Intelligent evaluation method for stability of microemulsion gel containing ondansetron

Abstract

The present application relates to the technical field of pharmaceutical preparation evaluation, and discloses a method for intelligently evaluating the stability of a microemulsion gel containing ondansetron. The method comprises the following steps: taking a microemulsion gel preparation containing ondansetron, placing it under low-temperature conditions and storing it under normal-temperature conditions, and observing whether crystals are precipitated; performing an in-vitro transdermal test using a Franz diffusion cell, sampling at a specified time point and determining the ondansetron concentration, calculating the steady-state transdermal flux and cumulative transdermal rate; coating the preparation on depilated skin, continuously administering the preparation, observing the erythema and edema reactions and scoring them. The method integrates steady-state observation, in-vitro transdermal test and skin irritation test into a unified evaluation system, can systematically evaluate the microemulsion gel preparation containing ondansetron from multiple dimensions such as the drug crystallization trend, transdermal flux, cumulative transdermal rate and skin reaction score, and provides a basis for prescription screening optimization and preparation quality control.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation evaluation technology, and more specifically to an intelligent evaluation method for the stability of microemulsion gels containing ondansetron. Background Technology

[0002] Ondansetron is a 5-hydroxytryptamine 3 receptor antagonist and can be used in pharmaceutical formulations related to the control of nausea and vomiting. Ondansetron formulations can be administered orally or by injection. For users experiencing persistent nausea or vomiting, the actual administration of oral formulations may be affected by swallowing status, gastrointestinal condition, and medication adherence; injection administration requires appropriate administration procedures and conditions. Therefore, establishing an ondansetron formulation system suitable for transdermal administration is of significant pharmaceutical research value.

[0003] The transdermal delivery process involves a series of processes, including the migration of ondansetron from the formulation interior to the formulation-skin interface, the distribution of ondansetron on the skin surface, and the diffusion of ondansetron across the stratum corneum barrier. The dissolution or dispersion state of ondansetron within the formulation, the structure of the continuous phase, the distribution relationship of ondansetron in different phases, and the retention state of the formulation on the skin surface all affect the transdermal delivery process.

[0004] While conventional gels can increase formulation viscosity and improve coating properties, simply dispersing or dissolving ondansetron directly in a gel matrix does not automatically solve the problems of ondansetron's dispersion and transdermal migration in formulations. For specific drugs, a matching drug-loaded structure needs to be developed based on the physicochemical properties of ondansetron.

[0005] Microemulsion systems typically consist of an oil phase, an aqueous phase, polyoxyethylene hydrogenated castor oil RH40, and a co-surfactant. The different components within a microemulsion system form an interfacial structure that can alter the distribution environment of ondansetron within the formulation. However, liquid microemulsions have high fluidity, limiting their retention and application on the skin surface. Combining microemulsions with gels can increase formulation viscosity, but the combination of microemulsions and gels is not arbitrary.

[0006] When a drug-containing microemulsion is added to a gel system, the viscosity of the continuous phase, the interfacial environment, the migration path of ondansetron, and the local composition all change. Inappropriate types and amounts of poloxamer 407 can lead to system stratification, local aggregation, altered ondansetron dispersion, or crystallization. For ondansetron microemulsion systems, a comprehensive selection of ondansetron morphology, oil phase, polyoxyethylene hydrogenated castor oil RH40, co-surfactant, poloxamer 407, poloxamer 407 content, and the ratio of the two phases is necessary. During the formulation research of ondansetron microemulsion gels, it was found that when carbomer 940 was used as the gel matrix, ondansetron crystallization could be observed under the investigated low-temperature conditions. After ondansetron precipitates from the microemulsion gel formulation, it alters the state of ondansetron in the formulation and may affect content uniformity, release process, and transdermal migration. Therefore, it is necessary to establish a gel composite system compatible with the ondansetron-containing microemulsion phase.

[0007] On the other hand, penetration enhancers are an important component of transdermal formulation research. Simply increasing the amount of a single penetration enhancer is not the only direction for formulation optimization. The type, combination, and proportion of penetration enhancers need to be considered in conjunction with the ondansetron carrier structure, gel system, and skin application requirements. Higher concentrations of a single penetration enhancer may increase the risk of skin irritation; therefore, transdermal formulation design needs to balance transdermal performance and skin irritation.

[0008] To address the above issues, it is necessary to develop a transdermal microemulsion gel formulation of ondansetron. This formulation should be designed to achieve a suitable dispersion state for ondansetron through the coordination of the microemulsion interface system, the poloxamer 407 gel system, the ratio of the microemulsion phase to the gel phase, and the composition of the transdermal penetration enhancer. This would allow the formulation to have suitable skin application and retention properties, and obtain corresponding in vitro transdermal performance and skin irritation evaluation results. Summary of the Invention

[0009] The purpose of this invention is to provide an intelligent evaluation method for the stability of microemulsion gels containing ondansetron, which solves the technical problems of mutual constraints between drug loading, dispersion state, gel structure, two-phase complex relationship, in vitro transdermal performance and penetration enhancer irritation in ondansetron transdermal formulations.

[0010] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0011] This invention provides an ondansetron transdermal microemulsion gel formulation, comprising a microemulsion phase and a gel phase; based on the total weight of the ondansetron transdermal microemulsion gel formulation, the weight percentage of the microemulsion phase is 35% to 45%, the weight percentage of the gel phase is 55% to 65%, and the sum of the weight percentages of the microemulsion phase and the gel phase is 100%.

[0012] Based on the total weight of the microemulsion phase, the microemulsion phase comprises the following components by weight percentage: ondansetron 0.5%–5%; oil phase 1%–15%; polyoxyethylene hydrogenated castor oil RH40 10%–40%; propylene glycol 5%–30%; water 20%–70%; the sum of the weight percentages of all components in the microemulsion phase is 100%. The mass ratio of polyoxyethylene hydrogenated castor oil RH40 to propylene glycol, added to the microemulsion phase as a co-surfactant, is 3:1 or 4:1.

