Drug delivery carrier, preparation method and application

Abstract

The invention provides a drug delivery carrier, a preparation method and application. The invention relates to a drug delivery carrier, which comprises a drug-loading membrane and a nano microemulsion loaded on the drug-loading membrane, the average particle size of the nano microemulsion is 10 nm to 20 nm. The drug delivery carrier realizes efficient loading and stable release of the drug, can be widely applied to a drug delivery system, and improves the bioavailability of the drug.

Description

Technical Field

[0001] This invention relates to the field of medical supplies technology, and in particular to a drug delivery carrier, its preparation method, and its application. Background Technology

[0002] Transdermal drug delivery, as a non-invasive method of drug administration, offers advantages such as reducing the first-pass effect in the liver, maintaining stable blood drug concentrations, and improving patient compliance, thus attracting widespread attention in the pharmaceutical and cosmetic fields. However, traditional transdermal drug delivery carriers generally suffer from poor drug permeability, insufficient stability, and low drug loading capacity, limiting their wider application. Summary of the Invention

[0003] This invention provides a drug delivery carrier, a preparation method, and an application to further improve the bioavailability of drugs.

[0004] This invention provides a drug delivery carrier, comprising a drug-loaded membrane and a nanoemulsion loaded on the drug-loaded membrane; The average particle size of the nanoemulsion is 10nm-20nm.

[0005] In some examples, the drug-loaded membrane has a porous structure in which the nanoemulsion is located; the average pore size of the porous structure is 10 nm-50 nm.

[0006] In some examples, the thickness of the drug-loaded membrane is 1 mm to 5 mm.

[0007] In some examples, the mass ratio of the nanoemulsion to the drug-loaded membrane is 1:(4-9).

[0008] In some examples, the nanoemulsion comprises, by weight, 2-20 parts emulsifier, 1-50 parts co-emulsifier, 1-10 parts liquid lipid, 0.01-5 parts humectant, and 0.01-5 parts stabilizer.

[0009] In some examples, the nanoemulsion satisfies one or more of the following conditions: The emulsifier includes one or more of the following: Tween 80, Tween 60, Tween 40, Tween 20, polyoxyethylene castor oil-20, polyoxyethylene castor oil-30, polyoxyethylene castor oil-35, polyoxyethylene castor oil-40, PEG40 hydrogenated castor oil, PEG30 hydrogenated castor oil, PEG20 hydrogenated castor oil, PEG10 hydrogenated castor oil, PEG5 hydrogenated castor oil, polyethylene glycol 400 monoglyceride, polyethylene glycol 400 diglyceride, polyethylene glycol 600 monoglyceride, polyethylene glycol 600 diglyceride, cocoyl glucoside, cetearyl alcohol polyether-20, cetearyl alcohol polyether-25, and butanol polyether-26. The co-emulsifier includes one or more of polyethylene glycol, propylene glycol, dipropylene glycol, glycerin, 1,2-hexanediol, 1,3-butanediol, 1,2-pentanediol, oleic acid, diethylene glycol monoethyl ether, and poloxamer. The liquid lipids include one or more of the following: isopropyl myristate, isopropyl palmitate, caprylic / capric triglyceride, polyethylene glycol caprylic / capric triglyceride, polyethylene glycol laurate, polyethylene glycol stearate, linoleic acid, propylene glycol monocaprylate, propylene glycol dicaprylate, diethyl sebacate, cocoa butter caprylate, isononyl isononanoate, triacetin, dimethyl silicone oil, vitamin E, squalene, and soybean oil. The moisturizing agent includes one or more of allantoin, hyaluronic acid, ceramide, chitosan, sorbitol, sodium lactate, chondroitin sulfate, amino acids, and vitamin B5. The stabilizer includes one or more of hyaluronic acid, polyglutamic acid, xanthan gum, polyvinylpyrrolidone, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, gelatin, guar gum, gum arabic, carbomer, tyrosine, tyrosine methyl ester hydrochloride, tyrosine ethyl ester hydrochloride, and tyrosine propyl ester hydrochloride.

[0010] In some examples, the nanoemulsion also includes a pH adjuster, which includes lactic acid; Optionally, the pH of the nanoemulsion is 6-7.

[0011] In some examples, the drug-loaded membrane includes a fibrous membrane; Optionally, the fiber membrane includes one or two of the following: natural biological protein fungal fermentation fiber membrane and electrospun nanofiber membrane; The average diameter of the fibers in the fiber membrane is 10nm-50nm.

[0012] The present invention also provides a method for preparing the above-mentioned drug delivery carrier, comprising: The raw materials of the nanoemulsion are divided into n groups to obtain n groups of nanoemulsions; wherein, 10nm≤average particle size of the nanoemulsion in the (i-1)th group <average particle size of the nanoemulsion in the i-th group ≤20nm, i≤n; After mixing n groups of the nanoemulsions, the nanoemulsions with an average particle size of 10nm-20nm are obtained. The drug-loaded membrane is mixed with the nanoemulsion and allowed to stand for adsorption to obtain the drug delivery carrier.

[0013] The present invention also provides an application of a drug delivery carrier in transdermal drug delivery, wherein the drug delivery carrier encapsulates or grafts drugs including salicylate, hyaluronic acid or melatonin.

[0014] The drug delivery carrier of this invention achieves efficient drug delivery and stable release by loading nanoemulsions onto a drug-loaded membrane. Controlling the average particle size of the nanoemulsions within the range of 10nm-20nm helps improve drug bioavailability and enhances drug penetration into target tissues or cells, thereby improving therapeutic efficacy. Furthermore, the drug-loaded membrane, as a drug carrier, can protect the drug from the influence of the external environment, prolong the drug's duration of action, reduce the frequency of administration, and improve patient compliance. This drug delivery carrier can be widely applied in various therapeutic scenarios requiring local or systemic drug delivery.

