Transdermal drug delivery preparation carrying traditional Chinese medicine prescription active ingredients and preparation method of transdermal drug delivery preparation

Abstract

The invention relates to the field of traditional Chinese medicine treatment, and discloses a transdermal drug delivery preparation carrying traditional Chinese medicine prescription active ingredients and a preparation method of the transdermal drug delivery preparation, and the transdermal drug delivery preparation comprises 4-6% of the active ingredients, 26-28% of a carrier system, 3-5% of a natural penetration enhancer, 1.3-3% of a function regulator and 63-66.7% of a solvent system. The active ingredients comprise 2.5 to 3.5 percent of tanshinone and 1 to 1.5 percent of astragalus polysaccharide; the carrier system is prepared from 15 to 17 percent of medium chain triglyceride, 6 to 8 percent of phosphatidylcholine and 2 to 3 percent of poloxamer; the natural penetration enhancer is prepared from 2 to 2.5 percent of menthol and 0.5 to 1 percent of D-limonene; the function regulator is prepared from 0.3 to 0.5 percent of sodium hyaluronate and 0.8 to 1 percent of chitosan quaternary ammonium salt; the solvent system is prepared from 18 to 18.7 percent of propylene glycol and 48 to 48.7 percent of water. Through the innovative formula design, active ingredients such as tanshinone and astragalus polysaccharide can be stably conveyed to the deep layer of skin, the compatibility of the skin and the preparation is enhanced through the function regulator, the concentration of the menthol-limonene natural penetration enhancer is reduced by 40% compared with that of traditional azone, and the penetration enhancing efficiency of the synergistic effect of the menthol-limonene natural penetration enhancer is improved by 50%.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine treatment, and specifically to a transdermal drug delivery preparation carrying active ingredients of a traditional Chinese medicine prescription and a preparation method thereof. Background Art

[0002] Transdermal Chinese medicine preparations, a product that combines traditional Chinese medicine with modern formulation technologies, demonstrate significant potential in clinical treatment and healthcare due to their advantages, including avoiding the first-pass liver effect, reducing gastrointestinal irritation, and being easy to use. Transdermal drug delivery is gaining increasing attention because it allows drugs to enter the bloodstream directly through the skin barrier, maintaining stable blood concentrations and achieving long-lasting therapeutic effects.

[0003] However, current transdermal formulations of traditional Chinese medicine face many challenges in practical application. On the one hand, the active ingredients of traditional Chinese medicine, such as alkaloids, polysaccharides, and flavonoids, are mostly large molecules or highly polar substances. The skin's stratum corneum, as the body's natural barrier, has extremely low permeability to such substances, making it difficult for drugs to penetrate the skin's stratum corneum and enter the body to exert their efficacy. This not only seriously affects the therapeutic effect of the drugs, but also significantly slows the speed of effect, limiting the clinical application scope of transdermal formulations of traditional Chinese medicine. On the other hand, to improve the transdermal permeability of drugs, existing formulations often rely on high concentrations of chemical penetration enhancers, such as azone. Although chemical penetration enhancers can enhance the penetration effect of drugs to a certain extent, they also bring side effects that cannot be ignored. High concentrations of chemical penetration enhancers can easily cause skin irritation. For patients with sensitive skin, skin damage such as erythema, itching, and even ulcers are very likely to occur after use. In addition, existing technologies have difficulty in effectively balancing the relationship between penetration enhancement effect and safety. In the pursuit of efficient penetration enhancement, the safety of medication is often sacrificed, resulting in poor patient experience and compliance. Summary of the Invention

[0004] In response to the deficiencies in the prior art, the present invention provides a transdermal drug delivery preparation containing active ingredients from a traditional Chinese medicine prescription and a method for preparing the same. This solves the problem that, during use, the active ingredients of existing transdermal drug delivery preparations of traditional Chinese medicine (such as alkaloids, polysaccharides, and flavonoids) are mostly macromolecules or highly polar substances and are difficult to penetrate the stratum corneum of the skin, which not only affects the therapeutic effect and speed of the drug, but also the existing preparations rely on high concentrations of chemical penetration enhancers (such as azone) that are prone to causing skin irritation.

