetically stirred at room temperature for 15 hours, and ultrasonically degassed for 20 minutes to prepare a PLA core layer emulsion spinning solution; the core-shell spinning solution was sucked into 2 10 mL syringes respectively, installed on a micro-injection pump, and connected to the two interfaces of the coaxial needle. Electrospinning dressings were prepared under the conditions of voltage 25 kV, propulsion speed 0.8 mL / h, and receiving distance 15 cm.

[0159] Prescriptions 4-31: Add the hyaluronic acid of M1 and the gelatin of M2 to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio X:Y) to swell, then add 0.30% chlorogenic acid, 0.20% ferulic acid, and 0.17% zinc acetate to the above solution, mix well, and obtain a uniform electrospinning solution; use an electrospinning instrument to prepare an electrospinning dressing under the conditions of voltage U, propulsion speed v, and receiving distance d.

[0160] The process parameters of prescriptions 4 to 31 are shown in Table 9:

[0161] Table 9 Process parameters of each recipe

[0162]

[0163]

[0164] Prescription 32: Add 3% hyaluronic acid and 15% gelatin to 10mL of a mixed solution of hexafluoroisopropanol and water (7:3) to swell, then add 0.75% chlorogenic acid, 0.50% ferulic acid, and 0.43% zinc acetate to the above solution, mix well, and obtain a uniform electrospinning solution; use an electrospinning instrument to prepare an electrospinning dressing under the conditions of a voltage of 25kV, a propulsion speed of 0.8mL / h, and a receiving distance of 13cm.

[0165] Prescription 33: Add 3% hyaluronic acid and 15% gelatin to 10mL of a mixed solution of hexafluoroisopropanol and water (7:3) to swell, then add 1.50% chlorogenic acid, 1.00% ferulic acid, and 0.85% zinc acetate to the above solution, mix well, and obtain a uniform electrospinning solution; use an electrospinning instrument to prepare an electrospinning dressing under the conditions of a voltage of 25kV, a propulsion speed of 0.8mL / h, and a receiving distance of 13cm.

[0166] The results showed that the above prescriptions can all be made into electrospinning dressings. Fig.16 The following are the appearance of the dressing with the composition of prescription 25 and the appearance of the dressing after it is permeated with water on the hand for 10s, 20s and 30s. It can be seen that the dressing can quickly permeate and form a film on the skin after it comes into contact with water.

[0167] Example 9: Retention of gel in skin

[0168] The test method is the same as that of Example 5, except that the PEG400-containing pharmaceutical composition solution in Example 5 is replaced with 1 g of gel (with the same composition as prescription 19 in Example 6), and the basic composition (i.e., the same pharmaceutical composition as in Example 5) is used as a comparison.

[0169] Table 10 The amount of drug retained in the skin of the pharmaceutical composition gel (x±s, n=3)

[0170]

[0171] The results are as follows Figure 6 As shown: The cumulative permeation of chlorogenic acid, ferulic acid, and zinc acetate in the basic composition for 24 hours was (3.54±0.87) μg / cm 2 、(9.53±0.78)μg / cm 2 、(3.01±1.26)μg / cm 2 The cumulative permeation amounts of chlorogenic acid, ferulic acid, and zinc acetate in the gel for 24 h were (128.59±2.44) μg / cm 2 、(87.63±0.94)μg / cm 2 、(73.78±1.89)μg / cm 2 , indicating that the gel formulation can significantly improve the transdermal ability of chlorogenic acid, ferulic acid, and zinc acetate. As shown in Table 10: The skin retention of chlorogenic acid, ferulic acid, and zinc acetate in the gel was increased by 28.2 times, 8.5 times, and 21.8 times, respectively, indicating that the gel formulation can significantly improve the retention of chlorogenic acid, ferulic acid, and zinc acetate in the basal layer of the skin, which is beneficial for the drug to exert its therapeutic effect at the disease target.

[0172] Example 10: Pharmacodynamics of the pharmaceutical composition gel against skin toxicity caused by EGFRIs

[0173] BALB / c mice (about 20g, female) were fed for 3 days to adapt to the environment and then randomly divided into 2 groups according to body weight. They were randomly divided into a blank group and an erlotinib hydrochloride group, with 6 mice in the blank group and 24 mice in the erlotinib hydrochloride group. Preparation of erlotinib hydrochloride suspension: Take 500mg of erlotinib hydrochloride, add 0.25% sodium carboxymethyl cellulose, add pure water to 50mL, ultrasonicate for 30min, and shake well when administering. The day before administration, the back of BALB / c mice was depilated and erlotinib hydrochloride solution was given by gavage at a dose of 150mg / kg, once a day, and skin toxicity appeared after continuous administration (about 48d).

