Heparin sodium cream and preparation method thereof

Abstract

The invention discloses heparin sodium cream and a preparation method thereof, and belongs to the technical field of pharmaceutical preparation production. The heparin sodium cream is prepared from the following components: heparin sodium, propylene glycol, ethylparaben, lauryl sodium sulfate, glyceryl monostearate and glyceryl distearate, octadecanol, liquid paraffin, white vaseline and water. The preparation method comprises the following steps: preparing an oil phase and a mixed water phase; emulsifying a part of the mixed water phase and the oil phase to form a water-in-oil primary emulsion; adding the residual mixed water phase into the primary emulsion, inducing phase transformation into oil-in-water emulsifiable paste under a mild condition, and performing vacuum defoaming and gradient cooling to obtain a finished product. Through a controlled phase inversion emulsification process, efficient emulsification is realized under mild conditions of 80 DEG C or below and 3000 rpm or below, the emulsion droplet particle size (D99) is less than 5 [mu] m, the problem that the active substance heparin sodium loses activity under severe conditions is thoroughly solved, and the product stability is significantly improved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparation, and in particular relates to a heparin sodium cream and a preparation method thereof. BACKGROUND

[0002] As an acidic mucopolysaccharide, heparin sodium has important application value in the medical field. However, the stability problem of heparin sodium in cream preparation has always been a technical challenge faced by those skilled in the art. Studies have shown that heparin sodium is significantly sensitive to temperature, mechanical shear force and pH change, which puts strict requirements on the process development and product quality control of heparin sodium in cream preparation.

[0003] At present, the conventional production process of heparin sodium cream preparation mainly adopts one-step emulsification method. This method usually mixes the oil phase, the water phase containing heparin sodium and the emulsifier at one time, and then completes the emulsification process under the condition of high temperature above 80℃ and high speed homogenization above 3000rpm. Although this method is widely used in industrial production, its inherent process defects have become increasingly prominent. Specifically, the high-speed homogenization step in the above one-step emulsification method produces intense mechanical shear force, which not only leads to local heat production concentration, but also introduces a large amount of bubbles into the system. For heparin sodium, which is a heat-sensitive and shear-sensitive active ingredient, this harsh process environment can easily cause the degradation of its molecular structure, resulting in a significant loss of biological activity. In addition, the presence of heat and bubbles also has a negative impact on the microstructure and physical stability of the cream, such as causing oil-water separation, promoting product rancidity, etc., ultimately affecting the shelf life and safety of the product.

[0004] To avoid the problems of heat production and bubbles caused by high-speed homogenization, researchers have tried to adopt the strategy of reducing the homogenization speed. However, under the condition of low-speed homogenization below 3000rpm, although the damage to the activity of heparin sodium can be reduced, due to the insufficient homogenization strength, it is often difficult to fully emulsify the oil phase and the water phase, resulting in large particle size and uneven distribution of the formed emulsion droplets. This insufficient emulsification state also causes the cream system to be unstable, prone to problems such as delamination, rancidity, etc., which cannot meet the product quality requirements.

[0005] In summary, the preparation process of existing heparin sodium cream is trapped in a difficult technical contradiction: on the one hand, in order to obtain ideal emulsion droplet size and emulsification effect, harsh conditions of high temperature and high speed are needed, but this will sacrifice the activity of heparin sodium and the stability of the product; on the other hand, in order to protect the activity of heparin sodium, mild conditions are adopted, which cannot guarantee the sufficiency of emulsification, also leading to insufficient product stability. SUMMARY

[0006] The application aims to provide a heparin sodium cream and a preparation method thereof, which can realize sufficient emulsification under mild process conditions, effectively control the droplet size, eliminate bubbles, and maximize the biological activity of heparin sodium.

[0007] To achieve the above-mentioned purpose, the application provides a preparation method of a heparin sodium cream, comprising the following steps: In a stirring state, white petrolatum and liquid paraffin are mixed, and after temperature treatment, octadecanol and glycerol monostearate and distearate are added, and the oil phase is obtained by continuous stirring under temperature preservation; The first water phase is obtained by mixing propylene glycol and hydroxyphenyl ethyl ester at room temperature; After the water is heated, sodium dodecyl sulfate and heparin sodium are added, and the second water phase is obtained by continuous stirring; The mixed water phase is obtained by mixing the first water phase and the second water phase; The water-in-oil primary emulsion is obtained by homogenously emulsifying 50wt%-70wt% of the mixed water phase and the oil phase; The heparin sodium cream is prepared by adding the remaining mixed water phase into the water-in-oil primary emulsion, uniformly stirring, and sequentially performing homogenization treatment, defoaming treatment, and gradient cooling treatment.

[0008] Further, the temperature after temperature treatment is 60°C-80°C, the stirring speed during the preparation of the oil phase is 10rpm-30rpm, and the continuous stirring time is 30min-60min.

[0009] Further, the stirring speed during the preparation of the first water phase is 1000rpm-2500rpm, and the stirring time is 30min-60min.

