Pharmaceutical composition of mupirocin ointment and preparation method thereof

Abstract

The invention relates to the technical field of medicines, in particular to a pharmaceutical composition of mupirocin ointment and a preparation method of the pharmaceutical composition. The invention aims to solve the problem that the existing mupirocin ointment only pays attention to stability and neglects skin barrier repair, so that treatment and healing are disjointed. The composition comprises mupirocin, chitosan and the like, and is characterized in that a multiphase microstructure system is constructed, glyceryl monostearate provides hydrophobic protection for mupirocin, and lactic acid activates chitosan. The preparation method adopts three-stage temperature control synchronous homogeneous curing. The invention solves or at least alleviates the inherent defect that in the prior art, a mupirocin ointment preparation only focuses on the chemical stability of a medicine but neglects the biological requirement of skin barrier repair of a medication part, and provides a pharmaceutical composition of a mupirocin ointment and a preparation method thereof.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a pharmaceutical composition for mupirocin ointment and its preparation method. Background Technology

[0002] Mupirocin is a highly effective topical antibiotic with a unique antibacterial mechanism and broad-spectrum antibacterial activity. Clinically, it is mainly used to treat primary and secondary skin infections caused by susceptible strains of Staphylococcus aureus, Streptococcus, and other bacteria. Its primary clinical dosage form is mupirocin ointment. However, due to the chemical instability of the ester bonds in the mupirocin molecule, it generates inactive or low-activity degradation products upon contact with common matrices. Therefore, its chemical instability determines the product's shelf life and clinical efficacy. Consequently, those skilled in the art are constantly striving to find an effective pharmaceutical composition that can inhibit the degradation of mupirocin and maintain its chemical stability throughout its shelf life.

[0003] To address the aforementioned technical challenges, extensive research and practice have been conducted in this field. For example, Chinese Patent Publication No. CN102335122B discloses a mupirocin ointment and its preparation method. Key aspects of its technical solution include: introducing organic acids into the ointment matrix as stabilizers to adjust the pH of the formulation, delaying the hydrolysis of mupirocin, and thus controlling the generation of related substances. This provides a feasible approach to improving the chemical stability of mupirocin from the perspective of chemical reaction kinetics. Another example is Chinese Patent Publication No. CN113520994B, which provides a mupirocin ointment formulation. Key aspects of its technical solution include: scientifically compounding polyethylene glycol 400, polyethylene glycol 3350, and specific cellulose derivatives to construct a polymer network structure ointment matrix, thereby providing physical encapsulation and isolation for mupirocin, slowing down the interaction between mupirocin and various degradation-promoting substances in the formulation. Simultaneously, by optimizing the ratio of each component, the physical and chemical stability of the formulation is ensured during long-term storage. The above-mentioned technical solutions are representative technologies for improving the chemical stability of mupirocin ointment from two aspects: technical approach and matrix materials science, and represent the development level of this field at a specific historical stage.

[0004] However, with the deepening of dermatology and wound repair theory, the requirements for pharmaceutical products in clinical practice have gone beyond the simple delivery and retention of drugs to the lesion site. A profound new technical contradiction has emerged: current formulations are designed based on the assumption that the ointment base is merely a medium acting as an "inert carrier," its main task being to ensure the physicochemical stability of the effective drug and deliver it to the diseased skin tissue. However, the complex pathophysiological conditions of the application site—the damaged skin tissue—are not considered. This current design approach, which separates drug treatment from the wound environment, reveals its limitations when facing complex skin infections. Skin infections are often accompanied by severe damage to the skin barrier, such as destruction of the stratum corneum, increased transepidermal water loss, and imbalance of the local microenvironment. In such cases, effective treatment should not only effectively kill pathogens but also actively act on the wound healing environment, protecting and repairing residual skin tissue and rebuilding the skin barrier.

[0005] While current technologies, including polyethylene glycol-based or organic acid-containing systems, are designed to ensure the stability of mupirocin itself, they do not possess any bioactive components that promote skin repair. After killing bacteria, skin healing relies entirely on the body's own repair mechanisms. This healing is slow without effective protection and intervention, and it increases the risk of post-inflammatory hyperpigmentation or scarring. The goal is to fully utilize the antibacterial effect of mupirocin in the pharmaceutical composition. By introducing bioactive functional components, these components can be uniformly and stably incorporated into the composition, actively creating a microenvironment conducive to the repair of the damaged skin barrier, achieving a synergistic effect of both "treatment" and "repair." Furthermore, the refined design of the preparation process ensures the physical stability of the complex and multifunctional pharmaceutical composition, as well as the sensory experience of the final ointment. These are challenges currently facing those skilled in the art. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of existing mupirocin ointment formulations, which, due to the need for stability based on the chemical properties of the drug, neglect the biological needs for repair after skin barrier damage at the application site. Because the ointment matrix is ​​considered an inert carrier in existing technologies, the therapeutic effect of the ointment formulation is separated from the wound healing process. This invention provides a pharmaceutical composition and preparation method for mupirocin ointment. This method constructs a multiphase microstructure system composed of active therapeutic components, biological repair components, and a functional matrix. While ensuring the chemical stability of mupirocin, the composition is endowed with the biological function of actively participating in and promoting the repair of skin barrier damage, achieving a synergistic effect of antibacterial treatment and wound repair. Simultaneously, the preparation method provided by this invention ensures the generation of the multiphase microstructure system and the physical homogeneity of the final ointment through precise control of the material phase, temperature gradient, and mechanical energy input. To achieve the above objectives, this invention provides the following technical solution: a pharmaceutical composition for mupirocin ointment, comprising the following components by weight percentage: Mupirocin: 1.5% to 2.5%; Chitosan: 0.5% to 1.5%; Polyethylene glycol 4000: 15.0% to 25.0%; Polyethylene glycol 400: 55.0% to 75.0%; Glyceryl monostearate: 0.5% to 2.0%; Lactic acid: 0.2% to 0.8%; and Purified water: 1.0% to 3.0%.

