Method for preparing four-yellow-three-seed ointment and product thereof

Abstract

The invention discloses a method for preparing a four-yellow three-seed ointment and a product thereof, and the method comprises the following steps: heating, stirring and uniformly mixing stearic acid, white vaseline, stearyl alcohol, Tefose 63 and Labrafil M1944CS to serve as an oil phase; mixing glycerol, triethanolamine, sodium benzoate and the Shuangsangui extract, supplementing the balance of distilled water, heating, stirring and uniformly mixing to obtain a water phase; under the isothermal condition, slowly pouring the oil phase into the water phase, stirring while adding along the same direction, stopping heating, adding the volatile oil after the temperature is reduced, and continuously stirring until the temperature is reduced to room temperature. The traditional Chinese medicine is developed into an external preparation, the preparation method is simple, the process is stable, and the preparation has the advantages of reducing administration times, being convenient to use, improving medication compliance of patients and the like; through skin administration, not only can the good treatment effect be maintained, but also the adverse reaction can be reduced, and the side effect can be reduced.

Description

Technical Field

[0001] The invention relates to a method for preparing Sihuangsanzi ointment and the product thereof, belonging to the field of pharmaceutical preparations. Background Art

[0002] Sihuang Sanzi Decoction is clinically used for the treatment of eczema and eczematoid dermatitis, and has a good therapeutic effect. It is composed of 13 kinds of medicinal flavors: coptis root, rhubarb, phellodendron, scutellaria, kochia fruit, cnidium monnieri, xanthium sibiricum, smilax glabra, white ringworm peel, sophora flavescens, houttuynia cordata, saposhnikovia divaricata, and alum. The main components of this prescription and some active ingredients have obvious anti-allergic, anti-inflammatory, and immunomodulatory effects. In the prescription, coptis root is bitter and cold, clears heat and dampness, purges fire and detoxifies, and rhubarb is bitter and cold, clears heat and detoxifies, cools blood and removes blood stasis. The two medicines are combined to form the meaning of Dahuang Huanglian Xiexin Decoction in "Treatise on Febrile Diseases", and they are all monarch drugs. Scutellaria baicalensis and phellodendron are both bitter and cold, clear heat and dampness, purge fire and detoxify, and they are all minister drugs. Together with the monarch drug, they form the meaning of Sanhuang Decoction in "Bihua Yijing". Kochia scoparia is bitter and cold, clears away heat, removes dampness and relieves itching; Smilax glabra is sweet and flat, removes toxins and removes dampness; Dictamni is bitter and cold, clears away heat, removes toxicity and relieves itching; Sophora flavescens clears away heat, dries dampness, dispels wind and kills insects; Dictamni is bitter and cold, clears away heat, removes toxicity and relieves itching; Sophora flavescens is bitter and cold, clears away heat, dries dampness and relieves itching; Houttuynia cordata is bitter, pungent and slightly cold, clears away heat and dries toxicity, and can treat locusts and drowning sores; Saposhnikovia divaricata dispels wind and removes dampness; Alum is salty and astringent, dries dampness and detoxifies, dispels wind and relieves itching; they are all adjuvants to help the power of the monarch and minister four yellows. Cnidium monnieri is pungent, pungent and warm, dispels cold, removes wind, and kills dampness; Xanthium sibiricum is sweet, bitter and warm, dispels wind and overcomes dampness, treats tinea and relieves itching. The two medicines are all guiding medicines, which can dispel wind and overcome dampness, and can also control the bitterness and coldness of other medicines. The above medicines are used together to play the role of clearing heat, removing dampness, and dispelling wind and relieving itching. At present, the preparations related to this prescription are external lotions, which can avoid the first-pass liver effect and gastrointestinal irritation that may occur with oral administration through external application on the skin, and increase the drug concentration in the local affected area. However, the lotion is inconvenient to carry after decoction, and the drug is easily lost. It will cause greater irritation to patients with skin surface trauma caused by scratching, and it also restricts the patient's medication environment.

[0003] Ointment is a semi-solid topical preparation made by uniformly mixing a suitable matrix with a drug, which is applied evenly to the skin lesions to produce a continuous therapeutic effect. Although there are patents for traditional Chinese medicine ointments for treating eczema in the prior art, there is no research on Sihuang Sanzi ointment. Summary of the invention

[0004] Purpose of the invention: The technical problem to be solved by the present invention is to provide a method for preparing Sihuang Sanzi ointment and its product.

[0005] Technical solution: In order to solve the above technical problems, the present invention provides a method for preparing Sihuangsanzi ointment, comprising the following steps: placing stearic acid, white vaseline, stearyl alcohol, Tefose 63, and Labrafil M1944 CS in a beaker, heating and stirring to mix, as an oil phase; placing glycerin, triethanolamine, sodium benzoate, and Sihuangsanzi extract in a beaker, supplementing the balance with distilled water, heating, stirring and mixing to form a water phase; under isothermal conditions, slowly pouring the oil phase into the water phase, adding and stirring in the same direction, continuously stirring, stopping heating, adding volatile oil after the temperature drops, and continuing to stir manually until it cools to room temperature to obtain the ointment.

[0006] Among them, the preparation method of the Sihuangsanzi extract includes the following steps: accurately weighing the Sihuangsanzi decoction pieces, cutting them into pieces, soaking them in water, decocting and extracting, and concentrating them to obtain the Sihuangsanzi extract.

[0007] Wherein, the volatile oil is obtained by synchronous extraction from the Sihuangsanzi decoction pieces by steam distillation.

[0008] Among them, the mass volume ratio of the Sihuang Sanzi decoction pieces to water is 1:8~10g / mL.

