Salvianolic acid B compound hydrogel preparation and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a salvianolic acid B compound hydrogel preparation and a preparation method thereof.The salvianolic acid B compound hydrogel preparation prepared through the method has good viscosity, fine and smooth feeling, spreading performance and moistening feeling; meanwhile, due to the addition of astragaloside, the transdermal absorption of the salvianolic acid B is promoted to a certain extent while the curative effect is enhanced, the salvianolic acid B compound hydrogel preparation is different from traditional injection and oral administration preparations, the prepared salvianolic acid B compound hydrogel preparation can play the effects of removing blood stasis, promoting blood circulation, clearing and activating the channels and collaterals of the salvianolic acid B through external smearing on the skin, and the salvianolic acid B compound hydrogel preparation is convenient to use and has a good application prospect. The medicine can be prevented from being damaged by gastrointestinal tracts, the medication compliance of patients is improved, and wide application prospects are achieved.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a compound hydrogel preparation of salvianolic acid B and astragaloside IV and a preparation method thereof. Background Art

[0002] Salvianolic Acid B is a natural phenolic acid compound, mainly extracted from the root of Salvia miltiorrhiza Bunge, a plant of the Labiatae family. Salvianolic Acid B is one of the main active ingredients in Salvia miltiorrhiza, and has the effects of protecting the myocardium, protecting cardiac microvascular endothelial cells, preventing and treating atherosclerosis, improving cardiac function, improving memory function, resisting liver and kidney fibrosis, and even anti-tumor. Astragaloside IV is one of the main active ingredients of Astragalus, and has the effects of anti-oxidation and scavenging free radicals, protecting brain damage caused by ischemia, protecting the myocardium, enhancing heart function, inhibiting liver and lung fibrosis, promoting blood circulation, strengthening metabolic function, anti-virus, and analgesia.

[0003] At present, the pharmaceutical research of salvianolic acid B is mainly focused on injection preparations and oral preparations. However, the instability of salvianolic acid B in aqueous solution will reduce the bioavailability and clinical efficacy of the drug during use. The clinical solution to this problem must be to increase the number of administrations, resulting in reduced patient compliance. At the same time, there are relatively few studies on topical preparations of salvianolic acid B, especially gel preparations. Therefore, it is of positive clinical significance to prepare a convenient, transdermal phenolic acid B compound hydrogel preparation. Summary of the invention

[0004] In order to overcome the problems in the above-mentioned background technology, the present invention provides a salvianolic acid B compound hydrogel preparation and a preparation method thereof. The salvianolic acid B compound hydrogel preparation prepared by the present method has good viscosity, fine texture, spreadability and moisturizing feeling. At the same time, the addition of astragaloside IV not only enhances the therapeutic effect but also promotes the transdermal absorption of salvianolic acid B to a certain extent, enriches the pharmaceutical dosage form and administration method of salvianolic acid B, and improves the patient's medication compliance.

[0005] The invention firstly provides a prescription component of a salvianolic acid B compound hydrogel preparation, comprising a drug component, a gel matrix, a moisturizer, an antibacterial agent, a skin penetration enhancer and a solvent.

[0006] The present invention further provides the components and contents of the above-mentioned salvianolic acid B compound hydrogel preparation, the specific contents of which are as follows:

[0007] (1) The drug components in the preparation composition are salvianolic acid B and astragaloside IV, and the content of the drug components in the preparation composition is 30-40wt%, preferably 30wt%.

[0008] The salvianolic acid B comes from salvianolic acid B extract powder (content is 50.14%); the astragaloside IV comes from astragaloside IV extract (content is 0.37wt%); the mass ratio of salvianolic acid B extract powder to astragaloside IV extract is 4:1.

[0009] (2) The gel matrix in the formulation components is one of sodium carboxymethylcellulose and hydroxypropyl methylcellulose, and the content of the gel matrix is ​​1 to 3 wt %, preferably 2 wt %.

