A poly-I-cell external preparation and its preparation method

Abstract

The present invention discloses a polymyxin external preparation and a preparation method thereof; the external preparation comprises an active ingredient of polymyxin and an external preparation adjuvant, wherein the adjuvant comprises a dispersion medium, an emulsifier, and other pharmaceutically acceptable external preparation adjuvants; in terms of the mass percentage of the total weight of the polymyxin external preparation, the active ingredient accounts for 0.5-10%, the emulsifier accounts for 5-15%, the dispersion medium accounts for 60-85%, and other pharmaceutically acceptable external preparation adjuvants account for 0-34%. The emulsifier is selected from one or more of polyoxyethylene ether, polysorbate, and Span; preferably, it is composed of polysorbate, Span, and fatty alcohol polyoxyethylene ether. The preparation of the present invention has stable properties, stable release, good skin permeability, and the effect of inhibiting the proliferation of viruses such as herpes zoster and flat warts.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and relates to a poly IL-60 preparation for external use and a preparation method thereof, and in particular to a poly IL-60 preparation for external use with stable properties, stable release and good skin permeability and a preparation method thereof. Background Art

[0002] Poly I:C, also known as polyinosinic acid, polyinosinic acid cytosine nucleotide, polyinosinic acid-polycytidylic acid, etc. It was first discovered and synthesized by American chemists David R. Davies and Alexander Rich in 1958. It is a copolymer of polyinosinic acid (Poly I) and polycytidylic acid (Poly C). In 1967, American scientists Field and Tytell and others discovered that Poly I:C had a strong IFN induction function when studying various highly effective interferon (IFN) inducers. Since then, a wave of research on Poly I:C has been set off worldwide. Poly I:C is a highly effective interferon (IFN) inducer with broad-spectrum antiviral, phagocytic stimulation, immune adjustment, anti-tumor, and anti-infection of certain bacteria and protozoa. It has been widely used in human medicine to treat hepatitis, herpes virus, mumps virus infection and some tumor diseases. In addition, poly I-C can be used in cosmetics to eliminate skin growths such as acne and flat warts. In veterinary medicine, poly I-C is mainly used to prevent and treat viral diseases in poultry and livestock. It is easy to use and widely used. It can be used with many drugs at the same time and has a synergistic or additive effect. At the same time, double-chain poly I-C is also an immune adjuvant. When used at the same time as vaccine immunization, it can significantly improve the immune effect and prevent the occurrence of immune stress and other viral diseases.

[0003] Regarding poly I-17 preparations, in addition to the most commonly used poly I-17 injections and eye drops, patent CN103599071A discloses a method for preparing double-chain poly I-17 dry powder, and CN105079024A discloses a pharmaceutical composition prepared from poly I-17 for preventing and treating oral ulcers, but no cream preparations have been reported.

[0004] "Huaihai Medicine" reported on the use of polymyxin injection to directly apply to treat herpes simplex at the corners of the mouth on page 67, Vol. 17, No. 3, September 1999; "Dermatology and Venereology" reported on the use of polymyxin injection to treat flat warts on page 25, Vol. 25, No. 2, 2003. However, studies have found that when polymyxin injection is applied to the skin alone, it has no adhesion and cannot maintain sustained efficacy. It also needs to be combined with intramuscular injection of polymyxin. Therefore, it is necessary to develop a polymyxin external preparation with high skin permeability. Summary of the invention

[0005] The purpose of the present invention is to overcome the deficiencies of the above-mentioned prior art and to provide a poly I-20 preparation for extracellular use and a preparation method thereof.

[0006] The objective of the present invention is achieved through the following technical solutions:

[0007] The present invention relates to a poly I-cell external preparation, comprising an active ingredient of poly I-cell and external preparation excipients, wherein the external preparation excipients comprise a dispersion medium, an emulsifier, and other pharmaceutically acceptable external preparation excipients; in terms of mass percentage of the total weight of the poly I-cell external preparation, the active ingredient accounts for 0.5-10%, the emulsifier accounts for 5-15%, the dispersion medium accounts for 60-85%, and other pharmaceutically acceptable external preparation excipients account for 0-34%.

