Antibacterial and anti-inflammatory ointment for treating psoriasis and preparation method of antibacterial and anti-inflammatory ointment

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to an antibacterial and anti-inflammatory ointment for treating psoriasis and a preparation method thereof.The antibacterial and anti-inflammatory ointment is prepared from, by mass, 0.3%-0.7% of heparin sodium, 12.3%-13.5% of a humectant, 0.05%-0.1% of a penetration enhancer, 0.3%-0.4% of a pH regulator, 0.3%-0.7% of a thickening agent, 0.1%-0.2% of a preservative, 0.1%-0.2% of essence and the balance solvent. The antibacterial and anti-inflammatory ointment for treating psoriasis prepared by the invention has relatively high transdermal absorbability and a good treatment effect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to an antibacterial and anti-inflammatory ointment for treating psoriasis and its preparation method. Background Technology

[0002] Heparin is a negatively charged, heterogeneous glycosaminoglycan macromolecule with a relative molecular mass (MW) between approximately 2000 and 40000 Da. It consists of alternating residues of D-glucosamine and iduxuronic acid and is usually prepared as its sodium salt, namely sodium heparin. Sodium heparin is highly water-soluble but insoluble in organic solvents. It possesses in vitro and in vivo anticoagulant activity and recognized anti-inflammatory effects, and is mainly used clinically for local anticoagulation, deep vein thrombosis prevention, and blood sample preservation. Currently, clinically used sodium heparin is primarily derived from porcine mesenteric mucosa. Hydrolysis with heparinase yields low molecular weight heparin sodium (LMH, Mw < 5000 Da) and other heparin derivatives, exhibiting various physiological activities such as antitumor, anti-inflammatory, and antiviral effects. In the cosmetics field, sodium heparin is mainly used to improve skin condition and enhance skin health through its antioxidant, anti-inflammatory, and anticoagulant properties.

[0003] For example, patent CN108606976A discloses the application of heparin sodium in the preparation of topical medications for treating hemorrhoids. It utilizes the dermatological drug heparin (heparin sodium cream) to treat internal and external hemorrhoids, mixed hemorrhoids, and acute thrombosed hemorrhoids. The anticoagulant, blood-activating, and thrombolytic effects of heparin sodium are applied to reduce swelling and pain; it also helps to clear, shrink, and restore blood vessels, thereby curing hemorrhoids. Apply once or twice daily to the anus (discontinue use if bleeding occurs). It is safe, convenient, and effective.

[0004] Patent CN118986780A discloses the use of sodium heparin to improve the skin feel of sodium hyaluronate solution. Sodium heparin interacts with sodium hyaluronate through hydrogen bonds, thereby reducing the sticky feel of sodium hyaluronate. When sodium heparin is combined with Dendrobium officinale polysaccharide, the sticky feel of sodium hyaluronate can be further reduced. The patent also provides a moisturizing composition and its applications in cosmetics.

[0005] None of the above patents studied the transdermal absorption of heparin sodium. When heparin sodium is used as an anticoagulant and anti-inflammatory component, its transdermal absorption rate is low, and its therapeutic effect on skin diseases is limited. Therefore, developing an antibacterial and anti-inflammatory ointment containing heparin sodium with good transdermal absorption has become one of the current research priorities. Summary of the Invention

[0006] To address the problems existing in the prior art, the purpose of this invention is to obtain a heparin sodium transdermal absorption rate and a good therapeutic effect antibacterial and anti-inflammatory ointment for treating psoriasis.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows: This invention provides an antibacterial and anti-inflammatory ointment for treating psoriasis, comprising, by weight percentage (100%), the following ingredients: 0.3-0.7% sodium heparin, 12.3-13.5% humectant, 0.05-0.1% penetration enhancer, 0.3-0.4% pH adjuster, 0.3-0.7% thickener, 0.1-0.2% preservative, 0.1-0.2% fragrance, with the balance being solvent.

[0008] In some embodiments, the humectant is a composition of propylene glycol, glycerin, 1,3-butanediol and betaine, wherein the mass ratio of the four is 1:(0.6-1.2):(0.06-0.1):(0.4-0.5).

