A zinc gluconate ointment and a method for preparing the same

Abstract

The present application relates to the field of external ointment preparation, and provides a zinc gluconate ointment and a preparation method thereof.The ointment comprises, by mass fraction: 0.3-2.0 parts of zinc gluconate, 0.05-1.5 parts of L-histidine, 0.05-1.0 parts of polysaccharide, and the balance of purified water, wherein the polysaccharide is chitosan oligosaccharide or hyaluronic acid oligomer.The zinc gluconate, L-histidine and polysaccharide are dispersed to form hydrogel microdroplets under the condition of pH 5.0-6.0, and are further dispersed in the continuous phase of the oil phase.By establishing a complex system in a weak acid environment and using a double constraint structure of microdroplet dispersion and oil phase, the free Zn 2+ The initial release rate is reduced, skin irritation caused by the initial release of traditional preparations is avoided, and a high 24-hour cumulative release amount is maintained.The ointment exhibits excellent physical stability and particle size uniformity during storage, avoids oil-water layering and crystallization, and has both sustained release and good use feeling.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of zinc gluconate ointment, and in particular to a zinc gluconate ointment and a preparation method thereof. BACKGROUND

[0002] Zinc gluconate is a commonly used external drug ingredient, which has the effects of anti-inflammatory, promoting wound healing and improving skin barrier function. Zinc gluconate ointment is usually prepared by emulsification process of oil phase and water phase, and has been applied in the treatment of acne vulgaris, mild inflammation and small area injury. The existing zinc gluconate ointment still has deficiencies in use and storage. The common prescription system is prone to oil-water separation or unstable texture, which affects the appearance of the preparation and the quality of the shelf life; at the same time, the initial release rate of the drug in the preparation is fast, which can easily cause skin irritation, thereby reducing the use comfort and compliance of patients.

[0003] Previous studies have tried to improve it by changing the type of emulsifier, adjusting the oil-water ratio or adding thickening agent, but these improvements are often accompanied by problems such as decreased spreadability of the ointment or poor skin feel, and the effect is still not ideal. For example, the composition containing zinc oxide and acidic ingredients is disclosed in Chinese patent CN102846660A, which aims to reduce skin irritation by adjusting ion release. In TW201811798A patent, the influence of emulsifier type and oil-water ratio on the stability and spreadability of the cream is disclosed, and it is pointed out that if the ratio is not properly controlled, the preparation is prone to delamination or poor skin feel. In addition, TWI514999B patent discloses the addition of an anti-crystallization agent in transdermal preparations to improve the appearance and physical stability during storage. The above-mentioned documents have tried to improve the stability and performance of the ointment by adjusting the oil-water ratio, changing the emulsifier or adding auxiliary agents. However, these improvement measures often bring new deficiencies, such as too hard ointment, poor spreadability or poor skin feel, and the control of initial release of zinc ions and improvement of long-term stability of the system have not achieved ideal results.

[0004] Therefore, the technical problem to be solved in the art is how to prepare a zinc gluconate ointment that can maintain stability during storage and use and avoid initial irritation. SUMMARY

[0005] The purpose of the present application is to overcome the above-mentioned problems existing in the prior art, and to provide a zinc gluconate ointment and a preparation method thereof, so as to maintain the stability of the zinc gluconate ointment while reducing the initial irritation of the zinc gluconate ointment.

[0006] In order to achieve the above-mentioned purpose, the first aspect of the present application provides a zinc gluconate ointment comprising the following ingredients by mass fraction:

[0007] Zinc gluconate 0.3-2.0 parts;

[0008] L-histidine 0.05-1.5 parts;

[0009] Polysaccharide 0.05-1.0 parts;

[0010] Purified water balance;

[0011] The polysaccharide is selected from one of chitosan oligosaccharide or hyaluronic acid oligomer; the zinc gluconate, L-histidine and the polysaccharide are dispersed to form hydrogel microdroplets under the condition of pH 5.0-6.0, and the hydrogel microdroplets are further dispersed in the continuous phase of oil phase.

[0012] The zinc gluconate ointment of the present application forms a stable quaternary complex system in the pH range of 5.0-6.0, which exhibits the characteristics of reduced initial release rate in Franz diffusion cell experiment and maintains a relatively stable cumulative release amount within 24 hours. At the same time, the sample shows good storage stability in the accelerated storage test, without crystallization or delamination. The effect of the technical solution shows that, while controlling the release, the early burst of free Zn 2+ can be significantly reduced, and the potential irritant reaction can be reduced. The formation of the system significantly reduces the instantaneous concentration of free zinc ions, thereby avoiding the skin tingling sensation and local erythema reaction caused by the excessive release of free Zn 2+ at the initial stage of use of the conventional zinc gluconate ointment.

[0013] In addition, the present application forms gel-like complex microdroplets in the aqueous phase first, and then disperses them in the continuous phase of oil phase, which gives the preparation a double spatial constraint. The hydrogel structure allows the active ingredients to be uniformly dispersed and fixed inside the aqueous phase, and the continuous distribution of the oil phase further retards the leakage of Zn 2+ . This double microencapsulation structure not only exhibits a curve changing from rapid burst release to smooth and stable release in in vitro release experiment, but also maintains significant physical stability during long-term storage. After storage at 40℃ for one month, the ointment still does not show oil-water separation or solid precipitation, which is an effect that cannot be achieved by the traditional emulsified zinc gluconate ointment.

