Cream or patch for scar local treatment and preparation method thereof

Abstract

The invention relates to the technical field of medical materials, and provides a scar local treatment cream or patch and a preparation method thereof. The cream or patch is an external preparation integrating hormone, antibiotics and chemotherapeutic drugs for scar treatment, through the synergistic effect of the three components, the cream or patch has multiple effects of sterilizing, diminishing inflammation, inhibiting fibroblast and vascular hyperplasia, inhibiting scar hyperplasia, promoting scar softening, preventing infection and the like, and the scar treatment effect is improved. The preparation does not need injection treatment and can be purely externally applied or applied, so that the preparation is greatly convenient for patients to use, the purpose of preventing and treating scars is achieved, and a safe and effective scar treatment means with multiple effects is provided.

Description

Technical Field

[0001] The invention relates to the technical field of medical materials, and in particular to an external preparation for scar treatment which integrates hormones, antibiotics and chemotherapy drugs, and a preparation method thereof. Background Art

[0002] Scars mainly include hypertrophic scars and keloids. Hypertrophic scars are caused by tissue hyperplasia due to injury factors such as burns and trauma. The scope of scar hyperplasia is usually limited to the injury site; keloids are usually caused by tissue hyperplasia caused by acne, mosquito bites or surgery, which usually exceeds the injury range and expands outward like a tumor. Hypertrophic scars and keloids not only cause damage to the appearance, but are also accompanied by pain and itching symptoms, seriously affecting the quality of life.

[0003] There are many methods for scar treatment at present, usually using drug therapy, pressure therapy and laser therapy. Drug therapy includes silicone gel, centella asiatica cream, Contractubex, etc., which are applied topically for external use, but the efficacy is limited, especially for scars and keloids with rapid proliferation. Clinically, mixed injection of hormones (Diprosone or triamcinolone, etc.) and chemotherapy drugs (5-fluorouracil, bleomycin or mitomycin C, etc.) shows good results, especially for keloids, and is a more commonly used treatment method. The main function of hormones is to inhibit inflammation in scars and inhibit fibroblast and blood vessel proliferation; the function of 5-fluorouracil is to destroy fibroblasts and blood vessels and promote scar regression. However, at present, both are mainly injected by injection, and patients experience severe pain during injection, so most patients are unwilling to accept it clinically. If patches or creams are used, they may be more universal.

[0004] Furthermore, we recently discovered that there is a "bacterial overload" phenomenon in hypertrophic scars and keloids. The "bacterial overload" phenomenon, which is mainly Staphylococcus aureus, is found in hypertrophic scars, which may be one of the root causes of chronic inflammation and hyperplasia of hypertrophic scars and keloids. Therefore, if an external patch or cream can be designed to have the functions of anti-inflammatory, antibacterial and promoting scar regression, it will help improve patient acceptance. Summary of the invention

[0005] The present invention is based on the above needs and is intended to design an external ointment or patch, which mainly contains antibiotics, hormones and chemotherapy drugs. Through the synergistic effect of multiple components, it produces bactericidal and anti-inflammatory effects, inhibits fibroblast and vascular proliferation, and achieves multiple effects such as inhibiting scar proliferation, promoting scar softening, and preventing infection, thereby improving the scar treatment effect. The preparation does not require injection treatment, and can be simply applied externally or pasted, which greatly facilitates the use of patients and achieves the purpose of preventing and treating scars.

[0006] The invention studies the formula and preparation process of external ointment and patch, and prepares cream and scar long-acting sustained-release transdermal patch. Then, an animal model of rabbit ear hypertrophic scar is established to verify its effect, and the results show that the three-drug mixed group is significantly better than the control group (P<0.01), hydrocortisone butyrate group (P<0.01), 5-fluorouracil group (P<0.01), and fusidic acid group (P<0.05), and there are significant differences compared with these groups.

[0007] Based on the above research, the technical solution to be protected by the present invention is as follows:

[0008] The main purpose of the present invention is to provide an external preparation for local treatment of scars, and also to provide a corresponding preparation method. The external preparation is preferably a cream or a patch.

[0009] The active ingredients of the cream or patch are the same, all consisting of hormones, antibiotics and chemotherapy drugs. The mass ratio between the three is 1:1:1, and the sum accounts for 1% to 10% of the total.

[0010] Preferably, hormones are selected from Diprosone, Triamcinolone, Dexamethasone, etc., with a content of 0.1%-2%; antibiotics are selected from Fusidic acid, Bactroban, Erythromycin, etc., with a content of 0.1%-2%; chemotherapy drugs are selected from Bleomycin or 5-fluorouracil, etc., with a content of 0.1%-2%.

