A heparin sodium cream and a preparation method thereof

Abstract

The application discloses heparin sodium cream and a preparation method thereof, and belongs to the technical field of pharmaceutical preparation production. The heparin sodium cream comprises the following components: heparin sodium, propylene glycol, hydroxyphenyl ethyl ester, sodium dodecyl sulfate, glycerol monostearate and distearate, octadecanol, liquid paraffin, white vaseline and water. The preparation method comprises the following steps: preparing an oil phase and mixing an aqueous phase; taking part of the mixed aqueous phase and the oil phase to form a water-in-oil type primary emulsion; then adding the remaining mixed aqueous phase into the primary emulsion, inducing phase transition into an oil-in-water type cream under mild conditions, and obtaining the finished product after vacuum defoaming and gradient cooling. The application realizes high-efficiency emulsification under mild conditions below 80 DEG C and 3000 rpm through a controlled phase inversion emulsification process, so that the particle size (D99) of the emulsion droplets is less than 5 microns, and the problem that the active substance heparin sodium loses activity under severe conditions is solved completely, and the stability of the product is improved significantly.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical preparation manufacturing technology, and specifically relates to a heparin sodium cream and its preparation method. Background Technology

[0002] Sodium heparin, an acidic mucopolysaccharide, has significant applications in the pharmaceutical field. However, its stability in cream formulations has been a persistent technical challenge for those skilled in the art. Studies have shown that sodium heparin exhibits significant sensitivity to changes in temperature, mechanical shear stress, and pH, posing stringent requirements for process development and product quality control in cream formulations.

[0003] Currently, the conventional production process for heparin sodium cream formulations mainly employs a one-step emulsification method. This method typically involves mixing the oil phase, the aqueous phase containing heparin sodium, and the emulsifier in a single step, followed by emulsification at a high temperature above 80°C and high-speed homogenization conditions above 3000 rpm. Although this method is widely used in industrial production, its inherent process defects are becoming increasingly apparent. Specifically, the high-speed homogenization step in the aforementioned one-step emulsification method generates intense mechanical shear forces, which not only leads to localized heat concentration but also introduces a large number of bubbles into the system. For heat-sensitive and shear-sensitive active ingredients like heparin sodium, this harsh process environment can easily trigger the degradation of its molecular structure, resulting in a significant loss of biological activity. Furthermore, the presence of heat and bubbles can negatively impact the microstructure and physical stability of the cream, such as causing oil-water separation and promoting product rancidity, ultimately affecting the product's shelf life and safety.

[0004] To avoid the heat generation and bubble formation problems caused by high-speed homogenization, researchers attempted to reduce the homogenization speed. However, while low-speed homogenization below 3000 rpm reduced the damage to heparin sodium activity, insufficient homogenization often resulted in inadequate emulsification of the oil and aqueous phases, leading to larger and unevenly distributed droplets. This incomplete emulsification also caused instability in the cream system, making it prone to stratification, rancidity, and other problems, thus failing to meet product quality requirements.

[0005] In summary, the existing preparation process of heparin sodium cream is caught in an irreconcilable technical contradiction: on the one hand, to obtain the ideal droplet size and emulsification effect, harsh conditions of high temperature and high speed are required, but this will sacrifice the activity of heparin sodium and the stability of the product; on the other hand, mild conditions are used to protect the activity of heparin sodium, but the emulsification cannot be guaranteed to be sufficient, which also leads to insufficient product stability. Summary of the Invention

[0006] The purpose of this application is to provide a heparin sodium cream and its preparation method, which can achieve full emulsification under mild process conditions to effectively control droplet size, eliminate bubbles, and maximize the preservation of the bioactivity of heparin sodium.

[0007] To achieve the above objectives, this application provides a method for preparing heparin sodium cream, comprising the following steps:

[0008] While stirring, mix white petrolatum and liquid paraffin, heat the mixture, then add octadecanol and glyceryl mono- and di-stearates, and continue stirring while keeping the mixture warm to obtain the oil phase.

[0009] Propylene glycol and ethylparaben were mixed at room temperature to obtain the first aqueous phase.

[0010] After heating the water, sodium dodecyl sulfate and sodium heparin were added, and the mixture was stirred continuously to obtain the second aqueous phase.

[0011] The first aqueous phase and the second aqueous phase are mixed to obtain a mixed aqueous phase;

[0012] Take 50wt%~70wt% of a mixed aqueous phase and an oil phase and perform homogenization emulsification to obtain a water-in-oil primary emulsion;

[0013] The remaining aqueous phase was added to the water-in-oil colostrum, stirred evenly, and then subjected to homogenization, defoaming, and gradient cooling treatments to obtain heparin sodium cream.

[0014] Furthermore, the temperature after the heating treatment is 60℃~80℃, the stirring speed during the oil phase preparation process is 10rpm~30rpm, and the stirring time is 30min~60min.

[0015] Furthermore, the stirring speed during the preparation of the first aqueous phase is 1000 rpm to 2500 rpm, and the stirring time is 30 min to 60 min.

[0016] Furthermore, the water heating temperature is 50℃~60℃, the stirring speed during the preparation of the second aqueous phase is 1000rpm~2500rpm, and the stirring time is 30min~60min.

[0017] Furthermore, the stirring speed during the preparation of the mixed aqueous phase is 1000 rpm to 2500 rpm, the stirring time is 10 min to 30 min, and the mixing temperature is 60℃ to 80℃.