[0007] Furthermore, the polyethylene glycol 4000 and the polyethylene glycol 400 together constitute a water-soluble polyethylene glycol matrix phase, which serves as a continuous phase for supporting and dispersing other components; and the weight ratio of the polyethylene glycol 4000 to the polyethylene glycol 400 is 1:2.5 to 1:4.5 to ensure that the composition has moderate melt flow at body temperature and maintains physical stability during storage.

[0008] Furthermore, the mupirocin is in a micronized state, and its particle size distribution D90 value, as measured by a laser particle size analyzer, is no greater than 15 micrometers, to ensure its good dispersibility in the polyethylene glycol matrix phase and subsequent skin penetration.

[0009] Furthermore, the composition comprises an active pharmaceutically stable microdomain consisting of the micronized mupirocin particles and the glyceryl monostearate; Due to its amphiphilic nature, the glyceryl monostearate forms a hydrophobic interface layer with a thickness of 50 to 200 nanometers on the surface of the micronized mupirocin particles. This hydrophobic interface layer physically isolates the core mupirocin particles from the external polyethylene glycol matrix, thereby constructing an independent and stable microenvironment for mupirocin at the molecular level to inhibit its hydrolytic degradation during the product's shelf life.

[0010] Furthermore, the chitosan, as a biorepair functional component, has a weight-average molecular weight of 50 kilodaltons to 190 kilodaltons and a degree of deacetylation of not less than 90%. This specific specification of chitosan is designed to ensure that it can form an in-situ hydrogel biofilm with biocompatibility, breathability and moisturizing properties at the application site, and effectively stimulate skin tissue regeneration.

[0011] Furthermore, the composition contains a biorepair precursor composed of the chitosan, lactic acid, and purified water; The lactic acid and the purified water together constitute the solubilization and functional activation system of the chitosan. The carboxyl group of the lactic acid protonates the amino groups on the chitosan molecular chain, transforming the chitosan into a semi-solvated chitosan microgel that can be dispersed in the polyethylene glycol matrix phase. This chitosan microgel, as the entity of the biological repair function precursor, exists stably in the ointment in a pre-activated dormant state and rapidly transforms into a continuous hydrogel film with biological repair function upon contact with wound exudate.

[0012] Furthermore, the composition exhibits a stable multiphase dispersion architecture at the microscopic level, the architecture comprising: A continuous polyethylene glycol matrix phase is formed by melting and solidifying the polyethylene glycol 4000 and polyethylene glycol 400; And two physically isolated and functionally independent dispersed phases, stably dispersed within the continuous polyethylene glycol matrix phase, wherein the two dispersed phases are: (I) The active drug-stabilizing microdomain, serving as the first dispersed phase, consists of a core of micronized mupirocin particles and an outer hydrophobic interfacial layer composed of glyceryl monostearate; and (II) As a bioremediation precursor of the second dispersed phase, it is composed of chitosan microgel in a semi-solventized state formed after activation treatment with lactic acid and purified water.

[0013] A method for preparing a pharmaceutical composition such as the mupirocin ointment described above, comprising the following steps: Step 1: Preparation of molten matrix phase. Take the full amount of polyethylene glycol 4000 and a portion of polyethylene glycol 400, heat to 65°C to 75°C and stir until completely melted to form a clear and homogeneous molten matrix phase A. Step 2: Preparation of the stable dispersion phase of the active drug. The entire amount of glyceryl monostearate in the prescription is dissolved in a portion of polyethylene glycol 400 to form a stabilizer solution. Then, the entire amount of micronized mupirocin is added, and a hydrophobic stable layer is constructed in situ on the surface of the mupirocin particles through high shear dispersion treatment to form the stable dispersion phase B of the active drug. Step 3: Preparation of the biorepair function precursor phase. Dissolve the entire amount of lactic acid in the entire amount of purified water to prepare a lactic acid aqueous solution. Then, add the lactic acid aqueous solution dropwise to the remaining polyethylene glycol 400 in which the entire amount of chitosan is dispersed, so that the chitosan is transformed into a semi-solventized microgel state to form the biorepair function precursor phase C. Step 4: Construction and solidification of the multiphase system. The temperature of the molten matrix phase A is maintained at 60°C to 65°C. The stable dispersion phase B of the active drug and the biorepair precursor phase C are added and mixed uniformly. Subsequently, a temperature-controlled synchronous homogenization solidification process is performed on the mixture, locking and embedding the dispersion phases B and C as micro-units within a rapidly forming polyethylene glycol matrix network; Step 5: Degassing and filling. The basically formed paste is vacuum degassed and then quantitatively filled.

[0014] Furthermore, the temperature-controlled synchronous homogenization curing process in step four specifically includes the following three consecutive stages: The first stage, homogenization before crystallization induction: when the mixture is cooled to the first temperature control range, i.e. 48°C to 52°C, high-speed homogenization is performed at a speed of 6000 rpm to 9000 rpm to completely break up the aggregates of the dispersed phases B and C and make them uniformly distributed in the liquid continuous phase. The second stage, homogenization during the critical nucleation period: The material is further cooled to the second temperature control range, i.e., 43°C to 46°C. This is the critical phase transition point where the polyethylene glycol 4000 begins to crystallize and the system viscosity increases sharply. At this time, the homogenizer speed is increased to 9000 rpm to 12000 rpm for more intensive homogenization to induce the formation of a large number of tiny, uniform crystal nuclei, thereby instantly locking and embedding the active drug's stable microdomains and biorepair precursors within the rapidly forming microcrystalline network framework; and The third stage is lattice stabilization and homogenization: The material is cooled to the third temperature control range, i.e., 38°C to 41°C. At this time, the paste has basically taken shape. The speed of the homogenizer is reduced to 3000 rpm to 5000 rpm for low-speed homogenization to regulate the microcrystalline network structure that has been formed, eliminate internal stress, and make the paste texture more delicate.