[0014] As a further improvement of the present application, the molar ratio of the zinc gluconate, L-histidine and the polysaccharide is 1:(0.8-2.5):(0.05-0.5).

[0015] The molar ratio of zinc gluconate, L-histidine and polysaccharide in the composite system can make the complexation reaction in a stable interval. If the proportion of histidine is too low, the complexing capacity is insufficient, the amount of free zinc ions increases, and the initial irritation is easy to cause; if the proportion of histidine is too high, the solubility of the complex decreases, and precipitation or colloidal instability occurs. Similarly, when the proportion of polysaccharide is too low, it cannot provide sufficient steric stabilization effect and hydrophilic protective film outside the complex, and when the proportion is too high, the water phase is excessively thickened, affecting the release rate of the active ingredient.

[0016] Within the set molar ratio interval, the complex can maintain appropriate stability constant and solubility, form a transparent or translucent hydrogel state, and maintain good particle size uniformity when subsequently dispersed into an oil phase. This ratio control directly determines the release kinetics of zinc ions, which can avoid rapid burst release and maintain effective concentration for a long time. Therefore, in the in vitro diffusion experiment, it shows the characteristics of two stages of initial slow release and long-term stable concentration.

[0017] As a further improvement of the present application, the median particle size D 50 is 0.5-2.0 μm, and the distribution range is 0.2-5.0 μm.

[0018] By controlling the median particle size of the hydrogel microdroplets to be 0.5-2.0 μm and limiting the overall distribution range to be 0.2-5.0 μm, the microdroplets can maintain a stable and uniform dispersion state in the oil phase. When the particle size is too large, the microdroplets are prone to sedimentation or coalescence during storage, leading to phase separation and rough cream; when the particle size is too small, although the dispersibility is improved, the specific surface area is too large, the release of zinc ions is too fast, and the purpose of slow release cannot be achieved.

[0019] Within the appropriate particle size range, the surface tension of the microdroplets and the viscosity of the oil phase reach a dynamic balance, avoiding aggregation and ensuring the controllability of the release of active ingredients. In the experiment, it can be observed that within this particle size interval, the release curve shows a stable slow release at the initial stage, and then gradually maintains a stable concentration, rather than the common rapid burst release or rapid decay.

[0020] At the same time, this particle size distribution is more consistent with the microstructure of the skin surface. The microdroplets can form uniform coverage in the stratum corneum, enhancing the adhesion and uniformity of the cream, and thus prolonging the residence time.

[0021] As a further improvement of the present application, the polysaccharide is a chemically modified chitosan oligosaccharide or hyaluronic acid oligomer, and the modification is carboxymethylation or sulfation.

[0022] The carboxymethylated chitosan oligosaccharide or sulfated hyaluronic acid oligomer can significantly improve the stability and function of the complex when combined with zinc gluconate and L-histidine. The modified polysaccharide has more carboxyl or sulfate groups than the unmodified natural polysaccharide, which provides stronger coordination sites and higher charge density, enabling it to form a more stable complex bond with zinc ions. In this way, zinc ions are no longer easily present in free form, effectively reducing the irritation at the initial use.

[0023] In the aqueous phase, the introduction of this modified polysaccharide improves the solubility and dispersibility of the complex. Carboxymethylation can enhance the hydrophilicity of the molecule, allowing the entire system to remain transparent or translucent in a colloidal state at a higher concentration, without precipitation due to excessive complexation. Sulfated hyaluronic acid can form a stable charge barrier on the surface of the microdroplets due to its strong negative charge, preventing aggregation and fusion between the hydrogel microdroplets. This allows the formulation to exhibit excellent physical stability during storage and transportation, and even at high temperatures of 40℃ or under centrifugal conditions, without oil-water separation or turbidity.

[0024] As a further improvement of the present application, the oil phase continuous phase includes the following ingredients by mass fraction: white petrolatum 20-45 parts, liquid paraffin or medium-chain triglyceride 10-25 parts, and octadecanol or glycerol monostearate 1-5 parts.

[0025] In the oil phase continuous phase, white petrolatum and liquid paraffin provide a continuous oily matrix, ensuring uniform dispersion of the hydrogel microdroplets and forming a stable environment; medium-chain triglyceride imparts a lighter skin feel, avoiding greasiness and heaviness; thus balancing the flowability and structural hardness of the entire ointment system.

[0026] Octadecanol or glycerol monostearate as a crystalline aid can form a certain skeletal structure in the oil phase, significantly improving the support of the oil phase to the microdroplets, thereby reducing the risk of oil-water separation. If the proportion of such components is insufficient, the oil phase will be too soft to maintain stable distribution of the microdroplets; if the proportion is too high, the ointment will be too hard, and the spreadability will decrease significantly. Within the limited range, the ointment exhibits both flexibility and appropriate strength, forming a stable covering layer on the skin surface.

[0027] This oil phase system not only ensures physical stability, but also improves the spreadability of the ointment and the user experience. In the in vitro stability test, the ointment remains uniform without obvious oil-water separation under cold and hot cycling and centrifugal conditions; in the spreading test, it exhibits smooth and extended spread without whitening. Therefore, the rational design of the oil phase composition and the stable dispersion of the hydrogel microdroplets complement each other, providing a guarantee for the long-term stability and good skin feel of the entire preparation.

[0028] As a further improvement of the present application, the oil phase continuous phase further contains 0.1-1.0 parts by mass of a rheological network builder selected from a hydrophobically associating polyurethane or a modified starch ester.