[0009] In some embodiments, the method for preparing the penetration enhancer includes the following steps: (1) Add sodium hyaluronate to sodium hydroxide solution and stir for 20-30 min. Then add allyl glycidyl ether and react at 35-45℃ for 6-8 h. Then adjust the pH to 7-8 and dry to obtain modified sodium hyaluronate. (2) Add 1-hydroxymethylazazepine-2-one and 2-methyl-3-butenoic acid to tetrahydrofuran, heat to 65-75℃, add sulfuric acid, react for 5-6 hours, and obtain the compound by column chromatography and drying; (3) The compound obtained in step (2) and the modified sodium hyaluronate and initiator obtained in step (1) are added to a solvent and reacted at 40-50℃ for 1-2 hours. The mixture is then washed and dried to obtain the penetration enhancer.

[0010] While heparin sodium has antipruritic, anti-inflammatory, anti-allergic, microcirculation-improving, and metabolism-promoting effects on the skin, its transdermal absorption is poor, resulting in low drug utilization. Therefore, it often requires the addition of penetration enhancers. However, traditional azone-based penetration enhancers are relatively weak in enhancing the penetration of hydrophilic substances. This invention prepares a new penetration enhancer with good skin compatibility, which effectively promotes the absorption of heparin sodium by the skin and improves drug utilization. This may be because the ether bonds and alkane segments present on the penetration enhancer increase its compatibility with skin cells. Furthermore, the compound obtained by reacting 1-hydroxymethylazazepine-2-one with 2-methyl-3-butenoic acid is polymerized with modified sodium hyaluronate. This allows the azone structure to exist in the branched structure of the penetration enhancer and has a small steric hindrance effect, enabling it to alternate with the modified sodium hyaluronate. The two synergistically enhance the hydration of the stratum corneum of skin cells, promoting the penetration of heparin sodium.

[0011] In some embodiments, the sodium hyaluronate has a molecular weight of 500 kDa - 1.5 MDa.

[0012] In some embodiments, the mass ratio of sodium hyaluronate to allyl glycidyl ether is 1:(0.1-0.4).

[0013] In some embodiments, the mass ratio of the compound to the modified sodium hyaluronate in step (3) is (0.15-0.3):1.

[0014] In some embodiments, the pH adjuster is triethanolamine.

[0015] In some embodiments, the thickener is carbomer or carboxymethyl cellulose.

[0016] In some embodiments, the preservative is methylparaben, and the solvent is water.

[0017] The second aspect of this invention provides a method for preparing an antibacterial and anti-inflammatory ointment for treating psoriasis, comprising the following steps: S1. Heat the humectant to 55-65℃, add preservative, thickener and solvent, stir at 300-400r / min for 1-2h, then add heparin sodium and penetration enhancer and continue stirring for 1-2h, then add pH adjuster and stir for 50-70min to obtain a mixture. S2. At 25-30℃, add fragrance to the mixture obtained in step S1 and stir for 15-25 minutes to obtain an antibacterial and anti-inflammatory ointment for treating psoriasis.

[0018] Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention uses heparin sodium and various preferred adjuvants with good compatibility to obtain an antibacterial and anti-inflammatory ointment. The heparin sodium in the ointment has high utilization rate, fast absorption and good therapeutic effect.

[0019] (2) This invention prepares a new penetration enhancer that has good compatibility with the skin and can effectively promote the absorption of heparin sodium by the skin, thus solving the problem of poor transdermal absorption of heparin sodium; in addition, the ether bond and alkane chain in the penetration enhancer, under the synergistic effect of the moisturizer, solves the problem that the use of a large amount of moisturizer and sodium hyaluronate can easily cause the skin to absorb water in reverse, resulting in a decrease in the therapeutic effect of the ointment.