[0018] Furthermore, the preparation process of the water-in-oil colostrum includes: taking 50wt% to 70wt% of the mixed aqueous phase as a percentage of the total mixed aqueous phase mass and mixing it with the oil phase, stirring at a speed of 1000rpm to 2500rpm for 10min to 30min, and homogenizing at a speed of 1500rpm to 2500rpm for 10min to 30min to obtain the water-in-oil colostrum.

[0019] Furthermore, when mixing the water-in-oil type primary emulsion with the remaining mixed water phase, the stirring speed is 10 rpm to 30 rpm and the time is 10 min to 30 min; the homogenization speed is 1500 rpm to 2500 rpm and the time is 10 min to 30 min.

[0020] Furthermore, the gradient cooling process includes: maintaining a vacuum of ≤-0.07MPa and a stirring speed of 10rpm~30rpm, cooling the reaction product to 65℃~70℃ with cooling water at 50℃~65℃; switching to cooling water at 35℃~45℃ to cool the reaction product to 50℃~55℃; and switching to cooling water at 20℃~30℃ to continue cooling the reaction product to 35℃~40℃.

[0021] This application also provides a heparin sodium cream prepared by the above method, comprising the following components in weight percentage: heparin sodium 0.1%~1.0%, propylene glycol 5.0%~10.0%, ethylparaben 0.05%~0.15%, sodium dodecyl sulfate 0.5%~1.5%, glyceryl mono- and di-stearates 5.0%~10.0%, stearyl alcohol 8.0%~12.0%, liquid paraffin 8.0%~12.0%, white petrolatum 8.0%~12.0%, and the balance being water; wherein the heparin sodium cream has a D99 particle size <5μm, an efficacy value of 99%~102%, and a pH value of 6.9~7.3.

[0022] Furthermore, the heparin sodium cream comprises the following components by weight percentage: 0.15%~0.45% heparin sodium, 6.5%~8.0% propylene glycol, 0.09%~0.11% ethylparaben, 0.9%~1.1% sodium lauryl sulfate, 6.5%~8.0% glyceryl mono- and di-stearyl esters, 9.5%~10.5% stearyl alcohol, 9.5%~10.5% liquid paraffin, 9.5%~10.5% white petrolatum, and the balance being water.

[0023] In summary, this application has the following advantages:

[0024] This application achieves thorough emulsification of heparin sodium cream through a controlled phase inversion process (i.e., firstly, a portion of the aqueous and oil phases are mixed and homogenized to form a W / O structure, then the remaining aqueous phase is added and homogenized again, resulting in a controlled phase inversion and ultimately an O / W structure cream). The phase transition generates a significant release of interfacial energy, greatly enhancing emulsification efficiency and spontaneously promoting a sharp reduction in droplet size and a tendency towards uniform distribution. Therefore, unlike traditional methods that rely on high shear forces for forced dispersion, this application utilizes the inherent physicochemical changes within the system to achieve highly efficient emulsification. This method allows for smaller and more uniform droplet sizes compared to traditional high-speed homogenization methods, under significantly milder temperature conditions (e.g., below 80°C) and lower shear forces (1000 rpm to 2500 rpm). It can be seen that this mild process environment minimizes thermal degradation and mechanical shear damage to heparin sodium molecules, effectively protecting their bioactivity, while the fine droplet structure ensures the long-term physical stability of the final cream product. Attached Figure Description

[0025] To more clearly illustrate the technical solutions of the embodiments of this application, the drawings used in the description of the embodiments of this application will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0026] Figure 1 This is a microscope photograph of the heparin sodium cream proposed in Example 1 of this application.

[0027] Figure 2 This is a microscopic photograph of the heparin sodium cream presented in the comparative example of this application. Detailed Implementation

[0028] The technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0029] Existing heparin sodium cream preparation processes suffer from a core contradiction: they cannot simultaneously satisfy the two key technical requirements of preserving heparin sodium activity and maintaining cream system stability. Therefore, this application develops a novel method for preparing heparin sodium cream formulations. This method can be implemented under mild process conditions, including a temperature below 80°C and a homogenization speed below 3000 rpm. It ensures thorough emulsification, effectively controls droplet size and distribution, and eliminates air bubbles within the system. Ultimately, it achieves effective assurance of cream formulation stability while maximizing the preservation of heparin sodium's biological activity.

[0030] Specifically, in the first aspect, this application provides a method for preparing heparin sodium cream, comprising the following steps:

[0031] S1. Mix white petrolatum and liquid paraffin under stirring, heat the mixture, add octadecanol and glyceryl mono- and di-stearates, and continue stirring under heat to obtain the oil phase.

[0032] In the specific implementation, the temperature after the heating treatment in step S1 is 60℃~80℃, the stirring speed during the oil phase preparation process is 10rpm~30rpm, and the stirring time is 30min~60min. Low stirring speed is sufficient to ensure uniform mixing during the oil phase preparation process.

[0033] S2. Propylene glycol and ethylparaben are mixed at room temperature to obtain the first aqueous phase.

[0034] In a specific embodiment, the stirring speed in step S2 is 1000 rpm to 2500 rpm, and the stirring time is 30 min to 60 min. Since ethylparaben has limited solubility in water but good solubility in propylene glycol, mixing the two first ensures that ethylparaben is fully dissolved and uniformly dispersed, preventing crystallization in the final product.

[0035] S3. After heating the water, add sodium dodecyl sulfate and sodium heparin, and continue stirring to obtain the second aqueous phase.