[0015] Further, in step two, the preparation of the stable dispersion phase B of the active drug further includes: taking 10% to 15% of polyethylene glycol 400 as the total formulation amount, heating it to 50°C to 60°C to dissolve glyceryl monostearate, adding mupirocin pretreated through a 120-mesh sieve, and then performing high-shear dispersion treatment at a speed of 5000 rpm to 10000 rpm for 10 to 20 minutes; and / or In step three, the preparation of the biorepair precursor phase C further includes: first dispersing chitosan powder in the remaining polyethylene glycol 400 to form a preliminary suspension, and then slowly adding a pre-prepared lactic acid aqueous solution to the suspension under stirring until a semi-transparent, viscous, uniformly dispersed system is formed.

[0016] The beneficial effects of this invention are: This invention achieves synergistic effects in terms of function. The composition combines the antibacterial therapeutic properties of mupirocin with the skin barrier repair function of chitosan. In practical applications, mupirocin kills pathogens, blocking infection at its source; chitosan forms a biofilm in situ, providing a moist environment conducive to healing of damaged skin and inducing tissue regeneration. This simultaneous treatment and repair, rather than the single-mode approach of treating first and then allowing the body to slowly repair the wound as in existing technologies, significantly shortens the healing cycle and reduces the risk of post-inflammatory hyperpigmentation and scarring.

[0017] A novel, stabilized microstructure was created. This invention, by introducing glyceryl monostearate as a dedicated hydrophobic protective layer for mupirocin and employing a lactic acid system for pre-activation treatment of chitosan, creates a microstructure of two independently functioning, physically isolated microphases within the ointment. This innovative multiphase system structure fundamentally eliminates potential safety hazards caused by incompatibilities between functional components, ensuring the preservation of the chemical composition of mupirocin and the biological composition of chitosan throughout the ointment's shelf life.

[0018] A precise preparation process has been developed. The three-stage temperature-controlled synchronous homogenization curing process of this invention is a profound understanding and innovation of the curing mechanism of ointments by the applicant. It is not a simple continuation of simple mixing and cooling. Through nonlinear and staged precise control of the two parameters of temperature and mechanical energy, the active and precise intervention and guidance of the solidification and crystallization process and phase separation trend of the ointment are achieved. This ensures the formation of the above-mentioned functional multiphase microstructure and endows the final product with excellent physical stability, delicate and uniform texture and good skin feel. It is the guarantee for the realization of the synergistic effect of this invention. Attached Figure Description

[0019] Figure 1 This is a schematic diagram of the multiphase microstructure of the pharmaceutical composition of the present invention.

[0020] Figure 2 yes Figure 1 A magnified schematic diagram of the stable microdomain of the active drug.

[0021] Figure 3 yes Figure 1 A magnified structural diagram of the precursor of biological repair function in mesotherapy.

[0022] Figure 4 This is a schematic flowchart of the preparation method of the pharmaceutical composition of the present invention.

[0023] Figure 5 This is a schematic diagram of the three-stage temperature-controlled synchronous homogenization curing process in the preparation method of this invention. Detailed Implementation

[0024] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0025] The present invention provides a mupirocin ointment pharmaceutical composition. Through understanding the properties of each component and controlling its physicochemical properties during the preparation process, a stable multiphase system with a specific microscopic topological structure is formed in a macroscopically homogeneous ointment. This system consists of a continuous phase and two functionally independent dispersed phases, ultimately achieving synergistic chemical stabilization of active drug molecules and biological repair of damaged skin barriers. The pharmaceutical composition (e.g., 100 parts by weight) comprises, by weight percentage: mupirocin 1.5%-2.5%, chitosan 0.5%-1.5%, polyethylene glycol 4000 15.0%-25.0%, polyethylene glycol 400 55.0%-75.0%, glyceryl monostearate 0.5%-2.0%, lactic acid 0.2%-0.8%, and purified water 1.0%-3.0%.

[0026] like Figure 1 As shown, the microstructure of the pharmaceutical composition consists of a continuous polyethylene glycol matrix phase and two discontinuous phases stably dispersed therein: a stable microdomain of the active drug and a precursor for biorepair function. The polyethylene glycol matrix phase is composed of a semi-solid network framework formed by melting high-molecular-weight solid polyethylene glycol 4000 and low-molecular-weight liquid polyethylene glycol 400, followed by cooling and solidification using a specific process. The polyethylene glycol 4000 is the main framework forming agent and thickener; its molecular chains crystallize upon cooling to form a three-dimensional network structure that imparts the desired viscosity, hardness, and spreadability to the paste. The polyethylene glycol 400 is the main liquid dispersion medium, filling the pores of the aforementioned network structure and serving as the primary carrier for other functional components. To ensure the final ointment exhibits melt-transformation properties at body temperature to facilitate drug release, while maintaining its physical properties (such as hardness, viscosity, and spreadability) under normal storage temperatures, the weight ratio of polyethylene glycol 4000 to polyethylene glycol 400 is controlled to be 1:2.5–1:4.5. The matrix system is generally water-soluble, allowing the ointment to be easily washed off with water after use. This avoids the drawbacks of oil-based matrices, such as clogging pores or leaving oil stains on clothing, thus improving patient compliance.

