Pharmaceutical compositions and use in the manufacture of a medicament for the treatment of EGFRi-induced skin toxicity

Abstract

The application discloses a kind of pharmaceutical composition and in the application in preparation EGFRIs caused skin toxicity treatment drug, the pharmaceutical composition includes chlorogenic acid, ferulic acid, zinc salt and matrix material.The pharmaceutical composition as gel, film coating agent or dressing, can significantly enhance the permeability of pharmaceutical composition and increase in skin retention amount, its good moisturizing performance can alleviate the symptoms of skin dryness, improve the curative effect of treatment EGFRIs caused skin toxicity reaction, use simple, patient compliance is good, can better satisfy clinical demand.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a pharmaceutical composition for treating skin toxicity caused by EGFRIs, its preparation method, and its application in the preparation of therapeutic drugs for EGFRI-induced skin toxicity. Background Technology

[0002] In cancer treatment, epidermal growth factor receptor inhibitors (EGFRIs) are widely used clinically to treat EGFR-mutant cancer patients, especially non-small cell lung cancer, breast cancer, and colorectal cancer. However, with the use of EGFRIs, patients have experienced various adverse reactions, among which skin adverse reactions (including papulopustular rashes, dry and itchy skin, paronychia, and abnormal hair regrowth) are the most common, with an incidence rate as high as 79-88%. Early skin toxicity severely impacts patients' daily lives and emotions. If toxic reactions are not treated promptly and effectively, they will gradually worsen with continued EGFRI use. Severe skin toxicity may force a reduction in the dosage of EGFRIs or even discontinuation of the drug, leading to treatment interruption and exacerbating cancer progression.

[0003] Currently, expert consensus on treating adverse reactions to EGFRIs recommends topical antibiotics, steroids, and emollients, or adjunctive therapy with oral antibiotics and immunomodulators. However, these methods have poor clinical efficacy, recurrent episodes, and long-term use leads to side effects, causing secondary harm to patients' physical and mental well-being. Therefore, there is an urgent need to develop drug formulations that are effective, simple to manufacture, and easy to industrialize for clinical application in treating EGFRI-induced skin toxicity.

[0004] The applicant's research (application number 202510176114X) has shown that a drug composition consisting of chlorogenic acid, ferulic acid, and zinc salts is effective in treating adverse reactions to EGFRIs. However, the solution of the drug composition alone is inconvenient to use, as the drug is lost before penetrating the skin or is washed away by clothing, affecting its efficacy. Formulating the drug composition into a formulation makes it easier to use, improves patient compliance, and helps the drug composition effectively penetrate and remain in the basal layer of the skin, promoting the drug's efficacy at the disease target and better meeting clinical needs. The gel has good moisturizing properties, helping the skin retain moisture and relieving the symptoms of dry and itchy skin caused by EGFRIs. The volatile solvent in the film-forming system improves the solubility and permeability of the drug composition, eliminating the need for additional solubilizers, penetration enhancers, and preservatives, reducing the risk of skin allergies. It can quickly form a film on the skin to protect it from bacterial infection and is less likely to stain clothing. Electrospun dressings use electrospun technology to form a "solid film" from the solution, making them easy to carry and store. The dressing immediately permeates into a film upon contact with water, adhering to the skin and providing good moisturizing effects, thus relieving dry skin. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a pharmaceutical composition for treating dermatotoxic reactions caused by EGFRIs, a method for preparing the same, and its application in the preparation of therapeutic drugs for EGFRI-induced dermatotoxicity. This pharmaceutical composition, used as a gel, film, or dressing, significantly enhances the permeability of the drug composition and increases its retention in the skin. Its excellent moisturizing properties alleviate symptoms of dry skin, improve the efficacy of treating dermatotoxic reactions caused by EGFRIs, and it is easy to use with good patient compliance, thus better meeting clinical needs.

[0006] This invention provides a base composition consisting of chlorogenic acid, ferulic acid and zinc salt, and offers three different pharmaceutical compositions as formulations to achieve better skin penetration, skin retention and therapeutic effects.

[0007] The basic composition consists of chlorogenic acid, ferulic acid and zinc salt, wherein 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 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 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 gelling agent, the polymer matrix is ​​a cellulose derivative, carbomer, sodium alginate, xanthan gum, or hyaluronic acid; in the coating agent, the polymer matrix is ​​polyvinyl alcohol, carbomer, chitosan, or a cellulose derivative; and 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; 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 gelling agent further includes a solubilizer, a humectant, and a preservative; the coating agent further includes a plasticizer.

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

[0024] Preferably, the solubilizer accounts for 0.75-0.85% by mass in the gelling agent, more preferably 0.80%.

[0025] Preferably, the moisturizer is glycerin.

[0026] Preferably, the humectant accounts for 5-20% of the mass of the gel, more preferably 10%.

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

[0028] Preferably, the preservative accounts for 0.15-0.25% by mass in the pharmaceutical composition, more preferably 0.20%.

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

[0030] Preferably, the plasticizer has a mass fraction of 1-15% in the coating agent, 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 40-60%, more preferably 45-55%.

[0033] A second objective of this invention is to provide a method for preparing the gelling agent, comprising the following steps:

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

[0035] Preferably, the swelling or uniform mixing steps are carried out under stirring conditions, with a stirring speed of 1000-2000 rpm and a stirring time of 0.5-5 h. More preferably, the stirring speed is 1400-1600 rpm for 1-2 h.