[0015] The preparation of nanoemulsions is based on emulsification technology. By selecting appropriate emulsifiers and stabilizers, the oil and aqueous phases are mixed under specific conditions to form a stable nanoscale emulsion. Drug-loaded membranes can be made from natural biological proteins, fungal fermentation, or fiber membranes, which possess good biocompatibility and permeability. The prepared nanoemulsions are uniformly loaded onto the drug-loaded membrane, and the physical and chemical properties of the membrane are utilized to achieve slow release and targeted delivery of the drug, thereby improving drug bioavailability. Detailed Implementation

[0016] The embodiments described in this invention are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without inventive effort are within the scope of protection of this invention.

[0017] Traditional transdermal drug delivery carriers generally suffer from problems such as poor drug permeability, insufficient stability, and low drug loading capacity. For example, drugs in ordinary creams are easily blocked by the skin barrier, and the transdermal efficiency is usually less than 15%. Although liposome carriers can promote permeation, they are prone to particle size growth and drug leakage during storage, and their stability at room temperature is less than 3 months. Nanoparticle carriers face the contradiction of balancing drug loading capacity and skin compatibility, and when the drug loading capacity exceeds 5%, it is prone to causing skin irritation. Therefore, developing a drug delivery carrier that combines high permeability, stable drug loading capacity, and good biocompatibility has become an urgent technical challenge to be solved in the field of transdermal drug delivery.

[0018] The present invention provides a drug delivery carrier, including a drug-loaded membrane and a nanoemulsion loaded on the drug-loaded membrane; the average particle size of the nanoemulsion is 10nm-20nm.

[0019] The drug delivery carrier of this invention achieves efficient drug delivery and stable release by loading nanoemulsions onto a drug-loaded membrane. Controlling the average particle size of the nanoemulsions within the range of 10nm-20nm helps improve drug bioavailability and enhances drug penetration into target tissues or cells, thereby improving therapeutic efficacy. Furthermore, the drug-loaded membrane, as a drug carrier, can protect the drug from the influence of the external environment, prolong the drug's duration of action, reduce the frequency of administration, and improve patient compliance. This drug delivery carrier can be widely applied in various therapeutic scenarios requiring local or systemic drug delivery.

[0020] Understandably, when the average particle size of nanoemulsions is less than 10 nm, although they can penetrate through the gaps in the stratum corneum, they are easily cleared by the skin's immune system and the process is quite difficult; when the average particle size of nanoemulsions is greater than 20 nm, they are difficult to penetrate the lipid bilayer of the stratum corneum, resulting in a significant reduction in bioavailability.

[0021] As an example, the average particle size of nanoemulsions can be 10nm, 12nm, 14nm, 16nm, 18nm, 20nm, etc.

[0022] In some examples, the drug-loaded membrane has a porous structure, with nanoemulsions located within the porous structure; the average pore size of the porous structure is 10 nm-50 nm.

[0023] The aforementioned drug-loaded membrane can have a porous structure. Specifically, the nanoemulsion is positioned within the porous structure, forming a highly ordered composite system. Furthermore, the average pore size of these porous structures is controlled within the range of 10 nm to 50 nm. This pore size range not only contributes to the stable loading of the nanoemulsion but also provides an ideal channel for subsequent drug release.

[0024] Specifically, by layering a drug-loaded membrane with specific pore size requirements and controlling the average pore size of the membrane within the aforementioned range, not only is the overall contact surface area of ​​the membrane significantly increased, but its biocompatibility is also greatly improved. Furthermore, it effectively enhances drug solubility and stability, preventing premature degradation or inactivation of the drug in vivo. Simultaneously, this design also facilitates drug penetration and absorption, enabling the drug to be distributed more rapidly and uniformly into the target tissue.

[0025] Furthermore, this composite membrane structure can prolong the circulation time of drugs in the body, reducing the possibility of rapid drug clearance and thus improving drug bioavailability. More importantly, it significantly enhances the targeted delivery capability of drugs, enabling them to accurately reach the lesion site and exert maximum therapeutic effect. At the same time, it also reduces the aggregation phenomenon that may occur in nanoemulsion systems during long-term use, thereby enabling stable drug release and efficient utilization.

[0026] Therefore, controlling the average pore size of the drug-loaded membrane within the aforementioned range not only provides a stable containment space for the nanoemulsion but also facilitates the sustained release of the drug during administration. Simultaneously, combined with the nanoemulsion's own 10nm-20nm particle size, the two work synergistically to further enhance the drug's penetration and bioavailability in the skin, thereby better achieving the therapeutic effect of transdermal drug delivery.

[0027] As an example, the average pore size of the hole structure can be 10nm, 20nm, 30nm, 40nm, 50nm, etc.

[0028] The average particle size of nanoemulsions and the average pore size of drug-loaded membranes can be tested using the following methods. For example, nano-computed tomography (nano-CT) can be used for testing.

[0029] In some examples, the thickness of the drug-loaded membrane is 1mm-5mm.

[0030] The thickness of the drug-loaded membrane is one of the key factors affecting drug loading and release rate. Controlling the membrane thickness within the aforementioned range not only provides sufficient drug loading space but also maintains the integrity and stability of the membrane structure. For example, thinner membranes (e.g., 1mm-2mm) facilitate rapid adsorption and drug release from nanoemulsions but may reduce the mechanical strength of the membrane; thicker membranes (e.g., 4mm-5mm) provide higher drug reserves and prolong release time but may affect drug penetration efficiency. In practical applications, the choice should be made comprehensively based on the drug type, treatment needs, and administration site. For example, a 1mm-2mm membrane can be used for local treatments requiring rapid onset of action; a medium-thickness membrane of 2mm-3mm is suitable for chronic disease treatments requiring long-term maintenance of efficacy. By optimizing membrane thickness parameters, a precise match between drug release kinetics and treatment requirements can be achieved.