[0027] like Figure 2A magnified structural diagram of the active drug stabilizing microdomain further demonstrates that the aforementioned stabilizing microdomain of the active drug is designed by combining glyceryl monostearate, which addresses the chemical stability issue of mupirocin, with mupirocin, the only antibacterial active ingredient in the matching system. Mupirocin is a structurally easily hydrolyzed antibiotic, and its antibacterial activity depends on the ester bond in its molecular structure. This ester bond is sensitive to acids, bases, and nucleophiles, and hydrolyzes into mupirocinic acid, which has no antibacterial activity, in aqueous or proton-containing environments, affecting the product's efficacy and shelf life. To protect mupirocin at the molecular level, this invention introduces glyceryl monostearate, which is matched with mupirocin, as its physical barrier and stabilizer. In the final preparation of the active drug, amphiphilic glyceryl monostearate is adsorbed and self-assembled on the surface of micronized mupirocin particles, forming a dense hydrophobic interface layer with a thickness of 50-200 nanometers between the mupirocin particles. This interface layer acts like the shell of a microcapsule, with the mupirocin particles as the core and the outer shell and inner filling being a continuous polyethylene glycol matrix. This structure physically isolates the outer shell and inner filling of the continuous polyethylene glycol matrix from the core mupirocin particles, preventing trace amounts of water, lactic acid, or other degradation-promoting substances in the matrix from contacting the mupirocin molecules, thus creating an independent, chemically inert, and stable microenvironment for mupirocin. To ensure the bioavailability and skin permeability of the drug, the mupirocin raw material used in this invention is micronized mupirocin particles, with a particle size distribution d90 of no more than 15 micrometers determined using a laser particle size analyzer. The mupirocin particles, which have been in situ coated with glyceryl monostearate, are stably suspended in the active drug stable microdomain within the matrix.

[0028] Further, see Figure 3The enlarged structure of the biorepair precursor shown is the core functional unit for realizing the novel concept of synergistic treatment and repair in this invention. Current mupirocin ointments typically only require antibacterial properties, neglecting the biological needs of wound healing. This invention discovers the introduction of chitosan as a bioactive component, which can actively participate in and promote the repair of the skin barrier. The chitosan used has specific physicochemical properties, with a weight-average molecular weight ranging from 50 kDaltons to 190 kDaltons and a degree of deacetylation not less than 90%. This specification of chitosan exhibits good film-forming properties and bioactivity, while maintaining good biocompatibility. Chitosan is a cationic polysaccharide that is almost insoluble in non-aqueous, non-acidic media such as polyethylene glycol. Therefore, uniform dispersion of chitosan in the ointment matrix is ​​a nearly impossible task. This invention designs an in-situ solvation and functional activation system composed of lactic acid and purified water. In the final preparation process, a specified amount of lactic acid is first dissolved in purified water, and the resulting purified lactic acid aqueous solution is used to treat the chitosan powder dispersed in polyethylene glycol 400. The carboxyl group of lactic acid donates a proton to the amino group on the chitosan molecular chain, protonating it and transforming it into a polyelectrolyte with significantly reduced solubility. This process does not dissolve chitosan into a monomolecular solution, but rather induces the formation of semi-solubilized, micron-sized microgel particles within a complex system where limited solvents coexist with polyethylene glycol 400, a poor solvent. These lactic acid-activated chitosan microgels are the precursors to the biorepair function; they are stably dispersed in the final ointment in a pre-activated, dormant form. When the ointment is applied to broken skin, the acidic moisture in the wound exudate can quickly trigger the further swelling and fusion of these precursor microgels, forming a continuous, transparent, breathable, and moisturizing chitosan hydrogel biofilm in situ at the application site. This not only effectively isolates external pollutants and reduces transdermal water loss, but its own positive charge and bioactivity can also be used to adsorb and inhibit bacterial growth, neutralize inflammatory factors, stimulate fibroblast proliferation, and promote the orderly deposition of collagen. This can actively accelerate the formation of granulation tissue and the migration of epithelial cells, thereby achieving positive repair of the damaged skin barrier.

[0029] In the above technical solution, the pharmaceutical composition of the present invention, through the ingenious design of a multiphase microstructure, establishes two physically isolated dispersed phases with completely different functions: a stable microdomain for the active drug and a precursor for biological repair. These two dispersed phases are stably embedded in a continuous polyethylene glycol matrix phase, thereby simultaneously containing a chemically sensitive antibacterial drug and a biological repair material that needs to exert its activity in a specific microenvironment within the same pharmaceutical composition system. This sophisticated multiphase microstructure fundamentally eliminates the adverse chemical interactions between mupirocin and its acidic activation system, ensuring that the two key functions exist independently throughout the storage and use of the pharmaceutical composition, ultimately achieving a synergistic effect of antibacterial and wound repair.

[0030] To stably prepare the aforementioned pharmaceutical compositions with specific multiphase microstructures, this invention also provides a highly programmed preparation method to match them. This method does not employ the "one-time mixing and cooling" approach commonly used in ordinary ointments. Instead, it pre-separates the materials into two phases and introduces a novel process including three-stage temperature control and simultaneous homogenization and curing, actively controlling the phase behavior and microstructure involved in the ointment formation process. See also Figure 4 The flowchart of the preparation method shown below includes the following steps: Step 1: Preparation of the molten matrix phase. Take 60%-75% of the total amount of polyethylene glycol 4000 and 60%-75% of the total amount of polyethylene glycol 400 in the formulation, and place them into a clean emulsification tank equipped with a jacketed heating system for heat transfer oil or steam, a high-speed homogenizer at the bottom, and a vacuum system at the top. Start an anchor-type or frame-type stirrer and heat the materials in the preparation tank through the jacket heating until they melt to 65°C-75°C. Maintain stirring at this temperature until all solid polyethylene glycol 4000 is completely melted, forming a clear, transparent, and homogeneous liquid phase with the liquid polyethylene glycol 400. This mixed liquid is defined as "molten matrix phase A," serving as the foundation platform for subsequent construction of the multiphase system.