[0008] As an embodiment, the dispersion medium includes a water-soluble base and / or an oily base.

[0009] As an embodiment, the dispersion medium includes a water-soluble matrix and an oily matrix; in terms of mass percentage of the total weight of the poly I-cell extracellular preparation, the water-soluble matrix accounts for 50-60%, and the oily matrix accounts for 10-25%.

[0010] As an embodiment, the oil phase matrix is ​​selected from oil substances such as animal oil, vegetable oil, mineral oil, etc. Specifically, the oil phase matrix is ​​selected from vaseline, liquid paraffin, natural ceresin, microcrystalline wax, perhydrosqualene, dimethyl polysiloxane, methylphenyl polysiloxane, siloxane-ethylene glycol copolymer, triglyceride, acetylated monoglyceride, ethoxylated glyceride, alkyl esters of fatty acids, fatty acids and alcohols (including polyols), lanolin and lanolin derivatives, polyol esters, sterols, beeswax derivatives and polyethers, and amides of fatty acids.

[0011] As one embodiment, the aqueous base comprises water and propylene glycol.

[0012] As an embodiment, the emulsifier is selected from one or more of polyoxyethylene ether, polysorbate, and Span. The emulsifier is conducive to forming an oil-in-water and / or water-in-oil emulsified state of the active ingredient, so that the active ingredient can be more evenly dispersed in the preparation. Preferably, the emulsifier is composed of polysorbate, Span, and fatty alcohol polyoxyethylene ether.

[0013] As an embodiment, the other pharmaceutically acceptable external preparation excipients are selected from at least one of a thickener, a stabilizer, a preservative, a wetting agent, and a transdermal absorption enhancer. In terms of mass percentage of the total weight of the poly I-cell external preparation, the thickener accounts for 0-5%, the stabilizer accounts for 0-18%, the preservative accounts for 0-1.0%, the wetting agent accounts for 0-10%, and the transdermal absorption enhancer accounts for 0-5%.

[0014] As an embodiment, the thickener is selected from xanthan gum, pectin, palmitic acid, xanthan gum saline tolerance agent, hydroxypropyl cellulose, hydroxyethyl cellulose, water-soluble vinyl polymer (carbopol) and gum arabic, as well as magnesium aluminosilicate or magnesium aluminosilicate, etc., which can help improve the ductility of the preparation during use and facilitate application.

[0015] As an embodiment, the stabilizer is selected from stearyl alcohol and cetyl alcohol.

[0016] As an embodiment, the preservative is selected from sodium benzoate, benzyl alcohol, phenoxyethanol, parabens, methyl or ethyl parahydroxybenzoate, sorbate, imidazolidinyl urea derivatives, iodopropynyl butylamine formate and isothiazolinone, etc., which can inhibit the reproduction of microorganisms in the preparation and ensure the quality of the preparation within the specified shelf life.

[0017] As an embodiment, the transdermal absorption enhancer, i.e., penetration enhancer, is selected from glycerin, polyethylene glycol, laurocapram, peppermint oil, camphor, limonene, and the like.

[0018] As an embodiment, the wetting agent is glycerol or the like.

[0019] As an embodiment, the polyinosinic acid external preparation is preferably a polyinosinic acid cream.

[0020] As an embodiment, the polyinosin cream of the present invention has the following raw materials and auxiliary materials and prescription proportions (in terms of mass percentage of the total weight of the polyinosin cream):

[0021] Components Prescription ratio Poly I 0.8-5％ Oily base 15-25％ Stabilizer 5-10％ Emulsifier 6-10％ Wetting Agents 5-10％ Aqueous matrix 50-55％ preservative 0-1％ Thickener 0-5％ Penetration enhancers 0-5％

[0022] As an embodiment, the oil phase base consists of white petrolatum and liquid paraffin. As an embodiment, the stabilizer consists of stearyl alcohol and cetyl alcohol.

[0023] As an embodiment, the emulsifier consists of polysorbate, Span, and fatty alcohol polyoxyethylene ether.