[0031] As an example, the thickness of the drug-loaded membrane can be 1mm, 2mm, 3mm, 4mm, 5mm, etc.

[0032] In some examples, the mass ratio of nanoemulsion to drug-loaded membrane is 1:(4-9).

[0033] Controlling the mass ratio of nanoemulsions to drug-loaded membranes within the aforementioned range not only ensures sustained drug release but also maintains the physical stability of the membrane. For example, a lower ratio (e.g., 1:8-1:9) provides a more stable supporting structure and reduces the risk of nanoemulsion leakage, but may limit the total drug load. A higher ratio (e.g., 1:4-1:6) increases the drug content per unit area and improves the initial release concentration, but may affect the structural integrity of the membrane. In practical applications, the ratio can be adjusted according to drug properties and therapeutic needs. For example, for drugs requiring rapid onset of action, the proportion of nanoemulsions can be appropriately increased; for drugs requiring long-term maintenance of efficacy, the proportion of drug-loaded membrane can be increased. This adjustability allows the drug delivery carrier to adapt to the needs of different clinical scenarios, improving the flexibility and effectiveness of treatment.

[0034] As an example, the mass ratio of nanoemulsion to drug-loaded membrane can be 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, etc.

[0035] In some examples, by weight, the nanoemulsion comprises 2-20 parts emulsifier, 1-50 parts co-emulsifier, 1-10 parts liquid lipid, 0.01-5 parts humectant, and 0.01-5 parts stabilizer.

[0036] Emulsifiers are key components in the formation of nanoemulsions, and their selection directly affects the stability and particle size distribution of the emulsion. In this invention, the emulsifier can be selected from 2 to 20 parts, and the specific amount can be adjusted according to the type of liquid lipid and the desired particle size.

[0037] Co-emulsifiers help form stable nanoemulsions by reducing the interfacial tension between oil and water. Their dosage can be adjusted from 1 to 50 parts. For high-viscosity liquid lipids such as squalene, appropriately increasing the proportion of co-emulsifier (e.g., 30-50 parts) helps improve emulsion flowability; for low-viscosity lipids such as dimethyl silicone oil, 5-10 parts are sufficient to achieve the desired effect.

[0038] When liquid lipids are used as drug carriers, their dosage needs to balance drug solubility and emulsion stability; a range of 1 to 10 parts can cover most application scenarios. The addition of moisturizers not only improves skin compatibility but also influences the formation of nanoemulsions by adjusting the polarity of the medium; dosages of 0.01 to 5 parts can be optimized according to the properties of the target drug.

[0039] Stabilizers prevent droplet aggregation by creating steric hindrance or charge repulsion, and their dosage range of 0.01 to 5 parts ensures the long-term stability of nanoemulsions during storage and use. This part-by-weight formulation design not only ensures the synergistic effect between components but also provides flexible adjustment space for different drugs and dosing requirements, reflecting the scientific and practical nature of the formulation design.

[0040] In some examples, nanoemulsions satisfy one or more of the following conditions: The emulsifiers include one or more of the following: Tween 80, Tween 60, Tween 40, Tween 20, polyoxyethylene castor oil-20, polyoxyethylene castor oil-30, polyoxyethylene castor oil-35, polyoxyethylene castor oil-40, PEG40 hydrogenated castor oil, PEG30 hydrogenated castor oil, PEG20 hydrogenated castor oil, PEG10 hydrogenated castor oil, PEG5 hydrogenated castor oil, polyethylene glycol 400 monoglyceride, polyethylene glycol 400 diglyceride, polyethylene glycol 600 monoglyceride, polyethylene glycol 600 diglyceride, cocoyl glucoside, cetearyl alcohol polyether-20, cetearyl alcohol polyether-25, and butanol polyether-26. Co-emulsifiers include one or more of polyethylene glycol, propylene glycol, dipropylene glycol, glycerin, 1,2-hexanediol, 1,3-butanediol, 1,2-pentanediol, oleic acid, diethylene glycol monoethyl ether, and poloxamer. Liquid lipids include one or more of the following: isopropyl myristate, isopropyl palmitate, caprylic / capric triglyceride, polyethylene glycol caprylic / capric triglyceride, polyethylene glycol laurate, polyethylene glycol stearate, linoleic acid, propylene glycol monocaprylate, propylene glycol dicaprylate, diethyl sebacate, cocoa butter caprylate, isononyl isononanoate, triacetin, dimethyl silicone oil, vitamin E, squalene, and soybean oil. Moisturizers include one or more of allantoin, hyaluronic acid, ceramide, chitosan, sorbitol, sodium lactate, chondroitin sulfate, amino acids, and vitamin B5; Stabilizers include one or more of the following: hyaluronic acid, polyglutamic acid, xanthan gum, polyvinylpyrrolidone, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, gelatin, guar gum, gum arabic, carbomer, tyrosine, tyrosine methyl ester hydrochloride, tyrosine ethyl ester hydrochloride, and tyrosine propyl ester hydrochloride.

[0041] For different types of drug delivery carriers, the above-mentioned components can be selected and combined according to actual needs. For example, when it is necessary to prepare nanoemulsions with good stability and moisturizing effect, hyaluronic acid can be preferentially selected as a moisturizer and stabilizer, while combining it with a suitable emulsifier such as Tween 80 and a co-emulsifier such as glycerin, and then combining it with a suitable liquid lipid such as isopropyl myristate to construct a nanoemulsion system.

[0042] When selecting emulsifiers, different types of Tween emulsifiers have different hydrophilic-lipophilic balance (HLB) values. The appropriate Tween type can be chosen based on the properties required for the nanoemulsion. For example, Tween 80 has a high HLB value and is suitable for preparing oil-in-water nanoemulsions. As the number of polyoxyethylene castor oil emulsifiers increases, their molecular structure and properties also differ, and selection should be made according to specific requirements.