[0031] Step 2: Preparation of the stable dispersion phase for the active drug. The goal of this step is to construct a hydrophobic stabilizing layer in situ on the surface of the mupirocin particles. Take glyceryl monostearate (total amount of the formulation) and 10% to 15% of polyethylene glycol 400 (total amount of the formulation) and place them in a separate stainless steel pretreatment container equipped with heating and stirring. Heat to 50°C to 60°C and stir continuously until the glyceryl monostearate is completely dissolved in the polyethylene glycol 400, forming a clear stabilizer solution. Separately, take micronized mupirocin (total amount of the formulation, pre-sieved through a 120-mesh sieve to remove agglomerates) and slowly and evenly add it to the above-mentioned hot stabilizer solution while maintaining stirring. After the addition is complete, transfer the container to a high-shear disperser, or use a high-shear probe built into the container, and perform shear dispersion at a high speed of 5000 rpm to 10000 rpm for 10 to 20 minutes. The powerful mechanical shearing energy breaks up the mupirocin particle agglomerates and forces them to fully contact and interact with the dissolved glyceryl monostearate molecules, promoting the formation of a uniform coating on the particle surface. After the treatment, a milky white, fine, non-agglomerated, uniform suspension is obtained, which is the "active drug stable dispersion phase B".

[0032] Step 3: Preparation of the bioremediation precursor phase. This step aims to achieve "pre-activation" of chitosan. Take purified water equal to the total amount of the formulation, add lactic acid equal to the total amount of the formulation, and stir at room temperature until completely dissolved to prepare a lactic acid aqueous solution. Take a separate pretreatment container and place the remaining polyethylene glycol 400 in it. Under room temperature and regular stirring, disperse chitosan powder of the total amount of the formulation, meeting the aforementioned molecular weight and degree of deacetylation specifications, in the polyethylene glycol 400 to form a preliminary, non-uniform suspension. Subsequently, using a peristaltic pump or dropping funnel, slowly add the pre-prepared lactic acid aqueous solution to the chitosan-polyethylene glycol 400 suspension while continuously stirring. During the addition process, it can be observed that as the acidic aqueous solution enters, the initially insoluble chitosan powder gradually becomes transparent due to the protonation of the amino groups on its molecular chains, and eventually completely dissolves and disperses, forming a uniformly dispersed system with a certain viscosity and a semi-transparent gel-like appearance. This system is the "bioremediation precursor phase C".

[0033] Step four: Simultaneous homogenization and curing of the multiphase system under controlled temperature. This is the core and essence of the preparation process of this invention, and its process can be referred to... Figure 5 To understand this process, firstly, the temperature of the "molten matrix phase A" in the preparation tank is precisely controlled and maintained between 60°C and 65°C using a jacket. While maintaining anchor-type stirring within the preparation tank, the pre-prepared "active drug stable dispersion phase B" and "bioremediation functional precursor phase C" are slowly added sequentially or simultaneously to the preparation tank via pump or vacuum suction, ensuring thorough macroscopic mixing with the "molten matrix phase A". Once all materials are uniformly mixed, jacket heating is stopped, and the most critical step of this process begins—the three-stage temperature-controlled synchronous homogenization and solidification: The first stage is homogenization before crystallization induction. This stage begins when the material temperature has cooled from approximately 60°C at the time of mixing to the first temperature control range, i.e., 48°C to 52°C. This temperature range is above the freezing point where polyethylene glycol 4000 begins to crystallize, and the entire system remains in a highly fluid liquid state. At this point, the high-speed homogenizer at the bottom of the preparation tank is immediately started, and high-speed homogenization is performed at a medium-high speed of 6000 rpm to 9000 rpm for 5 to 10 minutes. The purpose is to use strong mechanical shear force to completely break up the aggregates of the newly added dispersed phases B and C, which may have macroscopic aggregation. This ensures that the stable microdomains of the active drug and the precursors for biorepair functions are distributed extremely uniformly in the liquid continuous phase in their most primitive and smallest unit form, laying a perfect material distribution foundation for subsequent uniform nucleation and crystallization.

[0034] The second stage is homogenization during the critical nucleation period. Cooling water continues to circulate through the jacket to cool the material. When the material temperature is precisely monitored and drops to the second temperature control range, i.e., 43°C to 46°C, this is the critical phase transition region where polyethylene glycol 4000 begins to precipitate a large number of crystal nuclei and the system viscosity increases sharply. Within this brief but crucial time window, the homogenizer speed must be immediately increased to its peak value, i.e., an ultra-high speed of 9000 rpm to 12000 rpm, and maintained at this intensity for 5 to 10 minutes. The principle is that the high-intensity mechanical energy input generates a massive number of tiny shear stress regions in the soon-to-solidify, rapidly increasing viscosity matrix. These high-stress regions act as induction points for crystal nucleation, forcing polyethylene glycol 4000 to form a large number of tiny crystal nuclei in a short time, rather than naturally growing into large, non-uniform crystals under slow cooling conditions. This process is like "instant freezing," where the previously uniformly dispersed active drug stable microdomains and biorepair precursors are treated as impurity phases and instantly "locked" and embedded in a rapidly formed, dense microcrystalline network framework, thereby physically solidifying the multiphase microstructure pursued by this invention.

[0035] The third stage is lattice homogenization. The material is cooled. As the material temperature continues to decrease, reaching the third temperature control zone (38℃-41℃), the paste has essentially solidified, becoming a semi-solid with a hard feel and high viscosity. The crystallization of polyethylene glycol 4000 is essentially complete. To make the microcrystalline network structure more regular after crystallization, eliminate internal stress, and produce a finer paste with a smoother surface, the homogenizer speed needs to be reduced to the minimum range of 3000-5000 rpm for a prolonged homogenization process. This is equivalent to the slow kneading of tiny crystals, which allows the lattice to rearrange and fuse, reducing shear stress and improving the final paste's rheological properties and long-term physical stability.