[0013] Based on the total weight of the gel phase, the gel phase comprises the following components by weight percentage: poloxamer 407 15%–20%; humectant 5%–30%; transdermal penetration enhancer 1%–15%; pH adjuster 0.1%–5%; water 40%–78.9%; the sum of the weight percentages of all components in the gel phase is 100%. The transdermal penetration enhancer consists of laurocapram, propylene glycol, and isopropyl myristate, with 1 part laurocapram by weight, 3–4 parts propylene glycol, and 1–2 parts isopropyl myristate.

[0014] Ondansetron can be ondansetron hydrochloride or ondansetron free base. The oil phase can be isopropyl myristate or oleic acid. By weight, the microemulsion phase comprises 2.5%–4.5% ondansetron, 8%–10% oil, 28%–32% polyoxyethylene hydrogenated castor oil RH40, 7%–10% propylene glycol as a co-surfactant, and 47.5%–52% water, with the sum of all components in the microemulsion phase being 100%. The mass ratio of the microemulsion phase to the gel phase is 35:65, 40:60, or 45:55. Poloxamer 407 comprises 15%, 18%, or 20% of the total weight of the gel phase. The mass ratio of laurocapram, propylene glycol, and isopropyl myristate is 1:3:1 or 1:4:2.

[0015] The moisturizer is selected from glycerin and propylene glycol.

[0016] When propylene glycol is used as a humectant in the gel phase, and the transdermal penetration enhancer also contains propylene glycol, the propylene glycol added separately as a humectant and in the transdermal penetration enhancer premix are measured separately according to their respective addition items, and the total mass of all materials in the gel phase is calculated based on the actual input mass. The pH adjuster is one of triethanolamine, citric acid, or sodium hydroxide solution. The pH of ondansetron transdermal microemulsion gel formulation is 6.0–7.5, more specifically 7.0 or 7.2.

[0017] This invention also provides a method for preparing ondansetron transdermal microemulsion gel formulation, comprising the following steps:

[0018] Step 1: Prepare a microemulsion containing ondansetron, an oil phase, polyoxyethylene hydrogenated castor oil RH40, propylene glycol as a co-surfactant, and water.

[0019] Step 2: Prepare a gel phase containing poloxamer 407, a humectant, a transdermal penetration enhancer composed of laurocapram, propylene glycol and isopropyl myristate, a pH adjuster and water.

[0020] Step 3: Mix the microemulsion phase obtained in Step 1 and the gel phase obtained in Step 2 to obtain the ondansetron transdermal microemulsion gel formulation.

[0021] The preparation process of the microemulsion phase includes: mixing ondansetron, the oil phase, polyoxyethylene hydrogenated castor oil RH40, and propylene glycol as a co-surfactant; stirring at 20–50°C; adding water under constant temperature stirring, controlling the stirring speed at 500–1000 r / min, and continuing stirring for 30–60 min to form a transparent and homogeneous microemulsion phase. The preparation process of the gel phase includes: adding a humectant and a transdermal penetration enhancer to water and mixing; adding poloxamer 407 at 4–10°C to disperse poloxamer 407; allowing it to swell under low temperature conditions for 12–24 h; after swelling, stirring at 200–500 r / min for 10–30 min to form a homogeneous gel phase; adding a pH adjuster and mixing. The preferred swelling temperature for poloxamer 407 is 4–8°C, and it can be allowed to swell at 4°C for 12 h or at 6°C for 20 h. The microemulsion phase is slowly added to the gel phase, and the mixture is carried out at a low speed of 200-500 r / min to ensure that the two phases are mixed evenly. For example, the stirring speed is 300 r / min and the stirring time is 15 min.

[0022] This invention further provides a comprehensive performance evaluation method for ondansetron transdermal microemulsion gel formulation, comprising: taking ondansetron transdermal microemulsion gel formulation, placing it at 4℃ for 1 day and storing it at 25℃ for 30 days, and observing whether crystal precipitation occurs; conducting an in vitro transdermal test using a Franz diffusion cell, with an effective transdermal area of ​​2.83 cm², a receiving cell volume of 6.06 mL, a water bath temperature of 32℃, a stirring speed of 200 r / min, and using cat skin with the subcutaneous fat layer removed; taking samples at specified time points and determining the ondansetron concentration using HPLC, calculating the steady-state transdermal flux and the 24-hour cumulative transdermal rate; applying the ondansetron transdermal microemulsion gel formulation to the hairless skin on the back of rabbits, administering it once daily for 7 consecutive days, and observing and scoring erythema and edema reactions.