[0029] The hydrophobically associating polyurethane or the modified starch ester is selected as the rheological network builder, and its mechanism of action is not only dependent on simple thickening or viscosity increase, but also spontaneously forms a spatial network in the oil phase environment through the interaction of hydrophobic groups. The composition of the network presents a highly reversible characteristic: in a stationary state, the hydrophobic association points in the network remain in a combined state, forming a three-dimensional structure with certain elasticity inside the oil phase. Such a structure can support and fix the hydrogel microdroplets dispersed therein, limiting their free migration, thereby significantly reducing the coalescence and delamination phenomenon caused by gravity settling or temperature fluctuations, so that the ointment remains uniform and appearance stable during storage.

[0030] When the ointment is subjected to external mechanical stress, such as during application on the skin surface, the association points in the rheological network will partially dissociate, and the local network will relax, and the ointment as a whole will exhibit smooth flowability and good spreadability, without the feeling of resistance or stringiness. This structural relaxation is reversible, and with the removal of shear force and the restoration of temperature conditions, the interaction between the hydrophobic groups occurs again, and the network structure is re-established, so that the ointment returns to a stable consistency state. This dynamic adjustment mechanism enables the ointment to maintain sufficient resistance to flow and structural stability in a stationary state, and to exhibit a soft and easy-to-push touch during use.

[0031] In addition, the introduction of the modified starch ester enables the network to obtain a more suitable balance between lipophilicity and hydrophilicity, and the hydrophilic substituents on its molecules can produce certain interaction with the surface of the hydrogel microdroplets, further enhancing the interfacial stability between the microdroplets and the oil phase. The hydrophobic segments are highly compatible with the oil phase, helping to build a more compact three-dimensional network. Therefore, this kind of rheological network not only simply increases the viscosity of the system, but also establishes a dynamically responsive constraint environment at the micro level, enabling the hydrogel microdroplets to obtain double stability: both physically supported and fixed, and effectively protected at the interface.

[0032] As a further improvement of the present application, the ointment further contains one or two of glycerol, propylene glycol or 1,3-propanediol in a total amount of 2-10 parts by mass.

[0033] The introduction of 2-10 parts of glycerol, propylene glycol or 1,3-propanediol in the ointment system not only improves the physicochemical properties of the water phase, but also directly improves the skin adaptability of the preparation. As a hydrophilic humectant, this kind of polyol can form hydrogen bond with the complex in the water phase, making the internal structure of the hydrogel microdroplet more stable, and at the same time improving the viscosity of the whole system, reducing the volatilization or migration of water during storage.

[0034] As a further improvement of the present application, the ointment further contains an emulsifier, which includes the following components by mass fraction: hydrogenated lecithin 0.2-1.0 parts and polyglyceryl-3 polyricinoleate 0.2-1.0 parts.

[0035] Hydrogenated lecithin is an amphiphilic molecule of natural origin, and its lipophilic part can firmly embed in the oil phase, and the hydrophilic head group is combined with the surface of the hydrogel microdroplet, thereby reducing the interfacial tension. Polyglyceryl-3 polyricinoleate as a non-ionic emulsifier, can further enhance the interfacial flexibility on the basis of lecithin, and improve the resistance of the whole system to temperature change and mechanical disturbance. The joint addition of the two can make the microdroplet dispersion more uniform, and even under high shear and long-term storage conditions, it is not easy to appear delamination and emulsification failure.

[0036] The second aspect of the present application provides a preparation method of the zinc gluconate ointment as described above, comprising the following steps:

[0037] (1) Dissolve zinc gluconate, L-histidine and the polysaccharide in purified water in turn, adjust the pH to 5.0-6.0, and form a gel water phase;

[0038] (2) Disperse the water phase in the oil phase containing an emulsifier, high-shear emulsify and homogenize at 200-400 bar high pressure, control the D 50 of the hydrogel microdroplet to be 0.5-2.0 μm;

[0039] (3) Add a rheological network builder in the continuous oil phase, stir and cool to obtain an ointment.

[0040] In the preparation process, first, dissolve zinc gluconate, L-histidine and polysaccharide in purified water in turn, and adjust the pH to 5.0-6.0, which can ensure that the complex system forms a uniform and stable gel state in the water phase. The control of this step not only avoids the problems of incomplete dissolution of components or precipitation of complexes, but also provides suitable starting conditions for the subsequent formation of microdroplets.

[0041] Subsequently, the formed water phase is dispersed into the oil phase containing emulsifier, and primary emulsification is realized under high shear, and then the micro-particle size is controlled in the range of 0.5-2.0 μm through high pressure homogenization process of 200-400 bar. The application of high pressure homogenization makes the micro-particle size distribution more concentrated, significantly reduces the risk of large particles or uneven dispersion, thereby directly determines the controllability of subsequent sustained release effect and the appearance uniformity of the preparation.

[0042] Finally, the rheological network builder is added into the oil phase, and the paste is completed under stirring and cooling conditions, which endows the system with a stable three-dimensional support network, so that the ointment is not prone to oil-water separation during storage and transportation, and can exhibit good fluidity and spreadability on the skin when used.

[0043] As a further improvement of the present application, in step (1), first, zinc gluconate and L-histidine are dissolved to form a complex, and then the polysaccharide is slowly added at a speed of 0.05-0.2 mL / min under the condition of 20-30℃, and stirring is carried out at 200-500 rpm.