[0036] In this specific embodiment, the temperature of the heated water is 50℃~60℃, the stirring speed during the preparation of the second aqueous phase is 1000rpm~2500rpm, and the stirring time is 30min~60min. Both sodium heparin and sodium dodecyl sulfate (the main emulsifier) ​​are water-soluble. Heating the water to 50℃~60℃ accelerates the dissolution of sodium heparin, ensuring its complete and uniform dispersion in the aqueous phase. Furthermore, the appropriate temperature helps sodium dodecyl sulfate dissolve better and extend its molecular chains, allowing it to migrate more quickly to the oil-water interface during subsequent emulsification, thereby improving emulsification efficiency.

[0037] S4. Mix the first aqueous phase and the second aqueous phase to obtain a mixed aqueous phase.

[0038] In a specific embodiment, the stirring speed in step S4 is 1000 rpm to 2500 rpm, the stirring time is 10 min to 30 min, and the mixing temperature is 60℃ to 80℃. Raising the temperature to 60℃ to 80℃ during the aqueous phase mixing process, making it close to the oil phase temperature, can avoid local demulsification or the formation of unstable crystal nuclei due to excessive temperature difference, thereby achieving stable and efficient emulsification.

[0039] S5. Take 50wt%~70wt% of the mixed aqueous phase and oil phase and homogenize and emulsify them to obtain a water-in-oil type primary emulsion.

[0040] In a specific embodiment, step S5 includes the following steps: taking 50wt%~70wt% of the mixed aqueous phase (accounting for a total mass of the mixed aqueous phase) and mixing it with the oil phase, stirring at 1000rpm~2500rpm for 10min~30min, and homogenizing at 1500rpm~2500rpm for 10min~30min. Step S5 is the first emulsification process. Under the action of the emulsifier, the reaction system naturally forms a W / O structure (i.e., water-in-oil primary emulsion) in which water droplets are dispersed in the oil. To ensure that the final O / W cream has a smaller particle size and narrower distribution, the internal structure of the water-in-oil primary emulsion obtained in step S5 needs to be uniform, preparing for the complete phase change that will occur after the remaining aqueous phase is added in step S6.

[0041] S6. Add the remaining mixed aqueous phase to the water-in-oil primary emulsion, stir evenly, and then sequentially undergo homogenization, defoaming, and gradient cooling to obtain heparin sodium cream. As the volume of the aqueous phase increases, the reaction system crosses the phase transition point. Under the action of the emulsifier, the continuous phase changes from the oil phase to the aqueous phase, ultimately forming the target oil-in-water (O / W) cream, thus achieving a highly efficient emulsification process.

[0042] In a specific implementation, during step S6, the stirring speed for mixing the water-in-oil primary emulsion with the remaining aqueous phase is 10 rpm to 30 rpm, and the time is 10 min to 30 min; the homogenization speed is 1500 rpm to 2500 rpm, and the time is 10 min to 30 min. Using a low stirring speed when adding the remaining aqueous phase avoids violent disturbances that could disrupt the ongoing, delicate phase transition process, ensuring a stable and controllable phase transition. After the phase transition is complete, a gentle homogenization is performed to homogenize the already formed, smaller O / W droplets, further reducing the particle size and making the distribution more concentrated, while completely eliminating any possible small number of large droplets.

[0043] In a specific embodiment, the gradient cooling process includes: maintaining a vacuum of ≤-0.07MPa and a stirring speed of 10rpm~30rpm, cooling the reaction product to 65℃~70℃ with cooling water at 50℃~65℃; switching to cooling water at 35℃~45℃ to cool the reaction product to 50℃~55℃; and switching to cooling water at 20℃~30℃ to continue cooling the reaction product to 35℃~40℃. This application uses a staged cooling process to avoid rapid cooling causing the oil phase in the cream to solidify, the crystal lattice to precipitate, or the droplet structure to be destroyed.

[0044] In a specific implementation, defoaming is performed after homogenization using the following method: The homogenization and wall-scraping stirring functions are turned off. The vacuum pump is maintained or restarted to achieve a vacuum level ≤-0.07 MPa. The vacuum is then stopped, and the wall-scraping stirring is turned on, setting the speed to 10 rpm to 30 rpm. The foaming is observed; if dense foam is continuously generated, air is slowly introduced to atmospheric pressure. This process is repeated until no more dense foam is generated. This application performs defoaming under vacuum (≤-0.07 MPa), utilizing the internal and external pressure difference to rapidly break and escape bubbles in the system. Combined with intermittent vacuum breaking and stirring, residual stubborn bubbles can be effectively driven away, fundamentally solving the bubble problem and ensuring the product's delicate texture and stability.

[0045] In summary, the preparation method of heparin sodium cream in this application is based on an innovative controlled phase inversion emulsification principle, fundamentally changing the cream formation mechanism and thus resolving the inherent contradiction between active ingredient protection and emulsification efficiency in traditional processes. Controlled phase inversion emulsification does not involve mixing and emulsifying all components at once, but rather constructing the final cream structure through a dynamic, staged phase transition process. Specifically, this method first premixes all the oil phase and a portion of the aqueous phase under the action of an emulsifier to form a water-in-oil (W / O) type primary emulsion. At this stage, the aqueous phase is dispersed in the continuous oil phase as tiny droplets. Subsequently, under continuous stirring and homogenization, the remaining aqueous phase containing heparin sodium is slowly added to the W / O type primary emulsion system in a controlled manner. As the volume fraction of the aqueous phase continues to increase, the phase equilibrium within the system is disrupted. Under the synergistic effect of emulsifiers, the roles of the dispersed phase and the continuous phase are reversed, that is, the system undergoes a phase transformation process from water-in-oil (W / O) to oil-in-water (O / W), and finally forms the target oil-in-water cream.