[0043] The role of co-emulsifiers is to assist emulsifiers in functioning better and to regulate the microstructure of nanoemulsions. Taking polyethylene glycol as an example, it can not only increase the stability of the system but also influence the particle size of nanoemulsions to some extent. Glycerin, on the other hand, has good moisturizing and solubility properties and can work synergistically with other ingredients to improve the overall performance of nanoemulsions.

[0044] Liquid lipids are an important component of nanoemulsions and determine their lipid properties. Isopropyl myristate has good permeability and lubricity, making nanoemulsions easier for the skin to absorb; caprylic / capric triglyceride is a mild lipid with low skin irritation, making it suitable for preparing skin-specific nanoemulsions.

[0045] Moisturizers provide hydration to nanoemulsions, keeping the skin moisturized. Allantoin promotes cell growth and repair, and also absorbs moisture from the air, thus providing a moisturizing effect. Ceramides are an important component of the stratum corneum; adding them to nanoemulsions can enhance the skin's barrier function and improve its moisturizing ability.

[0046] Stabilizers are crucial for maintaining the stability of nanoemulsions. Xanthan gum has excellent thickening and stabilizing properties, preventing nanoemulsions from layering and sedimentation; carbomer, on the other hand, can form a gel network structure in the system, enhancing the stability of nanoemulsions and ensuring they remain in good condition during storage and use.

[0047] In some embodiments, the nanoemulsion may also include a surfactant, including fatty alcohol polyoxyethylene ether.

[0048] Furthermore, nanoemulsions can also satisfy at least one of the following conditions: Condition 1: The viscosity range of the nanoemulsion is 5 mPa·s-50 mPa·s. This viscosity range ensures the stable residence of the nanoemulsion in the porous structure of the drug-loaded membrane while maintaining suitable fluidity to promote drug release.

[0049] Condition 2: The absolute value of the potential of the nanoemulsion is greater than or equal to 25 mV. Zeta potential testing shows that when the absolute value of the nanoemulsion potential is ≥25 mV, the electrostatic repulsion between droplets is significantly enhanced, effectively inhibiting aggregation. By optimizing the type of emulsifier (e.g., using a nonionic emulsifier) ​​and the ratio of co-emulsifier (co-emulsifier / emulsifier mass ratio 0.2-0.8), the potential can be stabilized in the range of -35 mV to -45 mV. This high potential characteristic allows the nanoemulsion to form a uniform monolayer distribution in the pores of the drug-loaded membrane, avoiding release hindrance caused by multilayer accumulation.

[0050] Condition 3: The polydispersity index (PDI) of the nanoemulsion is less than 0.3. Dynamic light scattering tests show that nanoemulsions with a PDI < 0.3 have a narrower particle size distribution, ensuring uniform drug loading within the pores of the drug-loaded membrane. By controlling the emulsification temperature (40℃-60℃) and homogenization pressure (500 bar-1500 bar), the PDI can be reduced from an initial 0.45 to below 0.22. The low PDI characteristic allows the nanoemulsion to form a more concentrated particle size distribution peak during skin penetration, improving targeted delivery efficiency by up to 31%.

[0051] In some examples, the nanoemulsion also includes a pH adjuster, such as lactic acid.

[0052] Lactic acid, as a pH regulator, can effectively maintain the acid-base stability of nanoemulsion systems, reducing the impact of pH fluctuations on the active pharmaceutical ingredient during storage and release, and significantly improving the compatibility of nanoemulsions with the stratum corneum of the skin. This pH regulation mechanism, together with potential stabilization and PDI control, forms a synergistic effect, jointly constructing a highly efficient drug delivery system.

[0053] Optionally, the pH of the nanoemulsion is 6-7.

[0054] Within this pH range, the nanoemulsions exhibited superior skin affinity. Skin irritation experiments confirmed that when the pH was between 6 and 7, the nanoemulsions caused less than 5% damage to the stratum corneum, while simultaneously promoting the orderly arrangement of intercellular lipids, facilitating drug molecules' penetration of the stratum corneum barrier. Further research showed that these pH conditions activated the activity of relevant enzymes in the acidic protective film of the skin surface, enhancing the skin's own defense function and creating a favorable microenvironment for drug delivery, thereby increasing bioavailability to over 42%.

[0055] Furthermore, by employing a buffer system and precise pH monitoring equipment, the pH value can be adjusted and maintained in real time within the 6-7 range, ensuring the performance stability of the nanoemulsion during preparation, storage, and use. This pH range not only helps maintain the integrity of the active pharmaceutical ingredients but also further promotes the penetration and absorption of the nanoemulsion into the skin layer, thereby enhancing the overall therapeutic effect.

[0056] In some examples, the drug-loaded membrane includes a fibrous membrane. This membrane can be made from natural or synthetic fibers. Natural fibers, such as cotton and linen, offer good biocompatibility and breathability, reducing skin irritation and providing a gentle environment for drug release. Synthetic fibers, such as polyester and polyamide fibers, offer high strength and stability, ensuring the structural integrity of the membrane during use. The pore size of the fibrous membrane is carefully designed to effectively load the nanoemulsion while controlling the drug release rate, allowing the drug to act on the skin continuously and stably for a longer period. Furthermore, the surface of the fibrous membrane can be specially treated to enhance its binding ability with the nanoemulsion, further improving drug loading and stability.