[0010] Further, the water heating temperature is 50°C-60°C, the stirring speed during the preparation of the second water phase is 1000rpm-2500rpm, and the continuous stirring time is 30min-60min.

[0011] Further, the stirring speed during the preparation of the mixed water phase is 1000rpm-2500rpm, the stirring time is 10min-30min, and the mixing temperature is 60°C-80°C.

[0012] Further, the preparation process of the water-in-oil primary emulsion comprises the following steps: mixing 50wt%-70wt% of the mixed water phase and the oil phase, stirring at a speed of 1000rpm-2500rpm for 10min-30min, and homogenizing at a speed of 1500rpm-2500rpm for 10min-30min to obtain the water-in-oil primary emulsion.

[0013] Further, the stirring speed of the water-in-oil type colostrum mixed with the residual mixed water phase is 10 rpm to 30 rpm, and the stirring time is 10 min to 30 min; the homogenization speed is 1500 rpm to 2500 rpm, and the homogenization time is 10 min to 30 min.

[0014] Further, the gradient cooling treatment comprises: maintaining a vacuum degree of ≤-0.07 MPa and a stirring speed of 10 rpm to 30 rpm, and cooling the reaction product to 65℃ to 70℃ by using cooling water at 50℃ to 65℃; switching to cooling water at 35℃ to 45℃ to cool the reaction product to 50℃ to 55℃; and switching to cooling water at 20℃ to 30℃ to continue cooling the reaction product to 35℃ to 40℃.

[0015] The application further provides a heparin sodium cream obtained by the preparation method, comprising the following components in percentage by mass: heparin sodium 0.1% to 1.0%, propylene glycol 5.0% to 10.0%, hydroxyphenyl ethyl ester 0.05% to 0.15%, sodium dodecyl sulfate 0.5% to 1.5%, monodiglyceride 5.0% to 10.0%, octadecanol 8.0% to 12.0%, liquid paraffin 8.0% to 12.0%, white vaseline 8.0% to 12.0%, and the balance being water; wherein the D99 particle size of the heparin sodium cream is <5 μm, the potency value is 99% to 102%, and the pH value is 6.9 to 7.3.

[0016] Further, the heparin sodium cream comprises the following components in percentage by mass: heparin sodium 0.15% to 0.45%, propylene glycol 6.5% to 8.0%, hydroxyphenyl ethyl ester 0.09% to 0.11%, sodium dodecyl sulfate 0.9% to 1.1%, monodiglyceride 6.5% to 8.0%, octadecanol 9.5% to 10.5%, liquid paraffin 9.5% to 10.5%, white vaseline 9.5% to 10.5%, and the balance being water.

[0017] In summary, the application has the following advantages: The present application realizes full emulsification of the heparin sodium cream through a controlled phase inversion process (i.e., first, a part of the water phase is mixed with the oil phase to form a W / O structure, then the remaining part of the water phase is added to the homogeneous emulsion, and the phase inversion is controlled, and finally, an O / W structure cream is obtained). The phase inversion instantaneously releases a huge interfacial energy, greatly improving the emulsification efficiency, and can spontaneously promote the rapid reduction of the emulsion droplet size and tend to uniform distribution. Therefore, unlike the traditional method which relies on high shear external force to forcibly disperse, the present application realizes high-efficiency emulsification by utilizing the inherent physical and chemical changes in the system. The method of the present application can obtain smaller and more uniform emulsion droplet size under significantly milder temperature (e.g., below 80℃) and lower shear force (1000 rpm~2500 rpm) conditions compared to the traditional high-speed homogenization method. As can be seen, this mild process environment minimizes the thermal degradation and mechanical shear damage to heparin sodium molecules, thereby effectively protecting the biological activity, and the fine emulsion droplet structure also ensures the long-term physical stability of the final cream product. BRIEF DESCRIPTION OF DRAWINGS

[0018] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed to be used in the description of the embodiments of the present application will be briefly introduced. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor.

[0019] Figure 1 is a microscope photo of the heparin sodium cream proposed by the embodiment 1 of the present application.

[0020] Figure 2 is a microscope photo of the heparin sodium cream proposed by the comparative example of the present application. DETAILED DESCRIPTION

[0021] The technical solutions in the embodiments of the present application will be described clearly and completely in the following with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, not all. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0022] Since the existing heparin sodium cream preparation process cannot reconcile the core contradictions, that is, it cannot simultaneously meet the two core technical requirements of heparin sodium activity retention and cream system stability. Based on this, a new heparin sodium cream preparation method is developed, which can be implemented under mild process conditions of a mild temperature below 80℃ and a homogenization speed below 3000rpm, while ensuring full emulsification, effectively controlling the size and distribution of emulsion droplets, and eliminating bubbles in the system, ultimately realizing the effective guarantee of the stability of the cream preparation under the premise of maximizing the retention of the biological activity of heparin sodium.