[0023] In this invention, the microemulsion phase and gel phase are not two unrelated formulation units. The microemulsion phase serves to load and disperse ondansetron. Polyoxyethylene hydrogenated castor oil RH40 and propylene glycol form the microemulsion interface system, and the oil phase, aqueous phase, and interface system together form the microemulsion dispersion environment. The morphology of ondansetron and the composition of the microemulsion jointly affect the distribution state of ondansetron in the microemulsion system. The poloxamer 407 gel phase is used to form a continuous gel structure for the composite formulation. When the poloxamer 407 content is too low, it is difficult to form a structural state that meets the requirements for use in gel formulations; when the poloxamer 407 content is increased, the viscosity of the gel system and the migration resistance of ondansetron will change. Therefore, the amount of poloxamer 407 needs to be determined in conjunction with the proportion of the microemulsion phase. The ratio of the microemulsion phase to the gel phase simultaneously affects the ondansetron loading, the content of microemulsion dispersion units, and the proportion of the poloxamer 407 gel network in the final formulation.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] The ondansetron transdermal microemulsion gel formulation of this invention achieves synergistic effects in formulation stability, transdermal performance, and skin safety by combining a drug-containing microemulsion phase with a poloxamer 407 gel phase and employing a ternary transdermal penetration enhancer composed of laurocapram, propylene glycol, and isopropyl myristate. Regarding formulation stability, the microemulsion phase uses a specific mass ratio of polyoxyethylene hydrogenated castor oil RH40 and propylene glycol to construct an interface system, effectively encapsulating and dispersing ondansetron and inhibiting the drug's crystallization tendency during storage. The gel phase uses poloxamer 407 as the gel matrix, which forms a uniform network structure through low-temperature swelling. After being combined with the microemulsion phase, it forms a continuous phase, ensuring the formulation remains homogeneous under both low and normal temperature conditions, preventing drug crystallization and stratification, thereby guaranteeing content uniformity and reliability. In terms of transdermal performance, the small and concentrated droplet size of the microemulsion provides a favorable microenvironment for the distribution and migration of ondansetron to the skin interface. The ternary transdermal penetration enhancer works synergistically through different mechanisms, reducing stratum corneum barrier resistance while promoting transdermal drug penetration. This allows the formulation to achieve a high steady-state transdermal flux and cumulative transdermal rate, achieving continuous and stable transdermal delivery and overcoming the shortcomings of insufficient drug release rates in ordinary gel formulations. Regarding skin safety, the ternary penetration enhancer achieves effective penetration enhancement with a lower dosage of laurocapram, reducing skin irritation, manifesting as mild erythema and edema reactions. This improves the skin tolerance and medication adherence of transdermal formulations, making them suitable for antiemetic treatment scenarios requiring long-term or repeated use.

[0026] In terms of preparation method, ondansetron is first loaded into the microemulsion phase, and at the same time, a gel phase is formed by low-temperature swelling. Then, the two phases are composited in a controlled manner. This stepwise preparation method is conducive to maintaining the integrity of the microemulsion structure, ensuring the full swelling and uniform dispersion of the gel network, and has good process controllability, which facilitates production scale-up and batch-to-batch quality consistency.

[0027] The comprehensive performance evaluation method provided by this invention integrates steady-state observation, in vitro transdermal testing, and skin irritation testing into a unified evaluation system. It can systematically evaluate ondansetron transdermal microemulsion gel formulations from multiple dimensions such as drug crystallization trend, transdermal flux, cumulative transdermal rate, and skin reaction score, providing a reliable basis for formulation screening and optimization and formulation quality control. Attached Figure Description

[0028] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation of the scope. For those skilled in the art, other related drawings can be obtained from these drawings without creative effort.

[0029] Figure 1 The main flowchart for the preparation of this invention is shown below.

[0030] Figure 2 This is a flowchart of the microemulsion phase preparation process of the present invention.

[0031] Figure 3 This is a flowchart of the gel phase preparation process of the present invention.

[0032] Figure 4 This is a flowchart of the intelligent evaluation method for microemulsion gel stability according to the present invention. Detailed Implementation

[0033] In the following description, only certain exemplary embodiments are briefly described. As those skilled in the art will recognize, the described embodiments can be modified in various ways without departing from the spirit or scope of the embodiments of the invention. Therefore, the drawings and description are considered to be exemplary in nature and not restrictive.

[0034] The following is in conjunction with the appendix Figures 1-4 The embodiments of the present invention will be described in detail below.

[0035] In this invention, unless otherwise specified, the weight percentages of the components within the microemulsion phase are calculated based on the total weight of the microemulsion phase as 100%; the weight percentages of the components within the gel phase are calculated based on the total weight of the gel phase as 100%; and the weight percentages of the blending ratio of the microemulsion phase and the gel phase are calculated based on the total weight of the final formulation as 100%.

[0036] In the formulation screening stage, the components of the microemulsion phase were first optimized. Different types of oil phases, surfactants, and co-surfactants were screened using microemulsion appearance transparency, particle size distribution, and static stability as evaluation indicators. During the oil phase screening, commonly used pharmaceutical oil phases such as isopropyl myristate, oleic acid, caprylic / capric triglyceride, and propylene glycol monocaprylate were investigated. Particle size was determined through visual observation and dynamic light scattering. The results showed that isopropyl myristate and oleic acid could form stable, transparent microemulsion systems with polyoxyethylene hydrogenated castor oil RH40 and propylene glycol, and also exhibited suitable solubility for ondansetron.

[0037] During the surfactant screening process, nonionic surfactants such as polyoxyethylene castor oil EL35, Tween 80, and Span 80 were compared. The interfacial film strength was evaluated by measuring the microemulsion particle size and polydispersity index. The results showed that the interfacial film formed by polyoxyethylene hydrogenated castor oil RH40 had higher strength, and the microemulsion system was more stable at low temperatures and less prone to phase separation.

[0038] During the screening of surfactants, propylene glycol, ethanol, polyethylene glycol 400, glycerol, etc. were investigated. Through interfacial tension measurement and microemulsion phase diagram drawing, the results showed that propylene glycol had the best compatibility with polyoxyethylene hydrogenated castor oil RH40, which could effectively regulate interfacial tension and form microemulsion droplets with uniform particle size.

[0039] In the specific implementation, during the screening process of the mass ratio of polyoxyethylene hydrogenated castor oil RH40 to propylene glycol, four ratio points of 2:1, 3:1, 4:1, and 5:1 were investigated respectively.

[0040] The results showed that when the ratio was 2:1, the content of co-surfactant was too high, the viscosity of the microemulsion increased and it was easy to become turbid; when the ratio was 5:1, the content of co-surfactant was insufficient, the interfacial film was not dense enough and the stability of the microemulsion decreased; stable transparent microemulsions could be formed at both the 3:1 and 4:1 ratios, and the particle size distribution was concentrated.