[0020] (3) The present invention reacts 1-hydroxymethylazazepine-2-one with 2-methyl-3-butenoic acid to obtain a compound, and polymerizes it with modified sodium hyaluronate, so that the azone structure exists in the branched structure of the penetration enhancer and has a small steric hindrance effect, and can be arranged alternately with modified sodium hyaluronate. The two work together to enhance the hydration of the stratum corneum of skin cells, and solve the problem that the penetration enhancement effect of traditional azone-type penetration enhancers on hydrophilic substances is relatively weak. Detailed Implementation

[0021] The present invention will be described below with reference to specific embodiments. It should be noted that the following embodiments are examples of the present invention and are used only to illustrate the invention, not to limit it. Other combinations and various modifications within the scope of the present invention can be made without departing from its spirit or scope.

[0022] In the following examples and comparative examples, the compounds and related reagents used are commercially available. Sodium hyaluronate-1 has a molecular weight of 800 kDa to 1.0 MDa, and sodium hyaluronate-2 has a molecular weight of 200 kDa to 400 kDa.

[0023] Preparation Example 1 The preparation method of penetration enhancer-1 includes the following steps: (1) Add 100g sodium hyaluronate-1 to 2L of sodium hydroxide solution with pH=11, stir for 25min, then add 30g allyl glycidyl ether and react at 40℃ for 7h. Then adjust the pH to 7 with acetic acid and dry to obtain modified sodium hyaluronate. (2) 0.1 mol of 1-hydroxymethylazazepone-2-one and 0.12 mol of 2-methyl-3-butenoic acid were added to 300 ml of tetrahydrofuran, heated to 70 °C, and then 2 ml of 85 wt% sulfuric acid was added. The reaction was carried out for 5.5 h, and the compound was obtained by column chromatography and drying. (3) Add 2.5g of the compound obtained in step (2), 10g of the modified sodium hyaluronate obtained in step (1), and 0.1g of azobisisobutyrazoline hydrochloride to 100ml of 70wt% ethanol aqueous solution and react at 45℃ for 1.5h. Wash and dry to obtain penetration enhancer-1.

[0024] Preparation Example 2 The preparation method of penetration enhancer-2 is the same as that of preparation example 1, except that sodium hyaluronate-1 is replaced by sodium hyaluronate-2 in equal amounts.

[0025] Preparation Example 3 The preparation method of penetration enhancer-3 is the same as that of preparation example 1, except that the amount of allyl glycidyl ether added is 45g.

[0026] Preparation Example 4 The preparation method of penetration enhancer-4 is the same as that of preparation example 1, except that the amount of compound added in step (3) is 3.5g.

[0027] Preparation Example 5 The preparation method of penetration enhancer-5 is the same as that of preparation example 1, except that in step (3), 2-methyl-3-butenoic acid is replaced by 2-butenoic acid in equal amounts.

[0028] Preparation Example 6 The preparation method of penetration enhancer-6 includes the following steps: (1) Add 100g of sodium hyaluronate to 2L of sodium hydroxide solution with pH=11, stir for 25min, then add 30g of allyl glycidyl ether and react at 40℃ for 7h. Then adjust the pH to 7 with acetic acid and dry to obtain modified sodium hyaluronate. (2) 2.5g of 1-hydroxymethylazazepine-2-one and 10g of the modified sodium hyaluronate obtained in step (1) were added to 100ml of 70wt% ethanol aqueous solution and reacted at 45℃ for 1.5h. After washing and drying, penetration enhancer-6 was obtained.

[0029] Example 1 An antibacterial and anti-inflammatory ointment for treating psoriasis, comprising the following ingredients by weight percentage (100%): 0.5% sodium heparin, 13% moisturizer, 0.08% penetration enhancer-1, 0.35% triethanolamine, 0.5% carbomer 940, 0.15% methylparaben, 0.15% water-soluble peppermint flavor, with the balance being sterile deionized water; The humectant is a composition of propylene glycol, glycerin, 1,3-butanediol and betaine, in a mass ratio of 1:0.9:0.08:0.45.