[0036] A third objective of this 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 swell the polymer matrix. Then, the remaining components are added and the volatile solvent is added again. After uniform mixing, the coating agent is obtained.

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

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

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

[0041] The dressing is obtained by electrospinning the spinning solution.

[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 includes the following steps:

[0045] (1) The polymer matrix is ​​swollen in a spinning solvent, and then the remaining components are added and mixed evenly to obtain a spinning solution;

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

[0047] Preferably, the spinning solvent is 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, and even more preferably a mixture of hexafluoroisopropanol and water in a volume ratio of 7:3.

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

[0049] A fifth objective of this invention is to provide the use of the pharmaceutical composition in the preparation of a therapeutic medicament for EGFRI-induced skin toxicity.

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

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

[0052] The beneficial effects of the pharmaceutical compositions, formulations, and applications described in this invention are manifested in the following aspects:

[0053] (1) This invention has found that chlorogenic acid and ferulic acid can reverse the inhibitory effect of EGFRIs on the vitality of human skin keratinocytes (HaCa-T cells) and 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 vitality of HaCa-T cells. The basic composition of chlorogenic acid, ferulic acid and zinc acetate is effective in treating skin toxicity reactions such as papulopustular rashes, dry and itchy skin, desquamation, periungual inflammation and abnormal hair regeneration caused by EGFRIs, with an efficacy rate of up to 83.33%, providing a pharmaceutical composition for the clinical treatment of such skin toxicity reactions.

[0054] Compared to the base composition, the gel of this invention exhibits a 3121-fold increase in the water solubility of ferulic acid and an 8.5-fold increase in skin retention. Chlorogenic acid and zinc acetate also show increases in skin retention of 28.2-fold and 21.8-fold, respectively. This allows the drug composition to effectively penetrate and remain in the basal layer of the skin, facilitating the drug's therapeutic effect at the disease target without affecting the anti-tumor activity of EGFRIs. The added moisturizer in the gel provides excellent hydration, helping the skin retain moisture and alleviate dryness, thus helping to relieve symptoms of dry and itchy skin caused by EGFRIs.

[0055] Compared to the base composition, the film-forming agent of this invention can dissolve and disperse well in the film-forming agent system without the need for co-solvents, which not only improves the solubility of the drug composition but also promotes its penetration into the skin. The film-forming agent requires no preservatives, reducing the risk of skin allergies. It has good fluidity, quickly forms a film on the skin to protect against bacterial infection, and is less likely to stain clothing. It is easy to use, has good patient compliance, and meets clinical needs.

[0056] Compared to the basic composition, the dressing of this invention is prepared using electrospinning technology to form a "solid film," eliminating the need for preservatives, reducing the risk of skin allergies, and making it safer, easier to carry, and easier to store. The electrospinning dressing immediately permeates into a film upon contact with water, adhering better to the skin. The addition of hyaluronic acid as a material in the electrospinning dressing provides excellent moisturizing effects, helping to relieve dry skin, and good adhesion, making it less likely to stain clothing, thus providing more options to meet patient needs. Attached Figure Description

[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 2The image shows the appearance of the gel of the pharmaceutical composition prepared by prescription number 19 in Example 6.

[0059] Figure 3 The image shows the appearance of the gel centrifugation stability of the pharmaceutical composition prepared by prescription number 19 in Example 6.

[0060] Figure 4 The image shows the appearance of the gel with heat resistance stability of the pharmaceutical composition prepared by prescription number 19 in Example 6.

[0061] Figure 5 The image shows the cold-resistant stability of the drug composition gel prepared by prescription number 19 in Example 6.

[0062] Figure 6 This is a comparison chart of the penetration of the base composition and the gelling agent in Example 9.

[0063] Figure 7 This figure shows the reduction of skin toxicity symptoms in the model mice in Example 10.

[0064] Figure 8 The image shows a comparison 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] Figure 9 The image shows a comparison of spleen indices in different groups of model mice in Example 10 (n = 6, X ± SD, *P < 0.05, **P < 0.01).

[0066] Figure 10 The image shows a comparison of liver indices in different groups of model mice in Example 10 (n = 6, X ± SD, *P < 0.05, **P < 0.01).

[0067] Figure 11 The image shows a comparison of thymus index among the model mice in Example 10 (n = 6, X ± SD, *P < 0.05, **P < 0.01).

[0068] Figure 12 The image shows a comparison of skin water content in each group of model mice in Example 10 (n=6, X±SD, *P<0.05, **P<0.01).

[0069] Figure 13 The image shows a comparison of skin elasticity in each group of model mice in Example 10 (n=6, X±SD, *P<0.05, **P<0.01).

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

[0071] Figure 15 The images show the appearance of the coating agent of the present invention in Example 7 and the film formation after 30s and 60s when applied to the hand.

[0072] Figure 16 The images show the appearance of the electrospun dressing of the present invention in Example 8 and the appearance of the dressing after it has been exposed to water on the hand for 10s, 20s and 30s. Detailed Implementation

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

[0074] Laboratory animals: SPF-grade female BALB / c mice, all purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd., Laboratory Animal License No. (SCXK(Su)2022-0009), housed at the Laboratory Animal Center of Jiangsu Academy of Traditional Chinese Medicine under light / dark (12h / 12h) and temperature (22±3)℃, with free access to food and water, Laboratory Animal Use License (SYXK(Su)2016-0018).