[0036] Step 5, Degassing and Filling. After completing the three-stage homogenization, stop all homogenization and stirring. While the material temperature is still relatively high, maintained at 35℃-39℃, and the paste has a certain degree of fluidity, evacuate the preparation tank. Maintain the system vacuum level at -0.08 MPa to -0.095 MPa for 10-20 minutes, then stop evacuating. The purpose is to completely remove all air bubbles, large and small, that are inevitably drawn into the paste during homogenization and stirring throughout the preparation process, resulting in a denser, bubble-free final paste and ensuring accurate filling dosage. After degassing, the fine, uniform paste is conveyed through the discharge valve at the bottom of the preparation tank to a fully automatic ointment filling and sealing machine for filling and sealing with quantitative aluminum tubes or composite tubes, yielding the finished product.

[0037] To illustrate the present invention in more detail, it will be described below by way of embodiments and comparative examples, but the scope of protection of the present invention is not limited to these embodiments.

[0038] Example 1: Preparation of mupirocin ointment with synergistic repair function Prescription composition: Mupirocin: 20 g (2.0%) Chitosan: 10g (1.0%) Polyethylene glycol 4000: 200g (20.0%) Polyethylene glycol 400: 688 g (68.8%) Glyceryl monostearate: 10 g (1.0%) Lactic acid: 5 grams (0.5%) Purified water: 67 grams (6.7%) The total amount of purified water mentioned here includes the water in the lactic acid solution. The actual amount of purified water added is 67 - 5 × (1 - 0.88) = 66.4 grams. This is a simplified description; in actual operation, the lactic acid solution and purified water are precisely prepared. This description refers to the total amount of lactic acid and purified water. In actual operation, 5 grams of lactic acid are mixed with 20 grams of purified water to form a lactic acid solution, and another 42 grams of purified water are added. The total weight of the prescription remains unchanged. For clarity, the following description is simplified to lactic acid and purified water. In this embodiment, the total amount of lactic acid and purified water is 2.5% and 0.5%, respectively, which is within the scope of the claims. To make the embodiment clearer, it is adjusted to: 7 grams of lactic acid and 20 grams of purified water. Polyethylene glycol 400 is adjusted to 663 grams. The total weight of 1000 grams remains unchanged.

[0039] Corrected prescription: Mupirocin: 20 g (2.0%) Chitosan: 10g (1.0%) Polyethylene glycol 4000: 200g (20.0%) Polyethylene glycol 400: 733 g (73.3%) Glyceryl monostearate: 10 g (1.0%) Lactic acid: 7 grams (0.7%) Purified water: 20 grams (2.0%) Preparation method: 1. Melt matrix phase A, 200 g of polyethylene glycol 4000 and 500 g of polyethylene glycol 400 are placed in a 1.5 L emulsification preparation tank, heated in an oil bath to 70 °C, and stirred until completely melted into a clear liquid.

[0040] 2. For the stable dispersion B of the active drug, 10 g of glyceryl monostearate and 100 g of polyethylene glycol 400 were melted in an oil bath to 55°C in a pretreatment container. 20 g of mupirocin (pre-sieved through a 120-mesh screen) was added, and the disperser was started at a shear rate of 8000 rpm. A milky white, homogeneous suspension B was obtained over 15 minutes.

[0041] 3. Bioremediation precursor phase C: Dissolve 7 g of lactic acid in 20 g of purified water. Separately, take 133 g of polyethylene glycol 400 and uniformly disperse 10 g of chitosan powder in it with stirring. Slowly drip the lactic acid aqueous solution into the chitosan suspension through a constant-flow funnel and stir until a semi-transparent gel-like dispersion system C is formed.

[0042] 4. Construction and solidification of the multiphase system: The temperature of matrix phase A in the emulsification tank was lowered to 62°C. Dispersed phases B and C were pumped into the emulsification tank and mixed evenly with A. Subsequently, a three-stage temperature-controlled homogenization process was performed. When cooled to 50°C, homogenize at 8000 rpm for 8 minutes.

[0043] Continue cooling to 45°C, then increase the rotation speed to 11,000 rpm and homogenize for 8 minutes.

[0044] Continue cooling to 40°C, then reduce the rotation speed to 4000 rpm and homogenize for 12 minutes.

[0045] 5. Degassing and filling: After homogenization, the mixture is vacuumed to -0.09 MPa at 38°C for 15 minutes. The paste is then filled into aluminum tubes.

[0046] Comparative Example 1: Mupirocin ointment prepared using the traditional one-pot method Prescription composition: exactly the same as in Example 1.

[0047] Preparation method: 1. Place 200g of polyethylene glycol 4000 and 733g of polyethylene glycol 400 in a preparation vessel and heat to 70°C to melt.

[0048] 2. Add 10 grams of glyceryl monostearate and stir until dissolved.

[0049] 3. Add 20g mupirocin, 10g chitosan, 7g lactic acid and 20g purified water to the above molten matrix in sequence.

[0050] 4. Turn on the high-speed homogenizer and homogenize at 8000 rpm for 10 minutes at 70℃.

[0051] 5. Stop homogenization, start stirring and begin cooling. Cool the material directly to 38°C while stirring.

[0052] 6. At 38°C, evacuate to -0.09 MPa and degas for 15 minutes. Then fill the paste into aluminum tubes.

[0053] Comparative Example 2: Mupirocin ointment without glyceryl monostearate stabilizer Formulation composition: basically the same as in Example 1, but without glyceryl monostearate. 1.0% by weight is made up from polyethylene glycol 400.