[0009] Among them, the components of the four-yellow and three-seed decoction pieces include coptis root, rhubarb, phellodendron, scutellaria, kochia fruit, cnidium monnieri, xanthium sibiricum, smilax glabra, white ringworm peel, sophora flavescens, houttuynia cordata, siler, and alum.

[0010] Wherein, the soaking time is 2 to 3 hours.

[0011] Wherein, the decoction and extraction are performed 1 to 3 times.

[0012] The decoction and extraction time for each time is 1.5 to 2.5 hours.

[0013] Wherein, the dosage of the stearic acid is 8-12%.

[0014] Furthermore, the amount of stearic acid used is 8-10%.

[0015] Wherein, the dosage of the white vaseline is 5-12%.

[0016] Furthermore, the dosage of the white vaseline is 5-9%.

[0017] Wherein, the usage amount of stearyl alcohol is 3-7%.

[0018] Furthermore, the amount of stearyl alcohol used is 5-7%.

[0019] Wherein, the usage of the glycerol is 8-14%.

[0020] Furthermore, the dosage of the glycerol is 8-12%.

[0021] Furthermore, the dosage of the glycerol is 10-12%.

[0022] Wherein, the dosage of the Sihuangsanzi extract is 2-5%.

[0023] Among them, the total usage of Tefose 63 and Labrafil M1944 CS is 12-18%.

[0024] Wherein, during the process of preparing the oil phase and the water phase, the heating temperature is 70-80°C.

[0025] The stirring time after the oil phase and the water phase are mixed is 10 to 20 minutes.

[0026] The invention also provides a Sihuangsanzi ointment prepared by the method.

[0027] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: the present invention uses the Sihuang Sanzi ointment provided by modern formulation technology to develop traditional Chinese medicine as an external preparation, the preparation method is simple, the process is stable, and it has the advantages of reducing the number of dosing times, being easy to use, and improving patients' compliance with medication; administration through the skin can not only maintain its good therapeutic effect, but also reduce its adverse reactions and reduce its side effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 To investigate the dosage of stearic acid;

[0029] Figure 2 To investigate the dosage of white vaseline;

[0030] Figure 3 To investigate the dosage of stearyl alcohol;

[0031] Figure 4 To investigate the amount of glycerol used;

[0032] Figure 5 To investigate the drug loading capacity. DETAILED DESCRIPTION

[0033] The technical solution of the present invention is further described below in conjunction with the accompanying drawings.

[0034] Example 1 Investigation of the preparation method of Sihuangsanzi extract

[0035] The single-factor experimental method was used, with berberine hydrochloride transfer rate and paste yield as investigation indicators, to examine the effects of soaking time, water addition amount (times), extraction times, extraction time, and vacuum concentration temperature on the extraction effect, in order to determine the optimal extraction process.

[0036] 1. Extraction method

[0037] The volatile oil was extracted from the Chinese medicine slices of Sihuang Sanzi Decoction by steam distillation, and the decoction was collected at the same time. The transfer rate of berberine hydrochloride and the rate of extract were used as the evaluation indicators to investigate the effects of soaking time, water addition (times), extraction times, and extraction time on the extraction effect, so as to determine the best extraction process. The extract was concentrated to prepare the extract, and the optimal temperature of the reduced pressure concentration was investigated with the berberine hydrochloride content as the evaluation indicator.

[0038] Accurately weigh the prescription amount of Chinese herbal medicine pieces (15g of Coptis chinensis, 15g of Rhubarb, 15g of Phellodendron chinense, 15g of Scutellaria baicalensis, 15g of Kochia scoparia, 15g of Cnidium monnieri, 15g of Xanthium sibiricum, 15g of Tuhuo Ling, 15g of White Ringworm Peel, 15g of Sophora flavescens, 15g of Houttuynia cordata, 15g of Saposhnikovia divaricata, and 30g of Alum) in a round-bottom flask, add several zeolites, add the corresponding multiple of double distilled water, soak and extract, and evaporate according to the 2020 edition of the Pharmacopoeia of the People's Republic of China (Volume 4). The operating steps of Method A of the oil determination method are as follows: connect the volatile oil determination device and the reflux condenser, add water to the volatile oil determination device until it overflows into the flask, soak for a corresponding time, place it on an electric heater and slowly heat it to boiling, and maintain a slightly boiling state until the corresponding heating time; after turning off the electric heater, remove the round-bottom flask, cool it at room temperature for a while, open the piston at the lower end of the determination device, slowly release the water first, then collect the extracted volatile oil, and calculate the volatile oil yield.

[0039] Volatile oil yield = volatile oil weight (g) / original medicinal material weight (g) × 100%

[0040] Combine multiple decoction extracts (volatile oil extraction and medicinal material decoction are carried out simultaneously, the volatile oil extractor is connected to the round-bottom flask, and the volatile oil is obtained by condensation and reflux. At this time, the decoction extract is in the round-bottom flask), and concentrate on a rotary evaporator at 60°C to prepare an extract. The relative density is measured to be maintained at 1.2-1.3 g / mL.

[0041] 1.2 Content determination

[0042] (1) Selection of detection wavelength

[0043] A Shimadzu C18 (250 mm × 4.6 mm, 5 μm) column was used, mobile phase A was 0.2% phosphoric acid solution, mobile phase B was methanol-acetonitrile (35:65), and elution was performed according to the time program in Table 1; column temperature was 30°C, injection volume was 20 μL, and volume flow rate was 1.0 mL / min. The theoretical plate number was not less than 5000 based on the berberine hydrochloride peak.