[0046] Secondly, based on a general inventive concept, this application provides a heparin sodium cream obtained by the above method, comprising the following components in weight percentage: heparin sodium 0.1%~1.0%, propylene glycol 5.0%~10.0%, ethylparaben 0.05%~0.15%, sodium lauryl sulfate 0.5%~1.5%, glyceryl mono- and di-stearates 5.0%~10.0%, stearyl alcohol 8.0%~12.0%, liquid paraffin 8.0%~12.0%, white petrolatum 8.0%~12.0%, and the balance being water.

[0047] Each component in this application has the following function:

[0048] (1) Sodium heparin is the main active ingredient of the cream. As an acidic mucopolysaccharide, sodium heparin has pharmacological activities such as anticoagulation, anti-inflammation, promoting local blood circulation and accelerating tissue repair. It is the core ingredient for the therapeutic effect of this cream.

[0049] (2) Propylene glycol is a moisturizer, penetration enhancer and solubilizer. Propylene glycol can keep the skin moist and prevent the cream from drying out. At the same time, it can increase the water content of the stratum corneum and promote the transdermal absorption of active ingredients such as heparin sodium. In addition, it can also be used to dissolve ingredients in creams that are not well water-soluble.

[0050] (3) Ethylparaben, a preservative. Also known as ethylparaben, it is used to inhibit the growth of microorganisms (bacteria, fungi) and prevent the cream from being contaminated and deteriorating during storage and use, thereby improving the safety and shelf life of the cream.

[0051] (4) Sodium dodecyl sulfate is the main emulsifier (water-soluble) and is an anionic surfactant.

[0052] (5) Glyceryl monostearate and glyceryl distearate, used as auxiliary emulsifiers, stabilizers and oil phase thickeners. It is a nonionic surfactant. When used in combination with main emulsifiers such as sodium dodecyl sulfate, it can enhance the strength and flexibility of the emulsion film and improve the stability of the cream.

[0053] (6) Octadecyl alcohol, as an oil phase component, co-emulsifier, stabilizer, thickener, and skin feel improver. Octadecyl alcohol is a higher fatty alcohol that, as part of the oil phase, can increase the consistency and structural strength of creams. It can form complexes with emulsifiers at the interface, further enhancing the stability of creams. In addition, it can give creams a smooth and moisturizing feel when applied.

[0054] (7) Liquid paraffin, as an oil phase component, humectant, and occlusive agent. It is a mineral oil that can form a hydrophobic film on the skin surface, effectively reducing skin moisture evaporation and playing a role in sealing and moisturizing. At the same time, it is also an important component of the oil phase structure of creams.

[0055] (8) White petrolatum, as an oil phase component, a powerful occlusive agent, and an excipient. White petrolatum is an extremely stable oil with strong occlusive and moisturizing properties, which can lock in moisture for a long time and soften the skin. It constitutes the oily matrix framework of the cream and is crucial to the final form and stability of the cream.

[0056] (9) Water, as a solvent and dispersion medium (continuous phase). Water is the most abundant component in this formulation, serving as a solvent to dissolve water-soluble components such as sodium heparin, propylene glycol, ethylparaben, and sodium lauryl sulfate. In the final oil-in-water (O / W) cream, water constitutes the external continuous phase.

[0057] Furthermore, the components in this application also exhibit synergistic effects. For example, the combination of sodium lauryl sulfate (anionic) and glyceryl mono- and di-stearates (nonionic) is a synergistic emulsification combination. The anionic emulsifier provides strong emulsifying capabilities, while the nonionic emulsifier enhances the elasticity and density of the interfacial film. The combination of the two forms a more stable and temperature- and pH-resistant interfacial film than a single emulsifier. Octadecyl alcohol, as a co-emulsifier, can insert its molecules into the interfacial film formed by the emulsifier, further strengthening the film's physical strength and preventing droplet aggregation, thereby significantly improving the long-term physical stability of the cream. For example, liquid paraffin and white petrolatum together constitute the oil phase framework of the cream. White petrolatum provides strong sealing and structural support, while liquid paraffin adjusts the consistency and spreadability of the oil phase, preventing the cream from becoming too sticky. The combination of these two ensures excellent moisturizing and water-locking effects while optimizing the product's feel on the skin. In the oil phase, octadecyl alcohol and glyceryl mono- and di-stearates not only act as emulsifiers but their solid wax properties also increase the melting point and viscosity of the oil phase, thus contributing to the formation of a stable semi-solid ointment at room temperature. For example, heparin sodium, as a water-soluble active ingredient, is safely dissolved in the aqueous phase, and gentle processes (especially phase-inversion emulsification) ensure that it is not destroyed during emulsification. Propylene glycol not only improves product performance as a moisturizer but, more importantly, acts as a penetration enhancer, helping the large molecular weight heparin sodium dissolved in the aqueous phase to penetrate the skin barrier more effectively and reach the target site, thereby significantly improving efficacy. The stable O / W cream structure itself provides a good platform for drug efficacy, and the occlusive effect of the oil phase components (petrolatum, paraffin) reduces moisture loss and hydrates the stratum corneum, which in turn further promotes the penetration-enhancing effect of propylene glycol, creating a microenvironment conducive to drug absorption. In summary, the formulation of this application, through the synergistic effect between components, forms a relatively stable system both thermodynamically and kinetically, effectively preventing quality problems such as layering, rancidity, and crystallization.

