An abider c cream for inhibiting hsv-2 and a method for preparing the same

Abstract

This disclosure provides an Arbidol hydrochloride cream for inhibiting HSV-2 and its preparation method. The aforementioned Arbidol hydrochloride cream for inhibiting HSV-2 comprises the following components in weight percentages: 0.5%–2% micronized Arbidol hydrochloride; 70%–95% cream matrix; and 8%–12% absorption enhancer; wherein the particle size of the micronized Arbidol hydrochloride is D90 ≤ 10 μm. The aforementioned Arbidol hydrochloride cream for inhibiting HSV-2... The aforementioned Arbidol hydrochloride cream for inhibiting HSV-2, through the combined use of micronized Arbidol hydrochloride with a particle size of D90≤10μm, cream matrix, and absorption enhancer, not only improves the uniformity of the Arbidol hydrochloride cream for inhibiting HSV-2, but also ensures a continuous and stable release rate, thereby enhancing efficacy and reducing the number of doses. Furthermore, it ensures the long-term storage stability of the prepared Arbidol hydrochloride cream for inhibiting HSV-2, making it better suited for the treatment of acute, large-area HSV-2 infections.

Description

Technical Field

[0001] This disclosure relates to the field of Arbidol hydrochloride cream technology, and in particular to an Arbidol hydrochloride cream for inhibiting HSV-2 and its preparation method. Background Technology

[0002] Arbidol hydrochloride is a broad-spectrum antiviral drug with a definite antiviral effect against HSV-1. Recent studies have found that arbidol hydrochloride also has anti-HSV-2 (Herpes Simplex Virus type 2) activity. For example, Chinese Patent Application No. 201611184528.4 discloses the application of arbidol hydrochloride in the preparation of drugs for the prevention and treatment of HSV-2, enabling arbidol hydrochloride to inhibit the late stage of the HSV-2 replication cycle by interfering with the viral assembly and release process. The application specifically discloses the use of arbidol hydrochloride in the preparation of drugs for the prevention and treatment of HSV-2, wherein the dosage form of the drug is pills, tablets, capsules, or oral liquid.

[0003] However, most of the Arbidol hydrochloride currently available on the market is in the form of tablets, capsules, dry suspensions, pills, oral liquids, or injections. The administration methods of these dosage forms often cause fluctuations in the peak and trough of the blood drug concentration, resulting in inconsistent effective concentrations of Arbidol hydrochloride in the body, thus affecting its efficacy.

[0004] Therefore, a topical application of arbidol hydrochloride has emerged on the market. For example, Chinese patent applications 202010184335.9 and 202010594075.2 disclose arbidol hydrochloride that can be formulated into ointments, but these do not specify the exact ingredients or preparation method of the arbidol hydrochloride ointment. Furthermore, because the ointment-form arbidol hydrochloride contains a significant amount of oily components, its texture is relatively thick, resulting in poor permeability and a slow drug release rate, thus prolonging treatment time and affecting efficacy. This makes it unsuitable for treating acute, large-area HSV-2 lesions. Summary of the Invention

[0005] The purpose of this disclosure is to overcome the shortcomings of the prior art and provide an arbidol hydrochloride cream for inhibiting HSV-2 that can improve the uniformity of the cream, ensure a continuous and stable release rate to enhance efficacy and reduce the number of doses, and ensure the long-term storage stability of the prepared arbidol hydrochloride cream for inhibiting HSV-2, thus better suited for the treatment of acute large-area HSV-2.

[0006] The purpose of this disclosure is achieved through the following technical solution:

[0007] An Arbidol hydrochloride cream for inhibiting HSV-2 comprises the following components by weight percentage:

[0008] Micronized Arbidol hydrochloride 0.5%–2%;

[0009] Cream base 70%–95%;

[0010] Absorption enhancer 8%–12%;

[0011] The particle size of the micronized Arbidol hydrochloride is D90≤10μm.

[0012] In one embodiment, the absorption enhancer includes at least one of propylene carbonate, propylene glycol, isopropanol, and polyethylene glycol.

[0013] In one embodiment, the cream base is a mixture of white beeswax, paraffin, liquid paraffin, and white petrolatum.

[0014] In one embodiment, by weight percentage, the white beeswax is 4% to 6%, the paraffin is 2% to 4%, the liquid paraffin is 12% to 16%, and the white petrolatum is 63% to 69%.

[0015] In one embodiment, the Arbidol hydrochloride cream for inhibiting HSV-2 maintains a constant and uniform release rate over a period of 6 hours.

[0016] In one embodiment, the droplets of the Arbidol hydrochloride cream for inhibiting HSV-2 are ≤25μm, and the content uniformity RSD of the Arbidol hydrochloride cream for inhibiting HSV-2 is 0.1% to 2.0%.

[0017] In one embodiment, the content of the Arbidol hydrochloride cream for inhibiting HSV-2 is ≥99.0%.

[0018] A method for preparing Arbidol hydrochloride cream for inhibiting HSV-2 includes the following steps:

[0019] Arbidol hydrochloride was micronized to obtain micronized Arbidol hydrochloride with a particle size of D90≤10μm;

[0020] The micronized Arbidol hydrochloride and the absorption promoter were first mixed and homogenized to obtain an Arbidol hydrochloride solution.

[0021] The white beeswax, paraffin, liquid paraffin and white petrolatum were mixed and homogenized a second time to obtain the cream base liquid;

[0022] The Arbidol hydrochloride solution and the cream base solution are mixed and homogenized in a third process to obtain an Arbidol hydrochloride emulsion.

[0023] The Arbidol hydrochloride emulsion was cooled to obtain the Arbidol hydrochloride cream for inhibiting HSV-2 in any of the above embodiments.

[0024] In one embodiment, the conditions for the first mixing and homogenization are: a homogenization temperature of 70°C to 90°C, a homogenization time of 5 min to 15 min, a homogenization speed of 5 k rpm to 10 k rpm; and / or,

[0025] The conditions for the second mixing and homogenization are: homogenization temperature of 70℃~90℃, homogenization time of 5min~15min; homogenization speed of 5krpm~10krpm; and / or,

[0026] The conditions for the third mixing and homogenization are as follows: homogenization temperature is 70℃~90℃, homogenization time is 5min~15min, and homogenization speed is 5krpm~10krpm.