[0010] (3) The moisturizing agent in the formulation components is one of glycerol and propylene glycol, and the content of the moisturizing agent is 5 to 15 wt %, preferably 15 wt %.

[0011] (4) The antibacterial agent in the preparation components is potassium sorbate, and the content is 0.1 to 1 wt%.

[0012] (5) The skin penetration enhancer in the preparation components is laurocapram, and the content is 0.1-1 wt%.

[0013] (6) The solvents in the formulation components are ethanol and distilled water, with the ethanol content being 5 wt% and the distilled water content being 30-50 wt%.

[0014] The preparation method of the above-mentioned salvianolic acid B compound hydrogel preparation comprises the following steps:

[0015] (1) Dissolve the salvianolic acid B extract and astragaloside IV extract in distilled water and stir to fully dissolve the drugs;

[0016] (2) adding anhydrous ethanol dropwise to the solution and stirring to mix evenly;

[0017] (3) slowly adding hydroxypropyl methylcellulose to the above solution while stirring continuously, so that the hydroxypropyl methylcellulose is evenly dispersed in the solution;

[0018] (4) Finally, propylene glycol, potassium sorbate and laurocapram are added in sequence, and the mixture is stirred continuously to fully dissolve and mix the mixture; the mixture is stirred overnight to obtain the salvianolic acid B compound hydrogel.

[0019] The beneficial effects of the present invention are:

[0020] The invention prepares a salvianolic acid B compound hydrogel preparation, wherein astragaloside IV is added to enhance the therapeutic effect and promote the transdermal absorption of salvianolic acid B, and can be applied externally on the skin to exert the effects of salvianolic acid B in removing blood stasis, activating blood circulation, and promoting blood circulation, and is easy to use, and has good viscosity, fine texture, spreadability and moisturizing feeling, can avoid the drug from being destroyed by the gastrointestinal tract, and improve the compliance of patients with medication. DETAILED DESCRIPTION

[0021] In the present invention, a double-chamber osmotic diffusion device is used to conduct an in vitro skin permeation experiment on SD rats on the compound hydrogel preparation of salvianolic acid B to explore the drug transdermal absorption rate and prove the effectiveness and feasibility of this drug dosage form.

[0022] The preparation method of the salvianolic acid B extract used in the following examples and comparative examples is as follows: weigh 100.0 g of danshen tablets (purchased from Bozhou Guandong Changjiu Chinese Medicinal Materials Planting Co., Ltd., and identified as the dried roots and rhizomes of the perennial herb Salvia mihiorrhiza Bge. of the Lamiaceae family), grind them using a grinder, add 500.0 mL of 50% ethanol, heat in a water bath at 50 degrees Celsius, soak and stir for 6 hours, filter to obtain an extract, concentrate by vacuum rotary evaporation to half of the original volume, and freeze-dry to obtain a salvianolic acid B extract powder. The content of salvianolic acid B in the extract was 50.14% as determined by HPLC.

[0023] The preparation method of the astragaloside extract used in the following examples and comparative examples is as follows: weigh 20.0 g of dried slices of Astragalus (purchased from Bozhou Guandong Changjiu Chinese Medicinal Materials Planting Co., Ltd., and identified as the dried rhizome of Mongolian Astragalus (Astragalus membranaceus (Fisch.) Bge.) of the Leguminosae family), wash and crush them, add 250.0 mL of 90% ethanol solution as the extraction solvent, heat in a water bath, reflux extraction for 3 hours, filter while hot, collect the filtrate, and evaporate the ethanol using a rotary evaporator to obtain a syrupy Astragaloside extract. HPLC detection showed that the content of astragaloside I in the extract was 0.37%.

[0024] The choice of gel matrix has a significant impact on the hydrogel preparation. Comparative Examples 1-3 use common gel matrices Carbomer 940, sodium carboxymethyl cellulose and hydroxypropyl methylcellulose as gel matrices, respectively, to observe and compare the gelling effects.