[0044] Table 1 Elution program

[0045] Time (min) Mobile phase A (%) Mobile phase B (%) 0.01 90 10 22 70 30 30 65 35 35 65 35 40 65 35 48 35 65 53 15 75 60 50 50 65 90 10

[0046] Preparation of reference solution: Accurately weigh 12.5 mg of berberine hydrochloride reference, dissolve it in methanol and adjust the volume to a 25 mL volumetric flask, shake well, filter with a 0.45 μm filter membrane, and make it contain about 500 μg of berberine hydrochloride per 1 mL. Accurately weigh 6.25 mg of baicalin reference, dissolve it in methanol and adjust the volume to a 25 mL volumetric flask, shake well, filter with a 0.45 μm filter membrane, and make it contain about 250 μg of baicalin per 1 mL. Accurately weigh 2 mg of wogonin reference, dissolve it in methanol and adjust the volume to a 20 mL volumetric flask, shake well, filter with a 0.45 μm filter membrane, and make it contain about 100 μg of wogonin per 1 mL.

[0047] Preparation of mixed reference solution: Accurately pipette 1 mL of the above three reference stock solutions into the same 10 mL brown volumetric flask, dilute to the scale with methanol, shake well, and filter with a 0.45 μm filter membrane to obtain a mixed reference solution with a concentration of 50 μg / mL berberine hydrochloride, 25 μg / mL baicalin, and 10 μg / mL wogonin.

[0048] Preparation of test solution: Collect 1 prescription amount of medicinal material extract, concentrate the drug solution under reduced pressure and make up to 250mL volumetric flask, shake well, then accurately pipette 2mL of the drug solution into an evaporating dish, evaporate to dryness, dissolve it with methanol and make up to 10mL volumetric flask, shake well, filter with a microporous filter membrane (0.45μm) to obtain the test solution.

[0049] Accurately pipette appropriate amounts of the mixed reference solution and the test solution, use methanol as a blank, and perform a full wavelength scan in the wavelength range of 200-800nm. The results show that the test solution has a stable maximum absorption at 271nm.

[0050] (2) Determination of transfer rate and extract yield

[0051] Accurately pipette 20mL of Chinese medicine extract, place it in an evaporating dish that has been dried to constant weight, evaporate it in a water bath, re-dissolve it in methanol, and transfer it to a 25mL volumetric flask to make up the volume. Filter out impurities through a 0.45μm filter membrane, use HPLC for determination, and finally calculate the transfer rate and extract yield of the berberine hydrochloride test sample in Sihuang Sanzi Decoction. The calculation formula is as follows:

[0052]

[0053]

[0054] 1.3 Investigation of soaking time

[0055] Weigh 5 portions of 1 / 5 prescription amount of Chinese herbal medicine slices accurately, cut them into pieces, put them in a round-bottom flask, add several zeolites, add double distilled water (Chinese herbal medicine slices: double distilled water = 1: 8g / mL), soak for 1, 1.5, 2, 2.5, 3h respectively, decoct and extract once, and decoct and extract for 2h. Collect volatile oils simultaneously during the decoction process. The specific steps are as follows: According to the operating steps of the volatile oil determination method A in the 2020 edition of the Pharmacopoeia of the People's Republic of China (Part 4), connect the volatile oil determination device and the reflux condenser, add water to the volatile oil determination device, and until it overflows into the flask, use the device and method to collect volatile oils during the decoction process. After the decoction and extraction of the medicinal materials, stop heating, remove the round-bottom flask, cool it at room temperature for a while, open the piston at the lower end of the determination device, slowly release water first, then collect the extracted volatile oil, and calculate the volatile oil yield. After extraction according to the above extraction method, calculate the transfer rate and paste rate of berberine hydrochloride, and the results are shown in Table 2. When the soaking time reached 2.5h, the transfer rate of berberine hydrochloride began to tend to equilibrium, but the paste yield decreased compared with 2h, and fluctuated around 23%. Therefore, three soaking time levels of 2, 2.5, and 3h were selected for subsequent orthogonal test investigations.

[0056] Table 2 Soaking time investigation

[0057]

[0058] 1.4 Investigation of material-liquid ratio

[0059] Weigh 3 portions of 1 / 5 of the prescription amount of medicinal slices, cut them into pieces, and place them in a 2000ml round-bottom flask. According to the method in the "immersion time investigation", the operation is carried out, where the fixed immersion time is 2.5h, the decoction is extracted once, and the decoction extraction time is 2h. Combined with the requirements of industrial production practice, the solid-liquid ratio (Chinese medicinal slices: double distilled water) is selected at 1:6, 1:8, and 1:10 (g / mL) levels, and the transfer rate and paste rate of berberine hydrochloride are calculated. The results are shown in Table 3. Under the condition of a solid-liquid ratio of 1:10g / mL, the transfer rate and paste rate of berberine hydrochloride basically reach the maximum balance. Combined with the economic benefits of large-scale production and the subsequent decompression and concentration operation, the solid-liquid ratio is selected at 1:8, 1:9, and 1:10g / mL for subsequent orthogonal test investigation.