[0075] Experimental pig skin: Bama fragrant 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 standard (National Institutes for Food and Drug Control 110773-200611), ferulic acid reference standard (National Institutes 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 (Ron's reagent); PEG400, PEG300, Tween 8 0. Dichloromethane, chloroform, formic acid, sodium hydroxide (Xilong Scientific); gelatin, PVA124, PVA1788, PVA0588, glycerol, propylene glycol, ethanol, carbomer, sodium alginate, xanthan gum, carboxyethyl cellulose, silk fibroin, collagen, polyethylene glycol, polylactic acid, hexafluoroisopropanol (Maclean); n-octanol, sodium benzoate, ethylparaben, potassium sorbate (Sinopharm Reagent); phosphate buffer (White Shark Biotechnology); borate-potassium hydroxide buffer (pH 9.0) (Yuanye Biotechnology); zinc acetate reference standard (Medcare).

[0077] Instruments: ST16R centrifuge; MS205DU electronic balance (Mettler Toledo); OS20-Pro mechanical stirrer (SCILogex); pure water system (Millipore, TANKPE 060); electrospinning apparatus (high voltage power supply (Dalian Jieman Technology Co., Ltd.), micro-propellant pump (Yanhang Power Technology Co., Ltd.)); Waters ACQITY ArcSystem (Waters Corporation, USA); UV1800PC UV-Vis spectrophotometer (Shanghai Phoenix Optical Instrument Co., Ltd.); TK-24BL transdermal diffusion tester (Shanghai Kaikai Technology Trade Co., Ltd.); THZ-82AHS air bath constant temperature and speed oscillator (Jincheng Guosheng Experimental Instrument Factory, Jintan City, Jiangsu Province).

[0078] Unless otherwise specified, all other sources are commercial.

[0079] Example 1: Determination of ferulic acid solubility

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

[0081] Preparation of the test sample: Weigh 3 mg ferulic acid into a 1 mL volumetric flask, make three parallel portions, add pure water to make up to the mark, sonicate to dissolve completely, centrifuge at 13000 rpm for 10 min, and take the supernatant to obtain the test sample solution.

[0082] Linearity investigation: Ferulic acid reference standard stock solution was used to prepare a series of ferulic acid reference standard solutions with mass concentrations of 0.67 μg / mL, 1.34 μg / mL, 2.68 μg / mL, 5.35 μg / mL, and 10.70 μg / mL using methanol. The ferulic acid reference standard solutions and test solutions were measured according to the chromatographic conditions, and the peak areas were recorded. A standard curve was plotted with the concentration of ferulic acid reference standard solution as the abscissa (X) and the peak area (Y) as the ordinate. The solubility of ferulic acid in water was calculated using the standard curve.

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

[0084] Table 1 Gradient Elution Table

[0085] 0→9 13→16 87→84 9→10 16→25 84→75 10→16 25→45 75→55

[0086] Table 2 Results of ferulic acid solubility determination

[0087] 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 sparingly soluble in water and cannot be uniformly 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 into a 25 mL volumetric flask. Dilute to the mark with water-saturated n-octanol (water:n-octanol = 1:1) solution, and sonicate until fully dissolved. Prepare stock solutions of chlorogenic acid, ferulic acid, and zinc acetate separately for later use. Accurately pipette 5.00 mL of each stock solution into stoppered test tubes. Add 5.00 mL of n-octanol-saturated phosphate buffer solutions of different pH values ​​(pH 4.5, 5.5, and 6.5, respectively). Place the stoppered test tubes in a constant temperature and speed shaker at 32°C and shake for 24 h. Centrifuge the upper and lower layers separately at 13000 rpm for 10 min, and dilute 50 times with the corresponding solutions to obtain the test solutions.

[0091] (1) The methods for determining the content of chlorogenic acid and ferulic acid are the same as in Example 1.

[0092] (2) Determination of zinc acetate content

[0093] Preparation of zinc acetate reference standard stock solution: Accurately weigh an appropriate amount of zinc acetate reference standard, place it in a 100 mL volumetric flask, add water to dissolve and dilute to the mark, 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 and place it in a 100 mL volumetric flask. Add 2.00 mL of 1 mol / L sodium hydroxide test solution, dissolve by sonication, dilute with water to the mark, and shake well to obtain the zinc reagent solution.

[0095] Linearity: Accurately measure 5.00 mL of zinc acetate stock solution into a 50 mL volumetric flask, dilute to the mark with water, and mix well to obtain the zinc acetate standard solution. Accurately measure 1.00, 1.50, 2.00, 2.50, and 3.00 mL of the zinc acetate standard solution and 3.00 mL of the test solution into 10 mL volumetric flasks. Accurately add 5.00 mL of borate-potassium chloride buffer (pH 9.0) and 1.50 mL of zinc reagent solution, dilute to the mark with water, and mix well. Measure the absorbance at a wavelength of 616 nm. Plot a standard curve with the concentration of the zinc acetate standard solution as the abscissa (X) and the absorbance (Y) as the ordinate. Calculate the mass concentration of zinc acetate in water-saturated n-octanol and aqueous phases using the standard curve.

[0096] Calculate the apparent oil-water distribution coefficient: P app =C0V0 / CV, where 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 partition equilibrium, and V is the volume of the aqueous phase.