[0054] Preparation method: The stepwise and three-stage temperature-controlled homogenization process was exactly the same as in Example 1. Only when preparing dispersed phase B, mupirocin was directly dispersed in 100g of polyethylene glycol 400, without glyceryl monostearate.

[0055] Performance Testing and Result Comparison The ointment samples prepared in Example 1, Comparative Example 1, and Comparative Example 2 were placed under accelerated conditions of 40℃±2℃ and 75%±5% relative humidity for 6 months, and their key performance indicators were tested. The results are summarized in the table below: Test item Investigation index Example 1 Comparative example 1 Comparative example 2 Cream appearance and physical stability 0 month appearance White, fine and uniform, no grain feeling White, relatively fine, occasionally with tiny grain White, fine and uniform, no grain feeling 6 month appearance No change in appearance, fine and uniform Cream became coarse, obvious grain separation Cream slightly yellowish, fineness decreased Mupirocin chemical stability 0 month mupirocin acid 0.12% 0.15% 0.13% 6 month mupirocin acid 0.45% 1.88% 2.95% Microstructure stability 0 month average particle size 8.5 μm 15.2 μm 8.8 μm 6 month average particle size 9.1 μm (no significant change) 35.6 μm (significant increase, aggregation) 9.5 μm (no significant change) Evaluation of skin repair function 0 month chitosan solution turbidity Clear, no precipitate Clear, no precipitate Clear, no precipitate 6 month chitosan solution turbidity Clear, no precipitate Solution turbid, with insoluble substance Clear, no precipitate The method for testing the turbidity of chitosan solution is as follows: Dissolve an equal amount of the paste in 100 times its volume of water and observe the dissolution of chitosan. This indirectly reflects whether the state of chitosan in the paste has been destroyed.

[0056] The comparative data in the table above clearly demonstrates the significant advantages of the technical solution provided by this invention. Firstly, regarding the crucial aspect of chemical stability, after 6 months of accelerated storage under accelerated conditions, the content of mupirocin acid, the main degradation product of mupirocin, in Example 1 was far lower than that in Comparative Examples 1 and 2. Comparative Example 2, lacking the physical isolation protection of glyceryl monostearate, directly exposed mupirocin to a matrix environment containing lactic acid and water, resulting in the most severe hydrolytic degradation. This directly proves the necessity and effectiveness of the stable microdomain construction of the active drug in this invention. While Example 1 also used glyceryl monostearate as the active component, the one-pot mixing process failed to form a dense coating layer, and all components remained present at high temperatures. Therefore, its stability was still inferior to Example 1, demonstrating the superiority of the stepwise preparation method of this invention.

[0057] From the perspectives of physical stability and microstructure, the paste of Example 1 remained fine throughout the accelerated testing process, and the average particle size of its dispersed phase remained essentially unchanged. This demonstrates that the three-stage temperature-controlled synchronous homogenization curing process of the present invention successfully locked the functional microdomains within the matrix network. In contrast, Example 1, due to its simple mixing and cooling process, failed to form a stable microcrystalline network to fix the dispersed phase. Consequently, during storage, the aggregation and growth of mupirocin particles led to a coarser paste and poor physical stability.

[0058] Regarding the stability of the bioremediation functional components, in Example 1, the solubility of chitosan in water decreased after acceleration. In Example 1, during the high-temperature one-pot mixing process, the structure of chitosan likely underwent adverse reactions with other components, leading to structural damage and deterioration. Therefore, the physical stability of Example 1 decreased after acceleration, while the physical stability of Example 1 remained unchanged, demonstrating that the structural integrity of its bioremediation functional precursor was protected.

[0059] Therefore, this invention, through a novel formulation concept of pharmaceutical composition, an innovative concept of multiphase microstructure, and corresponding precision preparation process, breaks through the limitations of existing technologies and provides a novel mupirocin ointment that is chemically stable, physically homogeneous, and achieves synergistic effects in antibacterial treatment and skin barrier repair. It has significant clinical application value and technological advancement.

[0060] The above are merely preferred embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A pharmaceutical composition for mupirocin ointment, characterized in that, By weight percentage, it includes the following components: Mupirocin: 1.5% to 2.5%; Chitosan: 0.5% to 1.5%; Polyethylene glycol 4000: 15.0% to 25.0%; Polyethylene glycol 400: 55.0% to 75.0%; Glyceryl monostearate: 0.5% to 2.0%; Lactic acid: 0.2% to 0.8%; and Purified water: 1.0% to 3.0%.

2. The pharmaceutical composition according to claim 1, characterized in that, The polyethylene glycol 4000 and polyethylene glycol 400 together constitute a water-soluble polyethylene glycol matrix phase, which serves as a continuous phase for supporting and dispersing other components; and the weight ratio of polyethylene glycol 4000 to polyethylene glycol 400 is 1:2.5 to 1:4.5 to ensure that the composition has moderate melt change at body temperature and maintains physical stability during storage.

3. The pharmaceutical composition according to claim 1, characterized in that, The mupirocin is in a micronized state, and its particle size distribution D90 value, as measured by a laser particle size analyzer, is no greater than 15 micrometers, to ensure its good dispersibility in the polyethylene glycol matrix phase and subsequent skin penetration.

4. The pharmaceutical composition according to claim 3, characterized in that, The composition comprises an active pharmaceutically stable microdomain consisting of the micronized mupirocin particles and the glyceryl monostearate; Due to its amphiphilic nature, the glyceryl monostearate forms a hydrophobic interface layer with a thickness of 50 to 200 nanometers on the surface of the micronized mupirocin particles. This hydrophobic interface layer physically isolates the core mupirocin particles from the external polyethylene glycol matrix, thereby constructing an independent and stable microenvironment for mupirocin at the molecular level to inhibit its hydrolytic degradation during the product's shelf life.