[0174] After the establishment of the animal model of skin toxicity caused by EGFRIs, the rats in the erlotinib hydrochloride group were grouped again and randomly divided into 6 rats in the erlotinib hydrochloride group (model group), 6 rats in the erlotinib hydrochloride + basic composition group (basic composition group), 6 rats in the erlotinib hydrochloride + blank gel matrix group (blank matrix group), and 6 rats in the erlotinib hydrochloride + pharmaceutical composition gel group (gel group). Each group of mice continued to be gavaged with 150 mg / kg of erlotinib hydrochloride once a day. On this basis, the drug group applied the corresponding preparation externally at a dose of 333.5 mg / kg, and the model group applied physiological saline externally once a day; the drug was administered continuously for 14 days. The blank matrix was prepared by adding only 4% CMC-Na, 0.8% PEG400, 10% glycerol, 0.2% sodium benzoate without adding the basic pharmaceutical composition, and adding pure water to 100g (Example 6 Prescription 19) using the process of Example 6 Prescription 19. The pharmaceutical composition gel was prepared by Example 6 Prescription 19.

[0175] After the animal experiment, the skin toxicity of each group of mice was observed and the severity of skin redness, swelling, herpes, and rash was statistically analyzed ( Figure 7 ), and the weight change curves of mice in each group were statistically analyzed ( Figure 8 ), and the water content and skin elasticity of a part of the mouse back skin were measured ( Fig.12 , Fig.13 ), the thymus, spleen and liver of mice in different groups were weighed, the organ index was calculated, and the differences between the groups were compared ( Fig. 9 , Fig.10 , Fig.11 ), HE and Oil Red staining of the skin was performed to observe the efficacy of the drug composition ( Fig.14 ).

[0176] The results are shown in Tables 11 to 13: From the severity of the dryness, desquamation, redness, swelling, herpes and rash of the mouse skin, it can be seen that the model group mice lost hair around the eyes, shoulders, necks and backs, and had dryness, desquamation, cracking and herpes around the mouth and limbs, and their activity status became worse; the drug solution group and the drug composition gel group had different degrees of therapeutic effects on skin toxicity, and the gel group had the best efficacy, significantly reducing the incidence of redness, swelling, herpes and rash on the mouse skin, the mouse hair resumed growth, and the symptoms disappeared significantly. The skin toxicity reaction was effectively treated, and the effective rate reached 83.33%.

[0177] Table 11 Statistics of the severity of redness and swelling of the limbs of mice

[0178] Group Number none Mild Moderate Severe Incidence / % blank 6 6 0 0 0 0 Model Group 6 0 0 4 2 100％ Basic composition group 6 4 2 0 0 33.33％ Blank matrix group 6 0 0 4 2 100％ Gel group 6 5 1 0 0 16.67％

[0179] Table 12 Statistics of severity of herpes in mice

[0180] Group Number none Mild Moderate Severe Incidence / % blank 6 6 0 0 0 0 Model Group 6 0 4 2 0 100％ Basic composition group 6 4 1 1 0 33.33％ Blank matrix group 6 0 4 2 0 100％ Gel group 6 6 0 0 0 0

[0181] Table 13 Statistics of the severity of skin rash in mice

[0182] Group Number none Mild Moderate Severe Incidence / % blank 6 6 0 0 0 0 Model Group 6 0 2 4 0 100％ Basic composition group 6 4 1 1 0 33.33％ Blank matrix group 6 0 2 4 0 100％ Gel group 6 6 0 0 0 0

[0183] During the course of treatment, the body weight of mice in the model group and the blank matrix group did not change significantly, while the body weight of mice in the basic composition group and the gel group increased (P < 0.05), indicating that the quality of life of mice can be improved after administration. The liver index and spleen index of mice in the model group were significantly increased, and the thymus index was reduced, indicating that erlotinib hydrochloride had a serious damage to the immune system of mice; after administration of the basic composition and the gel, they could recover to varying degrees (P < 0.05, P < 0.01, P < 0.001), indicating that the drug can have a certain reversal and protective effect on the organ damage caused by erlotinib hydrochloride, and compared with the basic composition, the effect of the gel was the most significant.