[0011] The first aspect disclosed in the present invention provides an ointment for local treatment of scars and a preparation method thereof.

[0012] (I) Formula composition

[0013] The cream comprises a drug component and a matrix component, wherein the drug component is as described above; and the matrix component comprises an oily matrix, an emulsifier, a moisturizer, a transdermal absorbent, and a bactericidal preservative.

[0014] Preferably, in the scar cream, the weight of the main drug, the oil phase matrix, the emulsifier, the moisturizer, the transdermal absorbent, and the bactericidal preservative is 1-10%, 50%-80%, 10%-30%, 0.5-5%, 0.5-5%, and 0.5-5%.

[0015] Further preferably, ① the oil phase matrix is ​​selected from one or more of stearic acid and white vaseline; ② the emulsifier is selected from one or more of glyceryl monostearate, sodium lauryl sulfate, and polysorbate 80; ③ the humectant is one or more of propylene glycol, glycerol, sorbitol and / or polyethylene glycol; ④ the transdermal absorbent is selected from one or more of azone, urea, peppermint oil, borneol and / or eucalyptus oil; ⑤ the bactericidal preservative is selected from ethyl paraben.

[0016] (II) Preparation method:

[0017] (1) Preparation of oil phase: Place the oil phase matrix, oily emulsifier, and transdermal absorbent in a container respectively, and heat in a water bath to melt them to form the oil phase.

[0018] (2) Preparation of aqueous phase: Add aqueous emulsifier, moisturizer and bactericidal preservative into distilled water and heat in a water bath to dissolve as the aqueous phase.

[0019] (3) Preparation of main drug phase: Add hormones, antibiotics, and 5-fluorouracil into distilled water as the main drug phase.

[0020] (4) Preparation of scar cream: Add the oil phase prepared in step (1) to the water phase prepared in step (2), control the temperature at 55°C during the process, heat and stir to mix, then keep stirring for 30 minutes at a stirring speed of 1300 r / min, then add the main drug phase, stop heating, continue stirring to room temperature at a stirring speed of 1300 r / min, and obtain a cream.

[0021] The second aspect disclosed by the present invention provides a long-acting sustained-release transdermal patch for local treatment of scars and a preparation method thereof.

[0022] (I) Structural composition

[0023] The scar long-acting sustained-release transdermal patch consists of three layers, namely, a backing layer, a drug-containing matrix layer, and a protective layer. The drug-containing layer is composed of hormones, antibiotics, 5-fluorouracil, pressure-sensitive adhesive, penetration enhancer, and tackifier. The content of each component of the drug-containing layer is as follows by weight: 20 parts of drugs (three ratios of 1:1:1), 200 parts of pressure-sensitive adhesive, 1 part of penetration enhancer, and 50 parts of tackifier.

[0024] Preferably, ① the backing layer is selected from polyethylene film, polyvinyl chloride film, polypropylene film, polyester film, aluminum foil, and the protective layer is selected from one of polyethylene film, polystyrene film, polypropylene film and anti-sticking paper treated with paraffin or dimethyl silicone oil release agent.

[0025] ②The drug consists of hormones, antibiotics and 5-fluorouracil.

[0026] ③ The pressure-sensitive adhesive may be any one or a combination of any of polyvinyl alcohol, cellulose acetate, acrylate containing a carboxyl group, acrylate containing a hydroxyl group, acrylate without a functional group, polybutene, polysiloxane and natural rubber.

[0027] ④ The penetration enhancer is composed of one or more of levulinic acid, triacetin, and propylene glycol. ⑤ The binder is preferably any one or a combination of polybutadiene, diene isoprene styrene star polymer, and poly (butyl methacrylate-methyl methacrylate) copolymer.

[0028] (II) Preparation method

[0029] Step 1: Place the pressure-sensitive adhesive and the adhesive in the same container, add the solvent, and shake to evenly disperse the adhesive in the base pressure-sensitive adhesive;

[0030] Step 2: adding hormones, antibiotics, 5-fluorouracil and penetration enhancers into a solvent and dissolving them into a clear solution;

[0031] Step 3: Transfer all the obtained clear solution to the dispersed matrix, keep shaking after protecting from light, stir evenly and let stand to obtain the drug-loaded matrix;

[0032] Step 4: coating the obtained drug-loaded matrix on the protective layer to obtain a drug-containing layer, and then drying it in an oven at 60°C for a period of time and then naturally cooling it to room temperature;

[0033] Step 5: Cover the drug-containing layer with a backing layer and cut it into pieces to obtain a transdermal patch.