[0027] In one embodiment, the micronization process is an air jet milling operation, wherein the feed pressure of the air jet milling operation is 5 bar to 7 bar, the milling pressure is 4 bar to 5 bar, and the feed speed is 2 rpm to 8 rpm.

[0028] Compared with the prior art, this disclosure has at least the following advantages:

[0029] 1) Because the added absorption enhancer can improve the penetration rate of Arbidol hydrochloride cream used to inhibit HSV-2, it increases the release rate of Arbidol hydrochloride, enabling Arbidol hydrochloride to effectively reach the lesion site to inhibit the HSV-2 replication cycle, thereby enhancing the efficacy of Arbidol hydrochloride and making it better suited for the treatment of acute large-area HSV-2.

[0030] 2) The added absorption enhancer directly reduces the difference in the ratio between micronized Arbidol hydrochloride and the cream matrix, avoiding the problem of uneven content of micronized Arbidol hydrochloride due to sedimentation caused by the large density difference between the two. Especially when used with micronized Arbidol hydrochloride with a particle size of D90≤10μm, this particle size effectively overcomes the characteristics of poor solubility, easy agglomeration, and difficulty in dispersion of Arbidol hydrochloride, further improving the content uniformity of Arbidol hydrochloride cream for HSV-2 inhibition. The content uniformity RSD of Arbidol Hydrochloride Cream is 0.1% to 2.0%, ensuring the quality of Arbidol Hydrochloride Cream for HSV-2 inhibition. This ensures that the prepared Arbidol Hydrochloride Cream for HSV-2 inhibition can maintain a constant and uniform release rate for 6 hours. This continuous and stable release rate not only ensures that the effective HSV-2 inhibition concentration is maintained for a longer period of time, thereby more effectively inhibiting HSV-2 replication and spread, but also reduces the number of times the user needs to take the medication, thus improving the convenience and comfort of medication. Furthermore, it ensures the long-term storage stability of the prepared Arbidol Hydrochloride Cream for HSV-2 inhibition. Attached Figure Description

[0031] To more clearly illustrate the technical solutions of the embodiments of this disclosure, the accompanying drawings used in the embodiments will be briefly described below. It should be understood that the following drawings only show some embodiments of this disclosure and should not be regarded as a limitation of the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0032] Figure 1 This is a flowchart of an embodiment of the Arbidol Hydrochloride Cream for inhibiting HSV-2 according to the present invention;

[0033] Figure 2 This is a linear regression equation graph showing the release rate of Arbidol Hydrochloride Cream used to inhibit HSV-2 in Examples 1-5 of this invention. Detailed Implementation

[0034] To facilitate understanding of this disclosure, a more complete description will be given below with reference to the accompanying drawings, which illustrate preferred embodiments of the present disclosure. However, this disclosure can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and complete understanding of the disclosure.

[0035] It should be noted that when an element is referred to as being "fixed to" another element, it can be directly attached to the other element or there may be an intervening element. When an element is referred to as being "connected to" another element, it can be directly connected to the other element or there may be an intervening element. The terms "vertical," "horizontal," "left," "right," and similar expressions used herein are for illustrative purposes only and do not represent the only possible implementation.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of this disclosure. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0037] This disclosure provides an Arbidol hydrochloride cream for inhibiting HSV-2, comprising the following components in weight percentage: 0.5% to 2% micronized Arbidol hydrochloride; 70% to 95% cream matrix; and 8% to 12% absorption enhancer; wherein the particle size of the micronized Arbidol hydrochloride is D90 ≤ 10 μm.

[0038] The aforementioned Arbidol hydrochloride cream for inhibiting HSV-2 has an increased permeability and release rate due to the addition of an absorption enhancer. This allows Arbidol hydrochloride to effectively reach the lesion site and inhibit the HSV-2 replication cycle, thus enhancing its efficacy and making it better suited for the treatment of acute, large-area HSV-2 infections. Furthermore, the added absorption enhancer directly reduces the difference in the ratio between micronized Arbidol hydrochloride and the cream matrix, avoiding the problem of uneven content of micronized Arbidol hydrochloride due to sedimentation caused by the large density difference between the two. Especially when used with micronized Arbidol hydrochloride with a particle size of D90≤10μm, this particle size effectively overcomes the characteristics of poor solubility, easy agglomeration, and poor dispersion of Arbidol hydrochloride, further improving the content uniformity of Arbidol hydrochloride cream for HSV-2 inhibition, thus enhancing the effectiveness of HSV-2 inhibition. The content uniformity RSD of the Arbidol Hydrochloride Cream is 0.1% to 2.0%, ensuring the quality of the Arbidol Hydrochloride Cream for HSV-2 inhibition. This ensures that the prepared Arbidol Hydrochloride Cream for HSV-2 inhibition can maintain a constant and uniform release rate for 6 hours. This continuous and stable release rate not only ensures that the effective HSV-2 inhibition concentration is maintained for a longer period of time, thereby more effectively inhibiting HSV-2 replication and spread, but also reduces the number of times the user needs to take the medication, thus improving the convenience and comfort of medication. Furthermore, it ensures the long-term storage stability of the prepared Arbidol Hydrochloride Cream for HSV-2 inhibition.

[0039] To better understand the technical solution and beneficial effects of this disclosure, the following detailed description is provided in conjunction with specific embodiments. One embodiment of Arbidol hydrochloride cream for inhibiting HSV-2 includes the following components in weight percentage: 0.5% to 2% micronized Arbidol hydrochloride; 70% to 95% cream matrix; 8% to 12% absorption promoter; wherein the particle size of the micronized Arbidol hydrochloride is D90≤10μm.

[0040] It is understandable that the added absorption enhancer can improve the penetration rate of Arbidol hydrochloride cream used to inhibit HSV-2, thereby increasing the release rate of Arbidol hydrochloride. This allows Arbidol hydrochloride to effectively reach the lesion site to inhibit the HSV-2 replication cycle, enhancing the efficacy of Arbidol hydrochloride and making it better suited for the treatment of acute, large-area HSV-2.