[0023] Specifically, in a first aspect, the present application provides a preparation method of heparin sodium cream, comprising the following steps: S1, mixing white vaseline and liquid paraffin under stirring, adding octadecanol and glycerol monostearate after temperature treatment, and continuously stirring under temperature preservation to obtain an oil phase.

[0024] In the specific embodiment, the temperature after temperature treatment in step S1 is 60℃-80℃, the stirring speed during the preparation of the oil phase is 10rpm-30rpm, and the continuous stirring time is 30min-60min. During the preparation of the oil phase, a low speed can ensure uniform mixing.

[0025] S2, mixing propylene glycol and hydroxyphenyl ethyl ester at room temperature to obtain a first water phase.

[0026] In the specific embodiment, the stirring speed in step S2 is 1000rpm-2500rpm, and the stirring time is 30min-60min. Since the solubility of hydroxyphenyl ethyl ester in water is limited, but the solubility in propylene glycol is better. The present application first mixes the two, which can ensure that the hydroxyphenyl ethyl ester is fully dissolved and uniformly dispersed, avoiding crystallization in the final product.

[0027] S3, heating water, adding sodium dodecyl sulfate and heparin sodium, and continuously stirring to obtain a second water phase.

[0028] In the specific embodiment, the temperature of the water after heating is 50℃-60℃, the stirring speed during the preparation of the second water phase is 1000rpm-2500rpm, and the continuous stirring time is 30min-60min. Heparin sodium and sodium dodecyl sulfate (main emulsifier) are water-soluble, heating the water to 50℃-60℃ can accelerate the dissolution of heparin sodium, ensuring that it is completely and uniformly dispersed in the water phase. And the appropriate temperature helps sodium dodecyl sulfate to better dissolve and stretch its molecular chain, so that it can migrate to the oil-water interface faster in the subsequent emulsification process, thereby improving the emulsification efficiency.

[0029] S4, mixing the first water phase and the second water phase to obtain a mixed water phase.

[0030] In the embodiment, the stirring speed of the mixing in step S4 is 1000 rpm-2500 rpm, the stirring time is 10 min-30 min, and the mixing temperature is 60°C-80°C. The temperature is raised to 60°C-80°C during the mixing of the water phase, so that the temperature of the water phase is close to the temperature of the oil phase, thereby avoiding local demulsification or unstable crystal nucleus caused by a large temperature difference, and realizing stable and efficient emulsification.

[0031] S5, taking 50wt%-70wt% of the mixed water phase and the oil phase to perform homogenization emulsification, to obtain a water-in-oil primary emulsion.

[0032] In the embodiment, step S5 includes the following steps: taking 50wt%-70wt% of the mixed water phase based on the total mass of the mixed water phase to mix with the oil phase, stirring at a speed of 1000 rpm-2500 rpm for 10 min-30 min, and homogenizing at a speed of 1500 rpm-2500 rpm for 10 min-30 min. Step S5 is the first emulsification process, and the reaction system naturally forms a W / O structure (i.e., a water-in-oil primary emulsion) with water droplets dispersed in oil under the action of the emulsifier. To ensure that the final O / W cream has a smaller particle size and a narrower distribution, the internal structure of the water-in-oil primary emulsion obtained in step S5 needs to be uniform, so as to prepare for the complete phase transition after the addition of the remaining water phase in step S6.

[0033] S6, 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 to obtain the heparin sodium cream. With the increase of the volume of the water phase, the reaction system crosses the phase transition point, and the continuous phase is transformed from the oil phase to the water phase under the action of the emulsifier, so as to finally form the target oil-in-water (O / W) cream, thereby realizing an efficient emulsification process.

[0034] In the embodiment, the stirring speed of the mixing of the water-in-oil primary emulsion and the remaining mixed water phase in step S6 is 10 rpm-30 rpm, and the time is 10 min-30 min; the homogenization treatment speed is 1500 rpm-2500 rpm, and the time is 10 min-30 min. When the remaining water phase is added, a low stirring speed is used to avoid the destruction of the ongoing and fine phase transition process caused by violent disturbance, so as to ensure that the phase transition is stable and controllable. After the phase transition is completed, a gentle homogenization is performed to homogenize the O / W emulsion droplets with a small particle size that have been formed, further reduce the particle size, and make the distribution more concentrated, while completely eliminating a small amount of large droplets that may exist.

[0035] In the embodiment, the gradient cooling treatment comprises: maintaining the vacuum degree ≤-0.07 MPa and the stirring speed of 10 rpm-30 rpm, and cooling the reaction product to 65-70°C by using cooling water at 50-65°C; switching to cooling water at 35-45°C to cool the reaction product to 50-55°C; and switching to cooling water at 20-30°C to continue cooling the reaction product to 35-40°C. The application avoids the phenomenon of solidification of the oil phase, lattice precipitation or damage to the emulsion droplet structure in the cream caused by rapid cooling through the staged cooling treatment.