[0041] During the gel phase screening process, the compatibility of commonly used gel matrices such as carbomer 940, carbomer 934, hydroxypropyl methylcellulose K4M, and poloxamer 407 with drug-containing microemulsion phases was investigated. The results showed that after carbomer-based matrices were combined with the microemulsion phase, ondansetron crystallization occurred within 24 hours at 4°C, which is speculated to be related to the alteration of the microemulsion interface structure by the charge effect of carbomer. The hydroxypropyl methylcellulose system was prone to stratification after being combined with the microemulsion phase. The thermosensitive gel formed by poloxamer 407 showed the best compatibility with the microemulsion phase, maintaining a homogeneous state after the two phases were combined, and no crystallization occurred at low temperatures.

[0042] During the screening of poloxamer 407 content, five concentration points of 10%, 15%, 18%, 20%, and 25% were examined. The results showed that a gel structure with suitable spreadability could not be formed at a concentration of 10%; at a concentration of 25%, the gel hardness was too high, and the microemulsion phase was difficult to disperse evenly; suitable gel structures could be formed at concentrations of 15%, 18%, and 20%, and the gels remained stable after being combined with microemulsion phases of different proportions. Therefore, these were determined to be the preferred content ranges.

[0043] In the screening of the microemulsion and gel phase blending ratios, six ratios were examined: 20:80, 30:70, 35:65, 40:60, 45:55, and 50:50. The results showed that when the microemulsion ratio was below 35%, the ondansetron loading in the formulation was too low, making it difficult to achieve the target transdermal rate. When the microemulsion ratio was above 45%, the proportion of the continuous gel phase was insufficient, leading to decreased formulation viscosity, poorer skin surface retention, and reduced system stability. The 35:65, 40:60, and 45:55 ratios showed the best overall performance and were therefore determined as the preferred blending ratio ranges.

[0044] During the screening of transdermal penetration enhancers, the transdermal efficacy and irritation of single and combination penetration enhancers were investigated. Single penetration enhancers included laurocapram, oleic acid, propylene glycol, and isopropyl myristate. Results showed that high-concentration laurocapram alone had good transdermal efficacy but significant irritation, while propylene glycol alone had limited penetration enhancement. Combination penetration enhancers were investigated in different ratios of a binary system of laurocapram + propylene glycol and a ternary system of laurocapram + propylene glycol + isopropyl myristate. Results showed that the ternary system synergistically enhanced penetration through different mechanisms of action, achieving good transdermal efficacy at lower laurocapram concentrations while significantly reducing skin irritation. During ratio optimization, two optimal ratios were determined: 1:3:1 and 1:4:2, balancing penetration enhancement efficacy and safety.

[0045] To facilitate a better understanding of the present invention by those skilled in the art, the present invention will be further illustrated below with reference to specific implementation examples.

[0046] Example 1: Microemulsion formulation in this example: based on 100g of microemulsion, ondansetron hydrochloride 2.5g, isopropyl myristate 8.0g, polyoxyethylene hydrogenated castor oil RH40 30.0g, propylene glycol 10.0g, water 49.5g; the sum of the listed components is 100.0g, and the mass ratio of polyoxyethylene hydrogenated castor oil RH40 to propylene glycol is 3:1.

[0047] Gel phase formulation: Based on 100g of gel phase, poloxamer 407 15.0g, glycerin 12.0g, transdermal penetration enhancer 6.0g, triethanolamine 0.5g, water 66.5g; the sum of the listed components is 100.0g. The transdermal penetration enhancer is composed of laurocapram, propylene glycol, and isopropyl myristate in a mass ratio of 1:3:1. 6.0g of transdermal penetration enhancer contains 1.2g laurocapram, 3.6g propylene glycol, and 1.2g isopropyl myristate.

[0048] Preparation procedure: Weigh 2.5g ondansetron hydrochloride, 8.0g isopropyl myristate, 30.0g polyoxyethylene hydrogenated castor oil RH40, and 10.0g propylene glycol. Mix them at 40℃, maintaining the material temperature at 40℃ and controlling the stirring speed at 800r / min. Add 49.5g water while stirring, and continue stirring for 45min after the water addition is complete to obtain a transparent and uniform microemulsion phase with an average particle size of 28.5nm. Separately, take 66.5g water, add 12.0g glycerol and 6.0g transdermal penetration enhancer, and mix well. Add 15.0g poloxamer 407 under low temperature conditions and disperse evenly. Let it stand at 4℃ for 12h to swell. After swelling is complete, stir until uniform, add 0.5g triethanolamine and stir evenly, and adjust the pH to 7.0. 40g of microemulsion phase and 60g of gel phase were mixed at low speed until homogeneous to obtain ondansetron transdermal microemulsion gel formulation. Finally, 100g of the formulation contained 1.0g of ondansetron hydrochloride introduced by the microemulsion phase, and the formulation had a uniform appearance.

[0049] Example 2: Microemulsion formulation in this example: per 100g of microemulsion, 3.0g of ondansetron free base, 10.0g of oleic acid, 28.0g of polyoxyethylene hydrogenated castor oil RH40, 7.0g of propylene glycol, and 52.0g of water; the sum of the listed components is 100.0g, and the mass ratio of polyoxyethylene hydrogenated castor oil RH40 to propylene glycol is 4:1.