[0041] It is also understandable that the added absorption enhancer directly reduces the difference in the ratio between micronized Arbidol hydrochloride and the cream matrix, avoiding the problem of uneven content of micronized Arbidol hydrochloride due to sedimentation caused by the large density difference between the two. Especially when used with micronized Arbidol hydrochloride with a particle size of D90≤10μm, this particle size effectively overcomes the characteristics of poor solubility, easy agglomeration, and poor dispersion of Arbidol hydrochloride, further improving the uniformity of Arbidol hydrochloride content in HSV-2 inhibitory creams, thereby enhancing the inhibition of HSV-2. The content uniformity RSD of the Arbidol Hydrochloride Cream used was 0.1% to 2.0%, ensuring the quality of the Arbidol Hydrochloride Cream for inhibiting HSV-2. This ensures that the prepared Arbidol Hydrochloride Cream for inhibiting HSV-2 maintains a constant and uniform release rate for 6 hours. This continuous and stable release rate not only ensures that the effective HSV-2 inhibition concentration is maintained for a longer period of time, thereby more effectively inhibiting HSV-2 replication and spread, but also reduces the number of times the user needs to take the medication, thus improving the convenience and comfort of medication, and ensuring the long-term storage stability of the prepared Arbidol Hydrochloride Cream for inhibiting HSV-2.

[0042] In one embodiment, the absorption enhancer includes at least one of propylene carbonate, propylene glycol, isopropanol, and polyethylene glycol to ensure that the added propylene carbonate, propylene glycol, isopropanol, and polyethylene glycol can increase the absorption rate and extent of Arbidol hydrochloride in the skin, thereby improving the bioavailability of Arbidol hydrochloride and ensuring a highly uniform and stable release rate.

[0043] It is understandable that while propylene carbonate can promote the penetration of Arbidol hydrochloride molecules through the HSV-2 cell membrane, thereby improving drug absorption efficiency, its relatively low toxicity means that long-term or high-dose use can still cause certain toxic effects, such as skin irritation or damage. Furthermore, propylene carbonate is relatively expensive, leading to higher production costs for Arbidol hydrochloride creams used to inhibit HSV-2 when used alone. Similarly, while isopropanol can promote the penetration of Arbidol hydrochloride molecules through the cell membrane, thus improving absorption efficiency, its high volatility means that when used alone, Arbidol hydrochloride creams used to inhibit HSV-2 will rapidly evaporate during storage or use, resulting in unstable concentrations of Arbidol hydrochloride and poor efficacy. This necessitates increasing the frequency of application. The use of arbidol hydrochloride cream to inhibit HSV-2 may lead to higher dosages in an attempt to enhance efficacy. While propylene glycol itself is a penetration enhancer that can improve the permeability of arbidol hydrochloride, allowing it to more easily contact and penetrate deeper into the skin lesions and increase efficacy, high concentrations of propylene glycol can exacerbate the condition and affect drug absorption and utilization in patients with cardiovascular disease risk, especially in cases of long-term or acute large-area HSV-2. Although polyethylene glycol can prolong the release time of arbidol hydrochloride molecules in the body, its use alone can slow down the release rate of arbidol hydrochloride cream used to inhibit HSV-2, failing to provide a rapid release rate and thus affecting treatment efficacy. This makes it unsuitable for treating acute large-area HSV-2.

[0044] Therefore, in this disclosure, the absorption enhancer is a mixture of propylene carbonate, isopropanol, propylene glycol, and polyethylene glycol, which enables the four to exert a good synergistic effect. This not only meets the safety requirements of users with cardiovascular disease risk for long-term or acute large-area HSV-2 administration, but also avoids the problem of high preparation cost caused by using propylene carbonate alone. It also facilitates the preparation of Arbidol hydrochloride cream for inhibiting HSV-2 with high uniformity, high content, a fast and uniform release rate that is maintained for 6 hours, and stable storage performance.

[0045] In one embodiment, the weight ratio of propylene carbonate, propylene glycol, isopropanol, and polyethylene glycol is 2:2:2:4 to ensure a good synergistic effect. In particular, the use of 4%–6% white beeswax, 2%–4% paraffin wax, 12%–16% liquid paraffin, and 63%–69% white petrolatum not only meets the safety requirements for long-term or acute large-area HSV-2 administration by users with cardiovascular disease risks, but also avoids the problem of high preparation costs caused by using propylene carbonate alone. It also ensures that the final product can be a highly uniform, high-content, fast and uniform release rate for 6 hours, and stable storage performance for inhibiting HSV-2.

[0046] In one embodiment, the cream base is a mixture of white beeswax, paraffin, liquid paraffin, and white petrolatum. Specifically, in one embodiment, by weight percentage, the white beeswax is 4%–6%, the paraffin is 2%–4%, the liquid paraffin is 12%–16%, and the white petrolatum is 63%–69%. This ensures that the white beeswax, paraffin, liquid paraffin, and white petrolatum can exert a good synergistic effect, providing a stable cream matrix for arbidol hydrochloride. This facilitates the uniform application of arbidol hydrochloride cream for HSV-2 inhibition to the affected skin. In particular, the use of a mixture of absorption enhancers, propylene carbonate, isopropanol, and polyethylene glycol, not only meets the safety requirements for long-term or acute large-area HSV-2 treatment for users at risk of cardiovascular disease, but also avoids the high preparation cost caused by using propylene carbonate alone. It also ensures the preparation of arbidol hydrochloride cream for HSV-2 inhibition with high uniformity, high content, a fast and uniform release rate for up to 6 hours, and stable storage performance.