[0060] Table 3 Investigation of material-liquid ratio

[0061] Solid-liquid ratio (g / mL) 1:6 1：8 1：10 Berberine hydrochloride transfer rate (%) 15.5 21.5 22.3 Cream yield (%) 19.8 22.6 23.6

[0062] 1.5 Study on decoction and extraction time

[0063] According to the method in "immersion time investigation", the operation was carried out, in which 5 portions of 1 / 5 of the prescription amount of medicinal materials were weighed in parallel, cut into pieces, placed in a 2000ml round-bottom flask, and soaked in distilled water for 2.5h. Decoction was performed for 1, 1.5, 2, 2.5, and 3h respectively. The transfer rate and paste rate of berberine hydrochloride were calculated, and the results are shown in Table 4. When the extraction time reached 2h, the transfer rate of berberine hydrochloride reached the maximum, and the paste rate still increased, reaching the maximum at 2.5h. Therefore, the extraction time selected three levels of 1.5, 2, and 2.5h for subsequent orthogonal test investigation.

[0064] Table 4 Decoction and extraction time investigation

[0065]

[0066] 1.6 Investigation of the number of decoction and extraction

[0067] The operation was carried out according to the method in "immersion time investigation", in which 5 portions of 1 / 5 of the prescription amount of medicinal materials were weighed in parallel, cut into pieces, placed in a 2000ml round-bottom flask, and soaked in distilled water for 2.5h under the condition of a fixed solid-liquid ratio of 1:10 and decoction extraction for 2h. The decoction extraction times were 1, 2, 3, 4, and 5 times respectively. The transfer rate and the paste rate of berberine hydrochloride were calculated, and the results are shown in Table 5. The experimental results show that when the berberine hydrochloride was extracted for the third time, the transfer rate and the paste rate of berberine hydrochloride began to increase slowly. Considering the cost, environmental protection and other factors, the extraction times were selected as 1, 2, and 3 times for subsequent orthogonal test investigation.

[0068] Table 5 Investigation of decoction extraction times

[0069]

[0070] 1.7 Orthogonal optimization of extraction process

[0071] The three levels of the four factors of soaking time (A), solid-liquid ratio (B), decoction extraction time (C), and decoction extraction times (D) were selected, and the orthogonal experimental design L9 (3 4 ) was optimized, with berberine hydrochloride transfer rate and paste yield as comprehensive evaluation indicators. The extraction process factors and levels of Sihuangsanzi decoction pieces are shown in Table 6, and the orthogonal experimental design and results of Sihuangsanzi decoction pieces extraction process are shown in Table 7.

[0072] Table 6 Factor level table

[0073]

[0074] Table 7 Orthogonal experimental design and results of Sihuang Sanzi decoction extraction process

[0075]

[0076]

[0077]

[0078] Note:

[0079] Among them, K1, K2, K3: These values ​​represent the sum of the test index values ​​of each factor at different levels. For example, K1 represents the sum of all test index values ​​of the factor at level 1, K2 represents the sum at level 2, and K3 represents the sum at level 3.

[0080] k1, k2, k3 means one third of K1, K2, K3.

[0081] R: Range, which indicates the magnitude of the influence of a factor on the result. The R value is obtained by calculating the maximum value minus the minimum value among the k values ​​of each factor. The larger the range, the greater the influence of the factor on the test result.

[0082] From the intuitive analysis of Table 7, we can see that the average values ​​of the three levels are A1>A3>A2, B3>B2>B1, C2>C3>C1, D3>D2>D1. According to the range RD>RC>RB>RA, the order of influence on the extraction process is D>C>B>A, and the optimal process is A1B3C2D3. From the variance analysis of Table 7 (Table 8), the order of influence of the four factors on the extraction process is consistent with the direct difference analysis, that is, the number of decoction extractions>decoction extraction time>solid-liquid ratio>immersion time, and the influence of factor D on the extraction process is significant, while other factors are small.

[0083] Table 8 Analysis of variance table of Sihuang Sanzi decoction extraction process

[0084]

[0085]

[0086] In summary, in order to ensure that the effective ingredients are extracted to the maximum extent and combined with production practice, the optimal extraction process of Sihuang Sanzi Decoction was finally determined to be A1B3C2D3, that is, the decoction pieces were added with 10 times the amount of water and soaked for 2 hours, decocted and extracted 3 times, each time for 2 hours.

[0087] 1.8 Research on vacuum concentration process

[0088] Referring to the orthogonal optimization process, the pieces of Sihuang Sanzi were weighed and the combined filtrate was extracted according to the optimal extraction process. The filtrate was divided into 3 parts on average, and concentrated under reduced pressure at 50°C, 60°C, and 70°C respectively to an extract with a relative density of 1.2 to 1.3 (60°C). Then, the transfer rate and retention rate of berberine hydrochloride in each extract at different temperatures were calculated using the transfer rate and retention rate of berberine hydrochloride as evaluation indicators. The results are shown in Table 9, and the calculation formula is:

[0089]

[0090]

[0091] Table 9 Investigation results of different concentration temperatures

[0092]

[0093] According to the analysis of Table 9, the total transfer rates of berberine hydrochloride at 50°C and 60°C were 40.2% and 40.0%, respectively, and the medicinal material retention rates were 52.8% and 52.6%, respectively. The transfer rate and medicinal material retention rate of berberine hydrochloride at the two temperatures were basically the same. When the temperature was 70°C, the transfer rate and medicinal material retention rate of berberine hydrochloride decreased. From the perspective of energy saving and operation time saving, the concentration temperature was selected to be 60°C.

[0094] Example 2 Preparation of Sihuang Sanzi Ointment

[0095] 1. Introduction to evaluation methods

[0096] Common ointment bases can be divided into three categories: oily bases, water-soluble bases and emulsion bases, among which emulsion bases can be divided into W / O type and O / W type. The weighted scoring method is used to select the base prescription with the highest score as the prescription to be optimized based on appearance, spreadability, centrifugal stability, heat stability and cold stability.