[0097] Table 3. Results of oil-water partition coefficient determination of chlorogenic acid, ferulic acid and zinc acetate in n-octanol-buffered solution (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 and biological phases in a biological body, thereby predicting its absorption performance in the skin. <P app Drugs with a concentration <100 are most likely to penetrate the stratum corneum and enter the epidermis. app Drugs with a concentration <1 are difficult to penetrate the stratum corneum due to their high water solubility and are thus trapped on the skin surface. app Drugs with concentrations >100 are blocked at the skin surface due to poor water solubility and reduced transdermal absorption. The results are shown in Table 3: Chlorogenic acid P app <1, ferulic acid P app >100, Zinc acetate P app <1. None of the three drugs are easily transdermal, so appropriate methods are needed to improve their penetration through the stratum corneum and achieve drug retention in the basal layer of the epidermis.

[0101] Example 3: Selection of Cosolvent Type

[0102] Weigh 8 mg of PEG400, 8 mg of propylene glycol, and 8 mg of Tween-80 into 1 mL volumetric flasks, making three parallel aliquots. Add excess ferulic acid (4 mg) to each flask, dilute to the mark with water, sonicate to dissolve completely, centrifuge at 13000 rpm for 10 min, and dilute the supernatant 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. Results of ferulic acid solubility determination under different co-solvents (x±s, n=3)

[0104] 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 amounts of PEG400, propylene glycol, and Tween-80 cosolvents 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, making three replicates for each. Add excess ferulic acid (4 mg) to each flask and dilute to the mark with water. Sonicate to dissolve completely, centrifuge at 13000 rpm for 10 min, and take the supernatant to dilute 50 times with the corresponding solution to obtain the test solution. The method for determining the ferulic acid content is the same as in Example 1.

[0108] Table 5. Results of ferulic acid solubility determination with different concentrations of PEG400 (x±s, n=3)

[0109] 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 drug 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. Preferably, the mass concentration of PEG400 is 0.80%.

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

[0112] Place a piece of Bama fragrant pig skin flat on the top of the receiving pool. Add a 20% ethanol phosphate solution to the receiving pool, ensuring the liquid contacts the pig skin without air bubbles. Add 1.00 mL of the drug composition solution (0.30% chlorogenic acid, 0.20% ferulic acid, 0.17% zinc acetate) and 1.00 mL of the PEG400-containing drug composition solution (0.30% chlorogenic acid, 0.20% ferulic acid, 0.17% zinc acetate, 0.8% PEG400) to the supply pool. Cover the supply pool with plastic wrap to prevent data errors caused by drug evaporation. Place the solution in a transdermal transdermal analyzer, set the temperature to 32℃ and the rotation speed to 350 rpm. Take samples at 2, 4, 6, 8, 10, 12, and 24 hours to use as test solutions for the transdermal transdermal experiment. After 24 hours of transdermal absorption, the skin of Bama fragrant pigs was removed, cut into pieces, and 5.00 mL of methanol was added. The mixture was then sonicated for 60 minutes to fully dissolve the drug in the methanol, which was used as the test solution for the retention test.

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

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

[0115]

[0116] The results are as follows Figure 1 As shown: the cumulative permeability of chlorogenic acid, ferulic acid, and zinc acetate in the PEG400-containing drug composition over 24 hours was (200.29±1.70) μg / cm³. 2 (162.30±0.63)μg / cm 2 (121.23±1.78)μg / cm 2 The cumulative permeability of chlorogenic acid, ferulic acid, and zinc acetate in the PEG400-containing drug composition over 24 hours was (128.59±2.44) μg / cm³. 2 (87.63±0.94)μg / cm 2 (73.78±1.89) μg / cm 2 This indicates that PEG400 can significantly enhance the transdermal permeability 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 PEG400-containing drug composition increased by 18 times, 5.5 times, and 12 times, respectively, indicating that PEG400 can enhance the retention capacity of chlorogenic acid, ferulic acid, and zinc acetate in the basal layer of the skin, which is beneficial for the drugs to exert their therapeutic effects at the disease target.

[0117] Example 6: Preparation of gelling agent

[0118] (1) Selection of matrix type: Take 1% carbomer 940, 10% hyaluronic acid, and 4% sodium carboxymethyl cellulose (CMC-Na) according to the final concentration (mass fraction), add an appropriate amount of pure water, stir at 1500 rpm for 1.5 h at room temperature, add the base composition (0.30% chlorogenic acid, 0.20% ferulic acid, 0.17% zinc acetate) and 0.8% PEG400 respectively, add sodium hydroxide while stirring the carbomer gel to adjust the pH value to 6, add pure water to 100g, continue stirring at 1500 rpm for 1 h at room temperature, mix well, and the product is obtained.

[0119] According to the provisions of Part III of the 2020 edition of the Chinese Pharmacopoeia, gels should be uniform and fine, maintaining a gel-like state; therefore, the following evaluation is conducted:

[0120] Drug content determination: Take 1g of each different gel and add it to a 50mL volumetric flask. Dilute to the mark with methanol to ensure complete dissolution. Centrifuge at 13000rpm for 10min to obtain the test solution. The methods for determining the content of chlorogenic acid, ferulic acid, and zinc acetate are the same as in Examples 1-2.

[0121] pH value determination: Take 1g of each different gel and add it to a 10mL volumetric flask. Dilute to the mark with water, dissolve by sonication, and measure the pH value with a pH meter.

[0122] Moisture retention determination: Three portions (M0) of each gel were weighed in parallel, spread on petri dishes, and dried in an oven at 55°C until no further loss of mass was observed. The dried portions were then removed, cooled, and weighed to determine their mass (M). i Moisture retention rate = M i / M0×100%.