[0047] It should be noted that although reducing the particle size of micronized Arbidol hydrochloride can effectively improve the uniformity of the content of Arbidol hydrochloride cream for inhibiting HSV-2, thus ensuring that the prepared Arbidol hydrochloride cream for inhibiting HSV-2 can maintain a constant and uniform release rate for 6 hours, the smaller particle size of micronized Arbidol hydrochloride has a relatively large specific surface area, resulting in higher hygroscopicity, which affects the stability of Arbidol hydrochloride cream for inhibiting HSV-2. Therefore, in this disclosure, when 4%–6% white beeswax, 2%–4% paraffin wax, 12%–16% liquid paraffin wax, 63%–69% white petrolatum, and the weight ratio of propylene carbonate, propylene glycol, isopropanol, and polyethylene glycol are used in a combination of 2:2:2:4, the micronized arbidol hydrochloride with small particle size can be uniformly dispersed in the protective film system of white beeswax, paraffin wax, liquid paraffin wax, white petrolatum, propylene carbonate, propylene glycol, isopropanol, and polyethylene glycol, which helps to form hydrochloric acid for inhibiting HSV-2. Arbidol cream has a droplet size ≤25μm. This improves the long-term storage stability of Arbidol hydrochloride cream for inhibiting HSV-2, while also enhancing the safety of users with cardiovascular disease risk during long-term or acute large-area HSV-2 treatment. It also avoids the high preparation cost caused by using propylene carbonate alone, ensuring that the final product is an Arbidol hydrochloride cream for inhibiting HSV-2 with high uniformity, high content, a fast and uniform release rate for up to 6 hours, and stable storage performance.

[0048] It can also be understood that the protective film system of micronized Arbidol hydrochloride, white beeswax, paraffin wax, liquid paraffin, white petrolatum, propylene carbonate, propylene glycol, isopropanol, and polyethylene glycol is a structurally stable multilayer structure. Propylene glycol and polyethylene glycol combine with micronized Arbidol hydrochloride to form the inner layer, white beeswax, paraffin wax, liquid paraffin, and white petrolatum form the middle layer, which combines with micronized Arbidol hydrochloride, propylene glycol, and polyethylene glycol to form a stable structure, while propylene carbonate and isopropanol form the outer layer. Furthermore, it combines with white beeswax, paraffin, liquid paraffin, and white petrolatum to form a stable structure, ensuring that the resulting protective film system is a stable multilayer structure. In this way, while improving the long-term storage stability of Arbidol hydrochloride cream for inhibiting HSV-2, it also ensures that the prepared Arbidol hydrochloride cream for inhibiting HSV-2 has high uniformity, high content, and a relatively fast and uniform release rate within 6 hours, so as to better suit the application of acute large-area HSV-2.

[0049] It is understandable that if the droplets of Arbidol hydrochloride cream used to inhibit HSV-2 are larger than 25μm, the larger droplets cannot be evenly distributed on the lesion skin, which will not only reduce the absorption efficiency of Arbidol hydrochloride, but also reduce the treatment effect. Furthermore, droplets larger than 25μm will prevent Arbidol hydrochloride from effectively penetrating into the deeper layers of the lesion skin, thereby reducing the inhibitory effect on HSV-2. In addition, larger droplets are more difficult to apply and are more likely to slip, resulting in waste during use. Therefore, in one embodiment, the droplets of the Arbidol hydrochloride cream for inhibiting HSV-2 are ≤25μm to ensure that droplets smaller than 25μm can be evenly distributed on the lesion skin, thereby improving the absorption efficiency of Arbidol hydrochloride; and droplets smaller than 25μm can penetrate well into the deep layers of the lesion skin, thereby reducing the inhibitory effect on HSV-2; and droplets smaller than 25μm are less likely to slip, thereby reducing waste during use and reducing the problem of decreased user comfort due to excessive irritation to the lesion skin caused by excessively large droplet size.

[0050] In one embodiment, the content uniformity RSD of the Arbidol Hydrochloride Cream for inhibiting HSV-2 is 0.1% to 2.0%, especially when used in conjunction with the use of the Arbidol Hydrochloride Cream for inhibiting HSV-2 having a content ≥99.0%, to ensure that the high content uniformity and high content of the Arbidol Hydrochloride Cream for inhibiting HSV-2 can ensure that the drug concentration remains consistent at different lesion sites, which helps the Arbidol Hydrochloride Cream for inhibiting HSV-2 to better inhibit the replication and spread of HSV-2 virus.

[0051] This disclosure also provides a method for preparing an Arbidol hydrochloride cream for inhibiting HSV-2, comprising the following steps: First, Arbidol hydrochloride is micronized to obtain micronized Arbidol hydrochloride with a particle size of D90≤10μm; then, the micronized Arbidol hydrochloride and an absorption promoter are first mixed and homogenized to obtain an Arbidol hydrochloride solution; subsequently, white beeswax, paraffin wax, liquid paraffin, and white petrolatum are second mixed and homogenized to obtain a cream base liquid; then, the Arbidol hydrochloride solution and the cream base liquid are third mixed and homogenized to obtain an Arbidol hydrochloride emulsion; finally, the Arbidol hydrochloride emulsion is cooled to obtain the Arbidol hydrochloride cream for inhibiting HSV-2 in any of the above embodiments.

[0052] To better understand the technical solutions and beneficial effects of this disclosure, the following detailed description is provided in conjunction with specific embodiments, such as... Figure 1As shown, a method for preparing Arbidol hydrochloride cream for inhibiting HSV-2 in one embodiment includes some or all of the following steps:

[0053] S101. Arbidol hydrochloride is micronized to obtain micronized Arbidol hydrochloride with a particle size of D90≤10μm for later use.

[0054] It is understandable that if the feed pressure of the air jet mill is less than 5 bar, the milling efficiency will be low. If the feed pressure is greater than 7 bar, the impact force of the Arbidol hydrochloride raw material on the milling chamber and conveying pipe will cause the Arbidol hydrochloride raw material to generate heat and decompose. Furthermore, excessive impact pressure will also cause wear on the air jet mill. If the milling pressure is less than 4 bar, the Arbidol hydrochloride raw material will not be milled sufficiently, making it impossible to obtain uniformly sized micronized Arbidol hydrochloride particles. If the milling pressure is greater than 5 bar... When the feed rate is too high, the friction and impact between the Arbidol hydrochloride raw material and the grinding chamber wall will be more intense, resulting in more heat generation and decomposition of the Arbidol hydrochloride raw material. If the feed rate is less than 2 rpm, the amount of Arbidol hydrochloride raw material entering the grinding chamber per unit time will be less, resulting in low space utilization in the grinding chamber. If the feed rate is greater than 8 rpm, the residence time of the Arbidol hydrochloride raw material in the grinding chamber will be insufficient, making it impossible to prepare micronized Arbidol hydrochloride particles with uniform particle size.