[0005] To achieve the above objectives, the present invention is implemented through the following technical solutions: a transdermal drug delivery preparation carrying an active ingredient of a traditional Chinese medicine prescription, comprising 4-6% of the active ingredient, 26-28% of a carrier system, 3-5% of a natural penetration enhancer, 1.3-3% of a functional regulator, and 63-66.7% of a solvent system;

[0006] The active ingredients include tanshinone 2.5-3.5% and astragalus polysaccharide 1-1.5%;

[0007] The carrier system includes 15-17% medium chain triglycerides, 6-8% phosphatidylcholine, and 2-3% poloxamer;

[0008] The natural penetration enhancer includes menthol 2-2.5% and D-limonene 0.5-1%;

[0009] The functional regulator comprises 0.3-0.5% sodium hyaluronate and 0.8-1% chitosan quaternary ammonium salt;

[0010] The solvent system includes 18-18.7% of propylene glycol and 48-48.7% of water.

[0011] A method for preparing a transdermal drug delivery preparation containing an active ingredient of a traditional Chinese medicine prescription comprises the following steps:

[0012] S1. Preparation of lipid phase: Pour phosphatidylcholine (PC) and MCT into a blender and heat the blender to 60°C for melting and mixing. Then add tanshinone and use an ultrasonic treatment device to form a lipid phase.

[0013] S2, aqueous phase preparation: dissolving poloxamer 188 and sodium hyaluronate in a propylene glycol / water mixture, and adding astragalus polysaccharide-PLGA nanoparticles;

[0014] S3, co-emulsification to form NLC: High-pressure microfluidization is then used to co-emulsify the lipid phase and the aqueous phase to form NLC with a particle size (D50) of 95 ± 10 nm;

[0015] S4, addition of natural penetration enhancer: menthol and D-limonene were premixed at a ratio of 1.3:1 and added to the carrier system in the form of microemulsion (particle size <50 nm);

[0016] S5. Preparation of nanogel: HACC was added to the carrier suspension and stirred using a magnetic stirrer to form a nanogel with a positive charge (Zeta potential +28 mV), thereby forming a finished product of the transdermal administration preparation.

[0017] Preferably, the ultrasonic treatment equipment parameters in step S1 are 250W, 15min.

[0018] Preferably, the astragalus polysaccharide-PLGA nanoparticles in step S2 are prepared and processed by a solvent evaporation method, and have a particle size of <200 nm.

[0019] Preferably, the high-pressure microjet pressure in step S3 is 1000 bar, and the processing is repeated three times.

[0020] The present invention provides a transdermal drug delivery preparation carrying active ingredients of a traditional Chinese medicine prescription and a preparation method thereof.

[0021] It has the following beneficial effects:

[0022] 1. The present invention significantly improves the drug's transdermal penetration rate through innovative formula design, such as the rapid-type embodiment 2, which increases the active ingredient content, strengthens the natural penetration enhancer combination, and introduces azone. Experimental data show that the 24-hour penetration of tanshinone in embodiment 2 is 96% higher than that of the control group, allowing the drug to quickly enter the blood circulation in a short period of time and quickly exert its efficacy, meeting the demand for rapid onset of acute diseases; the natural penetration enhancement system in balanced embodiment 1 is within the safety threshold, achieving a 66% increase in permeability coefficient (Kp) compared to the traditional azone group, which can stably deliver active ingredients to the deep layers of the skin and is suitable for the treatment of long-term chronic diseases.

[0023] 2, the present invention reduces the dependence on high concentration chemical penetration enhancers, adopts natural penetration enhancer to replace part of chemical penetration enhancers, as balanced embodiment one uses menthol-limonene natural penetration enhancer, compared with traditional azone concentration, irritation index (Draize scoring) is only 0.8 ± 0.2, compared with control group, it is reduced by 65%, significantly reduces skin irritation risk, and is friendly to skin sensitive patients. Potent type embodiment three, by optimizing formula and technology, while ensuring potent treatment, irritation index is 1.2, is also significantly lower than traditional preparations, effectively balances osmosis effect and safety.

[0024] 3. The nanocellulose in Example 3 of the present invention enhances the adhesion and controlled release capabilities of the formulation, enabling sustained and stable drug release. The six-month residual rate of tanshinone reached 94.7%. In addition, the functional modulator in the formulation, such as chitosan quaternary ammonium salt, destroys bacterial membranes through charge adsorption. The antibacterial rate of the balanced Example 1 reached 89%, significantly higher than the 62% of the control group, thus enhancing the antibacterial properties of the formulation. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 It is a flow chart of the preparation method of the present invention. DETAILED DESCRIPTION

[0026] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the drawings in the present specification. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0027] Example 1:

[0028] Please see the attached Figure 1The embodiment of the present invention provides a transdermal drug delivery preparation carrying an active ingredient of a traditional Chinese medicine prescription, comprising 4% of active ingredient, 26% of a carrier system, 3% of a natural penetration enhancer, 1.3% of a functional regulator, and 66.7% of a solvent system;

[0029] The active ingredients include tanshinone 2.5% and astragalus polysaccharide 1.5%;

[0030] The carrier system includes 15% medium chain triglycerides, 8% phosphatidylcholine, and 3% poloxamer;

[0031] The natural penetration enhancer includes menthol 2% and D-limonene 1%;

[0032] The functional regulator includes 0.5% sodium hyaluronate and 0.8% chitosan quaternary ammonium salt;

[0033] The solvent system includes 18.7% propylene glycol and 48% water.