[0044] This sequence and condition control avoids the problem of distribution disorder caused by the direct and rapid mixing of zinc gluconate, L-histidine and polysaccharide, so that the zinc ion is first combined with histidine in a relatively stable form, and then coated by the polysaccharide shell. The complex obtained by this process exhibits uniform particles in microscopy and particle size analysis, and shows the characteristics of two-stage release in in vitro release experiments: low release rate in the initial stage to avoid irritation, and stable concentration in the subsequent stage to prolong the drug efficacy time.

[0045] If this sequence and condition are not adopted, the polysaccharide may directly combine with the zinc ion, leading to imbalance of complex ratio or precipitation, thereby affecting the uniformity and stability of the ointment. The core-shell structure formed by this process not only has more stable physicochemical properties, but also shows superior comprehensive effect in drug release and skin tolerance.

[0046] The present application has the following beneficial effects by adopting the above technical solutions:

[0047] (1) The present application forms a stable complex of zinc gluconate, L-histidine and polysaccharide in a weak acid environment, and further utilizes the continuous phase of the oil phase to double-space constrain it. This can effectively control the free Zn 2+The instant concentration of the drug is avoided, and the skin irritation and erythema caused by the burst release of metal ions in the initial use of traditional preparations are avoided, and the tolerance of patients is significantly improved. Secondly, by strictly controlling the molar ratio of zinc gluconate, L-histidine and polysaccharide, and limiting the particle size of the hydrogel microdroplets to a reasonable range, the drug release process is changed from rapid burst release to a two-stage mode of initial slow release and long-term maintenance of concentration.

[0048] (2) The present application first forms stable hydrogel microdroplets in an aqueous phase, and then disperses them into a continuous oil phase to form a double-stable structure. In combination with the charge barrier formed by the modified polysaccharide on the surface of the microdroplets, the ointment can still be uniformly dispersed without oil-water separation or crystallization under harsh conditions such as high-temperature storage or centrifugation, significantly improving the storage stability and shelf life reliability of the ointment. BRIEF DESCRIPTION OF DRAWINGS

[0049] Figure 1 The curve graph of the in-vitro release test of Example 1, Comparative Example 3 and Comparative Example 4; wherein curve A is the test curve of the sample of Comparative Example 3, curve B is the test curve of the sample of Comparative Example 4, and curve C is the test curve of the sample of Example 1.

[0050] Figure 2 The D 50 The particle size change curve with storage time; curve A is the test curve of the sample of Comparative Example 4, curve B is the test curve of the sample of Comparative Example 3, and curve C is the test curve of the sample of Example 1. DETAILED DESCRIPTION

[0051] The specific embodiments of the present application will be described in detail below. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present application, and are not used to limit the present application.

[0052] Unless otherwise defined, all scientific and technical terms used in the present application have the same meanings as commonly understood by one of ordinary skill in the art to which the present application relates.

[0053] The technical solutions in the embodiments of the present application will be described in detail below. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by one of ordinary skill in the art without creative labor are within the scope of protection of the present application.

[0054] The materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

[0055] The present application will be described in detail below with reference to specific embodiments, which are used to understand rather than limit the present application.

[0056] Example 1

[0057] This example discloses a zinc gluconate ointment and a preparation method thereof, wherein the formulation of the zinc gluconate ointment comprises the following components in Table 1 by mass fraction.

[0058] Table 1

[0059]

[0060] The preparation method of the zinc gluconate ointment comprises the following steps:

[0061] (1) Preparation of an aqueous phase:

[0062] Take 37.7 parts of purified water into a stirred tank, stir at 25°C with a stirring speed of 250 rpm, and then add 1.0 part of zinc gluconate and 1.2 parts of L-histidine in sequence. After complete dissolution, detect the pH and adjust it to 5.5. Then add 0.15 parts of chitosan oligosaccharide and 5.0 parts of glycerol, and keep stirring at 25°C for 25 min to make the system form a uniform transparent gel-like aqueous phase.

[0063] (2) Preparation of an oil phase:

[0064] In another container, add 35.0 parts of white vaseline, 15.0 parts of liquid paraffin, 2.0 parts of octadecanol, and 2.0 parts of glycerol monostearate, heat and melt at 80°C, and stir at 350 rpm until completely transparent and uniform. Then add 0.5 parts of hydrogenated lecithin and 0.5 parts of polyglyceryl-3 ricinoleate, and continue stirring for 8 min to obtain a uniform oil phase.

[0065] (3) Emulsification and homogenization:

[0066] Slowly add the aqueous phase obtained in step (1) into the oil phase at 65°C at a speed of 0.5 mL / min, stirring (stirring speed 900 rpm) while adding, to complete the preliminary emulsification. Then send the pre-emulsion into a high-pressure homogenizer, and homogenize at a pressure of 300 bar for 20 min to obtain hydrogel microdroplets, and the median particle size (D50) is 1.0 μm, and the particle size distribution range is 0.2-5.0 μm.

[0067] (4) Cooling and ointment formation:

[0068] Transfer the homogenized emulsion into a stirred tank, stir at 200 rpm, and cool to 40°C at a rate of 1°C / min. Keep stirring during the cooling process, and do not add additional rheological network builders. Continue to cool to 25°C to obtain a zinc gluconate ointment with uniform texture and stability.

[0069] Example 2

[0070] The difference from Example 1 is that the proportion of L-histidine is increased to 2.0 parts.