[0057] Optionally, the fiber membrane includes one or both of the following: natural biological protein fungal fermentation fiber membrane and electrospun nanofiber membrane. The natural biological protein fungal fermentation fiber membrane is prepared using natural biological proteins through fungal fermentation, exhibiting good bioactivity and biodegradability. It provides a more natural and gentle environment for drug release and reduces skin irritation. The electrospun nanofiber membrane, on the other hand, is produced using electrospinning technology. Its fiber diameter can reach the nanometer level, possessing a large specific surface area and high porosity, which is beneficial for the loading of nanoemulsions and the rapid release and penetration of drugs, effectively improving drug bioavailability. In practical applications, one type of fiber membrane can be selected according to specific needs, or two types can be used in combination to fully utilize their respective advantages and achieve better therapeutic effects.

[0058] The average diameter of the fibers in the fiber membrane is 10nm-50nm. These dimensions allow for control over comfort and the porous structure.

[0059] Specifically, in the actual preparation process, by precisely controlling the electrospinning process parameters, such as voltage, solution concentration, and feed speed, it is possible to achieve precise control over the average fiber diameter within the range of 10nm-50nm. This precise control not only improves the physical properties of the fiber membrane, such as comfort, but also reduces discomfort caused by friction when the membrane composed of fibers of suitable diameter comes into contact with the skin, providing a more comfortable experience for the user. In terms of pore structure, the interweaving of fibers of different diameters forms pores of different sizes and distributions. A suitable pore structure is conducive to the stable loading of nanoemulsions and the uniform release of drugs, thereby ensuring that the drug delivery carrier exerts the best therapeutic effect.

[0060] Furthermore, the aforementioned fiber diameter range allows the fiber membrane to possess both sufficient mechanical strength to maintain structural stability and a suitable pore structure to facilitate the loading and drug release of nanoemulsions. In actual preparation, the fiber diameter can be precisely controlled by adjusting electrospinning process parameters (such as voltage, solution concentration, and propulsion speed) or fungal fermentation conditions (such as culture temperature, pH, and fermentation time), thereby meeting the performance requirements of different drug carrier systems. In addition, this range of fiber membrane diameters can effectively balance drug release rates and biocompatibility, providing a flexible material basis for the design of personalized drug delivery regimens.

[0061] An example of the present invention also provides a method for preparing the above-described drug delivery carrier, comprising: S1. Preparation of drug-loaded membrane: Fiber membranes are formed by fermenting natural biological protein fungi, with the average pore size of the pore structure controlled to be 10-50 nm; or fiber membranes are prepared by electrospinning technology. S2. Preparation of nanoemulsions: By weight, 2-20 parts of emulsifier, 1-50 parts of co-emulsifier, 1-10 parts of liquid lipid, 0.01-5 parts of moisturizer, 0.01-5 parts of stabilizer, and lactic acid as pH adjuster are mixed to obtain a mixture; the mixture is divided into n groups to obtain n groups of nanoemulsions; wherein, 10nm≤average particle size of the (i-1)th group of nanoemulsions<average particle size of the i-th group of nanoemulsions≤20nm, i≤n; after mixing the n groups of nanoemulsions, a nanoemulsion with an average particle size of 10nm-20nm is obtained.

[0062] The obtained microemulsion needs to be tested for particle size distribution to ensure that the particle size distribution is uniform and the particle size range meets the design requirements. If the particle size distribution does not meet the requirements, the homogenization conditions should be readjusted and homogenization should be performed again. The prepared nanoemulsions were sealed and stored in a sterile environment to prevent contamination. The storage temperature was controlled between 2 and 8 degrees Celsius to ensure the stability and activity of the nanoemulsions.

[0063] The selection of components involved in the preparation of nanoemulsions is based on the following criteria: the selection of emulsifiers and co-emulsifiers must be determined according to the properties of the liquid lipids to ensure the formation of a stable microemulsion structure; the liquid lipids, as the core component of the drug carrier, must possess good biocompatibility and drug solubility; humectants maintain the system's moisture balance to prevent the microemulsion from drying and clumping; stabilizers are used to inhibit particle size growth and stratification; lactic acid, as a pH adjuster, can precisely control the system's acidity and alkalinity to ensure stable drug activity. In the mixing process, temperature control at 40℃-60℃ promotes molecular motion of each component, and pressure set at 160MPa-300MPa achieves particle size refinement through high-pressure homogenization, ultimately obtaining nanoemulsions with uniform particle size distribution.

[0064] As an example, salicylate glycosides were prepared for topical analgesia and anti-inflammation. The mixture was divided into three groups, each with the same formulation but different temperatures and pressures. The temperatures and pressures for the three groups were as follows: Group 1: 40℃-45℃, 171 MPa; Group 2: 46℃-50℃, 165 MPa; Group 3: 50℃-56℃, 162 MPa.

[0065] Specifically, it may include the following steps: Step a: Mix and dissolve salicylic acid and / or its derivatives, emulsifiers, co-emulsifiers and liquid lipids to obtain the oil phase; Step b: Mix and dissolve the stabilizer, humectant, and water to obtain an aqueous phase; further, mix and dissolve the stabilizer, humectant, and water, filter the resulting solution, and obtain an aqueous phase. Step c: The aqueous phase obtained in step b is stirred and mixed with the oil phase obtained in step a to obtain an aqueous nanoemulsion formulation of acetylsalicylic acid and its derivatives. Steps a and b are not required to be in any particular order.

[0066] Furthermore, in step c, the stirring speed is 10 rpm / min-60 rpm / min, and the stirring time is 15 min-40 min.

[0067] As a further improvement of the present invention, in step a, the dissolution temperature is 35℃-80℃, preferably 38℃-70℃, and more preferably 40℃-65℃; the dissolution time is 10min-30min, preferably 12min-25min, and more preferably 15min-20min.

[0068] As a further improvement of the present invention, in step b, the dissolution temperature is 35℃-80℃, preferably 38℃-70℃, and more preferably 40℃-65℃; the dissolution time is 10min-30min, preferably 12min-25min, and more preferably 15min-20min.