[0034] A method for preparing a transdermal drug delivery preparation containing an active ingredient of a traditional Chinese medicine prescription comprises the following steps:

[0035] S1. Preparation of lipid phase: Pour phosphatidylcholine (PC) and MCT into a blender and heat the blender to 60°C for melting and mixing. Then add tanshinone and use an ultrasonic treatment device to form a lipid phase.

[0036] The ultrasonic treatment equipment parameters are 250W, 15min;

[0037] S2, aqueous phase preparation: dissolving poloxamer 188 and sodium hyaluronate in a propylene glycol / water mixture, and adding astragalus polysaccharide-PLGA nanoparticles;

[0038] The astragalus polysaccharide-PLGA nanoparticles are prepared and processed by a solvent evaporation method, and have a particle size of <200 nm;

[0039] S3, co-emulsification to form NLC: High-pressure microfluidization is then used to co-emulsify the lipid phase and the aqueous phase to form NLC with a particle size (D50) of 95 ± 10 nm;

[0040] The high-pressure microfluidic pressure is 1000 bar, and the processing is repeated three times;

[0041] S4, addition of natural penetration enhancer: menthol and D-limonene were premixed at a ratio of 1.3:1 and added to the carrier system in the form of microemulsion (particle size <50 nm);

[0042] S5. Preparation of nanogel: HACC was added to the carrier suspension and stirred using a magnetic stirrer to form a nanogel with a positive charge (Zeta potential +28 mV), thereby forming a finished product of the transdermal administration preparation.

[0043] Beneficial effects of Example 1: The formulation of Example 1 has a balanced composition ratio, and can stably deliver active ingredients such as tanshinone and astragalus polysaccharide to the deep layers of the skin. The carrier system and solvent system ensure the stability and dispersibility of the active ingredients, and the functional regulator enhances the compatibility of the skin and the formulation. The concentration of the menthol-limonene natural penetration enhancer is 40% lower than that of the traditional azone, and its synergistic effect increases the penetration efficiency by 50%, solving the problem that the active ingredients of traditional Chinese medicine (such as alkaloids, polysaccharides, and flavonoids) are mostly large molecules or highly polar substances, which are difficult to penetrate the stratum corneum of the skin. The existing formulations rely on high concentrations of chemical penetration enhancers (such as azone) and are prone to cause skin irritation, and cannot effectively balance the penetration effect and safety.

[0044] Example 2: A rapid transdermal drug delivery preparation carrying active ingredients of traditional Chinese medicine prescriptions, comprising 5% active ingredient, 22% carrier system, 6% natural penetration enhancer, 4% function modulator, and 63% solvent system;

[0045] The active ingredients include tanshinone 3% and astragalus polysaccharide 2%;

[0046] The carrier system includes medium chain triglycerides 12%, phosphatidylcholine 7%, and poloxamer 3%;

[0047] The natural penetration enhancer includes menthol 4% and D-limonene 2%;

[0048] The functional regulator comprises 0.8% sodium hyaluronate, 1.2% chitosan quaternary ammonium salt, and 2% azone;

[0049] The solvent system includes 18.7% propylene glycol and 48% water.

[0050] Example 2: Beneficial Effects: This Example 2 significantly improves the transdermal drug penetration rate by increasing the active ingredient content, strengthening the natural penetration enhancer combination, and introducing azone. Tanshinone and astragalus polysaccharide can quickly enter the bloodstream, rapidly exerting anti-inflammatory and immune-enhancing effects. It is suitable for the rapid relief of acute conditions such as sudden inflammation and acute muscle pain, quickly alleviating symptoms and providing timely and effective treatment for patients.

[0051] Example 3: A potent transdermal drug delivery preparation carrying an active ingredient of a traditional Chinese medicine formula, comprising 6% active ingredient, 28% carrier system, 4% natural penetration enhancer, 5% function modulator, and 61% solvent system;

[0052] The active ingredients include tanshinone 4% and astragalus polysaccharide 2%;

[0053] The carrier system includes medium chain triglycerides 16%, phosphatidylcholine 9%, and poloxamer 3%;

[0054] The natural penetration enhancer includes menthol 4% and D-limonene 2.5%;

[0055] The functional regulator comprises 1% sodium hyaluronate, 1.5% chitosan quaternary ammonium salt, and 2.5% nanocellulose;

[0056] The solvent system includes 20% propylene glycol and 41% water.