[0071] The preparation method is substantially the same as that of Example 1, but in order to control the median particle size of the hydrogel microdroplets to be about 0.8 μm, the pre-emulsification conditions are set to stirring at 1000 rpm for 12 min and a feeding rate of 0.5 mL / min; the homogenization temperature is 65 °C, the homogenization pressure is 350 bar, and the cycle is 3 times, with a total time of about 20 min.

[0072] Example 3

[0073] The difference from Example 1 is that the polysaccharide is hyaluronic acid oligomer 0.10 parts, and propylene glycol 4 parts is used to replace glycerol, and the oil phase composition is adjusted to white petrolatum 30 parts, liquid paraffin 20 parts, and glycerol monostearate 3 parts.

[0074] The preparation method is substantially the same as that of Example 1, but in order to obtain a median particle size of the hydrogel microdroplets of about 1.5 μm, the pre-emulsification conditions are set to stirring at 800 rpm for 8 min and a feeding rate of 1.0 mL / min; the homogenization temperature is 65 °C, the homogenization pressure is 250 bar, and the cycle is 1 time, with a total time of 10 min.

[0075] Example 4

[0076] The difference from Example 1 is that carboxymethyl chitosan oligosaccharide 0.10 parts is used, and the humectant is glycerol 4 parts.

[0077] The preparation method is substantially the same as that of Example 1, and the parameter settings are consistent with those of Example 1, and the median particle size of the obtained hydrogel microdroplets is about 1.0 μm.

[0078] Example 5

[0079] The difference from Example 3 is that the polysaccharide is sulfated hyaluronic acid oligomer 0.08 parts, and the humectant is 1,3-propanediol 4 parts.

[0080] The preparation method is substantially the same as that of Example 1, but in order to obtain a median particle size of the hydrogel microdroplets of about 0.9 μm, the pre-emulsification conditions are set to stirring at 950 rpm for 10 min and a feeding rate of 0.5 mL / min; the homogenization temperature is 65 °C, the homogenization pressure is 320 bar, and the cycle is 2 times, with a total time of 15-20 min.

[0081] Example 6

[0082] The difference from Example 4 is that hydrophobically associating polyurethane 0.4 parts is added to the oil phase as a rheological network builder, and the humectant is glycerol 3 parts.

[0083] The preparation method is substantially the same as that in Example 1, except that the rheological network builder is added after homogenization and cooling to 60°C, and the stirring is continued until uniform. The obtained hydrogel microdroplets have a median particle size of about 1.0 μm.

[0084] Example 7

[0085] The difference from Example 6 is that part of the liquid paraffin (reduced to 10 parts) is replaced by medium-chain triglyceride 20 parts in the oil phase, and the amount of octadecanol is 3 parts, and the humectant is 1,3-propanediol 5 parts.

[0086] The preparation method is substantially the same as that in Example 6, and the obtained hydrogel microdroplets have a median particle size of about 1.0 μm.

[0087] Example 8

[0088] The difference from Example 5 is that the proportion of emulsifiers is adjusted to hydrogenated lecithin 0.4 parts and polyglyceryl-3 ricinoleate 0.8 parts, and modified starch ester 0.5 parts is added as a rheological network builder in the oil phase.

[0089] The preparation method is substantially the same as that in Example 1, but the homogenization pressure is increased to 350 bar, and the cycle is 2 times, with a total time of 15-20 min. The obtained hydrogel microdroplets have a median particle size of about 1.0 μm.

[0090] Example 9

[0091] The difference from Example 3 is that the emulsifier is replaced by 5 parts of composite emulsifier TEFOSE 63 instead of lecithin and polyglyceryl-3 ricinoleate, and polyethylene glycol 6000 1 part is added as a thickening agent in the water phase.

[0092] The preparation method is substantially the same as that in Example 1, and the homogenization condition is 300 bar, with a cycle of 2 times, and a total time of about 20 min. The obtained hydrogel microdroplets have a median particle size of about 1.0 μm.

[0093] Example 10

[0094] The difference from Example 6 is that part of the liquid paraffin (10 parts) is replaced by lanolin 10 parts in the oil phase, and the amount of white petrolatum is 25 parts.

[0095] The preparation method is substantially the same as that in Example 1, and the homogenization condition is 300 bar, with a cycle of 2 times, and a total time of about 20 min. The obtained hydrogel microdroplets have a median particle size of about 1.0 μm.

[0096] Example 11

[0097] The difference from Example 8 is that the emulsifier is composite emulsifier TEFOSE 63 8 parts, and polyethylene glycol 6000 is no longer added.

[0098] The preparation method is substantially the same as that in Example 1, but the homogenization condition is set to 320 bar, 2 cycles, and a total time of about 20 min, and the median particle size of the obtained hydrogel microdroplets is about 1.2 μm.

[0099] Example 12

[0100] This example discloses a zinc gluconate ointment, which has a substantially same formulation as that in Example 6, except that the rheological network builder is hydrophobically associating polyurethane 0.35 parts. In preparation, after the high-pressure homogenization is completed, the rheological network builder is slowly added into the oil phase at 60°C, and is dispersed by stirring at a low speed for 10 min, and is kept for maturation at 45°C for 20 min before being cooled into an ointment.

[0101] Example 13

[0102] This example is similar to Example 8, except that the rheological network builder is modified starch ester 0.5 parts, which is octanoyl-decanoyl starch ester with a degree of substitution of 0.06. In preparation, the rheological network builder is added into the oil phase after the high-pressure homogenization and cooling to 55°C, and is uniformly dispersed by stirring and is kept for maturation at 40°C for 30 min before being cooled into an ointment.