[0034] Beneficial protection and effects of the present invention:

[0035] The present invention provides a scar topical treatment cream or patch and a preparation method thereof. The cream or patch mainly contains antibiotics, hormones and chemotherapeutic drugs, and through the synergistic effect of the three components, produces bactericidal and anti-inflammatory effects, inhibits fibroblast and vascular proliferation, achieves multiple effects such as inhibiting scar proliferation, promoting scar softening, preventing infection, and improving the scar treatment effect. The preparation does not require injection treatment, and can be simply applied externally or pasted, which greatly facilitates the use of patients, achieves the purpose of preventing and treating scars, and provides a multi-effect, safe and effective scar treatment method. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The present disclosure will be further described below in conjunction with the accompanying drawings, wherein these drawings are only for illustrating the embodiments of the present disclosure rather than for limiting the scope of the present disclosure.

[0037] Figure 1 A direct pictorial comparison of the different treatment groups for the treatment of hypertrophic scars on rabbit ears is shown.

[0038] Figure 2 Vancouver scores for scars in different treatment groups are shown. DETAILED DESCRIPTION

[0039] The following examples and experimental examples further illustrate the present invention and should not be construed as limiting the present invention. The examples do not include a detailed description of conventional methods, such as methods for constructing vectors and plasmids, methods for inserting protein-encoding genes into vectors and plasmids, or methods for introducing plasmids into host cells. Such methods are well known to those skilled in the art and are described in many publications.

[0040] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the present invention, and the preferred implementation methods and materials described in the specific implementation methods are for demonstration purposes only.

[0041] Example 1 Cream

[0042] (I) Formula composition

[0043] The cream comprises a drug component and a base component.

[0044] Among the drug ingredients, the hormone is selected from dexamethasone, with a content of 1%; the antibiotic is selected from fusidic acid, with a content of 1%; and the chemotherapy drug is selected from 5-fluorouracil, with a content of 1%.

[0045] The matrix components include oil phase matrix, emulsifier, moisturizer, transdermal absorbent and bactericidal preservative. The weight of the main drug, oil phase matrix, emulsifier, moisturizer, transdermal absorbent and bactericidal preservative is 3%, 70%, 20%, 3%, 3% and 1%.

[0046] The oil phase matrix is ​​selected from white vaseline, the emulsifier is selected from glyceryl monostearate and sodium lauryl sulfate, the moisturizer is propylene glycol, the transdermal absorbent is azone, and the bactericidal preservative is selected from ethyl paraben.

[0047] (II) Preparation method:

[0048] (1) Preparation of oil phase: Glyceryl monostearate, white vaseline and azone were placed in containers respectively and heated in a water bath to melt as the oil phase.

[0049] (2) Preparation of aqueous phase: Sodium lauryl sulfate, propylene glycol and ethylparaben are added into distilled water and heated in a water bath to dissolve as the aqueous phase.

[0050] (3) Preparation of main drug phase: Add hormones, antibiotics, and 5-fluorouracil into distilled water as the main drug phase.

[0051] (4) Preparation of scar cream: Add the oil phase prepared in step (1) to the water phase prepared in step (2), control the temperature at 55°C during the process, heat and stir to mix, then keep stirring for 30 minutes at a stirring speed of 1300 r / min, then add the main drug phase, stop heating, continue stirring to room temperature at a stirring speed of 1300 r / min, and obtain a cream.

[0052] Example 2 Cream

[0053] (I) Formula composition

[0054] The cream comprises a drug component and a base component.

[0055] Among the drug ingredients, the hormone is selected from Diprosone, with a content of 2%; the antibiotic is selected from Bactroban, with a content of 2%; and the chemotherapy drug is selected from Bleomycin, with a content of 2%.

[0056] The matrix components include oil phase matrix, emulsifier, moisturizer, transdermal absorbent and bactericidal preservative. The weight of the main drug, oil phase matrix, emulsifier, moisturizer, transdermal absorbent and bactericidal preservative is 6%, 62%, 20%, 5%, 5% and 2%.

[0057] The oil phase matrix is ​​selected from white vaseline, the emulsifier is selected from glyceryl monostearate and sodium lauryl sulfate, the moisturizer is glycerol, the transdermal absorbent is borneol, and the bactericidal preservative is selected from ethyl paraben.

[0058] (II) Preparation method:

[0059] (1) Preparation of oil phase: Glyceryl monostearate, white vaseline and borneol were placed in containers respectively and heated in a water bath to melt as the oil phase.