[0024] In some specific embodiments, the polyinosin cream comprises, by weight percentage of the total weight of the polyinosin cream: polyinosin 1-3%, oil phase matrix 20%, stabilizer 9%, emulsifier 7.5%, wetting agent glycerin 7%, propylene glycol 3.5%, water 50-52%; the oil phase matrix is ​​white vaseline and liquid paraffin, the stabilizer is octadecyl alcohol and hexadecanol, and the emulsifier is polysorbate 60, Span 60 and fatty alcohol polyoxyethylene ether. Preferably, the mass ratio of white vaseline and liquid paraffin is 1:3. Preferably, the mass ratio of octadecyl alcohol and hexadecanol is 1:1. Preferably, the mass ratio of polysorbate 60, Span 60 and fatty alcohol polyoxyethylene ether is (2-4.5): (1-2.5): (2-4). Further preferably, the mass ratio of polysorbate 60, Span 60 and fatty alcohol polyoxyethylene ether is 3.5:1:3.

[0025] The present invention also relates to a method for preparing a poly I-cell extracellular preparation, the method comprising the following steps:

[0026] S1. Preparation of aqueous phase: Take the aqueous phase matrix, add the active ingredient, poly I-cell, and stir to dissolve at 70-75°C;

[0027] S2. Preparation of oil phase: Take the oil phase matrix, add the prescribed amount of emulsifier, stir and dissolve at 75-80°C, and set aside;

[0028] S3. Slowly add the oil phase to the water phase at 75-80°C. After the addition is completed, continue to stir and emulsify at 75-80°C for 10-30 minutes, slowly stir and cool naturally to room temperature to obtain the product.

[0029] As an embodiment, in step S1, take the aqueous phase matrix, add the active ingredient raw material polyinosin, and other pharmaceutically acceptable external preparation excipients (such as preservatives, thickeners, transdermal absorption enhancers and wetting agents) except stabilizers, and stir to dissolve.

[0030] As an embodiment, in step S2, a stabilizer is added at the same time as the emulsifier.

[0031] The present invention also relates to the use of a polymyxin B external preparation as an external medicine for treating herpes simplex and / or flat warts.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] The invention provides a new polymyxin external preparation and a preparation method thereof. The preparation has stable properties, stable release, high preparation penetration percentage and good skin permeability; and provides an external preparation that is easy to use for patients with herpes zoster and flat warts. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Other features, objects and advantages of the present invention will become more apparent from the detailed description of non-limiting embodiments made with reference to the following drawings:

[0035] Figure 1 This is the in vitro release rate graph of the polyinosin cream of Example 1;

[0036] Figure 2 Schematic diagram of the transmittance of the polyinosin cream of Example 1;

[0037] Figure 3 This is a schematic diagram of the cumulative permeation amount of the polyinosin cream of Example 1. DETAILED DESCRIPTION

[0038] The present invention is described in detail below in conjunction with embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those of ordinary skill in the art, some adjustments and improvements can also be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

[0039] The poly I-cell external preparation of the present invention comprises an active ingredient of poly I-cell and an auxiliary material of the external preparation, wherein the auxiliary material comprises one or more of a dispersion medium, an emulsifier and / or other pharmaceutically acceptable auxiliary materials of the external preparation; wherein the mass percentage of the active ingredient is 0.5-10%; the dispersion medium comprises a water-soluble matrix and / or an oily matrix, the mass percentage of the water-soluble matrix is ​​50-60%, and the mass percentage of the oily matrix is ​​10-25%; the mass percentage of the emulsifier is 5-15%; other pharmaceutically acceptable auxiliary materials of the external preparation are selected from at least one of a thickener, a stabilizer, a preservative, a wetting agent, and a transdermal absorption enhancer; in the preparation formula, the mass percentage of the thickener is 0-5% by mass, the mass percentage of the stabilizer is 0-18% by mass, the mass percentage of the preservative is 0-1.0% by mass, the mass percentage of the wetting agent is 0-10% by mass, and the mass percentage of the transdermal absorption enhancer is 0-5% by mass.