[0036] In the embodiment, the defoaming is performed after the homogenization treatment by the following method: closing the homogenization and wall scraping stirring functions, maintaining or restarting the vacuum pump to make the vacuum degree ≤-0.07 MPa, stopping the vacuum, starting the wall scraping stirring, and setting the stirring speed to 10 rpm-30 rpm. The foam condition is observed, and if the dense foam is continuously generated, the air is slowly introduced to the normal pressure. The operation is repeated until the dense foam is no longer generated. The application defoams under the vacuum (≤-0.07 MPa), and the bubbles in the system are rapidly broken and escaped by using the pressure difference between the inside and the outside. In combination with the intermittent vacuum breaking treatment and the stirring treatment, the residual stubborn bubbles can be effectively driven away, the bubble problem is fundamentally solved, and the delicate texture and stability of the product are ensured.

[0037] In summary, the preparation method of the heparin sodium cream of the application is based on an innovative controlled phase inversion emulsification principle, which fundamentally changes the formation mechanism of the cream and solves the inherent contradiction between the active ingredient protection and the emulsification efficiency in the traditional process. The controlled phase inversion emulsification is not a one-time mixing and emulsification of all components, but a dynamic and staged phase change process to build the final cream structure. Specifically, the method first pre-mixes all the oil phase and part of the water phase under the action of the emulsifier to form a water-in-oil (W / O) type primary emulsion. In this stage, the water phase is dispersed in the continuous oil phase in the form of small droplets. Then, under the conditions of continuous stirring and homogenization, the remaining water phase containing heparin sodium is slowly added to the W / O type primary emulsion system in a controllable manner. With the continuous increase of the water phase volume fraction, the phase balance in the system is broken. Under the synergistic action of the emulsifier, the roles of the dispersed phase and the continuous phase are reversed, that is, the system undergoes a phase inversion process from water-in-oil (W / O) to oil-in-water (O / W), and finally forms the target oil-in-water cream.

[0038] In a second aspect, based on the overall inventive concept, the application provides a heparin sodium cream obtained by the above method, comprising the following components in mass percentage: heparin sodium 0.1% to 1.0%, propylene glycol 5.0% to 10.0%, hydroxyphenyl ethyl ester 0.05% to 0.15%, sodium dodecyl sulfate 0.5% to 1.5%, glycerol monostearate 5.0% to 10.0%, octadecanol 8.0% to 12.0%, liquid paraffin 8.0% to 12.0%, white petrolatum 8.0% to 12.0%, and the balance being water.

[0039] The components in the application have the following effects respectively: (1) Heparin sodium is the main active ingredient of the cream. As an acidic mucopolysaccharide, heparin sodium has pharmacological activities such as anticoagulation, anti-inflammation, promotion of local blood circulation, and acceleration of tissue repair, and is the core component of the cream for exerting therapeutic effect.

[0040] (2) Propylene glycol is a humectant, a penetration enhancer, and a cosolvent. 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 poorly water-soluble components in the cream.

[0041] (3) Hydroxyphenyl ethyl ester is a preservative. Also known as nipagin, it is used to inhibit the growth of microorganisms (bacteria, fungi) and prevent the cream from being contaminated and deteriorated during storage and use, thereby improving the safety and shelf life of the cream.

[0042] (4) Sodium dodecyl sulfate is a primary emulsifier (water-soluble) and an anionic surfactant.

[0043] (5) Glycerol monostearate is an auxiliary emulsifier, a stabilizer, and an oil phase thickening agent. It is a non-ionic surfactant that is used in combination with primary emulsifiers such as sodium dodecyl sulfate to enhance the strength and flexibility of the emulsion film and improve the stability of the cream.

[0044] (6) Octadecanol is an oil phase component, a co-emulsifier, a stabilizer, a thickening agent, and a skin feel improver. As a higher fatty alcohol, octadecanol is part of the oil phase that can increase the consistency and structural strength of the cream. It can form a complex with emulsifiers at the interface to further enhance the stability of the cream. In addition, it can also give the cream a smooth and moisturizing application skin feel.

[0045] (7) Liquid paraffin is an oil phase component, a humectant, and a occlusive agent. It is a mineral oil that can form a hydrophobic film on the skin surface, effectively reducing water evaporation from the skin, and playing a role in occlusion and moisturization. At the same time, it is also an important component of the oil phase structure of the cream.

[0046] (8) White petrolatum as oil phase ingredient, strong occlusive agent and excipient. White petrolatum is a very stable oil, with strong occlusive and moisturizing properties, can long-acting lock water, soften the skin. The oil matrix backbone of the cream, which is crucial to the final form and stability of the cream.

[0047] (9) Water as solvent, dispersion medium (continuous phase). Water is the highest content component in the formula, as a solvent to dissolve heparin sodium, propylene glycol, hydroxyethyl benzoate and sodium dodecyl sulfate and other water-soluble ingredients. In the final oil-in-water (O / W) cream, water constitutes the external continuous phase.