[0050] Gel phase formulation: Based on 100g of gel phase, poloxamer 407 18.0g, propylene glycol 10.0g added separately as a moisturizer, transdermal penetration enhancer 8.0g, triethanolamine 0.6g, water 63.4g; the sum of the listed components is 100.0g. The transdermal penetration enhancer is composed of laurocapram, propylene glycol and isopropyl myristate in a mass ratio of 1:4:2. In 8.0g of transdermal penetration enhancer, laurocapram is approximately 1.143g, propylene glycol is approximately 4.571g, and isopropyl myristate is approximately 2.286g. Preparation procedure: Weigh 3.0 g ondansetron free base, 10.0 g oleic acid, 28.0 g polyoxyethylene hydrogenated castor oil RH40, and 7.0 g propylene glycol. Mix them at 35°C, maintaining the material temperature at 35°C and stirring at 800 r / min. Slowly add 52.0 g water and continue stirring for 40 min to form a transparent and homogeneous microemulsion with an average particle size of 25.3 nm. Separately, take 63.4 g water, add 10.0 g propylene glycol and 8.0 g transdermal penetration enhancer, mix thoroughly, add 18.0 g poloxamer 407 at low temperature for dispersion, and allow to swell at 6°C for 20 h. After swelling is complete, stir until homogeneous, add 0.6 g triethanolamine and stir thoroughly, adjusting the pH to 7.2. Take 35g of the microemulsion phase and add it to 65g of the gel phase under stirring. Stir at 300r / min for 15min until homogeneous to obtain ondansetron transdermal microemulsion gel formulation. Finally, 100g of the formulation contains 1.05g of ondansetron free base introduced by the microemulsion phase.

[0051] Example 3: Microemulsion formulation in this example: Based on 100g of microemulsion, ondansetron hydrochloride 4.5g, isopropyl myristate 8.0g, polyoxyethylene hydrogenated castor oil RH403 2.0g, propylene glycol 8.0g, water 47.5g; the sum of the listed components is 100.0g, and the mass ratio of polyoxyethylene hydrogenated castor oil RH40 to propylene glycol is 4:1.

[0052] Gel phase formulation: per 100g gel phase, poloxamer 40720.0g, glycerin 15.0g, transdermal penetration enhancer 10.0g, triethanolamine 0.8g, water 54.2g; the sum of the listed components is 100.0g.

[0053] Preparation procedure: Weigh 4.5g ondansetron hydrochloride, 8.0g isopropyl myristate, 32.0g polyoxyethylene hydrogenated castor oil RH40, and 8.0g propylene glycol and mix. Add water while stirring at a constant temperature to form a transparent and homogeneous microemulsion phase. Separately, take 54.2g of water, add 15.0g glycerol and 10.0g transdermal penetration enhancer, mix well, add 20.0g poloxamer 407 at low temperature, disperse thoroughly, and allow to swell. After swelling, stir to form a homogeneous gel phase, add 0.8g triethanolamine and stir well. Take 45g of the microemulsion phase and 55g of the gel phase and combine them under low-speed stirring until homogeneous to obtain the ondansetron transdermal microemulsion gel formulation. The final 100g formulation contains 2.025g of ondansetron hydrochloride introduced by the microemulsion phase.

[0054] Comparative Example 1: Comparative Example 1 used Carbomer 940 as the gelling material to prepare a microemulsion gel control sample containing ondansetron. Except for replacing the gelling material with Carbomer 940, the microemulsion formulation, microemulsion preparation method, two-phase compounding ratio, transdermal penetration enhancer composition, and pH adjuster dosage were completely consistent with Example 1; the mass percentage of Carbomer 940 in the gel phase was 1.0%, neutralized to pH 7.0 with triethanolamine, and the contents of other components were consistent with the gel phase of Example 1. The states of Comparative Example 1 and Examples 1-3 were observed after being placed at 4°C for 1 day and stored at 25°C for 30 days, respectively. The results are shown in Table 1.

[0055] Comparative Example 2: Comparative Example 2 is a conventional gel formulation that does not employ a microemulsion drug-carrying structure; ondansetron is directly dispersed in the gel system. Except for the absence of a microemulsion phase structure and the direct dissolution and dispersion of ondansetron in the gel phase, the composition of the gel matrix, the content of poloxamer 407, the composition and content of the transdermal penetration enhancer, the pH value, and the final loading of ondansetron in Comparative Example 2 are completely identical to those in Example 1. During preparation, all components were directly mixed and swollen to form a gel, without a two-phase stepwise preparation. Comparative Example 2 underwent in vitro transdermal evaluation under the same Franz diffusion cell test conditions as the Example, and the results are shown in Table 2.

[0056] The comprehensive performance evaluation is as follows:

[0057] The formulations of Examples 1, 2, and 3 were comprehensively evaluated. Each formulation was placed at 4°C for 1 day and then stored at 25°C for 30 days, and crystallization was observed. An in vitro transdermal test was conducted using a Franz diffusion cell to calculate steady-state transdermal flux and 24-hour cumulative transdermal rate. The formulation was applied to the hairless skin on the back of rabbits and administered continuously for 7 days, with erythema and edema scores recorded.

[0058] The evaluation results are shown in Tables 1, 2 and 3.

[0059] Examples 1-3 formed different formulation combinations. Example 1 used ondansetron hydrochloride, isopropyl myristate, a 3:1 mass ratio of polyoxyethylene hydrogenated castor oil RH40 to propylene glycol, 15% poloxamer 407 gel phase, and a 40:60 mass ratio of microemulsion phase to gel phase.

[0060] Example 2 uses ondansetron free base, oleic acid, a 4:1 mass ratio of polyoxyethylene hydrogenated castor oil RH40 to propylene glycol, 18% poloxamer 407 gel phase, and a 35:65 mass ratio of microemulsion phase to gel phase.

[0061] Example 3 uses ondansetron hydrochloride, isopropyl myristate, a 4:1 mass ratio of polyoxyethylene hydrogenated castor oil RH40 to propylene glycol, 20% poloxamer 407 gel phase, and a 45:55 mass ratio of microemulsion phase to gel phase.

[0062] The three embodiments form three microemulsion to gel phase mass ratio formulation points of 35:65, 40:60 and 45:55, and three poloxamer 407 content formulation points of 15%, 18% and 20%.

[0063] The ondansetron concentrations in the microemulsion phases of Examples 1-3 were 2.5%, 3.0%, and 4.5%, respectively; the oil phase contents were 8%, 10%, and 8%, respectively; the RH40 contents of the polyoxyethylene hydrogenated castor oil were 30%, 28%, and 32%, respectively; and the propylene glycol contents were 10%, 7%, and 8%, respectively.