[0040] The preparation method of the poly I-cell external preparation of the present invention comprises the following steps:

[0041] 1) Preparation of aqueous phase: Take an aqueous phase matrix (such as water and propylene glycol), add the prescribed amount of the active ingredient raw material polyinosin, stir and dissolve at 70-75°C, add the prescribed amount of preservatives, thickeners, penetration enhancers and wetting agents (if any), stir and dissolve, and set aside.

[0042] 2) Preparation of oil phase: Take the oil phase matrix, add the prescribed amount of stabilizer and emulsifier, stir and dissolve at 75-80°C, and set aside.

[0043] 3) Slowly add the oil phase to the water phase at 75-80°C. After the addition is completed, continue to stir and emulsify at 75-80°C for 10-30 minutes, slowly stir and cool naturally to room temperature to obtain the product.

[0044] The polyoxyethylene ether used in the examples and comparative examples of the present invention is fatty alcohol polyoxyethylene ether (Brij TM C20 polyoxyethylene ether).

[0045] Specific application examples are as follows:

[0046] Example 1

[0047] This embodiment relates to a polyinosin cream, and its raw materials and proportions are as shown in Table 1:

[0048] Table 1

[0049] Raw materials Weight g Poly I 1 White Vaseline 5 Liquid paraffin 15 Octadecanol 4.5 Cetyl Alcohol 4.5 Polysorbate 60 3.5 Span 60 1 Fatty alcohol polyoxyethylene ether 3 glycerin 7 Propylene glycol 3.5 water 52

[0050] The preparation method of the polyinosin cream comprises the following steps:

[0051] 1) Preparation of aqueous phase: Take the prescribed amount of water, add the prescribed amount of the raw material polyinosin, stir to dissolve at 72°C, add the prescribed amount of propylene glycol and glycerol, stir to dissolve, and set aside.

[0052] 2) Preparation of oil phase: Take the prescribed amount of white vaseline and liquid paraffin, add the prescribed amount of octadecyl alcohol, hexadecanol, polysorbate 60, Span 60, and fatty alcohol polyoxyethylene ether, stir and dissolve at 78° C., and set aside.

[0053] 3) At 78°C, slowly add the oil phase dropwise to the water phase. After the addition is complete, continue to stir and emulsify at 78°C for 20 minutes, slowly stir and cool naturally to room temperature to obtain the product.

[0054] Embodiment 2-4

[0055] The raw materials and proportions of the polyinosin cream involved in Example 2-4 are shown in Table 2 below:

[0056] Table 2

[0057]

[0058] The preparation method is the same as Example 1.

[0059] Embodiment 5-6

[0060] The raw materials and proportions of the polyinosin cream involved in Examples 5-6 are shown in Table 3 below:

[0061] Table 3

[0062]

[0063]

[0064] The preparation method is the same as Example 1.

[0065] Comparative Examples 1-5

[0066] The raw materials and auxiliary materials and their proportions of the polyinosin creams of Comparative Examples 1-5 are shown in Table 4 below; the preparation method is the same as that of Example 1.

[0067] Table 4

[0068]

[0069] Comparative Example 6

[0070] This comparative example relates to a polyinosin cream, the raw material formula of which is as follows:

[0071] Raw materials Weight g Poly I 5.0 Xanthan gum 0.1 Mineral oil 29 Fatty alcohol polyoxyethylene ether 3.5 Octadecanol 2.0 Cetyl Alcohol 2.0 Phenoxyethanol 0.3 Benzyl alcohol 0.6 water 57.5

[0072] The above formula is prepared according to the following method:

[0073] 1) Aqueous phase: Take the prescribed amount of water, add the prescribed amount of the raw material polyinosin, stir to dissolve at 60°C, add the prescribed amount of xanthan gum and benzyl alcohol, stir to dissolve, and set aside.

[0074] 2) Oil phase: Take the prescribed amount of mineral oil, add the prescribed amount of octadecyl alcohol, hexadecanol, phenoxyethanol and fatty alcohol polyoxyethylene ether, stir and dissolve at 80°C, and set aside.