[0048] At the same time, the various components in the present application also have synergistic effect between each other. For example, sodium dodecyl sulfate (anionic) and glycerol mono-diestearate (nonionic) are emulsification synergistic combination. Anionic emulsifier provides strong emulsifying ability, while nonionic emulsifier can enhance the elasticity and density of the interface film, the combination of the two can form a more stable, more resistant to temperature and pH changes of the droplet interface film than single emulsifier. Stearyl alcohol as an emulsifying agent, its molecules can insert into the interface film formed by the emulsifier, further strengthen the physical strength of the film, prevent the coalescence of the droplets, thereby significantly improve the long-term physical stability of the cream. For example, liquid paraffin and white petrolatum together constitute the oil phase backbone of the cream, white petrolatum provides strong occlusion and structural support, while liquid paraffin adjusts the consistency and spreadability of the oil phase, so that the cream is not too sticky. The combination of the two not only ensures excellent moisturizing and water-locking effect, but also optimizes the use of skin feel of the product. Stearyl alcohol and glycerol mono-diestearate not only play an emulsifying auxiliary role in the oil phase, but also increase the melting point and consistency of the oil phase due to their solid wax characteristics, thereby helping to form a stable semi-solid paste at room temperature. For example, heparin sodium as a water-soluble main drug is safely dissolved in the aqueous phase, and the mild process (especially phase inversion emulsification) can ensure that it is not destroyed during the emulsification process; propylene glycol not only improves product performance as a humectant, but more importantly as a penetration enhancer, it can help the large molecule heparin sodium dissolved in the aqueous phase to penetrate the skin barrier more effectively, reach the target, thereby significantly improving the drug efficacy; the stable O / W cream structure itself also provides a good platform for drug efficacy, the occlusive effect of the oil phase ingredients (petrolatum, paraffin) reduces water loss, hydrates the stratum corneum, which in turn further promotes the penetration of propylene glycol, forming a microenvironment conducive to drug absorption. In summary, the formula of the present application forms a relatively stable system in thermodynamics and dynamics through the synergistic effect between components, which can effectively prevent delamination, rancidity, crystallization and other quality problems.

[0049] In some more preferable embodiments of the present application, the heparin sodium cream comprises the following components by mass percentage: heparin sodium 0.15% to 0.45%, propylene glycol 6.5% to 8.0%, hydroxyphenyl ethyl ester 0.09% to 0.11%, sodium dodecyl sulfate 0.9% to 1.1%, glycerin monostearate 6.5% to 8.0%, octadecanol 9.5% to 10.5%, liquid paraffin 9.5% to 10.5%, white vaseline 9.5% to 10.5%, and the balance is water.

[0050] The above technical solutions of the present application will be described in detail below in combination with specific embodiments.

[0051] Embodiment 1 The present embodiment provides a heparin sodium cream comprising the following components by mass fraction: heparin sodium 0.45%, propylene glycol 8.0%, hydroxyphenyl ethyl ester 0.11%, sodium dodecyl sulfate 0.9%, glycerin monostearate 8.0%, octadecanol 10.0%, liquid paraffin 10.5%, white vaseline 10.5%, and the balance is water.

[0052] The heparin sodium cream of the present embodiment, taking a total batch of 200 kg as an example, the oil phase is 78 kg and the water phase is 122 kg. It is prepared by the following method: S101. Add the formula amount of white vaseline and liquid paraffin in the emulsification tank in sequence, set the stirring speed to 20 rpm to start stirring, and open the jacket to heat to 60℃. Then add the formula amount of octadecanol and glycerin monostearate, continue to stir for 45 min, keep the temperature at 60℃, obtain the oil phase, and maintain the temperature and stirring state for standby.

[0053] S102. At room temperature, add the formula amount of propylene glycol and hydroxyphenyl ethyl ester to the stainless steel barrel, set the stirring speed to 1500 rpm and stir for 45 min, completely dissolved to obtain the first water phase for standby.

[0054] S103. Add purified water to the premix tank, start stirring at a speed of 1500 rpm and heat to 50℃, then add sodium dodecyl sulfate and heparin sodium under stirring, continue to stir for 45 min until completely dissolved, obtain the second water phase for standby.

[0055] S104. Mix the first water phase and the second water phase, and stir at a speed of 1500 rpm for 20 min, control the temperature at 60℃, obtain the mixed water phase for standby.

[0056] S105. Weigh 74 kg of the mixed water phase into the emulsification tank, and start the scraping stirring at a rotation speed of 20 rpm for 20 min until the bubbles in the tank cover the stirring blades. Start the homogenization at a rotation speed of 1500 rpm for 20 min while maintaining the scraping stirring, to complete the first emulsification process.

[0057] S106. Add the remaining mixed water phase into the emulsification tank of step S105, and perform the scraping stirring at a rotation speed of 20 rpm for 20 min until the bubbles cover the stirring blades. Then start the homogenization at a rotation speed of 1500 rpm for 20 min while maintaining the scraping stirring, to complete the second emulsification process.