[0097] The specific evaluation method is as follows:

[0098] Appearance: Visually inspect whether the matrix appearance is uniform and fine, and whether there are granularity and bubbles. The grades are divided into four levels: excellent (3 points), good (2 points), qualified (1 point), and unqualified (0).

[0099] Ointment scoring criteria

[0100]

[0101] Spreadability: Apply the matrix to the skin of the hands to observe whether it is easy to spread, evenly spread, and whether there is obvious greasy feeling. It is divided into four levels: excellent (3 points), good (2 points), qualified (1 point), and unqualified (0).

[0102] Centrifugal stability: Take an appropriate amount of each matrix, put it into a centrifuge tube, centrifuge it at 3000r / min, and observe whether there is stratification. The results are divided into four levels: excellent (3 points), good (2 points), qualified (1 point), and unqualified (0).

[0103] Cold stability: Take an appropriate amount of each matrix and place it in a -20℃ refrigerator for 24 hours. Observe the appearance of the ointment and the phenomenon of oil-water stratification. Divide it into four grades: excellent (3 points), good (2 points), qualified (1 point), and unqualified (0).

[0104] Heat stability: Place a certain amount of ointment in a 55℃ thermostat for 6 hours, and observe the appearance of the ointment to see if there is mildew or oil-water separation. The ointment is divided into four grades: excellent (3 points), good (2 points), qualified (1 point), and unqualified (0). The matrix formula with the highest score is selected for the next step of investigation.

[0105] 2. Preparation of oily matrix ointment

[0106] Take half of the prescribed amount of liquid paraffin and white vaseline, stir and heat in a water bath at 80°C until melted, slowly add the Chinese medicine extract and grind until it becomes a fine paste, then gradually add the remaining matrix to the full amount. When the room temperature drops to 40°C, add volatile oil, stir evenly while adding, and cool until it becomes a viscous paste.

[0107] 3. Preparation of aqueous matrix ointment

[0108] Place sodium carboxymethyl cellulose in a mortar, add glycerin and grind evenly, add appropriate amount of distilled water to completely dissolve, and keep constant temperature in a water bath at 50℃ for later use. Place the Chinese medicine extract sodium benzoate in a beaker, add appropriate amount of distilled water and heat in a water bath at 50℃ to dissolve and mix evenly, and add it to the sodium carboxymethyl cellulose at the same temperature. Cool the room temperature to about 40℃, add volatile oil, stir evenly while adding, and stir and cool until it becomes a viscous paste.

[0109] 4. W / O type matrix ointment

[0110] (1) Polyvalent soap

[0111] Place aluminum distearate, stearic acid, glyceryl monostearate, liquid paraffin, white vaseline, and beeswax in a beaker, heat to 80°C, and stir to mix well as the oil phase; place Chinese medicine extract, calcium hydroxide, and distilled water in a beaker, heat to 80°C, and stir to mix well as the water phase. Under isothermal conditions, slowly pour the water phase into the oil phase, stirring in the same direction, continue stirring for 10 minutes, stop heating, add volatile oil when the temperature drops to 40°C, and continue stirring manually until it cools to room temperature.

[0112] (2) Pan

[0113] Place liquid paraffin, white vaseline, stearic acid, glyceryl monostearate and Span-80 in a dry beaker and heat to 75-80°C to melt (oil phase); separately take Tween-80 and water (add Chinese medicine extract to dissolve), mix and dissolve, and heat to the same temperature (water phase); slowly add the water phase to the oil phase while stirring, stir at 75-80°C for 8-10 minutes, take out the mixed matrix and stir continuously, add volatile oil when the temperature drops to 40°C, and stir while adding until completely cooled.

[0114] 5. O / W type matrix ointment

[0115] (1) Ionic type

[0116] Put stearyl alcohol, white vaseline and lanolin in a beaker, heat to 80℃ and stir to mix, as the oil phase; put Chinese medicine extract, propylene glycol, sodium lauryl sulfate and water in another beaker, heat to 80℃ and stir to mix, as the water phase. Under isothermal conditions, slowly pour the water phase into the oil phase, stirring in the same direction, stirring continuously for 10 minutes, add ethyl paraben dissolved in a small amount of ethanol to continue emulsification, stop heating, add volatile oil when the temperature drops to 40℃, continue to stir manually until cooled to room temperature, and the product is obtained.

[0117] (2) Non-ionic

[0118] Prescription 1: Stearic acid, glyceryl monostearate, liquid paraffin, white vaseline, and lanolin are placed in a beaker, heated to 80°C and stirred to mix well as the oil phase; another dry beaker is added with Chinese medicine extract, triethanolamine, glycerin, and distilled water, mixed and heated to 80°C (water phase). Under isothermal conditions, slowly pour the water phase into the oil phase, stirring in the same direction, stirring continuously for 10 minutes, add ethyl paraben dissolved in a small amount of ethanol to continue emulsification, stop heating, add volatile oil when the temperature drops to 40°C, and continue to stir manually until cooled to room temperature.

[0119] Prescription 2: Place stearic acid, white vaseline, and Tween 80 in a beaker, heat to 80°C, and stir to mix, as the oil phase; place polyethylene glycol 400, triethanolamine, Chinese medicine extract, and distilled water in a beaker, heat to 80°C, and stir to mix, as the water phase. Under isothermal conditions, slowly pour the water phase into the oil phase, stirring in the same direction, stirring continuously for 10 minutes, add ethyl paraben dissolved in a small amount of ethanol to continue emulsification, stop heating, add volatile oil when the temperature drops to 40°C, and continue to stir manually until cooled to room temperature.