[0075] 3) At 80°C, slowly add the oil phase to the water phase. After the addition is completed, continue to stir and emulsify at 80°C for 15-20 minutes, slowly stir and cool naturally to room temperature to obtain the product.

[0076] Example 7, efficacy verification

[0077] 7.1 Centrifugation, cryogenic and freeze-thaw experiments

[0078] Examples 1-6 and Comparative Examples 1-6 were subjected to centrifugation experiments, low temperature experiments and freeze-thaw experiments. The centrifugation conditions were centrifugation at a speed of 4000 r / min for 15 min, the low temperature experiment conditions were: three cycles, each cycle was placed at 2-8°C for 2 days, placed at 40°C for 2 days, and a total of 12 days; the freeze-thaw experiment conditions were: three cycles, each cycle was placed at -10 to -20°C for 2 days, placed at 40°C for 2 days, and a total of 12 days.

[0079] The cream of Example 1-6 did not show stratification after centrifugation (15 min at 4000 r / min), low temperature experiment (three cycles, 2-8°C for 2 days each cycle, 40°C for 2 days, 12 days in total) and freeze-thaw experiment (three cycles, -10 to -20°C for 2 days each cycle, 40°C for 2 days, 12 days in total). The oil particles were uniform in size under a microscope.

[0080] The cream prepared in Comparative Example 1 did not show stratification under centrifugation conditions, low temperature experiments and freeze-thaw experiments.

[0081] The cream prepared in Comparative Example 2 did not show stratification under centrifugation conditions, low temperature experiments and freeze-thaw experiments.

[0082] In Comparative Example 3, the emulsifier did not contain polysorbate 60, and obvious stratification occurred during centrifugation.

[0083] Comparative Example 4: When only fatty alcohol polyoxyethylene ether was used as the emulsifier, the prepared cream was not stratified by centrifugation, but was slightly stratified under low temperature and freeze-thaw test conditions.

[0084] Comparative Example 5: When the emulsifiers are polysorbate 60, Span 60 and glyceryl monostearate, the cream is not stratified by centrifugation, but is slightly stratified under low temperature and freeze-thaw test conditions. Under a microscope, the oil particle size is uneven.

[0085] The cream prepared in Comparative Example 6 did not stratify under the conditions of centrifugation experiment, low temperature experiment and freeze-thaw experiment.

[0086] 7.2 The examples of the present invention and the comparative examples were subjected to a transdermal test.

[0087] 1) Method: Franz diffusion cell method;

[0088] 2) Instrument: RT800 vertical diffusion cell transdermal device, Shenzhen Ruituo Instrument Equipment Co., Ltd.;

[0089] 3) Skin: pig skin was used for the experiment, thickness 0.8-1 mm, contact diameter 2 cm;

[0090] 4) Receiving solution: normal saline;

[0091] 5) Receiving liquid temperature: 32±0.5℃;

[0092] 6) Rotation speed: 600 rpm;

[0093] 7) Samples: Spread the cream of each prescription evenly on the experimental pig skin, and repeat the application of 6 samples for each prescription. Accurately weigh about 300 mg of the cream sample, with a total phosphorus content of 6.4% in poly I-C. Meanwhile, the pig skin without the cream applied was used as blank pig skin.

[0094] 8) Diffusion cell volume: 27 ml;

[0095] 9) Sampling method: partial sampling, sampling volume 3.9 ml;

[0096] 10) Sampling time points: 2h, 4h, 6h, 10h, 21h, 24h;

[0097] 11) Sample analysis: Determined by UV-visible spectrophotometry (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0401)

[0098] Test solution 1: Accurately measure the appropriate amount of release solution at each time point, place in a Kjeldahl flask, add 3.0ml of 5mol / L sulfuric acid solution, and digest at 140-160℃ for 2-4 hours. When the solution turns yellow-brown, cool it, add 1-2 drops of 30% hydrogen peroxide, and continue digesting until the solution is transparent. After cooling, add 0.5ml of water, heat in a water bath for 10 minutes, cool it, transfer it to a 50ml volumetric flask, and add water to the scale. Accurately measure 1ml of this solution, add 2.0ml of water and 3ml of phosphorus determination reagent (6mol / L hydrochloric acid-water-2.5% ammonium molybdate-10% ascorbic acid 1:2:1:1), shake well, heat at 45℃ for 25 minutes, and immediately cool to room temperature.