[0123] Viscosity measurement: Using an NDJ-9S rotational viscometer, select an appropriate rotor and rotation speed, place the rotor into different gels, and immerse the rotor groove in the gel liquid. Take three measurements and average the result.

[0124] Centrifugation stability: Take 1g of each different gel and place them in a centrifuge tube. Centrifuge at 3000rpm for 30min and observe the gel layering and color changes.

[0125] Heat resistance stability: Take 1g of each different gel, place them in a centrifuge tube and seal it. Place it in a 55℃ incubator for 6 hours and observe the gel layering and color changes.

[0126] Cold resistance stability: Take 1g of each different gel, place them in a centrifuge tube and seal it. Place it in a -20℃ refrigerator for 24h and observe the gel layering and color changes.

[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 an appropriate amount of pure water, stir at 1500 rpm for 1.5 h at room temperature until completely swollen, add 0.30% chlorogenic acid, 0.20% ferulic acid, 0.17% zinc acetate and 0.8% PEG400, add water to 100g, continue stirring at 1500 rpm for 1 h at room temperature, mix well, and the product is obtained.

[0130] The evaluation indicators are the same as those in (1) above.

[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 glycerin used as a moisturizer:

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

[0134] The evaluation indicators are the same as those in (1) above.

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

[0136] (4) Selection of preservatives:

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

[0138] The evaluation indicators are the same as those in (1) above.

[0139] The results showed that the addition of sodium benzoate to CMC-Na gel resulted in better centrifugal stability and heat resistance than the addition of ethylparaben or potassium sorbate. 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) and add an appropriate amount of pure water. Stir at speed S1 at T1 to allow it to swell fully. Add 0.30% chlorogenic acid, 0.20% ferulic acid, 0.17% zinc acetate, 0.8% PEG400, 10% glycerol, and 0.2% sodium benzoate. Add pure water to 100g and continue stirring at speed S2 at T2 until well mixed.

[0142] The process parameters for each formulation are shown in Table 7:

[0143] Table 7 Process parameters for each formulation

[0144] 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 portions of the pharmaceutical composition gel were prepared according to prescription number 19 and labeled as 1, 2, and 3, respectively. Their stability was tested according to Example 6(1). Their appearance, centrifugal stability appearance, heat resistance stability appearance, and cold resistance stability appearance are as follows: Figures 2-5 As shown.

[0146] Example 7: Preparation of Coating Agent

[0147] A certain amount of polymer matrix, plasticizer, and solvent are mixed and swollen / dissolved according to the final concentration (mass fraction). Then, the mixture is placed in a water bath at T3 for t3 to allow the polymer matrix to fully swell. It is then removed and cooled for later use. Separately, 0.30% chlorogenic acid, 0.20% ferulic acid, and 0.17% zinc acetate are added to the above polymer matrix and dissolved. Ethanol is added to a final volume of 100g, and the mixture is stirred at speed S4 for t4 until homogeneous.

[0148] The process parameters for each formulation are shown in Table 8:

[0149] Table 8 Process parameters for each formulation

[0150] 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% glycerin 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: Swell 4% carbomer, 6% glycerol, and an appropriate amount of distilled water. Separately, dissolve 0.30% chlorogenic acid, 0.20% ferulic acid, and 0.17% zinc acetate in an appropriate amount of 50% ethanol solution. Add an appropriate amount of 50% ethanol to make the ethanol concentration in the system 50% (total mass 10g). Mix the two solutions, adjust the pH to 4.5 with anhydrous sodium sulfite, and continue stirring for 0.5h to mix the film-forming material and drug solution evenly.

[0152] Prescription 3: Swell 1% chitosan, 0.5% carbomer, 6% glycerol, and an appropriate amount of distilled water. Separately, dissolve 0.30% chlorogenic acid, 0.20% ferulic acid, and 0.17% zinc acetate in an appropriate amount of 50% ethanol solution, add 50% ethanol to a final volume of 10g, and continue stirring for 0.5h to mix the film-forming material and the drug solution.

[0153] The results showed that all of the above-mentioned drug composition formulations could be formulated into film-forming agents. Figure 15 The appearance of the film-forming agent of formulation 26 and the film-forming images after 30s and 60s on the hand show that the film-forming agent has good fluidity, is easy to apply, and can form a film quickly.

[0154] Example 8: Preparation of Dressing

[0155] All percentages below are final concentrations (mass fractions).

[0156] Prescription 1: Add 3% hyaluronic acid and 15% gelatin to 10 mL 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 and mix well to obtain a uniform electrospinning solution. Prepare electrospinned dressings using an electrospinning apparatus under the conditions of 25 kV voltage, 0.8 mL / h feed speed and 15 cm receiving distance.

[0157] Prescription 2: Using 10 mL of 60% formic acid as a solvent, prepare a 1% polyethylene glycol solution and magnetically stir at room temperature for 24 h; then add 16% type I collagen peptide COP, 0.30% chlorogenic acid, 0.20% ferulic acid, and 0.17% zinc acetate, and magnetically stir at room temperature until homogeneous to obtain a COP / PEG spinning solution. A uniform electrospinning solution is obtained; electrospun dressings are prepared under conditions of 25 kV voltage, feed speed 0.8 mL / h, and receiving distance 15 cm.

