External analgesic patch with aromatic and transparent double effects and preparation method of external analgesic patch

Abstract

The invention relates to the technical field of traditional Chinese medicine external preparations, in particular to an external analgesic patch which takes effect quickly and relieves pain for a long time through a perfuming double-effect technology. The external pain relieving plaster comprises the following components: a) an aromatic permeation promoting group: 0.5-2% of borneol and 0.3-1.5% of menthol; b) a fat-soluble targeting group: 1-5% of curcumin liposome (the encapsulation efficiency is greater than or equal to 90%) and 0.2-1% of frankincense AKBA (the purity is greater than or equal to 95%); c) a synergistic analgesia group: 0.5-3% of tetrahydropalmatine and 1-4% of notoginsenoside microspheres; d) an anti-allergy slow-release group: including glycyrrhetinic acid with 0.1-0.5% of beta-cyclodextrin; according to the invention, the external analgesic patch combining the aromatic penetration enhancer, the dual-carrier system and the dual-channel inhibitor is successfully realized, through the accurate component proportion and the innovative preparation technology, the quick transdermal (taking effect in 15 minutes) and long-acting analgesia (lasting effect in 24 hours) are realized, and meanwhile, the toxic and side effect risk of the traditional Chinese medicine patch is avoided.

Description

Technical Field

[0001] The invention relates to the technical field of traditional Chinese medicine external preparations, and in particular to an external analgesic patch that achieves rapid onset and long-acting analgesia through a fragrance-penetrating dual-effect technology. Background Art

[0002] External analgesic patches are absorbed through the skin, allowing the drug to quickly reach the lesion site and exert a local therapeutic effect. However, existing external analgesic patches are mostly based on Western medicine, such as vaseline, metronidazole, etc. as the main ingredients, and there are problems such as large irritation and short-lasting efficacy in clinical applications. The research and development of traditional Chinese medicine external analgesic patches is relatively insufficient and cannot meet clinical needs. There are some areas that can be improved in existing external analgesic patches.

[0003] For example, traditional Chinese medicine patches: (1) Low transdermal efficiency: The transdermal rate of conventional Chinese medicine matrices (such as rubber pastes and hydrogels) for fat-soluble components (such as curcumin and boswellic acid) is generally less than 5%, resulting in a delayed onset of action (>30 minutes), which makes it difficult to meet the rapid analgesia needs of acute pain; (2) Single ingredient combination: Existing patches mostly rely on a single anti-inflammatory pathway (such as COX-2 inhibition), while clinical pain often involves the coexistence of multiple mechanisms such as neuroinflammation (5-LOX pathway) and microcirculatory disorders (TNF-α mediated), making it difficult to achieve comprehensive analgesia with a single target.

[0004] Western medicine patches are commonly used in clinical practice, but they also have some technical problems that can be improved: (1) Significant skin irritation: Nonsteroidal anti-inflammatory drug (NSAIDs) patches, represented by diclofenac patches, are prone to cause contact dermatitis (incidence of about 12%-18%) after long-term use, and there is a risk of systemic exposure to the gastrointestinal tract and cardiovascular system; (2) Risk of drug resistance: After 2 weeks of continuous use, the analgesic effect of the μ-opioid receptor patch decreases by 35%-40%, forcing patients to increase the dose or change the drug.

[0005] There is an urgent need for innovative development of new patches in clinical practice. Summary of the invention

[0006] In view of the deficiencies of the prior art, the object of the present invention is to provide an external analgesic patch that achieves rapid onset and long-lasting analgesia through a dual-effect aroma-penetration technology (aromatic penetration enhancement + fat-soluble targeting).