[0058] S107. Turn off the homogenization and scraping stirring functions, adjust the vacuum degree in the emulsification tank to be ≤-0.07 MPa, then turn off the vacuum function and start the scraping stirring (at a rotation speed of 20 rpm), and observe the foam situation. If the dense foam still continuously generates, slowly introduce air to the normal pressure. Repeat step S107 until no dense foam is generated.

[0059] S108. Maintain the vacuum degree in the emulsification tank to be ≤-0.07 MPa, and perform the scraping stirring at a rotation speed of 20 rpm, and perform the gradient cooling treatment; specifically, first cool to a system temperature of 70℃ with cooling water at 65℃; then switch to cooling water at 45℃ to cool to a system temperature of 55℃; finally switch to cooling water at 30℃ until the system temperature is reduced to 40℃, and discharge to obtain the heparin sodium cream, whose microscope photograph is shown in FIG. 1 (the optical magnification is 20 times, and D99 is 1.32 μm). Figure 1

[0060] Example 2 The present example provides a heparin sodium cream, which comprises the following components by mass fraction: heparin sodium 1.0%, propylene glycol 10.0%, hydroxyphenyl ethyl ester 0.15%, sodium lauryl sulfate 1.5%, glyceryl monostearate 10.0%, octadecanol 12.0%, liquid paraffin 12.0%, white petrolatum 12.0%, and the balance is water.

[0061] The heparin sodium cream of the present example is prepared by the following method, taking a batch of total amount of 200 kg as an example: ​S201. Add the white petrolatum and liquid paraffin in the emulsification tank in turn, set the stirring speed to 30 rpm, and start stirring. Turn on the jacket heating to 80°C. Then add the octadecanol and glycerin monostearate and double stearate, continue stirring for 30 min, and keep the temperature at 80°C. Obtain the oil phase, and maintain the temperature and stirring state for standby.

[0062] S202. At room temperature, add the propylene glycol and hydroxyphenyl ethyl ester in the stainless steel barrel, set the stirring speed to 2000 rpm, and stir for 30 min to completely dissolve to obtain the first aqueous phase for standby.

[0063] S203. Add purified water in the premix tank, start stirring at a speed of 2000 rpm, and heat to 50°C. Then add the sodium dodecyl sulfate and heparin sodium under stirring, continue stirring for 30 min until completely dissolved to obtain the second aqueous phase for standby.

[0064] S204. Mix the first aqueous phase and the second aqueous phase, and stir at a speed of 2000 rpm for 10 min, and control the temperature at 80°C to obtain the mixed aqueous phase for standby.

[0065] S205. Weigh 54 kg of the mixed aqueous phase into the emulsification tank, start scraping wall stirring at a speed of 30 rpm, and stir for 10 min until the bubbles in the tank cover the stirring paddle. Start homogenization at a speed of 2000 rpm for 10 min while maintaining scraping wall stirring to complete the first emulsification process.

[0066] S206. Add the remaining mixed aqueous phase into the emulsification tank of step S205, and hang wall stirring at a speed of 30 rpm for 10 min until the bubbles cover the stirring paddle. Then start homogenization at a speed of 2000 rpm for 10 min while maintaining scraping wall stirring to complete the second emulsification process.

[0067] S207. Turn off the homogenization and scraping wall stirring functions, adjust the vacuum degree in the emulsification tank to ≤-0.07 MPa, then turn off the vacuum function and start scraping wall stirring (at a speed of 30 rpm), and observe the foam situation. If the dense foam still continuously generates, slowly introduce air to normal pressure. Repeat step S207 until no dense foam is generated.

[0068] S208. Maintain the vacuum degree in the emulsification tank at ≤-0.07 MPa, and perform scraping wall stirring at a speed of 30 rpm and gradient cooling treatment; specifically, first cool to the system temperature of 65°C with 50°C cooling water; then switch to 35°C cooling water to cool to the system temperature of 50°C; finally switch to 20°C cooling water until the system temperature drops to 35°C, and discharge to obtain the heparin sodium ointment.

[0069] Example 3 The present embodiment provides a heparin sodium cream, which comprises the following components by mass fraction: Heparin sodium 0.1%, Propylene glycol 5.0%, Hydroxyphenyl ethyl ester 0.05%, Sodium lauryl sulfate 0.5%, Glyceryl monostearate 5.0%, Octadecanol 8.0%, Liquid paraffin 8.0%, White petrolatum 8.0%, The balance is water.

[0070] The heparin sodium cream of the present embodiment is prepared by the following method, taking a total batch of 200 kg as an example: S301. Add the formula amount of white petrolatum and liquid paraffin in the emulsification tank in turn, set the stirring speed to 20 rpm, start stirring, and open the jacket to heat to 60°C. Then add the formula amount of octadecanol and glyceryl monostearate, continue stirring for 60 min, keep the temperature at 60°C, obtain the oil phase, and maintain the temperature and stirring state for standby.

[0071] S302. At room temperature, add the formula amount of propylene glycol and hydroxyphenyl ethyl ester to the stainless steel barrel, set the stirring speed to 1000 rpm, stir for 60 min, completely dissolve to obtain the first water phase for standby.