[0025] Example 1

[0026] Weigh 1.0g of salvianolic acid B extract powder and 0.25g of astragaloside IV extract, dissolve in 3.6mL of distilled water to prepare a drug aqueous solution of salvianolic acid B: astragaloside IV = 4:1, slowly add 0.15g of carbomer 940 under constant stirring, leave overnight, and add triethanolamine dropwise to adjust the pH value to 7. The experiment found that although the concentration of carbomer has reached 3%, the sample still failed to form, which may be due to the interaction between some active pharmaceutical ingredients in salvianolic acid B extract and astragaloside IV extract and carbomer 940, affecting its swelling and thickening properties, resulting in failure to gel.

[0027] Example 2

[0028] Weigh 1.0 g of salvianolic acid B extract powder and 0.25 g of astragaloside IV extract, dissolve them in 3.6 mL of distilled water to prepare a drug aqueous solution containing salvianolic acid B: astragaloside IV = 4:1, slowly add 0.15 g of sodium carboxymethyl cellulose while stirring continuously, and let it stand overnight to allow it to fully swell. The sample can form a gel.

[0029] Example 3

[0030] Weigh 1.0 g of salvianolic acid B extract powder and 0.25 g of astragaloside IV extract, dissolve them in 3.6 mL of distilled water to prepare a drug aqueous solution containing salvianolic acid B: astragaloside IV = 4:1, slowly add 0.15 g of hydroxypropyl methylcellulose while stirring continuously, and let it stand overnight to fully swell. The sample can form a gel and the skin feel is more delicate than the gel prepared in Comparative Example 2.

[0031] In Comparative Examples 4-5, glycerin and propylene glycol were respectively selected as moisturizers to observe and compare the properties of the prepared gels.

[0032] Example 4

[0033] Weigh 1.0 g of salvianolic acid B extract powder and 0.25 g of astragaloside IV extract, dissolve them in 3.6 mL of distilled water to prepare a drug aqueous solution containing salvianolic acid B: astragaloside IV = 4:1, slowly add 0.15 g of hydroxypropyl methylcellulose and 0.5 g of glycerol while stirring continuously, and let it stand overnight to fully swell to prepare a hydrogel preparation.

[0034] Example 5

[0035] 1.0 g of salvianolic acid B extract powder and 0.25 g of astragaloside IV extract were weighed and dissolved in 3.6 mL of distilled water to prepare a drug aqueous solution containing salvianolic acid B: astragaloside IV = 4:1. 0.15 g of hydroxypropyl methylcellulose and 0.5 g of propylene glycol were slowly added under continuous stirring, and the mixture was allowed to stand overnight to fully swell to prepare a hydrogel preparation. Compared with Comparative Example 4, the gel using glycerol as a moisturizer had a larger viscosity, while the gel using propylene glycol as a moisturizer had a more delicate skin feel and a better skin feel.

[0036] Example 6

[0037] Table 1. Orthogonal experimental design factor level table of salvianolic acid B compound hydrogel preparation

[0038]

[0039] According to the experiment, the appearance and viscosity of the compound hydrogel preparation of salvianolic acid B are affected by the content of each component in the prescription. An orthogonal test was designed, as shown in Table 1, where A is the content of the drug component salvianolic acid B, B is the content of the gel matrix hydroxypropyl methylcellulose, and C is the content of the moisturizer propylene glycol. The content of astragaloside IV extract in the prescription is 25wt% of the content of salvianolic acid B extract, and the other components are fixed to 5wt% ethanol, 1wt% laurocapram, 1wt% potassium sorbate, and distilled water is used to make up to 100wt%. The viscosity, fineness, spreadability and moisturizing feeling of the sample are used as the inspection criteria, and the total score of each of the four indicators is 25 points, for a total of 100 points. The three factors of drug component content, gel matrix content, and moisturizer content are investigated for the finished product quality of the compound hydrogel preparation of salvianolic acid B, and a three-factor, three-level orthogonal experiment is designed to screen the optimal prescription, and the results are shown in Table 2.