[0030] The preparation method of the antibacterial and anti-inflammatory ointment for treating psoriasis in this embodiment includes the following steps: S1. Heat the humectant to 60°C, add methylparaben, carbomer 940 and sterile deionized water, stir at 350 r / min for 1.5 h, then add heparin sodium and penetration enhancer-1 and continue stirring for 1-2 h, then add triethanolamine and stir for 60 min to obtain a mixture. S2. At 28°C, add water-soluble peppermint essence to the mixture obtained in step S1 and stir for 20 minutes to obtain an antibacterial and anti-inflammatory ointment for treating psoriasis.

[0031] Example 2 An antibacterial and anti-inflammatory ointment for treating psoriasis, comprising the following ingredients by weight percentage (100%): 0.3% sodium heparin, 12.3% moisturizer, 0.05% penetration enhancer-1, 0.3% triethanolamine, 0.3% carbomer 940, 0.1% methylparaben, 0.1% water-soluble peppermint fragrance, with the balance being sterile deionized water; The humectant is a composition of propylene glycol, glycerin, 1,3-butanediol and betaine, in a mass ratio of 1:0.6:0.06:0.4.

[0032] The preparation method of the antibacterial and anti-inflammatory ointment for treating psoriasis in this embodiment includes the following steps: S1. Heat the humectant to 55°C, add methylparaben, carbomer 940 and sterile deionized water, stir at 300 r / min for 2 h, then add heparin sodium and penetration enhancer-1 and continue stirring for 1 h, then add triethanolamine and stir for 50 min to obtain a mixture. S2. At 25°C, add water-soluble peppermint essence to the mixture obtained in step S1 and stir for 15 minutes to obtain an antibacterial and anti-inflammatory ointment for treating psoriasis.

[0033] Example 3 An antibacterial and anti-inflammatory ointment for treating psoriasis, comprising the following ingredients by weight percentage (100%): 0.7% sodium heparin, 13.5% moisturizer, 0.1% penetration enhancer-1, 0.4% triethanolamine, 0.7% carbomer 940, 0.2% methylparaben, 0.2% water-soluble peppermint fragrance, with the balance being sterile deionized water; The humectant is a composition of propylene glycol, glycerin, 1,3-butanediol and betaine, in a mass ratio of 1:1.2:0.1:0.5.

[0034] The preparation method of the antibacterial and anti-inflammatory ointment for treating psoriasis in this embodiment includes the following steps: S1. Heat the humectant to 65°C, add methylparaben, carbomer 940 and sterile deionized water, stir at 400 r / min for 1 h, then add heparin sodium and penetration enhancer-1 and continue stirring for 2 h, then add triethanolamine and stir for 70 min to obtain a mixture. S2. At 30°C, add water-soluble peppermint essence to the mixture obtained in step S1 and stir for 25 minutes to obtain an antibacterial and anti-inflammatory ointment for treating psoriasis.

[0035] Example 4 An antibacterial and anti-inflammatory ointment for treating psoriasis and its preparation method are described. The specific implementation method is the same as in Example 1, except that the penetration enhancer-1 is replaced with an equal amount of penetration enhancer-2.

[0036] Example 5 An antibacterial and anti-inflammatory ointment for treating psoriasis and its preparation method are described. The specific implementation method is the same as in Example 1, except that the penetration enhancer-1 is replaced with an equal amount of penetration enhancer-3.

[0037] Example 6 An antibacterial and anti-inflammatory ointment for treating psoriasis and its preparation method are described. The specific implementation method is the same as in Example 1, except that the penetration enhancer-1 is replaced with an equal amount of penetration enhancer-4.

[0038] Example 7 An antibacterial and anti-inflammatory ointment for treating psoriasis and its preparation method are disclosed. The specific implementation method is the same as in Example 1, except that the penetration enhancer-1 is replaced with an equal amount of penetration enhancer-5.

[0039] Example 8 An antibacterial and anti-inflammatory ointment for treating psoriasis and its preparation method are described. The specific implementation method is the same as in Example 1, except that the penetration enhancer-1 is replaced with an equal amount of penetration enhancer-6.

[0040] Example 9 An antibacterial and anti-inflammatory ointment for treating psoriasis and its preparation method are described. The specific implementation method is the same as in Example 1, except that the penetration enhancer-1 is replaced with an equal amount of laurocapram.