[0103] Example 14

[0104] This example is further adjusted based on Example 12, and the rheological network builder is a combination of hydrophobically associating polyurethane 0.25 parts and modified starch ester 0.2 parts. In preparation, both are added at 55-60°C after homogenization, and the maturation time is extended to 30 min.

[0105] Comparative Example 1

[0106] The difference from Example 1 is that the preparation method of the water phase is different. In this comparative example, zinc gluconate 1.0 part, L-histidine 1.2 part and chitosan oligosaccharide 0.15 part are added into 38.0 parts of purified water at one time, and glycerol 5 parts is added at the same time, and the water phase is directly obtained after uniform stirring at 25°C, without using the sequence of first dissolving zinc gluconate and L-histidine, and then slowly adding polysaccharide. Subsequently, the oil phase preparation, pre-emulsification and homogenization are carried out, and the homogenization condition is 300 bar, 2 cycles, and a total time of about 20 min.

[0107] Comparative Example 2

[0108] The difference from Example 4 is that the pH is adjusted to 6.8 instead of 5.5.

[0109] The preparation method is the same as that in Example 4, and the homogenization condition is set to 300 bar, 2 cycles, and a total time of 20 min.

[0110] Comparative Example 3

[0111] The difference from Example 1 is that no polysaccharide component is added, and the rest of the formulation and process parameters are the same.

[0112] Specifically: the water phase contains only 1.0 part of zinc gluconate, 1.2 parts of L-histidine, and 5 parts of glycerol, pH 5.5; the oil phase and emulsifier are the same as in Example 1; the homogenization conditions are 300 bar, 2 cycles, and a total time of 20 min.

[0113] Comparative Example 4

[0114] The difference from Example 1 is that no L-histidine is added to the water phase, and the rest of the formulation and process parameters are the same.

[0115] Specifically: the water phase contains only 1.0 part of zinc gluconate, 0.15 parts of chitosan oligosaccharide, and 5 parts of glycerol, pH adjusted to 5.5; the oil phase and emulsifier system are consistent with Example 1; the homogenization conditions are set to 300 bar, 2 cycles, and a total time of 20 min.

[0116] Comparative Example 5

[0117] The formulation is the same as Example 12, but the difference is that the rheological network builder is added to the oil phase before high-pressure homogenization.

[0118] Comparative Example 6

[0119] The formulation is the same as Example 13, but the modified starch used has an esterification degree of 0.20, and the addition amount is 0.8 parts.

[0120] Detection method

[0121] I. Samples and controls

[0122] The samples prepared in Examples (1-11) are taken as the test group, and the comparative examples (1-4) are taken as the control group. After the samples in each group are deaerated at room temperature for 24 h, they are detected.

[0123] II. Stability investigation

[0124] 1. Accelerated and cold-heat cycling: the samples are placed at 40°C (avoiding light) for up to 8 weeks, and the appearance, whether it is layered, and the particle size are observed and re-measured at different stages; another set of samples is subjected to cold-heat cycling (temperature change every 24 h, a total of 6 times) at 4°C / 40°C, and the appearance and particle size changes are observed immediately after cycling.

[0125] 2. Centrifugal stress: the samples are placed at 25°C and centrifuged at 3000 rpm for 30 min, and whether oil and water are layered is recorded.

[0126] The sample is considered "qualified (stable)" when it meets the following threshold values simultaneously; if any of them is not met, it is considered "unqualified":

[0127] (1) Appearance / delamination: "No delamination, no crystallization, no obvious phase change" after 8 weeks of accelerated test, cold and hot cycle and centrifugation;

[0128] (2) Particle size stability: ΔD50(8 weeks) ≤10%, and Span change ≤0.15;

[0129] (3) pH drift: |ΔpH| ≤0.10 (25 ℃).

[0130] The test results are shown in Table 2.

[0131] Table 2

[0132] Sample 40°C / 8 weeks appearance Cold heat cycle (4 / 40°C x 6 times) pH drift ΔpH ΔD50 (8 weeks) Example 1 homogeneous pass 0.05 6% Example 2 homogeneous pass 0.06 7% Example 3 homogeneous pass 0.05 8% Example 4 homogeneous pass 0.04 5% Example 5 homogeneous pass 0.03 4% Example 6 homogeneous pass 0.03 3% Example 7 homogeneous pass 0.04 4% Example 8 homogeneous pass 0.04 4% Example 9 homogeneous pass 0.05 6% Example 10 homogeneous pass 0.05 5% Example 11 homogeneous pass 0.07 9% Example 12 homogeneous pass 0.03 3% Example 13 homogeneous pass 0.04 4% Example 14 homogeneous pass 0.03 3% Comparative Example 1 hazy / layered fail 0.2 35% Comparative Example 2 hazy / precipitate fail 0.18 22% Comparative Example 3 slightly layered fail 0.16 18% Comparative Example 4 slightly layered fail 0.17 20% Comparative Example 5 slightly layered fail 0.14 12% Comparative Example 6 homogeneous pass 0.09 6%

[0133] As can be seen from Table 2, the appearance of Examples 1-14 remained uniform, without delamination or crystallization under the conditions of 8 weeks of accelerated test at 40℃ and cold and hot cycle (4 / 40℃ x 6 times); no oil-water delamination occurred under centrifugal stress. In terms of particle size, ΔD 50 was between 3% and 9%, far below the set threshold of 10%, and the pH drift was less than 0.10, and the prescription system showed good consistency in physical and chemical stability. Among them, the ΔD 50 of Examples 6, 8 and newly added Examples 12-14 was only 3%-4%, showing that on the basis of baseline stability, the stability of particle size and appearance could be further enhanced by introducing rheological network builder in the appropriate process window. In comparison, Comparative Examples 1-4 all showed obvious adverse changes under the same conditions, while Comparative Example 5 failed to form an effective network due to improper timing of adding the rheological network builder, resulting in mild delamination under cold and hot cycle and a significant increase in ΔD 50 ; Comparative Example 6 did not delaminate, but the system was too hard, indicating that when the rheological network builder parameters exceed the reasonable range, the overall properties of the ointment will be damaged.