[0040] Table 2 Orthogonal test results

[0041]

[0042] The optimal level combination selected by comparing the K value through the orthogonal table is A 1 B 2 C 3 , that is, the content of salvianolic acid B extract is 30wt%, the content of hydroxypropyl methylcellulose is 2wt%, and the content of propylene glycol is 15wt%. Through the range analysis, it is known that factor B, namely the content of hydroxypropyl methylcellulose, has the greatest impact on the results, factor A, the content of salvianolic acid B extract, is second, and factor C, the content of propylene glycol, has the least impact on the results. Therefore, the components in the final prescription of the salvianolic acid B compound hydrogel preparation are 30wt% salvianolic acid B extract, 2wt% hydroxypropyl methylcellulose, 15wt% propylene glycol, 7.5wt% astragalus extract, 5wt% ethanol, 1wt% laurocapram, 1wt% potassium sorbate and 38.5wt% distilled water.

[0043] Example 7

[0044] According to the orthogonal test results of Example 1, a prescription table of a salvianolic acid B compound hydrogel preparation is obtained, as shown in Table 3. The prescribed amounts of salvianolic acid B extract and astragaloside IV extract are weighed, dissolved in distilled water, and stirred to fully dissolve the drugs; a prescribed amount of anhydrous ethanol is added dropwise to the solution, and stirred to mix uniformly; a prescribed amount of hydroxypropyl methylcellulose is weighed and slowly added to the above solution under continuous stirring, so that the hydroxypropyl methylcellulose is uniformly dispersed in the solution; finally, the prescribed amounts of propylene glycol, potassium sorbate and laurocapram are added in sequence, and continuously stirred to fully dissolve and mix; and stirred overnight to obtain a salvianolic acid B compound hydrogel.

[0045] Table 3 Prescription of salvianolic acid B compound hydrogel preparation

[0046]

[0047] Example 8

[0048] Table 4 Prescription of Salvianolic Acid B Hydrogel Preparation

[0049]

[0050] According to the prescription table in Table 4, weigh the prescribed amount of salvianolic acid B extract, dissolve it in distilled water, and stir to fully dissolve the drug; add the prescribed amount of anhydrous ethanol to the solution, and stir to mix it evenly; weigh the prescribed amount of hydroxypropyl methylcellulose and slowly add it to the above solution while constantly stirring, so that the hydroxypropyl methylcellulose is evenly dispersed in the solution; finally, add the prescribed amount of propylene glycol, potassium sorbate and laurocapram in sequence, and stir continuously to fully dissolve and mix them; stir overnight to obtain the salvianolic acid B hydrogel preparation.

[0051] Example 9

[0052] According to the prescription table in Table 5, weigh the prescribed amount of hydroxypropyl methylcellulose and slowly add distilled water while stirring continuously to uniformly disperse the hydroxypropyl methylcellulose in the solution; add the prescribed amount of anhydrous ethanol, propylene glycol, potassium sorbate and laurocapram in sequence, stirring continuously to fully dissolve and mix them; stir overnight to obtain a blank hydrogel preparation.

[0053] Table 5 Blank hydrogel formulation prescription

[0054]