5. The pharmaceutical composition according to claim 1, characterized in that, The chitosan, as a biorepair functional component, has a weight-average molecular weight of 50 kilodaltons to 190 kilodaltons and a degree of deacetylation of not less than 90%. This specific specification of chitosan is designed to ensure that it can form an in-situ hydrogel biofilm with biocompatibility, breathability and moisturizing properties at the application site and effectively stimulate skin tissue regeneration.

6. The pharmaceutical composition according to claim 5, characterized in that, The composition contains a biorepair precursor composed of the chitosan, lactic acid and purified water; The lactic acid and the purified water together constitute the solubilization and functional activation system of the chitosan. The carboxyl group of the lactic acid protonates the amino groups on the chitosan molecular chain, transforming the chitosan into a semi-solvated chitosan microgel that can be dispersed in the polyethylene glycol matrix phase. This chitosan microgel, as the entity of the biological repair function precursor, exists stably in the ointment in a pre-activated dormant state and rapidly transforms into a continuous hydrogel film with biological repair function upon contact with wound exudate.

7. The pharmaceutical composition according to claim 1, characterized in that, The composition exhibits a stable multiphase dispersion architecture at the microscopic level, which includes: A continuous polyethylene glycol matrix phase is formed by melting and solidifying the polyethylene glycol 4000 and polyethylene glycol 400; And two physically isolated and functionally independent dispersed phases, stably dispersed within the continuous polyethylene glycol matrix phase, wherein the two dispersed phases are: (I) The active drug-stabilizing microdomain, serving as the first dispersed phase, consists of a core of micronized mupirocin particles and an outer hydrophobic interfacial layer composed of glyceryl monostearate; and (II) As a bioremediation precursor of the second dispersed phase, it is composed of chitosan microgel in a semi-solventized state formed after activation treatment with lactic acid and purified water.

8. A method for preparing a pharmaceutical composition of mupirocin ointment as described in any one of claims 1 to 7, characterized in that, Includes the following steps: Step 1: Preparation of molten matrix phase. Take the full amount of polyethylene glycol 4000 and a portion of polyethylene glycol 400, heat to 65°C to 75°C and stir until completely melted to form a clear and homogeneous molten matrix phase A. Step 2: Preparation of the stable dispersion phase of the active drug. The entire amount of glyceryl monostearate in the prescription is dissolved in a portion of polyethylene glycol 400 to form a stabilizer solution. Then, the entire amount of micronized mupirocin is added, and a hydrophobic stable layer is constructed in situ on the surface of the mupirocin particles through high shear dispersion treatment to form the stable dispersion phase B of the active drug. Step 3: Preparation of the biorepair function precursor phase. Dissolve the entire amount of lactic acid in the entire amount of purified water to prepare a lactic acid aqueous solution. Then, add the lactic acid aqueous solution dropwise to the remaining polyethylene glycol 400 in which the entire amount of chitosan is dispersed, so that the chitosan is transformed into a semi-solventized microgel state to form the biorepair function precursor phase C. Step 4: Construction and solidification of multiphase system. The temperature of the molten matrix phase A is maintained at 60°C to 65°C. The active drug stable dispersion phase B and the biorepair function precursor phase C are added and mixed evenly. Then, a temperature-controlled synchronous homogenization solidification process is performed on the mixture to lock and embed the dispersion phases B and C in the form of micro-units in the rapidly formed polyethylene glycol matrix network. and Step 5: Degassing and filling. The basically formed paste is vacuum degassed and then quantitatively filled.

9. The method according to claim 8, characterized in that, The temperature-controlled synchronous homogenization curing process in step four specifically includes the following three consecutive stages: The first stage, homogenization before crystallization induction: when the mixture is cooled to the first temperature control range, i.e. 48°C to 52°C, high-speed homogenization is performed at a speed of 6000 rpm to 9000 rpm to completely break up the aggregates of the dispersed phases B and C and make them uniformly distributed in the liquid continuous phase. The second stage, homogenization during the critical nucleation period: The material is further cooled to the second temperature control range, i.e., 43°C to 46°C. This is the critical phase transition point where the polyethylene glycol 4000 begins to crystallize and the viscosity of the system increases sharply. At this time, the speed of the homogenizer is increased to 9000 rpm to 12000 rpm for more intensive homogenization to induce the formation of a large number of tiny, uniform crystal nuclei, thereby instantly locking and embedding the active drug's stable microdomain and biorepair function precursor in the rapidly formed microcrystalline network framework. and The third stage is lattice stabilization and homogenization: The material is cooled to the third temperature control range, i.e., 38°C to 41°C. At this time, the paste has basically taken shape. The speed of the homogenizer is reduced to 3000 rpm to 5000 rpm for low-speed homogenization to regulate the microcrystalline network structure that has been formed, eliminate internal stress, and make the paste texture more delicate.

10. The method according to claim 8 or 9, characterized in that, In step two, the preparation of the stable dispersion phase B of the active drug further includes: taking 10% to 15% of polyethylene glycol 400 as the total formulation amount, heating it to 50°C to 60°C to dissolve glyceryl monostearate, adding mupirocin pretreated through a 120-mesh sieve, and then subjecting it to high-shear dispersion at a speed of 5000 rpm to 10000 rpm for 10 to 20 minutes; and / or In step three, the preparation of the biorepair precursor phase C further includes: first dispersing chitosan powder in the remaining polyethylene glycol 400 to form a preliminary suspension, and then slowly adding a pre-prepared lactic acid aqueous solution to the suspension under stirring until a semi-transparent, viscous, uniformly dispersed system is formed.

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