[0007] The present invention provides an external analgesic patch with a double effect of aroma and penetration, the analgesic patch comprises: an aroma-penetrating and penetration-promoting group, a fat-soluble targeting group, a synergistic analgesic group, an anti-allergic and sustained-release group, and the remainder is an auxiliary material matrix;

[0008] The aromatic penetration-promoting group is borneol and menthol;

[0009] The lipid-soluble targeting group is curcumin liposome and frankincense AKBA;

[0010] The synergistic analgesic group is tetrahydropalmatine and notoginseng saponin lipid microspheres;

[0011] The anti-allergic sustained-release group is β-cyclodextrin inclusion glycyrrhetinic acid;

[0012] The auxiliary material matrix is ​​one or more of a pressure-sensitive adhesive matrix, a temperature-sensitive gel, or a pH-responsive hydrogel.

[0013] Further, calculated by weight ratio (w / w),

[0014] a) Aromatherapy penetration enhancing group: 0.5-2% borneol, 0.3-1.5% menthol;

[0015] b) Lipid-soluble targeted group: 1-5% curcumin liposomes (encapsulation efficiency ≥ 90%), 0.2-1% frankincense AKBA (purity ≥ 95%);

[0016] c) Synergistic analgesia group: 0.5-3% tetrahydropalmatine, 1-4% notoginseng saponin lipid microspheres;

[0017] d) Anti-allergic sustained-release group: 0.1-0.5% β-cyclodextrin inclusion glycyrrhetinic acid.

[0018] Further, calculated by weight ratio (w / w),

[0019] The pressure-sensitive adhesive matrix is ​​polyacrylate: 60% to 80%;

[0020] Or the thermosensitive gel is poloxamer 407: 5% to 10%;

[0021] Or the pH responsive hydrogel is dimethylaminoethyl methacrylate: 5% to 10%.

[0022] Preferably, the particle size of the Panax notoginseng total saponin lipid microspheres is 150-200 nm.

[0023] Preferably, calculated by weight ratio (w / w), borneol 1.2%, menthol 0.8%, curcumin liposome 3.0%, frankincense AKBA 0.5%, tetrahydropalmatine 2.0%, notoginseng saponin lipid microspheres 2.5%, glycyrrhetinic acid inclusion complex 0.3%, and the balance is polyacrylate or poloxamer 407 or dimethylaminoethyl methacrylate.

[0024] Preferably, calculated by weight ratio (w / w), the mass ratio of tetrahydropalmatine to notoginseng saponin is 1:1.5.

[0025] A method for preparing an external analgesic patch with both aromatic and penetrating effects comprises the following steps:

[0026] (1) Preparation of liposoluble targeting group: Curcumin and phospholipids were dissolved in an organic solvent at a mass ratio of 1:3-5, and curcumin liposomes were formed by a thin film dispersion method, and then mixed with frankincense extract AKBA, and co-extruded at a controlled shear rate of 8000-12000 rpm and a temperature of 45±2°C;

[0027] (2) Synergistic analgesic group loading: Tetrahydropalmatine was dissolved in a fat-soluble matrix, and Panax notoginseng total saponins were dissolved in an aqueous phase. The lipid microsphere carrier was prepared by a high-pressure homogenization method. The particle size of the Panax notoginseng total saponins lipid microsphere was controlled at 150-200 nm;

[0028] (3) Composite matrix molding: Synthetic borneol and menthol are dissolved in ethanol as a quick-release layer, and β-cyclodextrin encapsulated glycyrrhetinic acid is used as a sustained-release layer. The mixture is mixed with the components obtained in steps (1) and (2) at a mass ratio of 1:1.2-1.5, coated on a non-woven fabric substrate, and dried and cut into patches.

[0029] Use of the pain-relieving patch described in any one of the above items or the pain-relieving patch prepared by the preparation method in preparing drugs for treating osteoarthritis, neuropathic pain or sports injuries.