[0134] III. In vitro release test

[0135] Franz diffusion cell (effective area about 1.77 cm 2 , receptor liquid citrate / Tris buffer pH 7.4, constant temperature at 32℃), membrane material was pre-equilibrated with conventional hydrophilic membrane. About 0.5 g was coated per well, and samples were taken at time points: high frequency in the first 0-2 h (such as 5, 15, 30, 60, 90, 120 min), and then 3, 6, 8, 12, 24 h; the Zn 2+ content in the receptor liquid was measured and replaced with an equal volume of new liquid.

[0136] The test results are shown in Table 3 and Figure 1 .

[0137] Table 3

[0138] Sample [K0 - 2h] BI Q 24 ]]> Example 1 14 0.22 95 Example 2 12 0.2 92 Example 3 18 0.24 100 Example 4 13 0.21 96 Example 5 12 0.19 98 Example 6 12 0.18 97 Example 7 13 0.2 99 Example 8 12 0.19 98 Example 9 14 0.21 96 Example 10 13 0.2 97 Example 11 16 0.23 101 Example 12 12 0.19 98 Example 13 12 0.19 98 Example 14 12 0.18 99 Comparative Example 1 28 0.42 85 Comparative Example 2 24 0.36 88 Comparative Example 3 34 0.48 90 Comparative Example 4 32 0.45 87 Comparative Example 5 22 0.3 92 Comparative Example 6 10 0.27 84

[0139] wherein k0-2h: release slope in the first 2 hours (μg·cm -2 ·h -1 ); Q 24 : 24-hour cumulative release amount (μg / cm²); BI: the proportion of 0-2-hour release amount in the total 0-24-hour release amount.

[0140] As can be seen from Table 3, Examples 1-14 all exhibit a low initial release rate (k0-2h controlled at 12-18 μg·cm -2 ·h -1 ), which is significantly lower than the comparative examples (generally more than 25 μg·cm -2 ·h -1 ), indicating that the formulation of the present application can effectively inhibit the early excessive release and reduce the burst phenomenon. The burst index (BI) further confirms this trend, and the examples are all in a reasonable range of 0.18-0.24, while the comparative examples are generally higher than 0.30, showing that the initial release proportion is too large to achieve steady release. At the same time, the 24-hour cumulative release amount (Q 24 ) of the examples is maintained at 92-100 μg / cm 2 , in a stable range close to the theoretical value. In particular, Examples 12-14 show that under the condition of introducing rheological network builders and reasonably controlling the amount and adding order, the overall release amount of the drug is not affected, but the stability of the release process is further improved. In contrast, Comparative Example 5 has a significantly high initial release rate due to the failure of network formation, and the burst phenomenon is prominent; Comparative Example 6 has a limited overall release due to an excessively strong network, and the cumulative release amount is insufficient.

[0141] Four, particle size and distribution uniformity

[0142] A wet laser particle size analyzer was used for detection, and the dispersion medium was an inert liquid (refractive index RI = 1.45) compatible with the oil phase. The sample was diluted by 1:20 and slightly stirred without ultrasonic treatment to avoid damaging the original structure. Each batch of sample was independently detected n = 3, and the results were averaged ± SD.

[0143] Record D 10 , D 50 , D 90 , and calculate the particle size distribution width Span = (D 90 -D 10 ) / D 50 ;

[0144] The test results are shown in Table 4 and Figure 2shown.

[0145] Table 4

[0146] Sample <![CDATA[D 10 ]]> <![CDATA[D 50 ]]>

[00003] D 90 ]] Span = (D 90 –D 10 ) / D 50 ]]> Delta D 50 (8 weeks) Example 1 0.6 1 1.6 1 6% Example 2 0.45 0.8 1.25 1 7% Example 3 0.9 1.5 2.3 0.93 8% Example 4 0.65 1 1.55 0.9 5% Example 5 0.5 0.9 1.35 0.94 4% Example 6 0.65 1 1.5 0.85 3% Example 7 0.6 1 1.5 0.9 4% Example 8 0.6 1 1.48 0.88 4% Example 9 0.62 1 1.54 0.92 6% Example 10 0.6 1 1.57 0.97 5% Example 11 0.7 1.2 2 1.08 9% Example 12 0.6 1 1.48 0.88 3% Example 13 0.6 1 1.5 0.9 4% Example 14 0.6 1 1.46 0.86 3% Comparative Example 1 1.2 2.5 5 1.52 35% Comparative Example 2 0.9 2 3.6 1.35 22% Comparative Example 3 0.7 1 1.9 1.2 18% Comparative Example 4 0.8 1.2 2.4 1.33 20% Comparative Example 5 0.65 1.05 1.05 1.19 12% Comparative Example 6 0.6 1 1 0.92 6%