[0120] Prescription 3: Place stearic acid, white vaseline, stearyl alcohol, Tefose 63 (polyethylene glycol-7-stearate), and Labrafil M1944 CS (oleic acid polyethylene glycol glyceride) in a beaker, heat to 80°C, and stir to mix well as the oil phase; place glycerol, triethanolamine, sodium benzoate, Chinese medicine extract, and distilled water in a beaker, heat to 80°C, and stir to mix well as the water phase. Under isothermal conditions, slowly pour the oil phase into the water phase, stirring in the same direction, stirring continuously for 10 minutes, stop heating, add volatile oil when the temperature drops to 40°C, and continue to stir manually until it cools to room temperature.

[0121] 6. Screening results of ointment matrix types

[0122] After the preparation of different types of matrix ointments was completed, the four different types of ointment matrices were scored according to the scoring criteria to determine the matrix type of the Sihuang Sanzi ointment. The results are shown in Table 10.

[0123] Table 10 Screening results of different ointment base types

[0124]

[0125] W / O type polyvalent aluminum distearate 1%, stearic acid Chinese medicine extract 5%, hydrogen and oxygen centrifugal stratification, 10

[0126]

[0127] The results showed that the oily matrix felt greasy and difficult to clean, and was slightly stratified and heat-resistant when heated; the aqueous matrix paste was rough and the water evaporated easily and dried; the W / O matrix was easily stratified when centrifuged and heated, and the prescription of the ionic emulsifier in the O / W matrix could not be formed. The prescription of the decoction pieces was complex and contained a lot of phenolic acid substances. Moreover, alum was an inorganic salt substance, and its main component was potassium aluminum sulfate [KAl(SO4)2·12H2O], which was easily soluble in water. The aqueous solution was acidic and easily reacted with the cream matrix to affect its stability, especially with the ionic emulsifier, resulting in roughness, emulsion rupture, and oil-water stratification. The non-ionic emulsifier prescription was more stable than the ionic one. Among them, the new non-ionic self-emulsifier Tefose 63 (polyethylene glycol-7 stearate) and the auxiliary emulsifier Labrafil M1944 CS were used in combination to prepare a relatively stable cream. Therefore, the preliminary screening of Sihuangsanzi ointment was O / W type, in which the oil phase was stearic acid, stearyl alcohol, and white vaseline, glycerin and triethanolamine were the aqueous phase, Tefose 63 and Labrafil M1944 CS were emulsifiers, and sodium benzoate was the preservative.

[0128] 7. Single factor study of matrix prescription

[0129] The single factor experimental method was used to investigate the effects of various factors on the preparation of ointments, with the amount of oil phase, drug loading and emulsifier (the ratio of Tefose 63 to auxiliary emulsifier Labrafil M1944 CS was 2:1) as single factors and the ointment scoring index as the standard.

[0130] 8. Investigation of oil phase dosage

[0131] (1) Investigation of the range of stearic acid dosage

[0132] Weigh different amounts of stearic acid (3%, 5%, 8%, 10% and 12%), white vaseline 5%, stearyl alcohol 5%, Tefose 63 10%, Labrafil M1944 CS 5%, put them in a beaker, heat to 80°C and stir to mix, as the oil phase; put 10% glycerol, 0.4% triethanolamine, 0.3% sodium benzoate, and 5% Chinese medicine extract in a beaker, make up the balance to 99.9969% with distilled water, heat to 80°C, and stir to mix as the water phase. Under isothermal conditions, slowly pour the oil phase into the water phase, stirring while adding in the same direction, stirring continuously for 10 minutes, stop heating, add volatile oil when the temperature drops to 40°C, and continue to stir manually until cooled to room temperature. The optimal dosage range of stearic acid is screened out according to the ointment scoring index, such as Figure 1 The experimental results show that when the stearic acid dosage is 10%, the paste has a uniform and delicate appearance, is easy to apply, has good stability, and has the highest comprehensive score. Therefore, the stearic acid dosage is selected at three levels of 8%, 10%, and 12%.

[0133] (2) Investigation of the dosage range of white vaseline

[0134] Weigh different amounts of white vaseline (2%, 5%, 7%, 9% and 12%), 10% stearic acid, 5% stearyl alcohol, 10% Tefose 63, and 5% Labrafil M1944 CS, put them in a beaker, heat to 80°C, stir and mix, as the oil phase; put 10% glycerol, 0.4% triethanolamine, 0.3% sodium benzoate, and 5% Chinese medicine extract in a beaker, make up the balance to 99.9969% with distilled water, heat to 80°C, and stir and mix as the water phase. Under isothermal conditions, slowly pour the oil phase into the water phase, stirring while adding in the same direction, stirring continuously for 10 minutes, stop heating, add volatile oil when the temperature drops to 40°C, and continue to stir manually until cooled to room temperature. The optimal dosage range of white vaseline is screened out according to the ointment scoring index, such as Figure 2 The experimental results show that when the dosage of white vaseline is 7%, the appearance of the paste is uniform and delicate, easy to apply, stable, and has the highest comprehensive score. Therefore, the dosage of white vaseline is selected at three levels: 5%, 7%, and 9%.