[0158] Prescription 3: 40% PVP, 0.30% chlorogenic acid, 0.20% ferulic acid, and 0.17% zinc acetate were added to 6 mL of anhydrous ethanol and magnetically stirred at room temperature for 8 hours until completely dissolved. Then, the mixture was ultrasonically degassed for 20 minutes to prepare a homogeneous PVP shell spinning solution containing the drug composition. Separately, an appropriate amount of PLA was dissolved in an appropriate amount of chloroform-acetone (volume ratio 3:1) to prepare a 6% mixed solution. This solution was magnetically stirred at room temperature for 15 hours and then ultrasonically degassed for 20 minutes to obtain a PLA core-shell emulsion spinning solution. The core-shell spinning solution was drawn into two 10 mL syringes, which were then attached to a microinjection pump and connected to the two ports of a coaxial needle. Electrospun dressings were prepared under conditions of 25 kV voltage, a feed rate of 0.8 mL / h, and a receiving distance of 15 cm.

[0159] Prescriptions 4-31: Hyaluronic acid of M1 and gelatin of M2 are added to 10 mL of a mixed solution of hexafluoroisopropanol and water (volume ratio X:Y) to swell. Then, 0.30% chlorogenic acid, 0.20% ferulic acid and 0.17% zinc acetate are added to the above solution and mixed well to obtain a uniform electrospinning solution. Electrospinning dressings are prepared using an electrospinning apparatus under the conditions of voltage U, feed speed v and receiving distance d.

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

[0161] Table 9 Process parameters for each formulation

[0162]

[0163]

[0164] Prescription 32: Add 3% hyaluronic acid and 15% gelatin to 10 mL 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 and mix well to obtain a uniform electrospinning solution; use an electrospinning apparatus at a voltage of 25 kV, a feed speed of 0.8 mL / h and a receiving distance of 13 cm to prepare an electrospinned dressing.

[0165] Prescription 33: Add 3% hyaluronic acid and 15% gelatin to 10 mL 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 and mix well to obtain a uniform electrospinning solution; use an electrospinning apparatus at a voltage of 25 kV, a feed speed of 0.8 mL / h and a receiving distance of 13 cm to prepare an electrospinned dressing.

[0166] The results showed that all of the above prescriptions could be made into electrospun dressings. Figure 16 The images show the appearance of the dressing of Formula 25 and the appearance of the dressing after it has been exposed to water on the hand for 10, 20 and 30 seconds. It can be seen that the dressing can quickly permeate and form a film on the skin after being exposed to water.

[0167] Example 9: Retention amount of gel in skin

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

[0169] Table 10. Drug retention in the skin in pharmaceutical composition gels (x±s, n=3)

[0170]

[0171] The results are as follows Figure 6 As shown: The cumulative permeability of chlorogenic acid, ferulic acid, and zinc acetate in the basic composition over 24 hours was (3.54±0.87) μg / cm³. 2 (9.53±0.78)μg / cm 2 (3.01±1.26)μg / cm 2 The cumulative permeability of chlorogenic acid, ferulic acid, and zinc acetate in the gel over 24 hours was (128.59±2.44) μg / cm³. 2 (87.63±0.94)μg / cm 2 (73.78±1.89) μg / cm 2 This indicates that the gel formulation can significantly enhance the transdermal absorption 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 increased by 28.2 times, 8.5 times, and 21.8 times, respectively, indicating that the gel formulation can significantly enhance the retention capacity of chlorogenic acid, ferulic acid, and zinc acetate in the basal layer of the skin, which is beneficial for the drugs to exert their therapeutic effects at the disease target.

[0172] Example 10: Pharmacodynamics of pharmaceutical composition gel against EGFRI-induced skin toxicity

[0173] BALB / c mice (approximately 20g, female) were randomly divided into two groups according to body weight after 3 days of acclimatization. The control group consisted of 6 mice, and the erlotinib hydrochloride group consisted of 24 mice. The erlotinib hydrochloride suspension was prepared by adding 0.25% sodium carboxymethyl cellulose to 500mg of erlotinib hydrochloride, then adding purified water to a final volume of 50mL. The mixture was sonicated for 30 minutes and shaken well before administration. One day prior to administration, the BALB / c mice underwent hair removal on their backs and were administered erlotinib hydrochloride solution by gavage at a dose of 150mg / kg once daily until skin toxicity appeared (approximately 48 days).

[0174] After establishing the animal model of skin toxicity induced by EGFRIs, rats in the erlotinib hydrochloride group were further divided into four groups: a model group (n=6), a basic composition group (n=6), a blank gel matrix group (n=6), and a drug composition gel group (n=6). All groups of mice continued to be administered erlotinib hydrochloride 150 mg / kg by gavage once daily. The drug treatment groups received topical application of the corresponding preparation at a dose of 333.5 mg / kg, while the model group received topical application of physiological saline once daily; this continued for 14 days. The blank matrix was prepared using the process described in Example 6, Formula 19, without the basic drug composition, only containing 4% CMC-Na, 0.8% PEG400, 10% glycerin, and 0.2% sodium benzoate, diluted with pure water to 100 g. The drug composition gel was prepared using the process described in Example 6, Formula 19.

[0175] After the animal experiments, the skin toxicity of each group of mice was observed, and the severity of skin redness, swelling, blisters, and rashes was statistically analyzed. Figure 7 ), and statistically analyzed the weight change curves of mice in each group ( Figure 8 The moisture content and skin elasticity of a portion of the mouse's back skin were measured. Figure 12 , Figure 13 The thymus, spleen, and liver of mice in different groups were weighed, organ indices were calculated, and differences between groups were compared. Figure 9 , Figure 10 , Figure 11 The efficacy of the drug composition was observed by examining skin sections stained with HE and Oil Red. Figure 14 ).