[0058] In some preferred embodiments of this application, the heparin sodium cream comprises the following components in weight percentages: 0.15%~0.45% heparin sodium, 6.5%~8.0% propylene glycol, 0.09%~0.11% ethylparaben, 0.9%~1.1% sodium lauryl sulfate, 6.5%~8.0% glyceryl mono- and di-stearyl esters, 9.5%~10.5% stearyl alcohol, 9.5%~10.5% liquid paraffin, 9.5%~10.5% white petrolatum, and the balance being water.

[0059] The technical solutions described above in this application will be explained in detail below with reference to specific embodiments.

[0060] Example 1

[0061] This embodiment provides a heparin sodium cream, which comprises the following components by mass fraction:

[0062] Heparin sodium 0.45%,

[0063] Propylene glycol 8.0%,

[0064] Ethylparaben 0.11%,

[0065] Sodium dodecyl sulfate 0.9%,

[0066] Glyceryl monostearate and glyceryl distearate 8.0%,

[0067] Octadecyl alcohol 10.0%,

[0068] Liquid paraffin 10.5%,

[0069] White petrolatum 10.5%,

[0070] The remainder is water.

[0071] In this embodiment, the heparin sodium cream, taking a batch with a total volume of 200 kg as an example, consists of 78 kg of oil phase and 122 kg of aqueous phase. It is prepared using the following method:

[0072] S101. Add the prescribed amounts of white petrolatum and liquid paraffin to the emulsification tank in sequence. Set the stirring speed to 20 rpm and start stirring. Turn on the jacket and heat to 60°C. Then add the prescribed amounts of octadecyl alcohol and glyceryl mono- and glyceryl di-stearates. Continue stirring for 45 minutes, maintaining the temperature at 60°C to obtain the oil phase. Maintain the temperature and stirring state for later use.

[0073] S102. At room temperature, add the prescribed amounts of propylene glycol and ethylparaben to a stainless steel container, set the stirring speed to 1500 rpm and stir for 45 minutes until completely dissolved to obtain the first aqueous phase for later use.

[0074] S103. Add purified water to the premixing tank, turn on the stirrer at 1500 rpm and heat to 50°C. Then add sodium dodecyl sulfate and sodium heparin while stirring, and continue stirring for 45 minutes until completely dissolved to obtain the second aqueous phase for later use.

[0075] S104. Mix the first aqueous phase and the second aqueous phase, and stir at 1500 rpm for 20 minutes while keeping the temperature at 60℃ to obtain a mixed aqueous phase for later use.

[0076] S105. Weigh 74 kg of the mixed aqueous phase into the emulsification tank, turn on the wall-scraping agitator, and stir at 20 rpm for 20 minutes until the air bubbles in the tank cover the agitator. Turn on the homogenization function and homogenize at 1500 rpm for 20 minutes while maintaining the wall-scraping agitator to complete the first emulsification process.

[0077] S106. Add the remaining mixed aqueous phase to the emulsification tank from step S105, and stir at 20 rpm for 20 minutes until the air bubbles cover the stirring paddle. Then, start the homogenizer and homogenize at 1500 rpm for 20 minutes while maintaining wall-scraping stirring to complete the second emulsification process.

[0078] S107. Turn off the homogenizing and wall-scraping stirring functions, adjust the vacuum degree in the emulsifying tank to ≤-0.07MPa, then turn off the vacuum function and turn on the wall-scraping stirring (at a speed of 20rpm). Observe the foaming situation. If dense foam continues to be generated, slowly introduce air to atmospheric pressure. Repeat step S107 until dense foam is no longer generated.

[0079] S108. Maintain a vacuum of ≤-0.07MPa in the emulsifying tank, perform wall-scraping stirring at 20rpm, and implement gradient cooling. Specifically, first cool to 70℃ with 65℃ cooling water; then switch to 45℃ cooling water to 55℃; finally switch to 30℃ cooling water until the system temperature drops to 40℃, then discharge to obtain heparin sodium cream. A microscopic image of the cream is shown below. Figure 1 As shown (optical magnification 20x, D99 is 1.32μm).

[0080] Example 2

[0081] This embodiment provides a heparin sodium cream, which comprises the following components by mass fraction:

[0082] Heparin sodium 1.0%,

[0083] Propylene glycol 10.0%,

[0084] Ethylparaben 0.15%,

[0085] Sodium dodecyl sulfate 1.5%,

[0086] Glyceryl monostearate and glyceryl distearate 10.0%,

[0087] Octadecyl alcohol 12.0%,

[0088] Liquid paraffin 12.0%,

[0089] White petrolatum 12.0%,

[0090] The remainder is water.

[0091] The heparin sodium cream in this embodiment, taking a batch of 200 kg as an example, was prepared by the following method:

[0092] S201. Add the prescribed amounts of white petrolatum and liquid paraffin to the emulsification tank in sequence. Set the stirring speed to 30 rpm and start stirring. Turn on the jacket and heat to 80°C. Then add the prescribed amounts of octadecyl alcohol and glyceryl mono- and glyceryl di-stearates. Continue stirring for 30 minutes, maintaining the temperature at 80°C to obtain the oil phase. Maintain the temperature and stirring state for later use.

[0093] S202. At room temperature, add the prescribed amounts of propylene glycol and ethylparaben to a stainless steel container, set the stirring speed to 2000 rpm and stir for 30 minutes until completely dissolved to obtain the first aqueous phase for later use.