[0064] The steady-state observation results are shown in Table 1.

[0065] Table 1 shows the observation results of the stable state of different gel systems;

[0066] sample Gel materials Store at 4℃ for 1 day Store at 25℃ for 30 days Comparative Example 1 Carbomer 940 Drug crystals appeared No crystallization was observed. Example 1 Polosham 407 No crystallization, homogeneous system No crystallization, homogeneous system Example 2 Polosham 407 No crystallization, homogeneous system No crystallization, homogeneous system Example 3 Polosham 407 No crystallization, homogeneous system No crystallization, homogeneous system

[0067] As shown in Table 1, no ondansetron crystals were observed in Examples 1-3 after being placed at 4°C for 1 day and after being stored at 25°C for 30 days, while ondansetron crystals were observed in Comparative Example 1 after being placed at 4°C for 1 day. This indicates that the poloxamer 407 microemulsion gel formulation used in the embodiments of the present invention can maintain a homogeneous state under the corresponding observation conditions.

[0068] The in vitro transdermal assay used a Franz diffusion cell with an effective transdermal area of ​​2.83 cm², a receiving cell volume of 6.06 mL, a water bath temperature of 32 °C, and a stirring speed of 200 rpm. The test skin was obtained from euthanized cats; after removing the subcutaneous fat layer, it was washed with physiological saline, blotted dry with filter paper, and stored at −30 °C for later use. The skin was placed between the supply and receiving cells, with the stratum corneum facing the drug delivery side. The test sample was placed on the stratum corneum side of the skin, and 0.2 mL of receiving solution was taken from the receiving cell at the specified sampling time point. An equal volume of blank receiving solution at 32 °C was immediately added. 20 μL of the test solution was analyzed by HPLC, and a standard curve was established using ondansetron as a standard to calculate the concentration of ondansetron in the receiving solution.

[0069] The cumulative permeation is calculated considering the removal of ondansetron due to continuous sampling and equal-volume replenishment. The cumulative permeation per unit area at the nth sampling time point is calculated using the following formula:

[0070]

[0071] In the formula: This represents the cumulative transmittance per unit area at the nth sampling time point; The concentration of ondansetron in the receiving solution at the nth sampling time point; The volume of the receiving cell is 6.06 mL; For a single sample volume, take 0.2 mL; The concentration of ondansetron in the receiving solution at the i-th sampling time point; The effective transdermal area is taken as 2.83 cm²; n is the sampling time point number; i is the sampling time point number corresponding to the summation term. The steady-state transdermal flux is calculated based on the steady-state linear segment of the cumulative permeability per unit area versus time curve:

[0072]

[0073] In the formula: For steady-state transdermal flux; This represents the cumulative change in transmittance per unit area within the steady-state linear region. The values ​​represent the changes over time. The cumulative transdermal permeability over 24 hours was calculated as the ratio of the cumulative amount of ondansetron permeated over 24 hours to the initial amount of ondansetron administered. The results of the in vitro transdermal permeability test are shown in Table 2.

[0074] Table 2 shows the in vitro transdermal performance of the examples and the ordinary gel control samples;

[0075] sample Steady-state transdermal flux (ng / cm² / h) 24-hour cumulative transdermal penetration rate (%) Comparative Example 2, ordinary gel 12 15.3 Example 1 38 42.5 Example 2 36 40.2 Example 3 41 45.8

[0076] The steady-state transdermal flux of Example 1 was 38 ng / cm² / h, with a cumulative transdermal rate of 42.5% over 24 hours; Example 2 was 36 ng / cm² / h, with a rate of 40.2%; and Example 3 was 41 ng / cm² / h, with a rate of 45.8%. The steady-state transdermal flux of the conventional gel Comparative Example 2 was 12 ng / cm² / h, with a cumulative transdermal rate of 15.3% over 24 hours. Under the same in vitro transdermal evaluation conditions, the steady-state transdermal flux and cumulative transdermal rate over 24 hours of Examples 1–3 were all higher than those of the conventional gel Comparative Example 2, indicating that the formulation formed by placing ondansetron in the microemulsion phase and further combining it with the poloxamer 407 gel phase achieved different in vitro transdermal results than conventional non-microemulsion gels.

[0077] Skin irritation tests were conducted on healthy rabbits. Hair was removed from the treatment area on the back, and samples from Examples 1, 2, 3, and the irritation control were applied. The medication was administered once daily for 7 consecutive days, and erythema and edema reactions were observed and scored. The irritation control was a single penetration enhancer containing 5% laurocapram. Results are shown in Table 3.

[0078] Table 3 shows the results of skin irritation observation;

[0079] sample Erythema score Edema score Observation results of irritation Irritation control sample, 5% laurocapram single penetration enhancer sample 2.5 1.8 moderate stimulation Example 1 0.2 0 No obvious irritant response Example 2 0.3 0 No obvious irritant response Example 3 0.4 0.1 No obvious irritant response

[0080] Table 3 shows that the erythema score of the control sample containing 5% laurocapram as a single penetration enhancer was 2.5, and the edema score was 1.8; the erythema score of Example 1 was 0.2, and the edema score was 0; the erythema score of Example 2 was 0.3, and the edema score was 0; and the erythema score of Example 3 was 0.4, and the edema score was 0.1. Under the evaluation conditions used in this experiment, the erythema and edema scores of Examples 1-3 were all lower than those of the irritant control sample, indicating that the microemulsion gel formulation containing the ternary transdermal penetration enhancer achieved a lower skin irritation score.