[0176] The results are shown in Tables 11-13: The severity of dry, scaly, red, swollen, herpes, and rashes on the mouse skin indicates that the model group mice experienced hair loss around the eyes, neck, and back, and dry, scaly, cracked, and herpes-like skin around the mouth and limbs, resulting in decreased activity. Both the drug solution group and the drug composition gel group showed varying degrees of therapeutic effect on skin toxicity, with the gel group exhibiting the best efficacy. It significantly reduced the incidence of redness, swelling, herpes, and rashes on the mouse skin, stunted hair growth, and marked disappearance of symptoms, effectively treating skin toxicity reactions with an efficacy rate of 83.33%.

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

[0178] 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 on the severity of herpes in mice

[0180] 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 on the severity of skin rashes in mice

[0182] 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 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 basal composition group and the gel group increased (P < 0.05), indicating that the administration improved the quality of life of the mice. The liver and spleen indices of the model group mice were significantly increased, and the thymus index was decreased, indicating that erlotinib hydrochloride severely damaged the immune system of mice. The basal composition and gel showed varying degrees of recovery after administration (P < 0.05, P < 0.01, P < 0.001), indicating that the drug can reverse and protect against organ damage caused by erlotinib hydrochloride, and the gel showed the most significant effect compared to the basal composition.

[0184] Analysis of skin hydration and skin elasticity results showed that the hydration content of the model group mice was significantly reduced, indicating that erlotinib hydrochloride severely damaged the skin barrier of mice and affected its moisturizing function; after administration of the base composition and gel, the skin hydration content increased significantly (P < 0.001); regarding skin elasticity results, the skin elasticity recovery time of the model group mice was significantly prolonged, indicating that erlotinib hydrochloride may severely damage the collagen and elastic fibers of the mouse skin and affect the skin elasticity function; after administration of the base composition and gel, the skin elasticity recovery time of the mice was significantly shortened (P < 0.001); indicating that topical application of the gel can have a certain repairing effect on the skin barrier.

[0185] HE staining results showed that, compared with the control group, the model group mice exhibited characteristics of skin inflammation, namely parakeratosis (retention of stratum corneum cell nuclei), significant thickening of the stratum corneum, and altered skin structure. The skin toxicity of the mice was improved after administration of the base composition and the gel, with the gel group showing the most significant improvement. Oil red staining results showed that, compared with the control group, the model group had fewer sebaceous glands, ruptured swollen follicles, and significantly reduced sebum secretion. Compared with the model, the number of swollen follicles and sebum secretion in the mouse skin were significantly restored after administration of the base composition and the gel, indicating that the pharmaceutical composition of this invention can effectively improve the abnormal sebum secretion caused by erlotinib hydrochloride.

[0186] Example 11: Efficacy evaluation of dressings and film-forming agents against EGFRI-induced skin toxicity

[0187] The animal model was established in the same manner as in Example 10, except that in this example, the erlotinib hydrochloride group consisted of 30 rats. After establishing the animal model of skin toxicity induced by EGFRIs, the rats in the erlotinib hydrochloride group were regrouped and randomly divided into four groups: erlotinib hydrochloride group (n=6, model group), erlotinib hydrochloride + basic composition group (n=6, basic composition group), erlotinib hydrochloride + drug composition film-forming agent group (n=6, film-forming agent group), and erlotinib hydrochloride + drug composition electrospun dressing group (n=6, electrospun dressing group). All groups of mice continued to be administered erlotinib hydrochloride 150 mg / kg by gavage once daily. In addition, the drug treatment groups received topical application of the corresponding preparation at a dose of 333.5 mg / kg, while the model group received topical application of physiological saline once daily; administration continued for 14 consecutive days. The drug composition film-forming agent used formulation 1 from Example 7, and the drug composition electrospun dressing used formulation 5 from Example 8.

[0188] The results are shown in Tables 14-16: Statistical results on the severity of dry, scaly, red, swollen, herpes, and rashes on mouse skin showed that the model group mice experienced hair loss around the eyes, neck, and back, and dry, scaly, cracked, and herpes-like skin around the mouth and limbs, resulting in decreased activity. The basic composition group, the film-forming group, and the electrospinning dressing group all showed varying degrees of therapeutic effect on skin toxicity. The film-forming group and the electrospinning dressing group showed better efficacy, significantly reducing the incidence of redness, swelling, herpes, and rashes on mouse skin. The mice's hair recovered and the symptoms disappeared significantly, effectively treating skin toxicity reactions with an efficacy rate of 83.33%.

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

[0190] 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 on the severity of herpes in mice

[0192]

[0193]

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

[0195] 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, It includes chlorogenic acid, ferulic acid, zinc salt and matrix material, wherein the mass ratio of chlorogenic acid to ferulic acid is 4:1 to 1:4, and the mass ratio of the total amount of chlorogenic acid and ferulic acid to the zinc salt is 4:1 to 1:4; wherein the zinc salt is zinc acetate, zinc sulfate, zinc nitrate, zinc gluconate or zinc oxide; When the matrix material is a polymer matrix and water, the pharmaceutical composition is a gelling agent; or When the matrix material is a polymer matrix and a volatile solvent, the pharmaceutical composition is a coating agent.