[0147] As can be seen from Table 4, the median particle size D 50 of the examples is concentrated in 0.8-1.5 μm, all falling within the target window (0.5-2.0 μm); the distribution span Span≈0.85-1.08 is overall uniform. After 8 weeks of acceleration, D 50 changes (ΔD 50 ) are all in 3-9%. Among them, the Span of Examples 6, 8 and newly added Examples 12-14 is narrower, and ΔD 50 maintained at 3%-4%, indicating that by introducing a rheological network builder after the homogenization window and moderate maturation, a microdroplet system with uniform particle size distribution and long-term stability can be obtained. In comparison, the distribution of the comparative examples is significantly widened and drifts upward, especially Comparative Example 5 shows a clear tendency of coalescence, with the Span increasing to 1.19 and ΔD 50 up to 12%, reflecting that a network deficiency makes it difficult to stabilize the microdroplets; although the particle size of Comparative Example 6 remains within the window range, the overall texture is hard, which is not consistent with the coating experience, indicating that excessive network strength will also disrupt the balance.

[0148] V. Anti-inflammatory performance

[0149] Three groups of samples were prepared, with Example 1 as the test group, commercially available zinc gluconate ointment as the control group, and the blank matrix group as the group with L-histidine and chitosan oligosaccharide removed.

[0150] Blank matrix group: same formula matrix without the main drug

[0151] An equal amount of sample was dissolved in pH 7.4 PBS buffer (1 mg / mL) and mixed with 1% ovalbumin solution, and the absorbance (560 nm) was measured after constant temperature at 60°C for 30 min.

[0152] The inhibition rate was calculated as (A0-A1) / A0×100%.

[0153] The test results are shown in Table 5 below.

[0154] Table 5

[0155] Group Inhibition rate (%) Commercial control 83.6 Example 1 84.1 Blank matrix 4.3

[0156] VI. Wound repair activity

[0157] The HaCaT cell scratch model was used, and the samples were diluted at 1%, 5% and 10%, and the migration closure rate was observed after 24 h.

[0158] The test results are shown in Table 6 below.

[0159] Table 6

[0160] Group 24 h migration closure rate (%) Commercial control 89.5 Example 1 90.2 Blank matrix 20.3

[0161] The above merely describes the preferred embodiments of the present application, and the protection scope of the present application is not limited to the above-mentioned embodiments. Any technical scheme falling within the concept of the present application shall fall within the protection scope of the present application. It should be noted that, for ordinary skilled in the art, some improvements and refinements without departing from the principles of the present application shall also be considered as the protection scope of the present application.

Claims

1. A zinc gluconate ointment, characterized in that, The following components are included by weight: Zinc gluconate 0.3–2.0 parts; L-histidine 0.05–1.5 parts; Polysaccharide 0.05–1.0 parts; Purified water balance; The polysaccharide is selected from chitosan oligosaccharide or hyaluronic acid oligomer; the zinc gluconate, L-histidine and the polysaccharide are dispersed with the polysaccharide at pH 5.0 to 6.0 to form hydrogel droplets, and the hydrogel droplets are further dispersed in the oil phase continuous phase; The oil phase continuous phase comprises the following components by mass: 20-45 parts white petrolatum, 10-25 parts liquid paraffin or medium-chain triglycerides, and 1-5 parts octadecyl alcohol or glyceryl monostearate. The oil phase continuous phase also contains 0.1 to 1.0 parts by mass of a rheology network building agent, wherein the rheology network building agent is selected from hydrophobic associative polyurethane or modified starch ester. The method for preparing zinc gluconate ointment includes the following steps: (1) Dissolve zinc gluconate, L-histidine and the polysaccharide in purified water in sequence, adjust the pH to 5.0-6.0, and form a gel aqueous phase; (2) dispersing the aqueous phase in an oil phase containing an emulsifier, high shear emulsification and high pressure homogenization at 200-400 bar to control the D 50 of the hydrogel droplets to be 0.5-2.0 μm; (3) Add a rheological network building agent to the oil phase continuous phase, stir and cool to obtain an ointment.

2. The zinc gluconate ointment according to claim 1, characterized in that, The molar ratio of zinc gluconate, L-histidine, and the polysaccharide is 1:(0.8-2.5):(0.05-0.5).

3. The zinc gluconate ointment according to claim 1, characterized in that, The median particle size D of the hydrogel microdroplets 50 The size ranges from 0.5 to 2.0 μm, and the distribution ranges from 0.2 to 5.0 μm.

4. The zinc gluconate ointment according to claim 1, characterized in that, The polysaccharide is a chemically modified chitosan oligosaccharide or hyaluronic acid oligomer, wherein the modification is carboxymethylation or sulfation.

5. The zinc gluconate ointment according to claim 1, characterized in that, The ointment further contains 2 to 10 parts by weight of one or both of glycerin and propylene glycol.

6. The zinc gluconate ointment according to claim 1, characterized in that, The ointment also contains an emulsifier, which, by weight, comprises the following components: 0.2 to 1.0 parts of hydrogenated lecithin and 0.2 to 1.0 parts of polyglycerol-3 polyricinoleate.

7. The zinc gluconate ointment according to claim 1, characterized in that, In step (1), zinc gluconate is first dissolved with L-histidine to form a complex, and then the polysaccharide is slowly added at a rate of 0.05 to 0.2 mL / min at 20 to 30°C, while stirring at 200 to 500 rpm.

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