[0069] As a further improvement of the present invention, in step c, the stirring speed is 15 rpm-55 rpm, preferably 15 rpm-55 rpm, more preferably 20 rpm-50 rpm; the stirring time is 15 min-40 min, more preferably 20 min-30 min. Simultaneously, the dissolved mixture is preferably added sequentially to a high-pressure homogenizer for high-pressure homogenization. This improved step is preferably performed in three groups at different temperatures and pressures. Finally, the three groups are mixed to utilize the different liquid surface tensions among them to form a stable target nano-dispersion system.

[0070] As a further improvement of the present invention, step d is included, in which the water-based nanoemulsion formulation of salicylic acid glycoside and its derivatives obtained in step a is filtered to obtain the finished product. This application does not specifically limit the filtration method, but preferably uses a filter membrane to filter out undissolved impurities. The pore size of the filter membrane is 0.22 μm-1.0 μm, more preferably 0.45 μm.

[0071] It is understood that achieving uniform particle size in nanoemulsions in this invention requires precise control across multiple stages, including formulation design, process parameters, equipment selection, temperature management, post-processing, and quality characterization. Deviations in any stage can lead to broadened particle size distribution, polymerization, or system instability, thus affecting particle size uniformity. Specifically, this includes: ① using high-precision online particle size monitoring (such as in-situ dynamic light scattering (DLS)) to find the optimal window period for the ternary phase diagram; ② optimizing the surfactant system and conducting multiple sets of experiments to match HLB (hydrophilic-lipophilic balance value); otherwise, insufficient or excessive emulsification area will result in oversized or uneven particle size; ③ using a Design of Experiments (DOE) system to screen process windows such as homogenization pressure and cycle number; ④ using segmented homogenization or microfluidic technology during scale-up to maintain shear uniformity, and fully considering the interaction forces between different dispersions under the same formulation to achieve optimal steady-state finished product.

[0072] S3. Mix the drug-loaded membrane with the nanoemulsion and allow it to stand at 25℃-35℃ for 2-4 hours to adsorb, so as to obtain the drug delivery carrier.

[0073] The prepared drug delivery carrier was placed in a simulated physiological environment (such as phosphate buffer at 37°C and pH 7.4) for stability testing. The particle size change and drug release were observed over 24 hours to ensure that the carrier maintained its structural integrity in the in vivo environment.

[0074] Meanwhile, unadsorbed nanoemulsions can be separated by centrifugation, the drug loading on the surface of the drug-loaded membrane can be determined, and the content of active drug components can be detected by high performance liquid chromatography to verify the actual drug loading efficiency of the drug delivery carrier.

[0075] The drug delivery carrier was freeze-dried to prepare a dry powder formulation that can be stored for a long time. At the same time, the particle size recovery rate and drug release kinetics after reconstitution were tested to evaluate its feasibility for industrial production.

[0076] In summary, as the basic structure for drug loading, the surface properties of the drug-loaded membrane must be compatible with those of the nanoemulsion to ensure effective drug molecule transfer at the interface. Controlling the average particle size of the nanoemulsion can enhance the interaction strength with the drug-loaded membrane. During the static adsorption process, maintaining the temperature between 25℃ and 35℃ can maintain the physical stability of the nanoemulsion while promoting the diffusion rate of drug molecules into the pores of the drug-loaded membrane. Setting the time to 2-4 hours can achieve adsorption equilibrium, resulting in a drug distribution uniformity of over 90% in the final drug delivery carrier.

[0077] The present invention also provides an application of a drug delivery carrier in transdermal drug delivery, wherein the drug delivery carrier encapsulates or grafts drugs including salicylate, hyaluronic acid or melatonin.

[0078] When salicylate is encapsulated in a drug delivery carrier, its anti-inflammatory and analgesic properties can be utilized to achieve targeted treatment of inflammatory skin diseases such as eczema and psoriasis. Experimental data show that this carrier can increase the skin penetration rate of salicylate to 2.3 times that of traditional formulations, while extending the drug's duration of action to more than 12 hours through the sustained-release effect of the fibrous membrane.

[0079] When hyaluronic acid is grafted, the drug delivery carrier can construct a three-dimensional hydration channel, promoting the penetration of active ingredients while moisturizing and repairing. Experimental data show that hyaluronic acid-containing carriers can increase skin moisture content by 45%, and when used in combination with whitening ingredients such as vitamin C, they can significantly improve the skin's tolerance to photosensitive ingredients.

[0080] For melatonin, the drug delivery carrier utilizes a lipid bilayer structure of nanoemulsions to mimic the skin barrier, enabling precise delivery of this circadian rhythm-regulating component. Experimental data show that this carrier can increase the bioavailability of melatonin by 38%, with 72% of the release occurring between 22:00 and 02:00, perfectly matching the human melatonin secretion cycle.

[0081] The aforementioned drug-carrier composite systems have all undergone skin irritation testing. After continuous administration over a 0.5 cm² area for 72 hours, the skin erythema index decreased by 67% compared to traditional formulations, and the epidermal cell survival rate remained above 92%. This multi-drug compatibility characteristic allows this drug delivery carrier to be widely used in cosmetic skincare fields such as anti-aging, skin whitening and spot removal, and post-operative repair, as well as in the transdermal treatment of chronic diseases such as arthritis and neurodermatitis.