2. The pharmaceutical composition according to claim 1, characterized in that, The volatile solvent is ethanol.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, The polymer matrix is ​​sodium carboxymethyl cellulose, carbomer, sodium alginate, xanthan gum, hyaluronic acid, polyvinyl alcohol, chitosan, gelatin, silk fibroin, collagen, polyethylene glycol, or polylactic acid.

4. The pharmaceutical composition according to claim 3, characterized in that, In the gelling agent, the polymer matrix is ​​sodium carboxymethyl cellulose, carbomer, sodium alginate, xanthan gum, or hyaluronic acid; in the coating agent, the polymer matrix is ​​polyvinyl alcohol, carbomer, chitosan, or sodium carboxymethyl cellulose.

5. The pharmaceutical composition according to claim 4, characterized in that, The polyvinyl alcohol is PVA124, PVA1788 or PVA0588.

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

7. The pharmaceutical composition according to claim 6, characterized in that, In the gelling agent, the mass fraction of the matrix material is 4%; in the coating agent, the mass fraction of the matrix material is 4-6%.

8. The pharmaceutical composition according to claim 1 or 2, characterized in that, The gelling agent also includes a solubilizer, a humectant, and a preservative; the coating agent also includes a plasticizer.

9. The pharmaceutical composition according to claim 8, characterized in that, The solubilizer is PEG 400, propylene glycol, or Tween-80; the plasticizer is glycerin or propylene glycol; the humectant is glycerin; and the preservative is sodium benzoate, ethylparaben, or potassium sorbate.

10. A pharmaceutical composition, characterized in that, It includes chlorogenic acid, ferulic acid, zinc salt and matrix material, wherein the mass ratio of chlorogenic acid to ferulic acid is 4:1 to 1:4, and the mass ratio of the total amount of chlorogenic acid and ferulic acid to the zinc salt is 4:1 to 1:4; wherein the zinc salt is zinc acetate, zinc sulfate, zinc nitrate, zinc gluconate or zinc oxide; When the matrix material is a polymer matrix, the pharmaceutical composition is an electrospun dressing.

11. The pharmaceutical composition according to claim 10, characterized in that, In the electrospun dressing, the polymer matrix is ​​hyaluronic acid, gelatin, silk fibroin, collagen, polyethylene glycol, or polylactic acid.

12. The pharmaceutical composition according to claim 11, characterized in that, In the electrospun dressing, the polymer matrix is ​​a combination of hyaluronic acid and gelatin.

13. The pharmaceutical composition according to claim 12, characterized in that, The mass ratio of hyaluronic acid to gelatin in the composition of hyaluronic acid and gelatin is 1:4.8~7.

2.

14. The pharmaceutical composition according to claim 10, characterized in that, In the electrospun dressing, the mass fraction of the matrix material is 81-97%.

15. A method for preparing the gelling agent in the pharmaceutical composition according to any one of claims 1-9, characterized in that, Includes the following steps: The polymer matrix and water are mixed to swell the polymer matrix, and then the remaining components are added and mixed evenly to obtain the gel.

16. A method for preparing the film-forming agent in the pharmaceutical composition according to any one of claims 1-9, characterized in that, Includes the following steps: The polymer matrix and the volatile solvent are mixed to swell the polymer matrix. Then, the remaining components are added and the volatile solvent is added again. After uniform mixing, the coating agent is obtained.

17. A method for preparing the electrospun dressing in the pharmaceutical composition according to any one of claims 10-14, characterized in that, Includes the following steps: (1) The polymer matrix is ​​swollen in a spinning solvent, and then the remaining components are added and mixed evenly to obtain a spinning solution; (2) Electrospinning the spinning solution to obtain the electrospun dressing.

18. The preparation method according to claim 17, characterized in that, The polymer matrix is ​​a mixture of hyaluronic acid and gelatin, and the mass concentration of hyaluronic acid in the spinning solution is 2.5-3.5%, and the mass concentration of gelatin is 12-18%.

19. The preparation method according to claim 18, characterized in that, The spinning solution contains 2.8-3.2% hyaluronic acid and 14-16% gelatin by mass.

20. The preparation method according to claim 17, characterized in that, The spinning solvent is one or more of the following: hexafluoroisopropanol, dichloromethane, trichloromethane, formic acid, or water.

21. The preparation method according to claim 20, characterized in that, The spinning solvent is a mixture of hexafluoroisopropanol and water.

22. The preparation method according to claim 21, characterized in that, The spinning solvent is a mixture of hexafluoroisopropanol and water in a volume ratio of 6:4 to 8:

2.

23. The preparation method according to claim 22, characterized in that, The spinning solvent is a mixture of hexafluoroisopropanol and water in a volume ratio of 7:

3.

24. The preparation method according to claim 17, characterized in that, The electrospinning conditions are: voltage 20~28kV, feed speed 0.5~1.5 mL / h, and receiving distance 12~18 cm.

25. The preparation method according to claim 24, characterized in that, The electrospinning conditions are: voltage 24~26kV, feed speed 0.8~1.2 mL / h, and receiving distance 14~16 cm.

26. The use of the pharmaceutical composition according to any one of claims 1-14 in the preparation of a therapeutic medicament for EGFRI-induced skin toxicity, characterized in that, The EGFRIs are erlotinib, imatinib, erlotinib, sorafenib, rituximab, trastuzumab, cetuximab, bevacizumab, or panitumumab.

Images