[0041] Example 10 An antibacterial and anti-inflammatory ointment for treating psoriasis and its preparation method are disclosed. The specific implementation method is the same as in Example 1, except that the moisturizer is a composition of propylene glycol, glycerin, 1,3-butanediol and betaine, with a mass ratio of 1:1.3:0.08:0.45.

[0042] Comparative Example 1 An antibacterial and anti-inflammatory ointment for treating psoriasis and its preparation method are disclosed. The specific implementation method is the same as in Example 1, except that the penetration enhancer-1 is replaced with an equal amount of sodium hyaluronate-1.

[0043] Performance testing 1. In vitro transdermal absorption test Preparation of ex vivo skin: Healthy mice weighing 20±5g were euthanized by cervical dislocation, the skin under the xiphoid process was separated, hair was removed with sodium sulfide, the abdominal skin was separated, subcutaneous tissue and fat were removed, the skin was washed with physiological saline, and small pieces of appropriate size were cut and stored at -15℃ for later use. Before use, the skin was thawed at room temperature, washed with physiological saline, and then spread flat on the receiving pool. (2) Using the Franz diffusion device, the prepared ex vivo skin was fixed between the drug delivery pool and the receiving pool. The effective permeation area of ​​the diffusion pool was 2.80cm². 2 The stratum corneum faces the supply chamber, while the dermis side contacts the receiving solution to remove air bubbles. The receiving solution is physiological saline. 1g of the ointment prepared in Examples 1-9 and Comparative Example 1 is weighed and applied to the skin, ensuring close contact. A small glass bead is placed in the receiving chamber to help agitate the receiving solution. The supply chamber is sealed with plastic wrap. The outside of the receiving chamber is kept at a constant temperature using a water bath at 37°C. After 6 hours, all the receiving solution is collected as a sample solution. The concentration of heparin sodium in the receiving solution is measured, and the total amount is calculated as the total absorption. The total amount of heparin sodium in 1g of ointment is taken as the total dosage. Transdermal absorption rate = total absorption / total dosage × 100%. The test results are shown in Table 1. Table 1

[0044] As shown by the experimental data in Table 1, the antibacterial and anti-inflammatory ointments obtained in Examples 1-3 have good transdermal effects. A comparison of the data from Examples 1 and 4 shows that the change in the molecular weight of sodium hyaluronate may have caused it to absorb water, swell, and clog pores, leading to a decrease in transdermal absorption. A comparison of the data from Examples 1 and 5 shows that the change in the ratio of sodium hyaluronate to allyl glycidyl ether may be due to an excessive reaction of the active groups of sodium hyaluronate, which could impair its hydration capacity, hinder stratum corneum penetration, and reduce transdermal permeability. A comparison of the data from Examples 1 and 6 shows that the change in the ratio of the compound to sodium hyaluronate may have led to excessive damage to the stratum corneum, causing the drug to remain in the skin, resulting in... Decreased transdermal permeability; a comparison of data from Example 1 and Example 7 shows that replacing 2-methyl-3-butenoic acid with an equal amount of 2-butenoic acid may reduce the hydrophobic methyl groups on the branched chain, affecting compatibility with the lipid layer, reducing drug diffusion channels, and thus decreasing transdermal permeability; a comparison of data from Example 1 and Example 8 shows that simply mixing sodium hyaluronate with 1-hydroxymethylazazepine-2-one directly results in poor transdermal permeability; a comparison of Example 1 and Example 9 shows that using the conventional penetration enhancer lauroazepine reduces transdermal performance; a comparison of data from Example 1 and Comparative Example 1 shows that replacing penetration enhancer-1 with an equal amount of sodium hyaluronate-1 results in poor transdermal absorption of the ointment.