[0184] From the analysis of the results of skin water content and skin rebound, the water content of the mice in the model group was significantly reduced, indicating that erlotinib hydrochloride had serious damage to the skin barrier of mice and affected its moisturizing function; the skin water content increased significantly after administration of the basic composition and the gel (P < 0.001); from the results of skin elasticity, the skin rebound time of the mice in the model group was significantly prolonged, indicating that erlotinib hydrochloride may have serious damage to the skin collagen and elastic fibers of mice and affect the skin elasticity function; the skin rebound time of the mice was significantly shortened after administration of the basic composition and the gel (P < 0.001); it shows that local application of the gel can have a certain repair effect on the skin barrier.

[0185] From the HE results, it can be seen that compared with the blank group, the characteristics of skin inflammation, i.e., parakeratosis (retention of stratum corneum cell nuclei), significant thickening of the stratum corneum, and changes in skin structure were observed in the model group mice. After the administration of the basic composition and the gel, the skin toxicity of the mice was improved, and the improvement in the gel group was the most obvious. The results of oil red staining showed that compared with the blank group, the oil red-stained sebaceous glands in the model group were reduced, the swollen follicles ruptured, and the oil secretion was significantly reduced. Compared with the model, the number of swollen follicles and oil secretion of the mouse skin were significantly restored after the administration of the basic composition and the gel, indicating that the pharmaceutical composition of the present invention can effectively improve the phenomenon of abnormal oil secretion of sebaceous glands caused by erlotinib hydrochloride.

[0186] Example 11: Evaluation of the efficacy of dressings and coatings on skin toxicity caused by EGFRIs

[0187] The establishment of the animal model is the same as that in Example 10, except that there are 30 rats in the erlotinib hydrochloride group in this example. After the establishment of the animal model of skin toxicity caused by EGFRIs, the rats in the erlotinib hydrochloride group were grouped again and randomly divided into 6 rats in the erlotinib hydrochloride group (model group), 6 rats in the erlotinib hydrochloride + basic composition group (basic composition group), 6 rats in the erlotinib hydrochloride + pharmaceutical composition coating group (coating group), and 6 rats in the erlotinib hydrochloride + pharmaceutical composition electrospinning dressing group (electrospinning dressing group). Each group of mice continued to be gavaged with 150 mg / kg of erlotinib hydrochloride once a day. On this basis, the drug group applied the corresponding preparation externally at a dose of 333.5 mg / kg, and the model group applied physiological saline externally once a day; the drug was administered continuously for 14 days. The pharmaceutical composition coating adopts prescription 1 in Example 7, and the pharmaceutical composition electrospinning dressing adopts prescription 5 in Example 8.

[0188] The results are shown in Tables 14 to 16: From the statistical results of the severity of dryness, desquamation, redness, swelling, herpes and rash on the mouse skin, it can be seen that the model group mice lost hair around the eyes, shoulders, neck and back, and had dry skin, desquamation, cracking and herpes around the mouth and limbs, and their activity status became worse; the basic composition group, the coating group and the electrospinning dressing group all had different degrees of therapeutic effects on skin toxicity. The coating group and the electrospinning dressing group had better therapeutic effects, significantly reducing the incidence of redness, swelling, herpes and rash on the mouse skin, the mouse hair resumed growth, and the symptoms disappeared significantly. The skin toxic reactions were effectively treated, and the effective rate reached 83.33%.

[0189] Table 14 Statistics of the severity of redness and swelling of the limbs of mice

[0190] Group Number none Mild Moderate Severe Incidence / % blank 6 6 0 0 0 0 Model Group 6 0 0 4 2 100％ Basic composition group 6 4 2 0 0 33.33％ Coating agent group 6 5 1 0 0 16.67％ Electrospinning Dressing Group 6 5 1 0 0 16.67％

[0191] Table 15 Statistics of severity of herpes in mice

[0192]

[0193]

[0194] Table 16 Statistics of the severity of skin rash in mice

[0195] Group Number none Mild Moderate Severe Incidence / % blank 6 6 0 0 0 0 Model Group 6 0 1 4 1 100％ Drug solution group 6 4 1 1 0 33.33％ Coating agent group 6 6 0 0 0 0 Electrospinning Dressing Group 6 6 0 0 0 0

Claims

1. A pharmaceutical composition, characterized in that comprising chlorogenic acid, ferulic acid, zinc salt and matrix material, When the matrix material is a polymer matrix and water, the pharmaceutical composition is a gel; When the matrix material is a polymer matrix and a volatile solvent, the pharmaceutical composition is a film coating agent; preferably, the volatile solvent is ethanol; When the matrix material is a polymer matrix, the pharmaceutical composition is a dressing.