[0060] (2) Preparation of aqueous phase: Sodium lauryl sulfate, glycerol and ethylparaben are added into distilled water and heated in a water bath to dissolve as the aqueous phase.

[0061] (3) Preparation of the main drug phase: Add hormones, antibiotics, and bleomycin into distilled water as the main drug phase.

[0062] (4) Preparation of scar cream: Add the oil phase prepared in step (1) to the water phase prepared in step (2), control the temperature at 55°C during the process, heat and stir to mix, then keep stirring for 30 minutes at a stirring speed of 1300 r / min, then add the main drug phase, stop heating, continue stirring to room temperature at a stirring speed of 1300 r / min, and obtain a cream.

[0063] Example 3 Long-acting sustained-release transdermal patch

[0064] (I) Structural composition

[0065] The scar long-acting sustained-release transdermal patch consists of three layers, namely, a backing layer, a drug-containing matrix layer, and a protective layer. The drug-containing matrix layer is composed of hormones, antibiotics, 5-fluorouracil, pressure-sensitive adhesive, penetration enhancer, and tackifier. The content of each component of the drug-containing layer is as follows by weight: 20 parts of drugs (three ratios of 1:1:1), 200 parts of pressure-sensitive adhesive, 1 part of penetration enhancer, and 50 parts of tackifier.

[0066] The backing layer is made of polyethylene film;

[0067] The drug is composed of dexamethasone, fusidic acid, and 5-fluorouracil, each at 1%;

[0068] The pressure-sensitive adhesive is polyvinyl alcohol;

[0069] Levulinic acid was selected as the penetration enhancer;

[0070] The binder selected was polybutadiene.

[0071] (II) Preparation method

[0072] Step 1: Place the pressure-sensitive adhesive and the adhesive in the same container, add the solvent, and shake to evenly disperse the adhesive in the base pressure-sensitive adhesive;

[0073] Step 2: adding hormones, antibiotics, 5-fluorouracil and penetration enhancers into a solvent and dissolving them into a clear solution;

[0074] Step 3: Transfer all the obtained clear solution to the dispersed matrix pressure-sensitive adhesive, keep shaking after protecting from light, stir evenly and let stand to obtain the drug-loaded matrix;

[0075] Step 4: coating the obtained drug-loaded matrix on the protective layer to obtain a drug-containing layer, and then drying it in an oven at 60°C for a period of time and then naturally cooling it to room temperature;

[0076] Step 5: Cover the drug-containing layer with a backing layer and cut it into pieces to obtain a transdermal patch.

[0077] Embodiment 4 Technical effect example:

[0078] Modeling: The animal model of rabbit ear hypertrophic scar was established, with 6 rabbit ear models, 4 wounds in each ear, and a total of 48 wounds. The wounds formed hypertrophic scars in 25 days, which were red, raised skin, and hard in texture.

[0079] Grouping and experimental methods: Scars were divided into 5 groups, a control group (no medication), a hydrocortisone butyrate cream group, a fusidic acid cream group, a 5-fluorouracil cream group, and a group of three mixed creams (Example 1). Each group had 8 scars in total. The medication was applied every other day and massaged for absorption. The experiment was terminated on the 50th day. Photos were taken before each medication application, and the scar score was calculated according to the Vancouver score.

[0080] The experimental results are as follows Figure 1 and Figure 2 As shown in the figure, scars were significantly reduced after treatment (50 days), and there were significant differences compared with the beginning of the experiment (25 days). However, compared with the differences before and after treatment, the three drug mixture groups were significantly better than the control group (P<0.01), hydrocortisone butyrate group (P<0.01), 5-fluorouracil group (P<0.01), and fusidic acid group (P<0.05), and there were significant differences compared with these groups.

[0081] The preferred embodiments of the present invention have been specifically described above, but the present invention is not limited to the embodiments. Those skilled in the art may make various equivalent modifications or substitutions without violating the spirit of the present invention. These equivalent modifications or substitutions are all included in the scope defined by the claims of this application.

Claims

1. A topical preparation for scar local treatment, characterized in that: The active ingredients of the drug are composed of hormones, antibiotics and chemotherapy drugs, with the mass ratio of the three being 1:1:1, and the sum of the three accounting for 1% to 10% of the total.

2. The topical scar treatment preparation according to claim 1, characterized in that: The hormone is selected from any one of Diprosone, Triamcinolone, and Dexamethasone, with a content of 0.1%-2%; the antibiotic is selected from any one of Fusidic acid, Bactroban, and Erythromycin, with a content of 0.1%-2%; the chemotherapy drug is selected from Bleomycin or 5-fluorouracil, with a content of 0.1%-2%.