[0094] S203. Add purified water to the premix tank, turn on the stirrer at 2000 rpm and heat to 50°C. Then add sodium dodecyl sulfate and sodium heparin while stirring, and continue stirring for 30 minutes until completely dissolved to obtain the second aqueous phase for later use.

[0095] S204. Mix the first aqueous phase and the second aqueous phase, and stir at 2000 rpm for 10 minutes while keeping the temperature at 80℃ to obtain a mixed aqueous phase for later use.

[0096] S205. Weigh 54 kg of the mixed aqueous phase into the emulsification tank, turn on the wall-scraping agitator, and stir at 30 rpm for 10 minutes until the air bubbles in the tank cover the agitator. Turn on the homogenization function and homogenize at 2000 rpm for 10 minutes while maintaining the wall-scraping agitator to complete the first emulsification process.

[0097] S206. Add the remaining mixed aqueous phase to the emulsification tank from step S205, and stir at 30 rpm for 10 minutes until the air bubbles cover the stirring paddle. Then, start the homogenizer and homogenize at 2000 rpm for 10 minutes while maintaining wall-scraping stirring to complete the second emulsification process.

[0098] S207. Turn off the homogenizing and wall-scraping agitation functions, adjust the vacuum degree in the emulsification tank to ≤-0.07MPa, then turn off the vacuum function and turn on the wall-scraping agitation (30rpm). Observe the foaming situation. If dense foam continues to be generated, slowly introduce air to atmospheric pressure. Repeat step S207 until dense foam is no longer generated.

[0099] S208. Maintain the vacuum degree in the emulsification tank ≤ -0.07MPa, perform wall scraping and stirring at a speed of 30rpm, and carry out gradient cooling treatment; specifically, first cool down to the system temperature of 65℃ with 50℃ cooling water; then switch to 35℃ cooling water to cool down to the system temperature of 50℃; finally switch to 20℃ cooling water until the system temperature drops to 35℃, discharge the material, and obtain heparin sodium cream.

[0100] Example 3

[0101] This embodiment provides a heparin sodium cream, which comprises the following components by mass fraction:

[0102] Heparin sodium 0.1%,

[0103] Propylene glycol 5.0%,

[0104] Ethylparaben 0.05%,

[0105] Sodium dodecyl sulfate 0.5%,

[0106] Glyceryl monostearate and glyceryl distearate 5.0%,

[0107] Octadecyl alcohol 8.0%,

[0108] Liquid paraffin 8.0%,

[0109] White petrolatum 8.0%,

[0110] The remainder is water.

[0111] The heparin sodium cream in this embodiment, taking a batch of 200 kg as an example, was prepared by the following method:

[0112] S301. Add the prescribed amounts of white petrolatum and liquid paraffin to the emulsification tank in sequence. Set the stirring speed to 20 rpm and start stirring. Turn on the jacket and heat to 60°C. Then add the prescribed amounts of octadecyl alcohol and glyceryl mono- and glyceryl di-stearates. Continue stirring for 60 minutes, maintaining the temperature at 60°C to obtain the oil phase. Maintain the temperature and stirring state for later use.

[0113] S302. At room temperature, add the prescribed amounts of propylene glycol and ethylparaben to a stainless steel container, set the stirring speed to 1000 rpm and stir for 60 minutes until completely dissolved to obtain the first aqueous phase for later use.

[0114] S303. Add purified water to the premix tank, turn on the stirrer at 1000 rpm and heat to 50°C. Then add sodium dodecyl sulfate and sodium heparin while stirring, and continue stirring for 60 minutes until completely dissolved to obtain the second aqueous phase for later use.

[0115] S304. Mix the first aqueous phase and the second aqueous phase, and stir at 1000 rpm for 30 minutes while keeping the temperature at 60℃ to obtain a mixed aqueous phase for later use.

[0116] S305. Weigh 90 kg of the mixed aqueous phase into the emulsification tank, turn on the wall-scraping agitator, and stir at 10 rpm for 30 minutes until the air bubbles in the tank cover the agitator. Turn on the homogenization function and homogenize at 1000 rpm for 30 minutes while maintaining the wall-scraping agitator to complete the first emulsification process.

[0117] S306. Add the remaining mixed aqueous phase to the emulsification tank from step S305, and stir at 10 rpm for 30 minutes until the air bubbles cover the stirring paddle. Then, start the homogenizer and homogenize at 1000 rpm for 30 minutes while maintaining wall-scraping stirring to complete the second emulsification process.

[0118] S307. Turn off the homogenizing and wall-scraping agitation functions, adjust the vacuum degree in the emulsification tank to ≤-0.07MPa, then turn off the vacuum function and turn on the wall-scraping agitation (10rpm). Observe the foaming situation. If dense foam continues to be generated, slowly introduce air to atmospheric pressure. Repeat step S307 until dense foam is no longer generated.

[0119] S308. Maintain the vacuum degree in the emulsification tank ≤-0.07MPa, perform wall scraping and stirring at a speed of 10rpm, and carry out gradient cooling treatment; specifically, first cool down to the system temperature of 70℃ with 60℃ cooling water; then switch to 40℃ cooling water to cool down to the system temperature of 50℃; finally switch to 20℃ cooling water until the system temperature drops to 35℃, discharge the material, and obtain heparin sodium cream.