[0072] S303. Add purified water to the premix tank, start stirring at a speed of 1000 rpm, heat to 50°C, then add sodium lauryl sulfate and heparin sodium under stirring, continue stirring for 60 min until completely dissolved, obtain the second water phase for standby.

[0073] S304. Mix the first water phase and the second water phase, stir at a speed of 1000 rpm for 30 min, control the temperature at 60°C, obtain the mixed water phase for standby.

[0074] S305. Take 90 kg of the mixed water phase into the emulsification tank, start wall scraping stirring at a speed of 10 rpm, stir for 30 min until the bubbles in the tank cover the stirring paddle. Start homogenization at a speed of 1000 rpm for 30 min, while maintaining wall scraping stirring, complete the first emulsification process.

[0075] S306. Add the remaining mixed water phase to the emulsification tank of step S305, hang wall stirring at a speed of 10 rpm for 30 min until the bubbles cover the stirring paddle. Then start homogenization at a speed of 1000 rpm for 30 min, while maintaining wall scraping stirring, complete the second emulsification process.

[0076] 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.

[0077] 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.

[0078] Comparative Example 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).

[0079] Experimental Example The heparin sodium cream prepared in Example 1 and the comparative example were subjected to quality testing, including: (1) Valence testing The standard adopted is from Part II of the 2010 edition of the Chinese Pharmacopoeia, namely: 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.

[0080] (2) D99 particle size 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.

[0081] (3) pH 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.

[0082] The test results are shown in Table 1.

[0083] Table 1 Quality test results of heparin sodium cream produced by different processes

[0084] In Table 1, the comparative example and Example 1 were produced in three batches, namely the first batch, the second batch and the third batch, according to the same method. 0 hour refers to the time when the production is completed, 6 months long-term refers to the storage in an environment of 25℃±2℃ and 60%RH±5%RH for 6 months, and 6 months acceleration refers to the storage in an environment of 40℃±2℃ and 75%RH±5%RH for 6 months.

[0085] From Table 1 and Figures 1-2 It can be seen that the heparin sodium cream product produced by the method of the present application has lower droplet particle size (D99 is stabilized below 5 μm), more uniform and stable heparin sodium potency (all maintained between 98% and 102%) and pH value (the fluctuation range is all less than 0.5) compared with the heparin sodium cream product produced by the conventional process under 0 hour, 6 months long-term condition (25℃±2℃, 60%RH±5%RH) and acceleration condition (40℃±2℃, 75%RH±5%RH). The data show that the process of the present application has the advantages of reducing the particle size of the cream, narrowing the particle size distribution, improving the stability and significantly retaining the biological activity of heparin sodium compared with the conventional process. Among them, Figure 1 The droplet particle size is obviously smaller than that in Figure 2 , which shows that the method of the present application can form an oil-in-water cream with smaller particle size and narrower distribution.

[0086] The controlled phase inversion emulsification process is adopted in Example 1 of the present application. First, part of the water phase and the oil phase are homogeneously emulsified to form a water-in-oil structure (in the water-in-oil structure, the oil is the continuous phase and the water is the dispersed phase, and under the microscope, the water is small bubbles), then the remaining water phase is added for homogenous emulsification to form an oil-in-water structure, thereby completing the phase inversion emulsification. Therefore, the heparin sodium cream of Example 1 has more water than oil, the water is the continuous phase and the oil is the dispersed phase, and in the microscope photo of Example 1 Figure 1 , the oil is in the form of small bubbles and the water is the background, that is, the inside of the bubbles is the oil phase and the outside is the water phase. The comparative example adopts the conventional one-step emulsification process, and the oil phase is directly added to the water phase for homogenous emulsification to form an oil-in-water structure, without the need for phase inversion.

[0087] In summary, compared with the prior art, the present application has the following significant beneficial effects: (1) High-efficiency emulsification is realized under mild conditions, and the biological activity of heparin sodium is maximally retained.

[0088] The application overturns the emulsification mode of traditional process which relies on high shear strength by using a controlled phase inversion emulsification process. The emulsification effect of the traditional one-step method at a high speed of 3000 rpm or more can be achieved at a lower homogenization speed of 1000 rpm to 2500 rpm. The damage of the sodium heparin molecular structure caused by severe shearing is fundamentally avoided, and the biological activity is effectively protected. Through the accelerated stability test and long-term sample inspection verification, the biological activity of the sodium heparin in the cream product prepared by the method of the application can still be stably maintained at 98% to 102% of the labeled content after long-term storage, and the activity retention rate is extremely high.

[0089] (2) Obtain ultra-fine and uniform emulsion droplet structure, fundamentally improve the physical stability of the product.