2. The pharmaceutical composition according to claim 1, characterized in that The polymer matrix is ​​a cellulose derivative, carbomer, sodium alginate, xanthan gum, hyaluronic acid, polyvinyl alcohol, chitosan, gelatin, silk fibroin, collagen, polyethylene glycol or polylactic acid; More preferably, in the gel, the polymer matrix is ​​a cellulose derivative, carbomer, sodium alginate, xanthan gum or hyaluronic acid; in the coating, the polymer matrix is ​​polyvinyl alcohol, carbomer, chitosan or a cellulose derivative; in the dressing, the polymer matrix is ​​hyaluronic acid, gelatin, silk fibroin, collagen, polyethylene glycol or polylactic acid; More preferably, the cellulose derivative is sodium carboxymethyl cellulose.

3. The pharmaceutical composition according to claim 2, characterized in that In the gel, the polymer matrix is ​​sodium carboxymethyl cellulose; In the coating agent, the polymer matrix is ​​polyvinyl alcohol, more preferably PVA124, PVA1788 or PVA0588, and most preferably PVA124; In the dressing, the polymer matrix is ​​a composition of hyaluronic acid and gelatin, and more preferably, the mass ratio of hyaluronic acid to gelatin is 1:(4.8~7.2).

4. The pharmaceutical composition according to claim 1, characterized in that In the gelling agent, the mass fraction of the matrix material is 2-6%, more preferably 4%; In the coating agent, the mass fraction of the matrix material is 2-8%, more preferably 4-6%; In the dressing, the mass fraction of the matrix material is 81-97%.

5. The pharmaceutical composition according to claim 1, characterized in that The gel also includes a solubilizer, a moisturizer and a preservative; the coating agent also includes a plasticizer; preferably, the solubilizer is PEG 400, propylene glycol or Tween-80; preferably, the plasticizer is glycerol or propylene glycol; preferably, the moisturizer is glycerol; preferably, the preservative is sodium benzoate, ethyl paraben or potassium sorbate.

6. The method for preparing the gel according to any one of claims 1 to 5, characterized in that: The steps include: The polymer matrix and water are mixed to make the polymer matrix swell, and then the remaining components are added and uniformly mixed to obtain the gel.

7. The method for preparing the coating agent according to any one of claims 1 to 5, characterized in that: The steps include: The polymer matrix and the volatile solvent are mixed to make the polymer matrix swell, and then the remaining components are added and the volatile solvent is added again, and then they are uniformly mixed to obtain the coating agent.

8. The method for preparing the dressing according to any one of claims 1 to 5, characterized in that: The steps include: The dressing is obtained by electrospinning the spinning solution; preferably, the polymer matrix is ​​a mixture of hyaluronic acid and gelatin, the mass concentration of hyaluronic acid in the spinning solution is 2.5-3.5%, and the mass concentration of gelatin is 12-18%, and more preferably, the mass concentration of hyaluronic acid in the spinning solution is 2.8-3.2%, and the mass concentration of gelatin is 14-16%.

9. The preparation method according to claim 8, characterized in that: The steps include: (1) swelling the polymer matrix in a spinning solvent, then adding the remaining components and uniformly mixing them to obtain a spinning solution; (2) electrospinning the spinning solution to obtain the dressing; Preferably, the spinning solvent is a combination of one or more of hexafluoroisopropanol, dichloromethane, chloroform, formic acid or water, preferably a mixture of hexafluoroisopropanol and water, more preferably a mixture of hexafluoroisopropanol and water in a volume ratio of 6:4 to 8:2, more preferably a mixture of hexafluoroisopropanol and water in a volume ratio of 7:3; Preferably, the electrospinning conditions are: voltage 20-28 kV, preferably 24-26 kV, propulsion speed 0.5-1.5 mL / h, preferably 0.8-1.2 mL / h, receiving distance 12-18 cm, preferably 14-16 cm.

10. Use of the pharmaceutical composition according to any one of claims 1 to 5 in the preparation of a therapeutic drug for EGFRIs-induced skin toxicity.

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