[0099] Test solution 2: Take the pig skin after 24 hours of transdermal experiment, scrape off the ointment on the surface, place it in a crucible, add 0.5-1ml sulfuric acid to moisten it, heat it at low temperature until the sulfuric acid vapor is completely removed, and burn it at 700-800℃ to completely ash it. Rinse the crucible with 3.0ml of 5mol / L sulfuric acid solution in batches and transfer it to a Kjeldahl flask, digest it at 140-160℃ for 2-4 hours. When the solution turns yellow-brown, cool it, add 1-2 drops of 30% hydrogen peroxide, and continue digesting until the solution is transparent. After cooling, add 0.5ml of water, heat it in a water bath for 10 minutes, cool it, transfer it to a 50ml volumetric flask, and add water to the scale. Accurately measure 1 ml of this solution, add 2.0 ml of water and 3 ml of phosphorus determination reagent (6 mol / L hydrochloric acid-water-2.5% ammonium molybdate-10% ascorbic acid 1:2:1:1), shake well, heat at 45°C for 25 minutes, and immediately cool to room temperature.

[0100] Reference solution: Accurately weigh 2.195g of potassium dihydrogen phosphate dried to constant weight at 105℃, place in a 500ml volumetric flask, add water to dissolve and dilute to scale, shake well, then accurately measure 5ml, place in a 500ml volumetric flask, add water to scale, shake well (each 1ml contains 10μg of phosphorus). Accurately measure 0.8ml of the solution, add 2.0ml of water and 3ml of phosphorus determination reagent (6mol / L hydrochloric acid-water-2.5% ammonium molybdate-10% ascorbic acid 1:2:1:1), shake well, heat at 45℃ for 25 minutes, and immediately cool to room temperature.

[0101] Determination method: Take appropriate amount of test solution 1 and 2 and reference solution, measure the absorbance at a wavelength of 660nm, and correct it with a blank experiment to calculate the total phosphorus content of test solution 1 and 2.

[0102] Permeability: The amount of drug released per unit area per unit time (in terms of total phosphorus, μg / cm 2 / h) versus time (h) to plot the permeability of the preparation in Example 1 Figure 1 .

[0103] Cumulative permeation: The amount of drug released per unit area (in terms of total phosphorus, μg / cm 2 ) is plotted against time (h). Figure 2 .

[0104] Percentage of penetration = cumulative amount of penetration / sample amount; the measured percentage of penetration of Example 1 is 80.66%.

[0105] The preparations of other Examples 2-6 and Comparative Examples 1, 2 and 6 were also subjected to skin penetration tests with reference to the above method. The results are shown in Table 6 below:

[0106] Table 6. Skin penetration test results of the examples and comparative examples

[0107] 24-hour average penetration percentage Example 1 80.66％ Example 2 72.41％ Example 3 73.65％ Example 4 68.51％ Example 5 81.22％ Example 6 65.78％ Comparative Example 1 45.57％ Comparative Example 2 48.92％ Comparative Example 6 38.62％

[0108] Conclusion: The penetration percentages of the preparations prepared in Examples 1-6 are significantly greater than those of other comparative examples, that is, the skin permeability is significantly better than that of other comparative examples, especially Examples 1 and 5 have the best effects.

[0109] 7.3 In vitro release test of the preparation of Example 1

[0110] 1) Method: Franz diffusion cell method;

[0111] 2) Instrument: SYSTEM 918-12 dry heating automatic transdermal system, manufacturer: Logan Instruments Corp.;

[0112] 3) Artificial membrane: cellulose acetate membrane, 0.45 μm, contact diameter 0.75 cm;

[0113] 4) Receiving solution: normal saline;

[0114] 5) Receiving liquid temperature: 32±0.5℃;

[0115] 6) Rotation speed: 600 rpm;

[0116] 7) Sample volume: Spread the cream of the prescription evenly on the artificial membrane, and repeat the application of 6 samples for each prescription. Weigh about 300 mg of the cream sample, and the total phosphorus content of poly I-C is 6.4%;

[0117] 8) Diffusion cell volume: 12 ml;

[0118] 9) Sampling method: all sampling;

[0119] 10) Sampling time points: 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 14h;

[0120] 11) Sample analysis: Determined by UV-visible spectrophotometry (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0401).