[0055] It is worth mentioning that during the air jet milling operation, the solid Arbidol hydrochloride raw material will experience significant collisions and friction with the inner wall of the milling chamber, leading to the Arbidol hydrochloride raw material itself generating heat. When Arbidol hydrochloride reaches 90.02℃, the weaker chemical bonds such as hydrogen bonds in the structure of Arbidol hydrochloride will break, resulting in the first weight loss decomposition of Arbidol hydrochloride, which is the degradation of Arbidol hydrochloride, thereby affecting the efficacy of Arbidol hydrochloride.

[0056] Therefore, in this disclosure, by effectively controlling the conditions of the micronization process, specifically, the micronization process is an air jet milling operation, wherein the feed pressure of the air jet milling operation is 5 bar to 7 bar, the milling pressure is 4 bar to 5 bar, and the feed speed is 2 rpm to 8 rpm, the feed pressure, milling pressure, and feed speed of the Arbidol hydrochloride raw material are ensured to be suitable, thereby ensuring that the Arbidol hydrochloride raw material is not prone to degradation during the milling process, and also improving the space utilization rate in the milling chamber, so as to realize the large-scale micronization of Arbidol hydrochloride raw material, thereby ensuring the preparation of micronized Arbidol hydrochloride particles with uniform particle size D90≤10μm, and also reducing the probability of wear of the air jet mill during the milling process, thereby improving the service life of the air jet mill.

[0057] In one embodiment, the Arbidol hydrochloride raw material was provided by Shijiazhuang Zhongshuo Pharmaceutical Co., Ltd. to ensure that micronized Arbidol hydrochloride with particle sizes of D90 of 5.22 μm, D50 of 1.52 μm, and D10 of 0.20 μm was prepared in batches.

[0058] In a preferred embodiment, when the absorption enhancer is a mixture of propylene carbonate, propylene glycol, isopropanol, and polyethylene glycol, propylene glycol and polyethylene glycol are first added and homogenized, followed by the addition of isopropanol and propylene carbonate for further mixing. This ensures that the added propylene glycol and polyethylene glycol can fully combine with the micronized Arbidol hydrochloride to form a structurally stable inner layer. The subsequently added isopropanol and propylene carbonate can be placed on the outer edge of the inner layer, which facilitates their combination with subsequent white beeswax, paraffin, liquid paraffin, and white petrolatum, thereby forming a structurally stable and non-stratified Arbidol hydrochloride emulsion. This ensures the long-term storage stability of the Arbidol hydrochloride emulsion, a uniformity RSD of 0.1% to 2.0%, an Arbidol hydrochloride content ≥99.0%, a constant and uniform release rate for 6 hours, and guarantees the comfort of medication use.

[0059] like Figure 2 As shown, in one embodiment, the Arbidol hydrochloride cream used to inhibit HSV-2 is released at a constant and uniform rate using a linear regression equation of y = ax + b, where y is the cumulative release amount of Arbidol hydrochloride per unit area, a is (0.1916 to 0.2067), x is the release time h, and b is (0.1822 to 0.2024).

[0060] S102. The micronized Arbidol hydrochloride and the absorption promoter are first mixed and homogenized to obtain an Arbidol hydrochloride solution, so as to ensure that the micronized Arbidol hydrochloride can be uniformly dispersed in the absorption promoter.

[0061] It is understandable that if the homogenization temperature is too high or the homogenization time is too long, it will affect the pharmacological components of micronized Arbidol hydrochloride. If the homogenization temperature is too low or the homogenization time is too short, a uniform and stable Arbidol hydrochloride solution cannot be prepared. If the homogenization speed is too fast, too much heat will be generated, which will affect the pharmacological components of micronized Arbidol hydrochloride. If the homogenization speed is too slow, a uniform and stable Arbidol hydrochloride solution cannot be obtained. Therefore, in one embodiment, the conditions for the first mixing and homogenization are: homogenization temperature of 70℃~90℃, homogenization time of 5min~15min, and homogenization speed of 5krpm~10krpm. This is to avoid excessive shear heat generation during the homogenization process, which could lead to degradation of the micronized Arbidol hydrochloride and affect its efficacy. This ensures the preparation of micronized Arbidol hydrochloride with small and uniform particle size and high efficacy, thereby guaranteeing that the content of Arbidol hydrochloride cream for inhibiting HSV-2 is ≥99.0%, and that the content of Arbidol hydrochloride cream for inhibiting HSV-2 is uniform. The uniformity RSD is 0.1%–2.0% to ensure that the release rate of Arbidol Hydrochloride Cream for HSV-2 inhibition remains constant and uniform within 6 hours, thereby enhancing the efficacy of Arbidol Hydrochloride Cream for HSV-2 inhibition. This also helps to prepare Arbidol Hydrochloride Cream for HSV-2 inhibition with droplets ≤25μm. Droplets ≤25μm ensure good permeability while reducing the irritation of large droplets to the affected skin, thus improving user comfort. Furthermore, it facilitates the preparation of Arbidol Hydrochloride Cream for HSV-2 inhibition with stable storage performance.

[0062] In a preferred embodiment, the conditions for the first mixing and homogenization are: homogenization temperature of 70°C to 80°C, homogenization time of 5 min to 15 min, and homogenization speed of 5 k rpm to 7 k rpm.

[0063] In one embodiment, micronized Arbidol hydrochloride and an absorption promoter are mixed at 70°C to 80°C and then homogenized at a speed of 5krpm to 7krpm for 5 to 10 minutes, thus achieving the first mixing and homogenization operation of micronized Arbidol hydrochloride and the absorption promoter.

[0064] S103. The white beeswax, paraffin, liquid paraffin and white petrolatum are mixed and homogenized for the second time to obtain the cream base liquid. This ensures that the cream base liquid has a small and uniform particle size. On the one hand, it is convenient to mix quickly and evenly with the Arbidol hydrochloride solution in S102, reducing the impact of subsequent shear heat on the active ingredients of Arbidol hydrochloride. On the other hand, it is beneficial to prepare a uniformly dispersed Arbidol hydrochloride cream for inhibiting HSV-2 with droplets ≤25μm.

[0065] In one embodiment, the conditions for the second mixing and homogenization are: a homogenization temperature of 70°C to 90°C, a homogenization time of 5 min to 15 min, and a homogenization speed of 5 k rpm to 10 k rpm, to ensure that a uniform, stable cream base liquid with small particle size is obtained.