[0135] (3) Investigation of the range of stearyl alcohol dosage

[0136] Weigh different amounts of stearyl alcohol (1%, 3%, 5%, 7% and 10%), 10% stearic acid, 7% white vaseline, 10% Tefose 63, and 5% Labrafil M1944 CS in a beaker, heat to 80°C, and stir to mix as the oil phase; separately, place 10% glycerol, 0.4% triethanolamine, 0.3% sodium benzoate, and 5% Chinese medicine extract in a beaker, make up the balance to 99.9969% with distilled water, heat to 80°C, and stir to mix as the water phase. Under isothermal conditions, slowly pour the oil phase into the water phase, stirring while adding in the same direction, and continue stirring for 10 minutes, stop heating, add volatile oil when the temperature drops to 40°C, and continue stirring manually until it cools to room temperature. The optimal dosage range of stearyl alcohol is screened out according to the ointment scoring index, such as Figure 3 The experimental results show that when the dosage of stearyl alcohol is 5%, the paste has a uniform and delicate appearance, is easy to apply, has good stability, and has the highest comprehensive score. Therefore, the dosage of stearyl alcohol is selected at three levels: 3%, 5%, and 7%.

[0137] 9. Screening of water phase dosage

[0138] (1) Investigation of the range of glycerol dosage

[0139] Weigh different amounts of glycerin (8%, 10%, 12%, 14% and 16%), triethanolamine 0.4%, sodium benzoate 0.3%, and Chinese medicine extract 5% and place them in a beaker, add distilled water to make up the balance to 99.9969%, heat to 80°C, and stir to mix as the water phase; 10% stearic acid, 7% white vaseline, 5% stearyl alcohol, 10% Tefose 63, and 5% Labrafil M1944CS are placed in a beaker, heated to 80°C, and stirred to mix as the oil phase. Under isothermal conditions, slowly pour the oil phase into the water phase, stirring while adding in the same direction, and continue stirring for 10 minutes, stop heating, add volatile oil when the temperature drops to 40°C, and continue to stir manually until it cools to room temperature. The optimal dosage range of glycerin is screened out according to the ointment scoring index, such as Figure 4 The experimental results show that when the amount of glycerol is between 8% and 14%, the paste has a uniform and delicate appearance, is easy to apply, and has good stability. When the amount of glycerol is further increased, the cold and heat resistance properties deteriorate. Therefore, the optimal amount of glycerol is 10%.

[0140] (2) Investigation of drug loading

[0141] Weigh different amounts of Chinese herbal extract (2.0%, 5.0%, 8.0%, 11.0% and 14.0%), 0.4% triethanolamine, 0.3% sodium benzoate, and 10% glycerol in a beaker, add distilled water to make up the balance to 99.9969%, heat to 80°C, and stir to mix as the water phase; 10% stearic acid, 7% white vaseline, 5% stearyl alcohol, 10% Tefose 63, and 5% LabrafilM1944CS are placed in a beaker, heated to 80°C and stirred to mix as the oil phase. Under isothermal conditions, slowly pour the oil phase into the water phase, stirring while adding in the same direction, stirring continuously for 10 minutes, stop heating, add volatile oil when the temperature drops to 40°C, and continue to stir manually until cooled to room temperature. The drug loading range is screened out according to the ointment scoring index, such as Figure 5 The results show that when the drug loading is 5%, the ointment has a uniform and delicate appearance, is easy to apply, has good stability, and has the highest comprehensive score. Therefore, the drug loading of Sihuang Sanzi ointment is determined to be 5%.

[0142] (3) Screening of the dosage of Tefose 63 and Labrafil M1944 CS (2:1) composite emulsifier

[0143] According to the performance of the preliminary experimental products, the best ratio of Tefose 63 and Labrafil M1944 CS is 2:1 when used together as a composite emulsifier. When the amount of Tefose 63 is greater than 8%, an O / W emulsion cream can be prepared. Therefore, the proportion of Tefose 63 is 8%, 10%, and 12%, and the proportion of Labrafil M1944 CS is 4%, 5%, and 6% as the emulsifier dosage range. Therefore, the dosage range of the composite emulsifier is 12%, 15%, and 18%.

[0144] 10. Optimization of matrix prescription by orthogonal experiment

[0145] Based on the single-factor experimental results, a four-factor three-level orthogonal test optimization was carried out with stearic acid (A), white vaseline (B), stearyl alcohol (C) and emulsifier dosage (D) as factors, and the optimal matrix prescription was screened out using the ointment scoring index. The factor level table of the Sihuang Sanzi ointment molding prescription study is shown in Table 10, and the orthogonal experimental design and results of the Sihuang Sanzi ointment molding prescription study are shown in Table 11.

[0146] Table 10 Factor level table

[0147]

[0148] Table 11 Orthogonal experimental design and results of Sihuang Sanzi decoction extraction process

[0149]

[0150]

[0151] From the intuitive analysis of Table 11, it can be seen that the average values ​​of the three levels are A2>A3>A1, B3>B2>B1, C2>C3>C1, D2>D3>D1. According to the range RD>RC>RB>RA, the order of influence on the extraction process is A>C>B>D, and the optimal process is A2B3C2D2. From the variance analysis of Table 11 (Table 12), it can be seen that the order of influence of the four factors on the extraction process is consistent with the direct difference analysis, that is, the amount of stearic acid>the amount of stearyl alcohol>the amount of white vaseline>the amount of emulsifier, and the impression of factor A on the extraction process is significant, and the other factors are small.

[0152] Table 12 Analysis of variance table of the matrix prescription study of Sihuang Sanzi Decoction

[0153] Sources of variance Sum of Squares of Deviations Degrees of Freedom Mean Square F-number P-value Significance A 24.7022 2 12.3511 22.4113 0.0427 * B 9.3422 2 4.6711 8.4758 0.1055 No significant difference C 15.3156 2 7.6578 13.8952 0.0671 No significant difference D 1.102222222 2 0.5511 1.0000 0.5 No significant difference

[0154] In summary, the final formula of the Sihuangsanzi ointment base was determined to be A2B3C2D2, namely 10% stearic acid, 9% white vaseline, 5% stearyl alcohol, and 15% composite emulsifier (10% Tefose 63, 5% Labrafil M1944 CS).