[0121] Test solution: Accurately measure the appropriate amount of release solution at each time point, place in a Kjeldahl flask, add 3.0ml of 5mol / L sulfuric acid solution, and digest at 140-160℃ for 2-4 hours. When the solution turns yellow-brown, cool it, add 1-2 drops of 30% hydrogen peroxide, and continue digesting until the solution is transparent. After cooling, add 0.5ml of water, heat in a water bath for 10 minutes, cool, transfer to a 50ml volumetric flask, and add water to the scale. Accurately measure 1ml of this solution, add 2.0ml of water and 3ml of phosphorus determination reagent (6mol / L hydrochloric acid-water-2.5% ammonium molybdate-10% ascorbic acid 1:2:1:1), shake well, heat at 45℃ for 25 minutes, and immediately cool to room temperature.

[0122] Reference solution: Accurately weigh 2.195g of potassium dihydrogen phosphate dried to constant weight at 105℃, place in a 500ml volumetric flask, add water to dissolve and dilute to scale, shake well, then accurately measure 5ml, place in a 500ml volumetric flask, add water to scale, shake well (each 1ml contains 10μg of phosphorus). Accurately measure 0.8ml of this solution, add 2.0ml of water and 3ml of phosphorus determination reagent (6mol / L hydrochloric acid-water-2.5% ammonium molybdate-10% ascorbic acid 1:2:1:1), shake well, heat at 45℃ for 25 minutes, and immediately cool to room temperature.

[0123] Determination method: Take appropriate amount of test solution and reference solution, measure the absorbance at a wavelength of 660nm, and calculate the total phosphorus content of the test solution.

[0124] The amount of drug released per unit area (in terms of total phosphorus, μg / cm 2 ) Square root of relative time The slope of the straight line generated represents the release rate of the preparation. The in vitro release rate of the preparation of Example 1 is shown in Figure 3 .

[0125] 7.4 Example 1 Preparation Stability Test

[0126] The accelerated stability test of the preparation of Example 1 (in a constant temperature and humidity chamber at a temperature of 40°C ± 2°C and a humidity of 75% ± 5% RH) was conducted to test the appearance, viscosity and release rate of the cream. The results are shown in Table 7 below:

[0127] Table 7

[0128]

[0129] The results of the accelerated stability test of the preparation in Example 1 showed that the cream prepared in Example 1 had good appearance, viscosity and release stability.

[0130] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art may make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A polyinosin cream, characterized in that The invention comprises active ingredients of polyinosin and auxiliary materials for external preparations. In terms of the mass percentage of the total weight of the polyinosin cream, polyinosin accounts for 0.8-5%, the emulsifier accounts for 6-10%, the oil phase matrix accounts for 15-25%, the water phase matrix accounts for 50-55%, the stabilizer accounts for 5-10%, the wetting agent glycerin accounts for 5-10%, the preservative accounts for 0-1%, the thickener accounts for 0-5%, and the transdermal absorption enhancer accounts for 0-5%; the emulsifier is composed of polysorbate, span and fatty alcohol polyoxyethylene ether in a mass ratio of (2-4.5):(1-2.5):(2-4); the oil phase matrix is ​​white vaseline and liquid paraffin, the stabilizer is octadecyl alcohol and hexadecanol in a mass ratio of 1:1; the water phase matrix is ​​water and propylene glycol.

2. The polyinosin cream according to claim 1, characterized in that The mass ratio of the polysorbate to Span and fatty alcohol polyoxyethylene ether is 3.5:1:

3.

3. Use of the polyinosin cream according to claim 1 or 2 in the preparation of an external medicine for treating herpes simplex and / or flat warts.

Images