[0066] In one embodiment, liquid paraffin, white beeswax, paraffin wax and white petrolatum are mixed, then heated to melt at 70°C to 90°C, and homogenized at 5krpm to 10krpm for 5min to 15min to complete the second mixing and homogenization of white beeswax, paraffin wax, liquid paraffin wax and white petrolatum.

[0067] S104. The Arbidol hydrochloride solution and the cream base liquid are subjected to a third mixing and homogenization to obtain an Arbidol hydrochloride emulsion. The conditions for the third mixing and homogenization are: homogenization temperature of 70℃~90℃, homogenization time of 5min~15min, and homogenization speed of 5krpm~10krpm, so as to prepare an Arbidol hydrochloride cream for inhibiting HSV-2 with a uniformity RSD of 0.1%~2.0%, droplet size ≤25μm, stable storage performance, Arbidol hydrochloride content ≥99.0%, and a constant and uniform release rate for 6 hours.

[0068] In one embodiment, the Arbidol hydrochloride solution and the cream base liquid are mixed under heating at 70°C to 90°C, and then homogenized at a speed of 5krpm to 10krpm for 5min to 15min to complete the third mixing and homogenization of the Arbidol hydrochloride solution and the cream base liquid.

[0069] S105. The Arbidol hydrochloride emulsion is cooled to obtain the Arbidol hydrochloride cream for inhibiting HSV-2 in any of the above embodiments. Specifically, the cooling temperature is 25°C to 30°C, and the cooling time is 40 min to 60 min.

[0070] The above-described method for preparing Arbidol hydrochloride cream for inhibiting HSV-2 involves first homogenizing micronized Arbidol hydrochloride and an absorption enhancer to obtain an Arbidol hydrochloride solution, followed by second homogenizing white beeswax, paraffin wax, liquid paraffin, and white petrolatum to obtain a cream base solution. This stepwise homogenization of the Arbidol hydrochloride solution and the cream base solution effectively avoids the problem of increased loss of active ingredients in Arbidol hydrochloride due to prolonged homogenization time. Furthermore, the use of a third homogenization step ensures the preparation of an Arbidol hydrochloride cream for inhibiting HSV-2 with a uniformity RSD of 0.1%–2.0%, droplet size ≤25μm, stable storage performance, Arbidol hydrochloride content ≥99.0%, and a consistent and uniform release rate maintained for 6 hours, making it better suited for acute, large-area HSV-2 applications.

[0071] Compared with the prior art, this disclosure has at least the following advantages:

[0072] 1) Because the added absorption enhancer can improve the penetration rate of Arbidol hydrochloride cream used to inhibit HSV-2, it increases the release rate of Arbidol hydrochloride, enabling Arbidol hydrochloride to effectively reach the lesion site to inhibit the HSV-2 replication cycle, thereby enhancing the efficacy of Arbidol hydrochloride and making it better suited for the treatment of acute large-area HSV-2.

[0073] 2) The added absorption enhancer directly reduces the difference in the ratio between micronized Arbidol hydrochloride and the cream matrix, avoiding the problem of uneven content of micronized Arbidol hydrochloride due to sedimentation caused by the large density difference between the two. Especially when used with micronized Arbidol hydrochloride with a particle size of D90≤10μm, this particle size effectively overcomes the characteristics of poor solubility, easy agglomeration, and difficulty in dispersion of Arbidol hydrochloride, further improving the content uniformity of Arbidol hydrochloride cream for HSV-2 inhibition. The content uniformity RSD of Arbidol Hydrochloride Cream is 0.1% to 2.0%, ensuring the quality of Arbidol Hydrochloride Cream for HSV-2 inhibition. This ensures that the prepared Arbidol Hydrochloride Cream for HSV-2 inhibition can maintain a constant and uniform release rate for 6 hours. This continuous and stable release rate not only ensures that the effective HSV-2 inhibition concentration is maintained for a longer period of time, thereby more effectively inhibiting HSV-2 replication and spread, but also reduces the number of times the user needs to take the medication, thus improving the convenience and comfort of medication. Furthermore, it ensures the long-term storage stability of the prepared Arbidol Hydrochloride Cream for HSV-2 inhibition.

[0074] Compared with the prior art, this disclosure has at least the following advantages:

[0075] The following are some specific examples. When %, it refers to a percentage by weight. It should be noted that the following examples do not exhaustively list all possible scenarios, and unless otherwise specified, the materials used in the examples are commercially available.

[0076] Arbidol hydrochloride was provided by Shijiazhuang Zhongshuo Pharmaceutical Co., Ltd., while other reagents or instruments whose manufacturers were not specified were all conventional products that could be obtained through commercial purchase.

[0077] Table 1 Formula Table

[0078]

[0079] Table 2 Homogenization process parameters

[0080]

[0081]

[0082] Examples 1-5 and Comparative Examples 1-7 were prepared according to the formulations in Table 1 and the homogenization process parameters in Table 2, including the following steps:

[0083] S101. Micronize Arbidol hydrochloride to obtain micronized Arbidol hydrochloride with a particle size of D90≤10μm. The Arbidol hydrochloride raw material is subjected to air jet milling operation with a feed pressure of 7 bar, a milling pressure of 5 bar, and a feed speed of 5 rpm to obtain micronized Arbidol hydrochloride particles with a particle size of D90≤10μm.

[0084] S102. After mixing the micronized Arbidol hydrochloride and the absorption promoter at the homogenization temperatures corresponding to those in Table 2, homogenize for the corresponding times at the homogenization speeds corresponding to those in Table 2 to obtain the Arbidol hydrochloride solution.

[0085] S103. Mix white beeswax, paraffin wax, liquid paraffin and white petrolatum, then heat and melt them at the homogenization temperature corresponding to Table 2, and then homogenize them at the homogenization speed corresponding to Table 2 for the corresponding time to obtain the cream base liquid.

[0086] S104. After mixing the Arbidol hydrochloride solution and the cream base liquid at the homogenization temperature corresponding to Table 2, homogenize them at the homogenization speed corresponding to Table 2 for the corresponding time to obtain the Arbidol hydrochloride emulsion.