[0090] The phase inversion process of the application itself is a high-efficiency spontaneous emulsification process, which can form emulsion droplets with smaller particle size and narrower distribution. In combination with emulsification and defoaming under vacuum conditions, not only the air bubbles introduced by high-speed shearing are completely eliminated, but also the potential threat of air bubble residues to product stability is avoided. The emulsion droplet particle size (D99) of the final product can be controlled below 5 μm, and the particle size distribution is highly concentrated. This fine and uniform microstructure endows the cream with excellent physical stability, fundamentally solving the problems of delamination and rancidity of traditional products, and significantly prolonging the shelf life of the product.

[0091] (3) The whole process is low-temperature and mild, which ensures the stability of active ingredients and is easy to be scaled up in industry.

[0092] The whole process system of the application, including the preparation of oil phase, the preparation of water phase, emulsification and subsequent cooling, is operated at a mild temperature of 80°C or below. At the same time, through the optimized gradient cooling program, the thermal history of the system is more gentle, which further ensures the stability of the heat-sensitive sodium heparin. This low-temperature process not only has low requirements for equipment and low energy consumption, but also has accurate process parameter control and good reproducibility, which shows excellent process robustness and fully meets the requirements of industrial production, and is easy to realize large-scale production.

[0093] Each embodiment in the specification is described in a progressive manner, and each embodiment focuses on the difference from other embodiments. The same and similar parts of each embodiment can be referred to each other. Although the preferred embodiments of the application have been described, those skilled in the art can make other changes and modifications to the embodiments once they know the basic creative concept. Therefore, the appended claims are intended to include the preferred embodiments and all changes and modifications falling within the scope of the embodiments of the application.

[0094] Finally, it is to be understood that the terms such as first and second, etc., are used herein for the purpose of differentiating one element from another only, and do not necessarily imply any actual relationship or order between such elements. Also, the terms "comprises", "comprising", or any other variations thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but can also include other elements not expressly listed or inherent to such process, method, article, or apparatus. An element proceeded by "comprises a... " does not, without more constraints, exclude the existence of additional identical elements in the process, method, article, or apparatus that comprises the element.

[0095] The principles and implementation manners of the present application are described by using specific examples in the present application, and the above example descriptions are only used to help understand the method and core idea of the present application; meanwhile, according to the idea of the present application, the specific implementation manners and application ranges will be changed by those skilled in the art, and in summary, the content of the present description should not be understood as a limitation of the present application.

Claims

1. A method for preparing a heparin sodium cream, characterized in that, Includes the following steps: 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. Propylene glycol and ethylparaben were mixed at room temperature to obtain the first aqueous phase. After heating the water, sodium dodecyl sulfate and sodium heparin were added, and the mixture was stirred continuously to obtain the second aqueous phase. The first aqueous phase and the second aqueous phase are mixed to obtain a mixed aqueous phase; Take 50wt%~70wt% of the mixed aqueous phase and the oil phase and perform homogenization and emulsification treatment to obtain a water-in-oil primary emulsion; The remaining aqueous phase is added to the water-in-oil type colostrum, stirred evenly, and then subjected to homogenization, defoaming, and gradient cooling treatments in sequence to obtain the heparin sodium cream.

2. The preparation method according to claim 1, characterized in that, 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.

3. The preparation method according to claim 1, characterized in that, 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.

4. The preparation method according to claim 1, characterized in that, The water is heated to a temperature of 50℃~60℃, and the stirring speed during the second aqueous phase preparation process is 1000rpm~2500rpm, with continuous stirring time of 30min~60min.

5. The preparation method according to claim 1, characterized in that, 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℃.

6. The preparation method according to claim 1, characterized in that, The preparation process of the water-in-oil type primary emulsion 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 type primary emulsion.

7. The preparation method according to claim 1, characterized in that, When the water-in-oil type primary emulsion is mixed 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 process was carried out at a speed of 1500 rpm to 2500 rpm for 10 min to 30 min.

8. The preparation method according to claim 1, characterized in that, The gradient cooling process includes: Maintain a vacuum of ≤-0.07MPa and a stirring speed of 10rpm~30rpm, and cool the reaction product to 65℃~70℃ with cooling water at 50℃~65℃; The reaction product was cooled to 50°C to 55°C by switching to cooling water at 35°C to 45°C. The reaction product was further cooled to 35°C to 40°C by switching to cooling water at 20°C to 30°C.

9. The heparin sodium cream obtained by the preparation method according to any one of claims 1-8, characterized in that, The product comprises the following components by weight percentage: sodium heparin 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%, with the balance being water; wherein the sodium heparin cream has a D99 particle size <5μm, an efficacy value of 99%~102%, and a pH value of 6.9~7.

3.

10. The heparin sodium cream according to claim 9, characterized in that, The product comprises the following components by weight percentage: sodium heparin 0.15%~0.45%, propylene glycol 6.5%~8.0%, ethylparaben 0.09%~0.11%, sodium dodecyl sulfate 0.9%~1.1%, glyceryl mono- and di-stearates 6.5%~8.0%, stearyl alcohol 9.5%~10.5%, liquid paraffin 9.5%~10.5%, white petrolatum 9.5%~10.5%, and the balance being water.

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