[0082] The following specific embodiments illustrate the solution of this application. It should be noted that these embodiments are for illustrative purposes only and should not be considered as limiting the scope of this application. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0083] Example 1 is as follows:

[0084] By weight, 2 parts of salicylic acid, 8 parts of methyl salicylate, 1.0 part of fatty alcohol polyoxyethylene ether, 20 parts of polyoxyethylene castor oil-40, 15 parts of propylene glycol, 5 parts of 1,3-butanediol, and 1 part of isopropyl myristate are dissolved in a water bath at 35°C to obtain the oil phase for later use. Add 0.05 parts of hydroxypropyl methylcellulose and 4 parts of allantoin to water, stir at 15 rpm for 10 min in a 35°C water bath, and filter through a 0.45 μm microporous membrane to obtain the aqueous phase. The aqueous phase was added to the oil phase to obtain a mixture; the mixture was then divided into three groups; the homogenization temperatures and pressures for the three groups were as follows: Group 1: temperature 40℃-45℃, pressure 171 MPa; Group 2: temperature 46℃-50℃, pressure 165 MPa; Group 3: temperature 50℃-56℃, pressure 162 MPa.

[0085] The three homogenized mixtures were combined and stirred at 15 rpm for 10 minutes in a 35°C water bath. The mixture was then filtered through a 0.45 μm microporous membrane to obtain the salicylic acid nanocomposite product.

[0086] The particle size of the nanocomposite was measured to be 13.9 nm.

[0087] The finished salicylic acid nanocomposition is dispersed in the porous structure of a fibrous membrane formed by the fermentation of natural biological protein fungi to obtain a drug delivery carrier.

[0088] Example 2 is as follows:

[0089] By weight, 10 parts of salicylic acid glycoside, 2 parts of Tween 40, 2 parts of polyoxyethylene castor oil-30, 1 part of polyethylene glycol 400 monoglyceride, 5 parts of dipropylene glycol, 11 parts of 1,2-hexanediol, 3 parts of polyethylene glycol, 3 parts of 1,2-pentanediol, 1 part of isopropyl palmitate, and 2 parts of polyethylene glycol glyceride caprylate were dissolved in a water bath at 50°C to obtain the oil phase. Add 0.1 parts of polyvinylpyrrolidone, 1 part of tyrosine ethyl ester hydrochloride, 0.5 parts of chitosan, and 2 parts of vitamin B5 to the remaining water. Stir at 30 rpm for 15 min in a 50°C water bath. Filter through a 0.45 μm microporous membrane to obtain the aqueous phase. The aqueous phase was added to the oil phase to obtain a mixture; the mixture was then divided into three groups; the homogenization temperatures and pressures for the three groups were as follows: Group 1: temperature 40℃-45℃, pressure 171 MPa; Group 2: temperature 46℃-50℃, pressure 165 MPa; Group 3: temperature 50℃-56℃, pressure 162 MPa. The three homogenized mixtures were combined and stirred at 30 rpm for 10 minutes in a 50°C water bath. The mixtures were then filtered through a 0.45 μm microporous membrane to obtain the acetylsalicylic acid nanocomposite product.

[0090] The particle size of the nanocomposite was measured to be 15.5 nm.

[0091] The finished acetylsalicylic acid nanocomposition is dispersed in the porous structure of a fibrous membrane formed by the fermentation of natural biological protein fungi to obtain a drug delivery carrier.

[0092] Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that the raw materials of the salicylic acid nanocomposition are not subjected to high-pressure homogenization in groups, but are directly mixed to obtain a water-based salicylic acid suspension.

[0093] A salicylic acid water-based suspension was dispersed in the porous structure of a fibrous membrane formed by the fermentation of natural biological protein fungi to obtain a drug delivery carrier.

[0094] Performance testing (1) Stability test The stability of the salicylic acid and its derivative nanocomposites obtained in Examples 1-2 and Comparative Example 1 were tested, and the results are shown in Table 1.

[0095] Table 1. Stability test results of the finished products of salicylic acid and its derivative nanocomposites in Examples 1-2 and Comparative Example 1

[0096] The stability test results in Table 1 show that the salicylic acid and its derivative nanocompositions prepared in the embodiments of the present invention exhibit no agglomeration or stratification, and the particle size is controlled between 10 nm and 20 nm, meeting the requirements for practical applications. Furthermore, no agglomeration or stratification was observed after 30 days of storage, and the particle size did not change significantly, still meeting the requirements for practical applications. It remained relatively stable, especially at high drug concentrations, with no crystallization or drug leakage observed. Therefore, the water-based nanoemulsion formulation of salicylic acid and its derivatives provided by the present invention has good stability.

[0097] In contrast, the salicylic acid nanocomposite obtained in Comparative Example 1 exhibited agglomeration and stratification after preparation, and after 30 days of storage, the salicylic acid glycosides showed signs of hydrolysis and oxidation, turning yellow, which failed to meet the requirements of practical applications.

[0098] (2) Transdermal test Transdermal tests were conducted on the drug delivery carriers obtained in Examples 1-2 and Comparative Example 1, and the results are shown in Table 2.

[0099] Test Method: Transdermal tests were conducted using the abdominal skin of male SD rats weighing 160g-220g as the barrier layer. Intact, undamaged skin was fixed between the receiving and supply pools (inner skin facing the receiving pool); the diffusion pool parameters were: effective diffusion area 3.14cm². 2 The receiving tank had a volume of approximately 7.0 mL and a magnetic stirring speed of 600 rpm. The receiving tank was filled with the release medium 4.5% cetearyl alcohol polyether-20% ethanol-physiological saline, and air bubbles were removed. The stirring was started and the temperature was kept constant at (37.0±0.5)℃. A drug-loaded membrane was evenly covered on the skin surface. At 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 12 h, 0.35 mL of the receiving liquid was taken out and 0.35 mL of the release medium was added. The receiving liquid was filtered through a 0.22 μm organic filter membrane. The concentration of salicylic acid and its derivatives in the filtered receiving liquid was determined by high performance liquid chromatography, and the cumulative transdermal drug delivery at different times was calculated.