[0045] 2. Clinical trials The antibacterial and anti-inflammatory ointments prepared in Examples 1-3 and Example 10 were subjected to clinical trials: Fifty patients with mild psoriasis were selected and volunteers agreed to undergo clinical research treatment with the antibacterial and anti-inflammatory ointments prepared according to the above embodiments, divided into groups of 10. Professional nursing staff applied the medication to the volunteers based on the size of the affected area. First, 0.1% mometasone furoate cream was applied, followed by the ointment prepared according to this invention after 30 minutes. The treatment was repeated three times a day. After 7 days, the treatment effect was recorded and the affected area was observed: fading of erythema and reduction in affected area were considered effective; the absence of these conditions indicated ineffectiveness. The blank cases were treated with only mometasone furoate cream.

[0046] The test results are shown in Table 2: Table 2

[0047] As shown in Table 2, the antibacterial and anti-inflammatory ointments for treating psoriasis in Examples 1-3 of this invention have good therapeutic effects. The change in the ratio of moisturizer in Example 10 may affect the synergistic effect with the penetration enhancer, resulting in a decrease in therapeutic effect.

[0048] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it. They should not be used to limit the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A medicinal ointment for treating psoriasis, characterized in that, Based on a 100% weight percentage, it contains the following raw materials: sodium heparin 0.3-0.7%, humectant 12.3-13.5%, penetration enhancer 0.05-0.1%, pH adjuster 0.3-0.4%, thickener 0.3-0.7%, preservative 0.1-0.2%, fragrance 0.1-0.2%, with the balance being solvent.

2. The antibacterial and anti-inflammatory ointment for treating psoriasis according to claim 1, characterized in that, The moisturizer is a composition of propylene glycol, glycerin, 1,3-butanediol and betaine, in a mass ratio of 1:(0.6-1.2):(0.06-0.1):(0.4-0.5).

3. The antibacterial and anti-inflammatory ointment for treating psoriasis according to claim 1, characterized in that, The method for preparing the penetration enhancer includes the following steps: (1) Add sodium hyaluronate to sodium hydroxide solution and stir for 20-30 min. Then add allyl glycidyl ether and react at 35-45℃ for 6-8 h. Then adjust the pH to 7-8 and dry to obtain modified sodium hyaluronate. (2) Add 1-hydroxymethylazazepine-2-one and 2-methyl-3-butenoic acid to tetrahydrofuran, heat to 65-75℃, add sulfuric acid, react for 5-6 hours, and obtain the compound by column chromatography and drying; (3) The compound obtained in step (2) and the modified sodium hyaluronate and initiator obtained in step (1) are added to a solvent and reacted at 40-50℃ for 1-2 hours. The mixture is then washed and dried to obtain the penetration enhancer.

4. The antibacterial and anti-inflammatory ointment for treating psoriasis according to claim 3, characterized in that, The molecular weight of the sodium hyaluronate is 500 kDa - 1.5 MDa.

5. The antibacterial and anti-inflammatory ointment for treating psoriasis according to claim 3, characterized in that, The mass ratio of sodium hyaluronate to allyl glycidyl ether is 1:(0.1-0.4).

6. The antibacterial and anti-inflammatory ointment for treating psoriasis according to claim 3, characterized in that, The mass ratio of the compound to the modified sodium hyaluronate in step (3) is (0.15-0.3):

1.

7. The antibacterial and anti-inflammatory ointment for treating psoriasis according to claim 1, characterized in that, The pH adjuster is triethanolamine.

8. The antibacterial and anti-inflammatory ointment for treating psoriasis according to claim 1, characterized in that, The thickener is carbomer or carboxymethyl cellulose.

9. The antibacterial and anti-inflammatory ointment for treating psoriasis according to claim 1, characterized in that, The preservative is methylparaben, and the solvent is water.

10. A method for preparing an antibacterial and anti-inflammatory ointment for treating psoriasis according to any one of claims 1-9, characterized in that, Includes the following steps: S1. Heat the humectant to 55-65℃, add preservative, thickener and solvent, stir at 300-400r / min for 1-2h, then add heparin sodium and penetration enhancer and continue stirring for 1-2h, then add pH adjuster and stir for 50-70min to obtain a mixture. S2. At 25-30℃, add fragrance to the mixture obtained in step S1 and stir for 15-25 minutes to obtain an antibacterial and anti-inflammatory ointment for treating psoriasis.

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