[0055] Example 10

[0056] The transdermal absorption rate of the compound hydrogel preparation of salvianolic acid B was investigated using a RYJ-6A drug transdermal diffusion tester and a vertical Franz diffusion cell. A SD rat weighing about 190 g was taken and killed by breaking the spine. The abdominal hair was shaved with an electric shaver, and the abdominal skin was taken and placed on a glass plate. The hair that was not shaved was quickly shaved with a blade, and the subcutaneous fat was removed as much as possible. The treated mouse skin was rinsed with physiological saline, and the stratum corneum was spread flat in a culture dish with a small amount of physiological saline, and soaked at low temperature for half an hour. The mouse skin was taken out and cut into three pieces of skin of similar size, numbered 1, 2, and 3, with the stratum corneum facing up and the inner side of the mouse skin facing down, respectively fixed in the middle of the supply pool and the receiving pool (the supply pool is on the top and the receiving pool is on the bottom); 6.5 mL of physiological saline was added to the receiving pool as the receiving liquid, and the bubbles in the supply pool were carefully removed; about 50 mg of the samples prepared in Example 7, Example 8, and Example 9 were evenly applied on the stratum corneum side. The instrument temperature was set to 37°C, the speed was set to 220rmp, and the timing was performed. 1 mL was aspirated from the receiving pool at 3 and 6 hours respectively, and 1 mL of physiological saline was immediately added to eliminate bubbles. The sample was filtered with a 0.22 μm filter membrane, placed in a 1 mL centrifuge tube, sent for sample detection and analysis by high performance liquid chromatography, and the content of salvianolic acid B was detected by the standard curve method. The transdermal absorption rate of each sample group was calculated, as shown in Table 6. It can be seen that compared with the blank hydrogel matrix, the salvianolic acid B hydrogel preparation and the compound hydrogel preparation of salvianolic acid B and astragaloside IV, salvianolic acid B can smoothly penetrate the rat skin. At the same time, the salvianolic acid B compound hydrogel preparation containing astragaloside IV has a significantly increased transdermal absorption rate of 57.45%, achieving the smooth release and absorption of salvianolic acid B, confirming the feasibility and applicability of the development of the salvianolic acid B compound hydrogel preparation of the present invention.

[0057] Table 6 Transdermal absorption rate of salvianolic acid B compound hydrogel preparation

[0058]

[0059] The above-described embodiments merely express the implementation methods of the present invention, but they cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that for those skilled in the art, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A salvianolic acid B compound hydrogel preparation, characterized in that: The invention comprises the following components: a drug component, a gel matrix, a moisturizer, an antibacterial agent, a skin penetration accelerator and a solvent; the drug component comprises salvianolic acid B and astragaloside IV.

2. The salvianolic acid B compound hydrogel preparation according to claim 1, characterized in that: The content of the drug component in the salvianolic acid B compound hydrogel preparation is 30-40wt%.

3. The salvianolic acid B compound hydrogel preparation according to claim 1, characterized in that: The gel matrix is ​​one of sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose; the content of the gel matrix in the salvianolic acid B compound hydrogel preparation is 1-3wt%.

4. The salvianolic acid B compound hydrogel preparation according to claim 1, characterized in that: The moisturizing agent is one of glycerol and propylene glycol; the content of the moisturizing agent in the salvianolic acid B compound hydrogel preparation is 5-15wt%.

5. The salvianolic acid B compound hydrogel preparation according to claim 1, characterized in that: The antibacterial agent is potassium sorbate; the content of the antibacterial agent in the salvianolic acid B compound hydrogel preparation is 0.1-1 wt%.

6. The salvianolic acid B compound hydrogel preparation according to claim 1, characterized in that: The skin penetration enhancer is laurocapram; the content of the penetration enhancer in the salvianolic acid B compound hydrogel preparation is 0.1-1 wt %.

7. The salvianolic acid B compound hydrogel preparation according to claim 1, characterized in that The solvents in the preparation components are ethanol and distilled water; the ethanol content in the penetration enhancer in the salvianolic acid B compound hydrogel preparation is 5wt%; the distilled water content in the penetration enhancer in the salvianolic acid B compound hydrogel preparation is 30-50wt%.

8. A method for preparing a salvianolic acid B compound hydrogel preparation, characterized in that: The steps include: (1) Dissolve the salvianolic acid B extract and astragaloside IV extract in distilled water and stir to fully dissolve the drugs; (2) adding anhydrous ethanol dropwise to the solution and stirring to mix evenly; (3) slowly adding hydroxypropyl methylcellulose to the above solution while stirring continuously, so that the hydroxypropyl methylcellulose is evenly dispersed in the solution; (4) Finally, propylene glycol, potassium sorbate and laurocapram are added in sequence, and the mixture is stirred continuously to fully dissolve and mix the mixture; the mixture is stirred overnight to obtain the salvianolic acid B compound hydrogel.

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