[0155] 11. Research on the Forming Technology of Sihuang Sanzi Ointment

[0156] (1) Screening of emulsification temperature

[0157] When preparing ointments by emulsification, too low or too high emulsification temperature will have a great impact on the results. Therefore, the test uses appearance and centrifugal stratification as indicators to examine the effects of emulsification temperatures of 70℃, 80℃, and 90℃ on matrix stability. Weigh different amounts of Chinese medicine extract 5.0%, triethanolamine 0.4%, sodium benzoate 0.3%, and glycerol 10% in a beaker, make up the balance to 99.9969% with distilled water, heat to 70℃, 80℃, and 90℃ respectively, and stir to mix as the water phase; 10% stearic acid, 7% white vaseline, 5% stearyl alcohol, 10% Tefose 63, and 5% Labrafil M1944 CS are placed in a beaker, heated to 70℃, 80℃, and 90℃ respectively, and stirred to mix as the oil phase. Under isothermal conditions, slowly pour the oil phase into the water phase, stirring in the same direction, stirring continuously for 10 minutes, stop heating, add volatile oil when the temperature drops to 40°C, and continue to stir manually until it cools to room temperature. The results show that when the emulsification temperature is 70°C, the texture is slightly thin, and there is a slight oil droplet oozing out after standing for 24 hours; when the emulsification temperature is 80°C, the cream is uniform, delicate, easy to apply, and centrifugal stable; when the emulsification temperature is 90°C, it is impossible to form a uniform and delicate cream, with heavy granularity and oil-water separation. Therefore, the emulsification temperature is selected to be 80°C.

[0158] (2) Screening of emulsification time

[0159] When preparing ointments by emulsification, the emulsification time will also have a great influence on the formability of the ointment. Therefore, the test uses appearance and centrifugal stratification as indicators to examine the effects of emulsification time of 5min, 10min, and 20min on matrix stability. Weigh different prescription amounts of Chinese medicine extract 5.0%, triethanolamine 0.4%, sodium benzoate 0.3%, and glycerol 10% in a beaker, add distilled water to the balance to 99.9969%, heat to 80°C, and stir to mix as the water phase; stearic acid 10%, white vaseline 9%, stearyl alcohol 5%, Tefose 63 10%, and Labrafil M1944 CS 5% in a beaker, heat to 80°C, and stir to mix as the oil phase. Under isothermal conditions, the oil phase was slowly poured into the water phase, stirring in the same direction, and continued stirring for 5 minutes, 10 minutes, and 20 minutes. The heating was stopped, and the volatile oil was added when the temperature dropped to 40°C. The mixture was stirred manually until it cooled to room temperature. The results showed that when the emulsification time was 5 minutes, the cream was thinner; when the emulsification time was 10 minutes and 20 minutes, a composite standard cream could be formed in terms of appearance and centrifugal stability. Considering the economic cost and drug loading stability, the emulsification time of 10 minutes was finally selected.

Claims

1. A method for preparing Sihuang Sanzi ointment, characterized in that: The following steps are involved: Stearic acid, white vaseline, stearyl alcohol, Tefose 63, and Labrafil M1944 CS are mixed, heated, and stirred to form the oil phase; glycerin, triethanolamine, sodium benzoate, and extract of four yellow three seeds are mixed, and the balance is supplemented with distilled water, and the mixture is heated and stirred to form the water phase; under isothermal conditions, the oil phase is slowly poured into the water phase while adding in the same direction, and the heating is stopped. After the temperature drops, volatile oil is added, and stirring is continued until the mixture is cooled to room temperature.

2. The method according to claim 1, characterized in that: The preparation method of the Sihuangsanzi extract comprises the following steps: accurately weighing Sihuangsanzi decoction pieces, cutting them into pieces, soaking them in water, decocting and extracting them, and concentrating them to obtain the Sihuangsanzi extract; the mass volume ratio of the Sihuangsanzi decoction pieces to water is 1:8-10 g / mL.

3. The method according to claim 2, characterized in that: The soaking time is 2 to 3 hours, the decoction extraction times are 1 to 3 times, the decoction extraction time each time is 1.5 to 2.5 hours, and the concentration temperature is 50 to 70°C.

4. The method according to claim 1, characterized in that: The volatile oil is obtained by synchronous extraction by steam distillation during the decoction extraction process of the Sihuang Sanzi medicinal pieces.

5. The method according to claim 2, characterized in that: The components of the four-yellow and three-seed decoction pieces are coptis root, rhubarb, phellodendron, scutellaria, kochia fruit, cnidium monnieri, xanthium sibiricum, radix polygoni multiflori, white ringworm peel, sophora flavescens, houttuynia cordata, siler and alum.

6. The method according to claim 1, characterized in that: The dosage of stearic acid is 8-12%, the dosage of white vaseline is 5-9%, the dosage of stearyl alcohol is 3-7%, the dosage of glycerin is 8-14%, the dosage of four yellow three seeds extract is 2-8%, and the total dosage of Tefose 63 and Labrafil M1944 CS is 12-18%.

7. The method according to claim 1, characterized in that: During the preparation of the oil phase and the water phase, the heating temperature is 70-80°C.

8. The method according to claim 1, characterized in that: The stirring time after the oil phase and the water phase are mixed is 10 to 20 minutes.

9. A Sihuangsanzi ointment prepared by the method according to any one of claims 1 to 8.

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