3. The topical scar treatment preparation according to claim 1, characterized in that: The external preparation is a cream or a patch.

4. The topical scar treatment preparation according to claim 3, characterized in that: in, The cream comprises a drug component and a matrix component; the drug component composition is as described in claim 1 or 2; the matrix component comprises an oil phase matrix, an emulsifier, a moisturizer, a transdermal absorbent and a bactericidal preservative, The weight ratio of the main drug component to the oil phase matrix, emulsifier, moisturizer, transdermal absorbent and bactericidal preservative is 1-10: 50-80: 10-30: 0.5-5: 0.5-5: 0.5-5.

5. The topical scar treatment preparation according to claim 4, characterized in that: in, The oil phase matrix is ​​selected from one or more of stearic acid and white vaseline; the emulsifier is selected from one or more of glyceryl monostearate, sodium lauryl sulfate, and polysorbate 80; the moisturizer is one or more of propylene glycol, glycerin, sorbitol and / or polyethylene glycol; the transdermal absorbent is selected from one or more of azone, urea, peppermint oil, borneol and / or eucalyptus oil; and the bactericidal preservative is selected from ethyl paraben.

6. The topical scar treatment preparation according to claim 5, characterized in that: The preparation method of the cream is as follows: (1) Preparation of oil phase: Place the oil phase matrix, oil emulsifier, and transdermal absorbent in a container, heat and melt them in a water bath to form the oil phase; (2) Preparation of aqueous phase: adding aqueous emulsifier, moisturizer and bactericidal preservative into distilled water and heating in a water bath to dissolve as the aqueous phase; (3) Preparation of the main drug phase: hormones, antibiotics, and 5-fluorouracil are added to distilled water to form the main drug phase; (4) Preparation of scar cream: Add the oil phase prepared in step (1) to the water phase prepared in step (2), control the temperature at 55°C during the process, heat and stir to mix, then keep stirring for 30 minutes at a stirring speed of 1300 r / min, then add the main drug phase, stop heating, continue stirring to room temperature at a stirring speed of 1300 r / min, and obtain a cream.

7. The topical scar treatment preparation according to claim 3, characterized in that: in, The patch is a long-acting sustained-release transdermal patch, which consists of three layers, namely, a backing layer, a drug-containing matrix layer, and a protective layer; The drug-containing matrix layer is composed of a main drug, a pressure-sensitive adhesive, a penetration enhancer and a tackifier. The contents of the components of the drug-containing layer are as follows: 20 parts of the main drug, 200 parts of the pressure-sensitive adhesive, 1 part of the penetration enhancer, and 50 parts of the tackifier. The main drug is the active ingredient of the drug according to claim 1 or 2.

8. The topical scar treatment preparation according to claim 7, characterized in that: in, The backing layer is selected from polyethylene film, polyvinyl chloride film, polypropylene film, polyester film, aluminum foil, and the protective layer is selected from polyethylene film, polystyrene film, polypropylene film and anti-sticking paper treated with paraffin or dimethyl silicone oil release agent; The pressure-sensitive adhesive is selected from any one or any combination of polyvinyl alcohol, cellulose acetate, acrylate containing carboxyl groups, acrylate containing hydroxyl groups, acrylate without functional groups, polybutene, polysiloxane and natural rubber; The penetration enhancer is composed of one or more of levulinic acid, triacetin, and propylene glycol; The binder is selected from any one of polybutadiene, diene isoprene styrene star polymer and poly (butyl methacrylate-methyl methacrylate) copolymer or any combination of several thereof.

9. The topical scar treatment preparation according to claim 7, characterized in that: The preparation method of the patch is as follows: Step 1: Place the pressure-sensitive adhesive and the adhesive in the same container, add the solvent, and shake to evenly disperse the adhesive in the base pressure-sensitive adhesive; Step 2: adding hormones, antibiotics, 5-fluorouracil and penetration enhancers into a solvent and dissolving them into a clear solution; Step 3: Transfer all the obtained clear solution to the dispersed matrix, keep shaking after protecting from light, stir evenly and let stand to obtain the drug-loaded matrix; Step 4: coating the obtained drug-loaded matrix on the protective layer to obtain a drug-containing layer, and then drying it in an oven at 60°C for a period of time and then naturally cooling it to room temperature; Step 5: Cover the drug-containing layer with a backing layer and cut it into pieces to obtain a transdermal patch.

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