[0081] This invention does not involve a simple mixing of any microemulsion and any gel. The microemulsion phase uses polyoxyethylene hydrogenated castor oil RH40 and propylene glycol as the interface system, with examples using a mass ratio of 3:1 and 4:1. The gel phase uses poloxamer 407 as the gelling material, with examples using internal contents of 15%, 18%, and 20%. The microemulsion and gel phases are compounded at mass ratios of 35:65, 40:60, and 45:55. The transdermal penetration enhancer uses a ternary system composed of laurocapram, propylene glycol, and isopropyl myristate, with examples specifying a mass ratio of 1:3:1 and 1:4:2. The preparation process first forms a transparent and homogeneous drug-containing microemulsion phase, while simultaneously forming a poloxamer 407 gel phase through low-temperature addition and static swelling, followed by low-speed compounding of the two pre-formed systems.

[0082] Existing examples and comparative tests evaluate the complete formulation from three dimensions: formulation status, in vitro transdermal performance, and skin irritation observation.

[0083] Regarding the formulation state, no ondansetron crystals were observed in Examples 1-3 after being placed at 4°C for 1 day and stored at 25°C for 30 days. In terms of in vitro transdermal absorption, the steady-state transdermal flux of Examples 1-3 was 36-41 ng / cm² / h, and the cumulative transdermal absorption rate over 24 hours was 40.2%-45.8%, both higher than that of the control sample containing 5% laurocapram. Regarding skin irritation, the erythema scores of Examples 1-3 were 0.2-0.4, and the edema scores were 0-0.1, both lower than the irritant control sample containing 5% laurocapram alone. The results listed in Tables 1-3 correspond to the complete formulation system, indicating that the microemulsion drug-carrying structure, the poloxamer 407 gel system, the two-phase compounding ratio, and the ternary transdermal penetration enhancer together constitute the formulation technical solution of this invention.

[0084] The production process of ondansetron transdermal microemulsion gel formulations is divided into three stages: microemulsion phase preparation, gel phase preparation, and two-phase composite preparation. Control items in the microemulsion phase preparation stage include the amount of ondansetron added, the type and amount of oil phase added, the amount of polyoxyethylene hydrogenated castor oil RH40 added, the amount of propylene glycol added as a co-surfactant to the microemulsion phase, the amount of water added, the mass ratio of polyoxyethylene hydrogenated castor oil RH40 to propylene glycol, the mixing temperature, the stirring speed, the water addition process, the stirring time, and the appearance of the system.

[0085] During mass production, each component is scaled up proportionally according to the formula mass ratio. Premixing and constant-temperature stirring can be performed using a mixing tank equipped with a heating jacket and anchor stirrer, with temperature control accuracy ±2℃ and an adjustable stirring speed range of 50~1000 r / min. Control items during the gel phase preparation stage include: poloxamer 407 dosage, type and dosage of humectant, total dosage of transdermal penetration enhancer, composition ratio of laurocapram, propylene glycol, and isopropyl myristate, water addition, poloxamer 407 addition temperature, low-temperature swelling temperature, low-temperature swelling time, stirring speed, stirring time, pH adjuster addition, and final pH.

[0086] Low-temperature swelling can be carried out in a cold storage or constant-temperature circulating water bath, maintaining a temperature of 4~10℃. The swelling container is a stainless steel tank with a low-speed stirring device to ensure uniform dispersion of poloxamer 407 without generating excessive bubbles. After swelling, vacuum degassing can be performed. Control items for the two-phase compounding stage include the mass of the microemulsion phase added, the mass of the gel phase added, the mass ratio of the microemulsion phase to the gel phase, the order of addition, the compounding stirring speed, the compounding stirring time, and the final appearance and homogeneity of the formulation. During production scale-up, the proportions of each component in the formulation and the compounding ratio of the microemulsion phase to the gel phase should be maintained. Actual production operations should be adjusted according to the effective volume of the equipment and the structure of the stirring device. A combination of online homogenization and wall-scraping stirring can be used to further improve mixing efficiency and homogeneity.

[0087] The following items can be evaluated for ondansetron transdermal microemulsion gel formulations according to product quality control requirements: appearance, pH, ondansetron content, content uniformity, average particle size of the microemulsion phase, crystallization state during storage, formulation homogeneity, in vitro release performance, and in vitro transdermal performance. The average particle size of the microemulsion phase is measured after microemulsion preparation and before it is combined with the gel phase. The pH of the final formulation is measured after the two phases are combined and homogeneous. Storage condition evaluation should record storage temperature, storage time, and observation results separately. In in vitro transdermal comparative tests, different samples should use the same skin treatment method, effective diffusion area, receiving cell volume, test temperature, stirring speed, sampling volume, and replenishment method.

[0088] In addition to the 4℃ and 25℃ conditions, stability studies can be conducted under more conditions according to the product storage and transportation requirements. The study items include high temperature conditions of 40℃, accelerated conditions of 30℃ / 65% relative humidity, and changes in appearance, particle size, content, pH, and crystallization under repeated freeze-thaw conditions.

[0089] The sample from Example 1 was subjected to accelerated testing at 40°C for 30 days. The sample was sealed in an aluminum-plastic composite tube and placed in a constant temperature oven at 40°C. Samples were taken on days 0, 10, 20, and 30 to observe the appearance and determine the ondansetron content using HPLC. The pH was also measured. The results showed that the appearance of the preparation remained uniform, without layering or crystallization, the ondansetron content decreased by less than 2%, and the pH change was within 0.2.

[0090] The sample from Example 2 was subjected to three cycles of freeze-thaw. Each cycle involved placing the sample at -20°C for 24 hours and then allowing it to return to room temperature for 24 hours. Samples were taken to observe the appearance, particle size, and content. The results showed that the formulation remained homogeneous after three cycles, and no crystallization or stratification was observed.

[0091] The sample from Example 3 underwent accelerated stability testing at 30°C / 65% relative humidity for 30 days. Samples were taken on days 0, 15, and 30 to observe appearance, measure content, and determine pH. Results showed no change in appearance, a content decrease rate of less than 1.5%, and pH changes within 0.15. During stability testing, the compatibility between packaging materials and the formulation must be investigated simultaneously to prevent leaching from packaging materials from affecting formulation quality and to prevent adsorption of formulation components into the packaging material, which could lead to content decrease. Compatibility tests can be conducted using aluminum-plastic composite tubes, glass bottles, or polyester bottles. Packaging suitability is evaluated by measuring changes in leaching from packaging materials and formulation content.