[0057] Beneficial effects of Example 3: Nanocellulose is added in Example 3, and its unique nanostructure and high specific surface area are utilized to enhance the adhesion and controlled-release ability of the preparation, so that the drug is released continuously and stably, and tanshinone and astragalus polysaccharide can act on the lesion site for a long time and at high concentrations, exerting powerful anti-inflammatory and immunomodulatory effects. It is suitable for the treatment of intractable diseases or serious diseases, such as severe skin inflammation, chronic autoimmune diseases, etc., and can effectively improve the condition and improve the treatment effect.

[0058] Comparative experiment:

[0059] 1. Experimental Group and Control Group

[0060] Experimental group:

[0061] Example 1 (balanced type), Example 2 (fast type), Example 3 (strong type)

[0062] Control group:

[0063] Traditional preparation (containing 5% azone)

[0064] Formula: Tanshinone 2.5%, Astragalus polysaccharide 1.5%, Azone 5%, Liposome carrier (soy lecithin 12%, propylene glycol 20%, water 66%)

[0065] 2. Test indicators and methods

[0066]

[0067]

[0068] 3. Experimental steps and parameters

[0069] 1. Transdermal permeation experiment (Franz diffusion cell)

[0070] step:

[0071] Pretreatment of ex vivo pig skin: after depilation, disinfect with ethanol, soak in saline for 1 hour, and remove subcutaneous fat to a thickness of 0.8±0.1mm.

[0072] The sample (0.2 g / cm 2) was evenly applied to the donor pool, and the receptor solution was PBS (pH 7.4) + 0.5% Tween 80, 37°C, and magnetic stirring (300 rpm).

[0073] Sampling was performed at 0.5 / 1 / 2 / 4 / 8 / 12 / 24 h, and the concentrations of tanshinone (λ=270 nm) and astragalus polysaccharide (phenol-sulfuric acid method) were detected by HPLC.

[0074] Key parameters:

[0075] Diffusion area: 1.77cm 2 (Effective aperture 9.5mm)

[0076] Receptor volume: 5mL

[0077] 2. Skin irritation test (Draize score)

[0078] step:

[0079] Rabbits (6 rabbits, 2 kg) were depilated on their backs for 24 hours, and 0.5 g of the preparation (2.5×2.5 cm, closed patch) was applied, and the patch was changed daily for 7 consecutive days.

[0080] Observe and record the degree of erythema / edema (scored according to ISO 10993-10) and calculate the irritation index.

[0081] Scoring criteria:

[0082] 0 points (no reaction); 1 point (mild erythema / edema); 2 points (moderate); 3 points (severe); 4 points (eschar / ulceration)

[0083] 3. Drug stability testing

[0084] Conditions: Stored in a constant temperature and humidity chamber (40°C ± 2°C, RH 75% ± 5%), with sampling time points at 0 / 1 / 3 / 6 months.

[0085] Test method:

[0086] Tanshinone: HPLC method (mobile phase: acetonitrile-0.1% phosphoric acid = 60:40, flow rate 1.0 mL / min)

[0087] Astragalus polysaccharide: phenol-sulfuric acid method (λ=490nm), with glucose as the reference

[0088] Preparation form: Visual observation of precipitation / stratification, laser particle size analyzer to detect particle size changes

[0089] 4. Antibacterial performance test (Escherichia coli ATCC25922)

[0090] step:

[0091] Prepare LB medium (pre-culture at 37°C for 12 h to a bacterial concentration of 1×10 6 CFU / mL).

[0092] The preparation was diluted to 0.5 / 1 / 2 / 4 mg / mL, inoculated with bacterial solution (V / V=1:9), and cultured at 37°C for 24 h.

[0093] Determine the OD600 value and calculate the inhibition rate:

[0094]

[0095] The bacterial membrane morphology was observed under a scanning electron microscope (observed after sample fixation, dehydration and gold spraying).

[0096] 5. Skin Retention Analysis

[0097] step:

[0098] The preparation (0.5 g) was applied to the backs of living rats (n=6), and the rats were killed 2 / 6 / 12 / 24 hours later, and the epidermis / dermis tissues were obtained.

[0099] The tissue was homogenized and extracted with acetonitrile, and the drug concentration was detected by HPLC.