[0087] S105. The Arbidol hydrochloride emulsion is cooled at 25°C for 40 minutes to obtain Arbidol hydrochloride cream for inhibiting HSV-2.

[0088] It is worth mentioning that when using multiple absorption promoters in Example 5, there is a requirement for the order of addition in step S102: first add propylene glycol and polyethylene glycol and homogenize for 5 minutes, then add isopropanol and propylene carbonate and homogenize for 10 minutes, and the rest remain unchanged.

[0089] Comparative Example 8

[0090] The difference from Example 1 is that "feed pressure 7 bar, crushing pressure 5 bar, feed speed 5 rpm" in step S101 is replaced with "feed pressure 7 bar, crushing pressure 3 bar, feed speed 5 rpm", while the rest remains unchanged.

[0091] Comparative Example 9

[0092] The difference from Example 1 is that "feed pressure 7 bar, crushing pressure 5 bar, feed speed 5 rpm" in step S101 is replaced with "feed pressure 7 bar, crushing pressure 6 bar, feed speed 5 rpm", while the rest remains unchanged.

[0093] The Arbidol hydrochloride creams for inhibiting HSV-2 obtained in Examples 1-5 and Comparative Examples 1-9 were subjected to appearance testing, and the experimental data are shown in Table 3.

[0094] Table 3

[0095]

[0096]

[0097] As can be seen from Table 3 above, due to the use of absorption promoters in Examples 1-5, the simultaneous use of a mixture of white beeswax, paraffin, liquid paraffin, and white petrolatum as the cream base, and the D90 of micronized Arbidol hydrochloride being ≤10μm, especially with the use of first and second mixing homogenization at a homogenization temperature of 70℃-90℃, a homogenization time of 5min-15min, and a homogenization speed of 5krpm-10krpm, the content of Arbidol hydrochloride prepared was ensured to be ≥99.0%, and the RSD of Arbidol hydrochloride content uniformity was 0.1%-2.0%, indicating that the Arbidol hydrochloride creams for inhibiting HSV-2 prepared in Examples 1-5 had good uniformity. Among them, Examples 3 and 5 had better overall indicators.

[0098] As can be seen from the comparison between Example 1 and Comparative Example 9, due to the high pulverization pressure of Comparative Example 9, the thermal degradation of Arbidol hydrochloride was more severe, resulting in a lower content in Comparative Example 9.

[0099] The particle size and fill weight of the Arbidol hydrochloride cream used to inhibit HSV-2 in Examples 1-5 and Comparative Examples 1-9 were analyzed, and the experimental data are shown in Table 4.

[0100] One sample was taken, and the contents were placed on a glass slide and coated into a thin layer. The area of ​​the thin layer was equivalent to the area of ​​the coverslip. A total of three slides were coated, and the particle size and particle size distribution were determined according to the method of determination of particle size and particle size distribution (General Chapter 0982 Method I of Chinese Pharmacopoeia 2020).

[0101] Content test: Take 5 samples per group according to the minimum content test method (General Chapter 0942 of Chinese Pharmacopoeia 2020). Remove the outer cap and label, clean and dry the outer wall of the container with purified water, accurately weigh each sample, remove the contents, wash and dry the container with a suitable solvent, and then accurately weigh the empty container.

[0102] Weight of contents (g) = Total weight - Weight of container

[0103] Content weight (%) = Weight of contents ÷ Labeled weight (10.0g) × 100%

[0104] Table 4

[0105]

[0106]

[0107] Examples 1 to 5 in Table 4 above all meet the standard of General Chapter 0942 of the 2020 edition of the Chinese Pharmacopoeia, that is, not less than 93% of the labeled content.

[0108] Furthermore, as can be seen from Example 1 and Comparative Example 4 in Table 4 above, the content index of Comparative Example 4 is lower than 10 because it lacks white petrolatum.

[0109] Furthermore, as can be seen from Examples 1 and Comparative Examples 8-9 in Table 4 above, the relatively low pulverizing pressure (3 bar) in Comparative Example 8 resulted in a larger particle size of the micronized Arbidol hydrochloride, leading to a content index of less than 10 in Comparative Example 8. Among them, Examples 2, 4, 5 and Comparative Example 2 showed better content indexes.

[0110] The content (n=6), droplet size, and droplet distribution of the Arbidol hydrochloride creams for inhibiting HSV-2 obtained in Examples 1-5 and Comparative Examples 1, 2, 3, 4, 8, and 9 were detected, and the experimental data are shown in Table 5.

[0111] The method for content determination is as follows:

[0112] 1) Test solution: Take an appropriate amount of this product (approximately equivalent to 20 mg of Arbidol hydrochloride), accurately weigh it, place it in a beaker, add about 30 ml of anhydrous ethanol, heat it in a water bath to dissolve it, then cool it in an ice bath, filter it, put the filtrate in a 100 ml volumetric flask, extract it 3 times in the same way, combine the filtrates in the volumetric flask, let it cool to room temperature, dilute it to the mark with anhydrous ethanol, and shake well.

[0113] 2) Reference solution: Accurately weigh an appropriate amount of Arbidol hydrochloride reference standard, add an appropriate amount of ethanol, sonicate to dissolve, and quantitatively dilute to prepare a solution containing approximately 10 μg per ml.

[0114] 3) Measurement method: The absorbance was measured at a wavelength of 257 nm using ultraviolet-visible spectrophotometry.

[0115] Table 5

[0116] Example 1 100.0 0.3 ≤25μm uniform Example 2 100.1 1.0 ≤25μm uniform Example 3 99.9 0.3 ≤25μm uniform Example 4 100.2 0.6 ≤25μm uniform Example 5 100.0 0.3 ≤25μm uniform Comparative Example 1 99.3 2.5 ≤25μm Uneven Comparative Example 2 100.1 2.1 ≤25μm Uneven Comparative Example 3 100.6 2.8 ≤25μm Uneven Comparative Example 4 100.7 2.2 ≤25μm Uneven Comparative Example 8 100.6 0.5 >25μm uniform Comparative Example 9 97.6 0.7 ≤25μm uniform

[0117] As can be seen from Table 5 above, the use of micronized Arbidol hydrochloride with a D90≤10μm, combined with the use of first and second mixed homogenization at a homogenization temperature of 70℃~90℃, a homogenization time of 5min~15min, and a homogenization speed of 5krpm~10krpm, helps to prepare a uniform and stable Arbidol hydrochloride cream for inhibiting HSV-2 with a droplet size ≤25μm.