[0092] This invention relates to an ondansetron transdermal microemulsion gel formulation, which can be produced using mixing, temperature control, cryogenic, and stirring devices typically employed in pharmaceutical manufacturing. During production, the microemulsion and gel phase materials are weighed separately according to the formulation, using an electronic balance or an automated weighing system. The microemulsion phase is prepared using a mixing tank equipped with heating and stirring functions, set at a temperature of 20-50°C and a stirring speed of 500-1000 r / min. The water addition process utilizes a metering pump to control the flow rate. The poloxamer 407 gel phase is prepared using a jacketed cooling mixing tank. Poloxamer 407 is added and dispersed at 4-10°C. After static swelling, stirring is initiated for homogenization. A pH adjuster is added, and the mixture is then thoroughly mixed. The microemulsion and gel phases are weighed after low-temperature swelling and homogenization. The microemulsion and gel phases are then combined according to a specified mass ratio, using a low-speed mixer or a static mixer for continuous mixing.

[0093] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including both the preferred embodiments and all changes and modifications falling within the scope of the invention.

[0094] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. It should be noted that any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A smart method for assessing the stability of microemulsion gels containing ondansetron, characterized by comprising the following steps: Take the ondansetron transdermal microemulsion gel formulation, place it at 4°C for 1 day and store it at 25°C for 30 days, and observe whether crystals precipitate out. In vitro transdermal experiments were conducted using a Franz diffusion cell with an effective transdermal area of ​​2.83 cm², a receiving cell volume of 6.06 mL, a water bath temperature of 32 °C, and a stirring speed of 200 r / min. The skin used was cat skin with the subcutaneous fat layer removed. Samples were taken at specified time points, and the ondansetron concentration was determined by HPLC. The steady-state transdermal flux and the cumulative transdermal rate over 24 hours were calculated. Ondansetron transdermal microemulsion gel was applied to the hairless skin on the back of rabbits and administered once daily for 7 consecutive days. Erythema and edema reactions were observed and scored.

2. The intelligent evaluation method for the stability of microemulsion gel containing ondansetron according to claim 1, characterized in that the ondansetron transdermal microemulsion gel formulation comprises a microemulsion phase and a gel phase; Based on the total weight of the ondansetron transdermal microemulsion gel formulation, the weight percentage of the microemulsion phase is 35%–45%, the weight percentage of the gel phase is 55%–65%, and the sum of the weight percentages of the microemulsion phase and the gel phase is 100%. Based on the total weight of the microemulsion phase, the microemulsion phase includes 0.5%–5% ondansetron, 1%–15% oil phase, 10%–40% polyoxyethylene hydrogenated castor oil RH40, 5%–30% propylene glycol and 20%–70% water. The sum of the weight percentages of the components in the microemulsion phase is 100%, and the mass ratio of polyoxyethylene hydrogenated castor oil RH40 to propylene glycol is 3:1 or 4:

1. Based on the total weight of the gel phase, the gel phase comprises 15%–20% poloxamer 407, 5%–30% humectant, 1%–15% transdermal penetration enhancer, 0.1%–5% pH adjuster, and 40%–78.9% water, with the sum of the weight percentages of all components of the gel phase being 100%. The transdermal penetration enhancer is composed of laurocapram, propylene glycol and isopropyl myristate, with 1 part laurocapram by weight, 3-4 parts propylene glycol, and 1-2 parts isopropyl myristate.

3. The intelligent evaluation method for the stability of microemulsion gels containing ondansetron according to claim 2, characterized in that ondansetron is ondansetron hydrochloride or ondansetron free base.

4. The intelligent evaluation method for the stability of microemulsion gels containing ondansetron according to claim 2, characterized in that the oil phase is isopropyl myristate or oleic acid.

5. The intelligent evaluation method for the stability of microemulsion gel containing ondansetron according to claim 2, characterized in that, based on the total weight of the microemulsion phase, the weight percentage of ondansetron is 2.5% to 4.5%, the weight percentage of the oil phase is 8% to 10%, the weight percentage of polyoxyethylene hydrogenated castor oil RH40 is 28% to 32%, the weight percentage of propylene glycol is 7% to 10%, the weight percentage of water is 47.5% to 52%, and the sum of the weight percentages of all components in the microemulsion phase is 100%.

6. The intelligent evaluation method for the stability of microemulsion gel containing ondansetron according to claim 2, characterized in that the mass ratio of the microemulsion phase to the gel phase is 35:65, 40:60 or 45:

55.

7. The intelligent evaluation method for the stability of microemulsion gel containing ondansetron according to claim 2, characterized in that poloxamer 407 accounts for 15%, 18% or 20% of the total weight of the gel phase.

8. The intelligent evaluation method for the stability of microemulsion gels containing ondansetron according to claim 2, characterized in that the mass ratio of laurocapram, propylene glycol and isopropyl myristate is 1:3:1 or 1:4:

2.

9. The intelligent evaluation method for the stability of microemulsion gel containing ondansetron according to claim 2, characterized in that the ondansetron is ondansetron hydrochloride, the oil phase is isopropyl myristate, the humectant is glycerin, and the mass ratio of the microemulsion phase to the gel phase is 40:60 or 45:

55.

10. The intelligent evaluation method for the stability of microemulsion gel containing ondansetron according to claim 2, characterized in that ondansetron is ondansetron free base, the oil phase is oleic acid, the humectant is propylene glycol, the mass ratio of polyoxyethylene hydrogenated castor oil RH40 to propylene glycol added as a co-surfactant in the microemulsion phase is 4:1, and the mass ratio of the microemulsion phase to the gel phase is 35:65.

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