[0100] 4. Comparison of experimental results

[0101]

[0102]

[0103] 5. Results Analysis

[0104] Transdermal efficiency

[0105] Example 2 (rapid type) Due to the synergistic effect of 4% menthol + 2% azone, the penetration of tanshinone increased by 96% (vs. the control group), meeting the demand for rapid effect on acute symptoms.

[0106] The natural penetration-enhancing system (3.5%) of Example 1 (balanced) achieved a Kp value within the safety threshold that was 66% higher than that of the azone group, and is suitable for long-term chronic disease applications.

[0107] Stability and security

[0108] Example 3 (Strong Effect) Due to the nanocellulose controlled release + high-pressure microfluidization process, the 6-month residual rate of tanshinone is 94.7%, and the irritation index (1.2) is significantly lower than that of traditional preparations.

[0109] Antibacterial properties

[0110] Example 1 Chitosan quaternary ammonium salt (HACC) destroyed bacterial membranes through charge adsorption (electron microscopy showed membrane perforation), with an inhibition rate of 89% (only 62% in the control group).

[0111] Release kinetics

[0112] The release curve of Example 3 is consistent with the Higuchi model (R 2 =0.98), the burst release rate was only 16% (34% in the control group), and long-term release was achieved.

[0113] VI. Conclusion

[0114] Experimental results support: The natural penetration-enhancing intelligent drug delivery system significantly optimizes the transdermal efficiency and safety of traditional Chinese medicine prescriptions:

[0115] The rapid type (Example 2) has a penetration rate twice that of the traditional preparation in acute conditions;

[0116] The potent type (Example 3) extends the duration of therapeutic effect to more than 48 hours through controlled release design;

[0117] The balanced type (Example 1) achieved a 65% reduction in irritation index, and its comprehensive performance met the ICH Q3C safety standard.

[0118] This technology provides an effective solution for breaking through traditional bottlenecks in transdermal preparations of traditional Chinese medicine.

[0119] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A transdermal drug delivery preparation carrying an active ingredient of a traditional Chinese medicine prescription, characterized in that: It includes 4-6% active ingredient, 26-28% carrier system, 3-5% natural penetration enhancer, 1.3-3% functional regulator, and 63-66.7% solvent system; The active ingredients include tanshinone 2.5-3.5% and astragalus polysaccharide 1-1.5%; The carrier system includes 15-17% medium chain triglycerides, 6-8% phosphatidylcholine, and 2-3% poloxamer; The natural penetration enhancer includes menthol 2-2.5% and D-limonene 0.5-1%; The functional regulator comprises 0.3-0.5% sodium hyaluronate and 0.8-1% chitosan quaternary ammonium salt; The solvent system includes 18-18.7% of propylene glycol and 48-48.7% of water.

2. The method for preparing a transdermal drug delivery preparation carrying active ingredients of a traditional Chinese medicine prescription according to claim 1, characterized in that: The following steps are involved: S1. Preparation of lipid phase: Pour phosphatidylcholine (PC) and MCT into a blender and heat the blender to 60°C for melting and mixing. Then add tanshinone and use an ultrasonic treatment device to form a lipid phase. S2, aqueous phase preparation: dissolving poloxamer 188 and sodium hyaluronate in a propylene glycol / water mixture, and adding astragalus polysaccharide-PLGA nanoparticles; S3, co-emulsification to form NLC: High-pressure microfluidization is then used to co-emulsify the lipid phase and the aqueous phase to form NLC with a particle size (D50) of 95 ± 10 nm; S4, addition of natural penetration enhancer: menthol and D-limonene were premixed at a ratio of 1.3:1 and added to the carrier system in the form of microemulsion (particle size <50 nm); S5. Preparation of nanogel: HACC was added to the carrier suspension and stirred using a magnetic stirrer to form a nanogel with a positive charge (Zeta potential +28 mV), thereby forming a finished product of the transdermal administration preparation.

3. The method for preparing a transdermal drug delivery preparation carrying active ingredients of a traditional Chinese medicine prescription according to claim 1, characterized in that: The ultrasonic treatment equipment parameters in step S1 are 250W, 15min.

4. The method for preparing a transdermal drug delivery preparation carrying active ingredients of a traditional Chinese medicine prescription according to claim 1, characterized in that: The astragalus polysaccharide-PLGA nanoparticles described in step S2 are prepared and processed by a solvent evaporation method, and the particle size is less than 200 nm.

5. The method for preparing a transdermal drug delivery preparation carrying active ingredients of a traditional Chinese medicine prescription according to claim 1, characterized in that: The high-pressure microfluidic pressure in step S3 is 1000 bar, and the processing is repeated three times.

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