[0100] The cumulative transdermal dose of salicylic acid and its derivatives per unit area can be calculated using the following formula:

[0101] Where: Qs is the cumulative transdermal dose per unit area; S is the effective diffusion area; V is the volume of physiological saline in the receiving pool; C i V represents the concentration of the salicylic acid and its derivative nanocomposite in the receiving solution during the i-th sampling; n is the number of samplings; Cn is the drug concentration in the receiving solution during the n-th sampling; and V represents the concentration of the drug in the receiving solution during the n-th sampling. i Let n be the volume taken from the receiving cell during the i-th sampling; i ≤ n.

[0102] The samples from Examples 1-2 and Comparative Example 1 were subjected to transdermal tests according to the method described above. Comparative Example 1 was a 10% aqueous suspension of salicylic acid and its derivatives. (Note: Salicylic acid has poor water solubility; a 10% solution cannot be obtained using conventional methods, and it can only exist in suspension form.) Table 2. Cumulative in vitro skin permeation (μg / cm³) of Examples 1-2 and Comparative Example 1 2 )

[0103] As shown in Table 2, the cumulative skin permeability of samples 1-2 was significantly higher than that of sample 1 in Comparative Example.

[0104] The skin permeability of the salicylic acid and its derivative nanocomposite product combined with a nanofiber membrane as a drug-loaded membrane in the embodiments of the present invention is significantly higher than that in Comparative Example 1, demonstrating excellent skin permeability. Example 2 is a water-based nanoemulsion formulation containing 10.0% salicylic acid. As can be seen from Table 2, the cumulative skin permeability of the sample in Example 2 is significantly higher than that in Comparative Example 1.

[0105] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A drug delivery vehicle, characterized in that, The drug-loaded film and the nano-microemulsion loaded on the drug-loaded film; The average particle size of the nano-microemulsion is 10-20 nm.

2. The drug delivery vehicle of claim 1, wherein, The drug-loaded film has a pore structure, and the nano-microemulsion is located in the pore structure; the average pore size of the pore structure is 10-50 nm.

3. The drug delivery vehicle of claim 1 or 2, wherein, The thickness of the drug-loaded film is 1-5 mm.

4. The drug delivery vehicle of any of claims 1-3, wherein, The mass ratio of the nano-microemulsion to the drug-loaded film is 1:(4-9).

5. The drug delivery vehicle of any of claims 1-4, wherein, The nano-microemulsion comprises, by weight fraction, 2-20 parts of an emulsifier, 1-50 parts of a co-emulsifier, 1-10 parts of a liquid lipid, 0.01-5 parts of a humectant, and 0.01-5 parts of a stabilizer.

6. The drug delivery vehicle of claim 5, wherein, The nano-microemulsion meets one or more of the following conditions: The emulsifier comprises one or more of Tween 80, Tween 60, Tween 40, Tween 20, polyoxyethylene castor oil-20, polyoxyethylene castor oil-30, polyoxyethylene castor oil-35, polyoxyethylene castor oil-40, PEG40 hydrogenated castor oil, PEG30 hydrogenated castor oil, PEG20 hydrogenated castor oil, PEG10 hydrogenated castor oil, PEG5 hydrogenated castor oil, polyethylene glycol 400 monoglyceride, polyethylene glycol 400 diglyceride, polyethylene glycol 600 monoglyceride, polyethylene glycol 600 diglyceride, cocoglycoside, ceteareth-20, ceteareth-25, butanol polyether-26; The co-emulsifier comprises one or more of polyethylene glycol, propylene glycol, dipropylene glycol, glycerol, 1,2-hexanediol, 1,3-butanediol, 1,2-pentanediol, oleic acid, diethylene glycol monoethyl ether, poloxamer; The liquid lipid comprises one or more of isopropyl myristate, isopropyl palmitate, caprylic capric triglyceride, caprylic capric polyethylene glycol glyceride, polyethylene glycol laurate glyceride, polyethylene glycol stearate glyceride, linoleic acid glyceride, propylene glycol monocaprylate, propylene glycol dicapryl caprate, diethyl sebacate, caprylic capric cocoa butter, isononyl isononanoate, triacetin, dimethyl silicone oil, vitamin E, squalene, and soybean oil; The humectant comprises one or more of allantoin, hyaluronic acid, ceramide, chitosan, sorbitol, sodium lactate, chondroitin sulfate, amino acid, and vitamin B5; The stabilizer comprises one or more of hyaluronic acid, polyglutamic acid, xanthan gum, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, gelatin, guar gum, gum arabic, carbomer, tyrosine, tyrosine methyl ester hydrochloride, tyrosine ethyl ester hydrochloride, and tyrosine propyl ester hydrochloride.

7. The drug delivery vehicle of any of claims 1-6, wherein, The nano-microemulsion further comprises a pH adjuster, and the pH adjuster comprises lactic acid. Optionally, the pH of the nano-microemulsion is 6-7.

8. The drug delivery vehicle of any of claims 1-7, wherein, The drug-loaded film comprises a fiber film; Optionally, the fiber film comprises one or both of a natural biological protein fungus fermentation fiber film and an electrospun nanofiber film. The average diameter of the fibers in the fiber film is 10-50 nm.

9. A method of preparing a delivery vehicle according to any one of claims 1 to 8, characterised in that, The drug-loaded film comprises a fiber film; The raw materials of the nano-microemulsion are divided into n groups to obtain n groups of the nano-microemulsion; wherein 10 nm≤the average particle size of the (i-1)th group of the nano-microemulsion<the average particle size of the ith group of the nano-microemulsion≤20 nm, i≤n; The n groups of the nano-microemulsion are mixed to obtain the nano-microemulsion with an average particle size of 10 nm-20 nm; The drug-loaded film is mixed with the nano-microemulsion, and after standing and adsorption, the drug delivery carrier is obtained.

10. Use of the administration vehicle according to any one of claims 1 to 9 for transdermal administration, characterized in that The drug loaded or grafted in the drug delivery carrier includes salicylate, hyaluronic acid or melatonin.

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