[0120] Comparative Example

[0121] This comparative example uses the same ingredients as Example 1, the difference being that the preparation process employs a conventional one-step emulsification method, i.e., directly mixing all the oil phase and water phase, followed by homogenization emulsification (3000 rpm, 80°C, 30 min) to obtain an O / W structure cream, the microscopic image of which is shown below. Figure 2 As shown (optical magnification 20x, D99 is 7.2μm).

[0122] Experimental Example

[0123] The heparin sodium cream prepared in Example 1 and the comparative example were subjected to quality testing, including:

[0124] (1) Valence testing

[0125] The standard adopted is from Part II of the 2010 edition of the Chinese Pharmacopoeia, namely:

[0126] Accurately weigh 2g each of the heparin sodium cream prepared in Example 1 and the comparative example, add 30mL of anhydrous ethanol, heat in a water bath to dissolve, cool to room temperature, transfer to a 100mL volumetric flask, dilute to the mark with 0.9% sodium chloride solution, shake well, place in a 4°C refrigerator overnight, remove, filter, accurately measure 50mL of the filtrate, evaporate in a water bath until no ethanol odor remains, transfer to a 50mL volumetric flask, dilute to the mark with 0.9wt% sodium chloride solution, shake well, and determine according to the method under the heparin sodium section. The potency refers to the unit of measurement for the biological activity of heparin sodium, used to characterize the intensity of its biological activity.

[0127] (2) D99 particle size

[0128] The particle size of heparin sodium cream was tested using a microscope. D99 means that 99% of the droplets measured had a diameter less than or equal to this D99 value.

[0129] (3) pH

[0130] Take 1g each of the heparin sodium cream prepared in Example 1 and the comparative example, add 10mL of water and mix well, then determine the pH value according to the method described in Appendix VI H. The pH value should be 6.5~8.5.

[0131] The test results are shown in Table 1.

[0132] Table 1. Quality test results of heparin sodium cream produced by different processes.

[0133]

[0134] In Table 1, the comparative example and Example 1 were produced in three batches using the same method, namely the first batch, the second batch, and the third batch. 0 hours refers to the time when production is completed, 6 months long-term refers to storage for 6 months in an environment of 25℃±2℃ and 60%RH±5%RH, and 6 months accelerated refers to storage for 6 months in an environment of 40℃±2℃ and 75%RH±5%RH.

[0135] From Table 1 and Figures 1-2It can be seen that, compared with heparin sodium cream produced by conventional processes, the heparin sodium cream produced by the method of this application exhibits lower droplet size (D99 stable below 5μm), more uniform and stable heparin sodium potency (maintained between 98% and 102%), and lower pH value (fluctuation range less than 0.5) under 0-hour, 6-month long-term conditions (25℃±2℃, 60%RH±5%RH), and accelerated conditions (40℃±2℃, 75%RH±5%RH). Furthermore, the data shows that the process of this application has advantages over conventional processes in reducing cream particle size, narrowing particle size distribution, improving stability, and significantly preserving the biological activity of heparin sodium. Figure 1 The droplet size is significantly smaller than Figure 2 The droplet size indicates that the method of this application can form oil-in-water creams with smaller droplet size and narrower distribution.

[0136] Example 1 of this application employs a controlled phase-inversion emulsification process. First, a portion of the aqueous and oil phases are homogenized and emulsified to form a water-in-oil structure (in this structure, oil is the continuous phase, and water is the dispersed phase; under a microscope, water appears as small bubbles). Then, the remaining aqueous phase is added and homogenized to form an oil-in-water structure, thus completing the phase-inversion emulsification. Therefore, in the heparin sodium cream of Example 1, water is more abundant than oil, water is the continuous phase, and oil is the dispersed phase. This is evident in the microscope photograph of Example 1 (…). Figure 1 In the first example, the oil phase has a small bubble structure with water as the background, meaning the inside of the bubble is the oil phase and the outside is the water phase. The comparative example uses a conventional one-step emulsification process, where the entire oil phase is directly added to the water phase for homogenization and emulsification, resulting in an oil-in-water structure that does not require phase inversion.

[0137] In summary, compared with the prior art, this application has the following significant advantages:

[0138] (1) Achieve efficient emulsification under mild conditions and retain the biological activity of heparin sodium to the maximum extent.

[0139] This application employs a controlled phase-inversion emulsification process, revolutionizing the traditional emulsification model that relies on high shear strength. At a relatively low homogenization speed of 1000 rpm to 2500 rpm, it achieves emulsification effects surpassing the high-speed homogenization of over 3000 rpm achieved by traditional one-step methods. This fundamentally avoids the damage to the molecular structure of heparin sodium caused by severe shearing, effectively protecting its biological activity. Accelerated stability tests and long-term storage observations have verified that the heparin sodium bioactivity of cream products prepared using this method remains stably maintained between 98% and 102% of the labeled content after long-term storage, demonstrating extremely high activity retention.

[0140] (2) Obtaining an ultra-micro and uniform droplet structure fundamentally improves the physical stability of the product.

[0141] The phase inversion process of this application is itself a highly efficient spontaneous emulsification process, capable of forming droplets with smaller particle size and narrower distribution. Combined with emulsification and defoaming under vacuum conditions, it not only completely eliminates air bubbles easily introduced by high-speed shearing but also avoids the potential threat to product stability posed by residual air bubbles. The final product's droplet size (D99) can be controlled below 5 μm, with a highly concentrated particle size distribution. This fine and uniform microstructure endows the cream with excellent physical stability, fundamentally solving problems such as layering and rancidity that are common in traditional products, and significantly extending the product's shelf life.