[0118] The Arbidol hydrochloride cream for inhibiting HSV-2 obtained in Examples 1-5 above was released in vitro, and the experimental data are shown in Table 6:

[0119] Transdermal assays were performed using a Franz transdermal diffusion cell. During the assay, skin was fixed to the diffusion cell and an appropriate amount of sample was applied, with a transdermal area of ​​2.8 ± 0.1 cm². The water bath temperature was 35°C, the stirring speed was 300 rpm, the receiving cell volume was 6 ml, and the receiving solution was 0.9% physiological saline. Samples were taken at 0.5, 1, 2, 4, and 6 hours, with 200 μl samples taken each time, and an equal volume of 35°C physiological saline was immediately added. The samples were analyzed using high-performance liquid chromatography (HPLC).

[0120] Acceptance solution processing method: Take 200 μL of the acceptance solution and place it in a centrifuge tube. Add 200 μL of mobile phase, shake for 2 min, centrifuge at 10000 rpm for 10 min, and take 20 μL of the supernatant for sample injection and detection.

[0121] Table 6

[0122]

[0123] As can be seen from Table 6 above, the active ingredient Arbidol hydrochloride in the Arbidol hydrochloride cream prepared in Examples 1-5 for inhibiting HSV-2 can penetrate the skin of miniature pigs and maintain a near constant and uniform release rate throughout the 6-hour test.

[0124] Furthermore, the slope of the linear regression equation for the release rate of the Arbidol hydrochloride cream used to inhibit HSV-2 prepared in Examples 1-5 ranged from 0.1916 to 0.2067, R0. 2 The values ​​range from 0.9862 to 0.9884, and the linear regression equation is y = ax + b, where y is the cumulative release per unit area of ​​Arbidol hydrochloride, a is (0.1916 to 0.2067), x is the release time h, and b is (0.1822 to 0.2024).

[0125] The stability of the Arbidol hydrochloride cream for inhibiting HSV-2 obtained in Examples 1-5 above was studied, and the experimental data are shown in Tables 7 and 8:

[0126] (1) Influencing Factors Experiment

[0127] Samples were subjected to influence factor tests at 50°C, 2–8°C, and under light conditions. The results showed that the Arbidol Hydrochloride Cream for HSV-2 inhibition in Examples 1–5, prepared according to the formulation and process of this disclosure, was stable.

[0128] Table 7

[0129]

[0130]

[0131]

[0132] (2) Accelerated, long-term and low-temperature cycling tests

[0133] Stability studies were conducted on samples under accelerated, long-term, and low-temperature testing conditions. The results showed that the Arbidol hydrochloride creams for inhibiting HSV-2 prepared according to the formulation and process of this disclosure in Examples 1-5 were stable.

[0134] Table 8

[0135]

[0136]

[0137] Among them, the low temperature test consists of three cycles. Each cycle of the low temperature test involves placing the sample at 2–8°C for 2 days, followed by placing it at 40°C for 2 days.

[0138] The embodiments described above are merely illustrative of several implementations of this disclosure, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the disclosed patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this disclosure, and these all fall within the protection scope of this disclosure. Therefore, the protection scope of this patent should be determined by the appended claims.

Claims

1. An Arbidol hydrochloride cream for inhibiting HSV-2, characterized in that, Includes the following weight percentages of each component: Micronized Arbidol hydrochloride 0.5%~2%; Cream base 70%~95%; Absorption enhancer 8%~12%; The particle size of the micronized Arbidol hydrochloride is D90≤10μm; The absorption enhancer includes at least one of propylene carbonate, propylene glycol, isopropanol, and polyethylene glycol; The cream base is a mixture of white beeswax, paraffin, liquid paraffin, and white petrolatum; The preparation method of the Arbidol hydrochloride cream for inhibiting HSV-2 includes the following steps: Arbidol hydrochloride was micronized to obtain micronized Arbidol hydrochloride with a particle size of D90≤10μm; wherein the micronization process was performed by air jet milling, and the feed pressure of the air jet milling operation was 5bar~7bar, the milling pressure was 4bar~5bar, and the feed speed was 2rpm~8rpm. Micronized Arbidol hydrochloride and an absorption promoter were first mixed and homogenized to obtain an Arbidol hydrochloride solution; wherein the conditions for the first mixing and homogenization were: homogenization temperature of 70℃~90℃, homogenization time of 5min~15min, and homogenization speed of 5krpm~10krpm; White beeswax, paraffin, liquid paraffin, and white petrolatum were mixed and homogenized in a second process to obtain an emulsion base liquid; wherein the conditions for the second mixing and homogenization were: homogenization temperature of 70℃~90℃, homogenization time of 5min~15min, and homogenization speed of 5krpm~10krpm; The Arbidol hydrochloride solution and the cream base liquid are subjected to a third mixing and homogenization to obtain an Arbidol hydrochloride emulsion; wherein the conditions for the third mixing and homogenization are: homogenization temperature of 70℃~90℃, homogenization time of 5min~15min, and homogenization speed of 5krpm~10krpm; The Arbidol hydrochloride emulsion was cooled to obtain the Arbidol hydrochloride cream.

2. The Arbidol Hydrochloride Cream for Inhibiting HSV-2 according to claim 1, characterized in that, By weight percentage, the white beeswax is 4% to 6%, the paraffin is 2% to 4%, the liquid paraffin is 12% to 16%, and the white petrolatum is 63% to 69%.

3. The Arbidol Hydrochloride Cream for Inhibiting HSV-2 according to claim 1, characterized in that, The Arbidol hydrochloride cream used to inhibit HSV-2 maintains a constant and uniform release rate over a period of 6 hours.

4. The Arbidol Hydrochloride Cream for Inhibiting HSV-2 according to claim 1, characterized in that, The droplets of the Arbidol hydrochloride cream used to inhibit HSV-2 are ≤25μm, and the RSD of the Arbidol hydrochloride content uniformity of the Arbidol hydrochloride cream used to inhibit HSV-2 is 0.1%~2.0%.

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