[0142] (3) The entire process is carried out at low temperature and with mild process, which ensures the stability of active ingredients and makes it easy to scale up industrially.

[0143] The entire process system of this application, including key steps such as oil phase preparation, aqueous phase formulation, emulsification, and subsequent cooling, operates under mild temperature conditions below 80°C. Simultaneously, an optimized gradient cooling program makes the thermal history of the system more gradual, further ensuring the stability of heat-sensitive heparin sodium. This low-temperature process not only has low equipment requirements and low energy consumption, but also features precise control of process parameters, good reproducibility, and excellent process robustness, fully meeting the requirements of large-scale industrial production and easily scalable for mass production.

[0144] The various embodiments in this specification are described in a progressive manner, with each embodiment focusing on its differences from other embodiments. Similar or identical parts between embodiments can be referred to interchangeably. Although preferred embodiments of this application 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 this application.

[0145] Finally, it should be noted that in this application, relational terms such as "first" and "second" are used merely to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or terminal device that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or terminal device. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or terminal device that includes the element.

[0146] This application uses specific examples to illustrate the principles and implementation methods of this application. The description of the above embodiments is only for the purpose of helping to understand the method and core ideas of this application. At the same time, for those skilled in the art, there will be changes in the specific implementation methods and application scope based on the ideas of this application. Therefore, the content of this specification should not be construed as a limitation of this application.

Claims

1. A process for the preparation of heparin sodium cream, characterized in that, The method comprises the following steps: mixing white petrolatum and liquid paraffin under stirring, adding octadecanol and glycerin monostearate and distearate after temperature treatment, and continuously stirring under temperature maintenance to obtain an oil phase; mixing propylene glycol and hydroxyphenyl ethyl ester at room temperature to obtain a first water phase; adding sodium dodecyl sulfate and sodium heparin to water after heating, and continuously stirring to obtain a second water phase; mixing the first water phase and the second water phase to obtain a mixed water phase; homogeneously emulsifying 50wt%-70wt% of the mixed water phase and the oil phase to obtain a water-in-oil primary emulsion; adding the remaining mixed water phase to the water-in-oil primary emulsion, uniformly stirring, and then sequentially performing homogenization treatment, defoaming treatment, and gradient cooling treatment to obtain the sodium heparin cream; the gradient cooling treatment comprises: maintaining a vacuum degree of ≤-0.07 MPa and a stirring speed of 10 rpm-30 rpm, and cooling the reaction product to 65°C-70°C by using cooling water at 50°C-65°C; switching to cooling water at 35°C-45°C to cool the reaction product to 50°C-55°C; switching to cooling water at 20°C-30°C to continuously cool the reaction product to 35°C-40°C; the preparation process of the water-in-oil primary emulsion comprises: mixing 50wt%-70wt% of the mixed water phase based on the total mass of the mixed water phase and the oil phase, stirring at a speed of 10 rpm, 20 rpm, or 30 rpm for 10 min-30 min, and homogenizing at a speed of 1500 rpm-2500 rpm for 10 min-30 min to obtain the water-in-oil primary emulsion; when the water-in-oil primary emulsion is mixed with the remaining mixed water phase, the stirring speed is 10 rpm-30 rpm, the stirring time is 10 min-30 min, the homogenization speed is 1500 rpm-2500 rpm, and the homogenization time is 10 min-30 min.

2. The production method according to claim 1, characterized by, the temperature after the temperature treatment is 60°C-80°C, the stirring speed in the preparation process of the oil phase is 10 rpm-30 rpm, and the continuous stirring time is 30 min-60 min.

3. The preparation method according to claim 1, characterized in that, the stirring speed in the preparation process of the first water phase is 1000 rpm-2500 rpm, and the stirring time is 30 min-60 min.

4. The production method according to claim 1, characterized by, the water heating temperature is 50°C-60°C, the stirring speed in the preparation process of the second water phase is 1000 rpm-2500 rpm, and the continuous stirring time is 30 min-60 min.

5. The preparation method according to claim 1, characterized in that, the stirring speed in the preparation process of the mixed water phase is 1000 rpm-2500 rpm, the stirring time is 10 min-30 min, and the mixing temperature is 60°C-80°C.

6. The heparin sodium cream prepared according to the process of any one of claims 1 to 5, characterized in that, The heparin sodium cream comprises the following components in percentage by mass: heparin sodium 0.1%-1.0%, propylene glycol 5.0%-10.0%, hydroxyphenyl ethyl ester 0.05%-0.15%, sodium dodecyl sulfate 0.5%-1.5%, monodouble stearic acid glyceride 5.0%-10.0%, octadecanol 8.0%-12.0%, liquid paraffin 8.0%-12.0%, white vaseline 8.0%-12.0%, and the balance is water; wherein the D99 particle size of the heparin sodium cream is <5 μm, the effective value is 99%-102%, and the pH value is 6.9-7.

3.

7. The heparin sodium cream according to claim 6, characterized in that, The heparin sodium cream comprises the following components in percentage by mass: heparin sodium 0.15%-0.45%, propylene glycol 6.5%-8.0%, hydroxyphenyl ethyl ester 0.09%-0.11%, sodium dodecyl sulfate 0.9%-1.1%, monodouble stearic acid glyceride 6.5%-8.0%, octadecanol 9.5%-10.5%, liquid paraffin 9.5%-10.5%, white vaseline 9.5%-10.5%, and the balance is water.

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