[0030] Technical effect of the present invention: The present invention successfully realizes an external analgesic patch of the combination of "aromatic penetration enhancer + dual carrier system + dual-channel inhibitor". The present invention, through precise component ratio and innovative formulation technology, has achieved rapid transdermal penetration (onset of effect in 15 minutes) and long-acting analgesia (24h continuous effect, dual-channel anti-inflammatory) through in vivo and in vitro experiments, while avoiding the risk of toxic and side effects of traditional Chinese medicine patches. DETAILED DESCRIPTION

[0031] Example 1: The aromatic double-effect external analgesic patch of the present invention

[0032] 1. Core formula:

[0033] 1. The core formula of the aromatic double-effect external analgesic patch of the present invention is as follows in Table 1:

[0034] Table 1. Core formula of the present invention

[0035]

[0036] Further, specifically:

[0037] 1. Aromatherapy penetration group

[0038] Borneol (synthetic borneol): 0.5% to 2.0% (w / w);

[0039] Menthol: 0.3% to 1.5% (w / w);

[0040] 2. Lipid-soluble targeted group

[0041] Curcumin liposomes (encapsulation efficiency ≥ 90%): 1.0% to 5.0% (calculated as curcumin);

[0042] Frankincense extract AKBA (purity ≥ 95%): 0.2% to 1.0%;

[0043] 3. Synergistic analgesia group

[0044] Tetrahydropalmatine (fat soluble): 0.5%~3.0%;

[0045] Panax notoginseng total saponin lipid microspheres (particle size 150-200nm): 1.0% to 4.0% (calculated as notoginseng saponin);

[0046] 4. Anti-allergic sustained-release group

[0047] Glycyrrhetinic acid β-cyclodextrin inclusion complex: 0.1% to 0.5%;

[0048] 5. Excipient Matrix

[0049] Pressure-sensitive adhesive matrix (polyacrylate): 60% to 80%;

[0050] Or thermosensitive gel (Poloxamer 407, optional): 5% to 10% (thermosensitive enhanced version);

[0051] or pH-responsive hydrogel (dimethylaminoethyl methacrylate, optional): 5% to 10% (gout enhanced version);

[0052] or one or more excipient matrices.

[0053] Further:

[0054] High permeability type: Curcumin liposome increased to 4.5%, borneol increased to 1.8%, can significantly improve the skin penetration rate. When the mass ratio of tetrahydropalmatine to notoginseng saponin is 1:1.5, the COX-2 inhibition rate can be significantly improved.

[0055] Anti-allergic type: Glycyrrhetinic acid inclusion complex increased to 0.5%, skin irritation score significantly reduced. Add 1% sodium hyaluronate to enhance skin barrier repair function.

[0056] 2. Technical features of the aromatic double-effect external analgesic patch of the present invention

[0057] (1) Unique penetration-enhancing mechanism: Borneol is used to destroy the lipid arrangement in the stratum corneum, change the order of lipids between stratum corneum cells, form channels that are easy for drugs to penetrate, and significantly enhance the transdermal penetration of drugs, so that analgesics can enter the body faster and more to exert their effects.

[0058] (2) Precise targeting: Menthol can activate TRPM8 ion channels, which are expressed on sensory nerve fibers. Once activated, it can produce a cooling sensation and regulate nerve conduction, precisely acting on pain-related nerves, effectively blocking the transmission of pain signals and achieving precise analgesia.

[0059] (3) Dual-effect synergistic analgesia: The penetration-promoting effect of borneol and the targeted analgesic effect of menthol cooperate with each other and synergize to enhance the effect. It not only improves the penetration efficiency of analgesics, but also enhances the analgesic effect, can quickly relieve pain symptoms, and bring patients a better analgesic experience.

[0060] (4) High safety: The ingredients used, such as borneol and menthol, are all natural substances with a wide range of sources and are relatively safe. While exerting analgesic and permeation-promoting effects, they can reduce toxic side effects on the skin and the whole body, thus improving the safety of product use and patient compliance.

[0061] 2. Preparation method

[0062] (I) Core component processing technology

[0063] 1. Treatment with aromatic penetration enhancing components

[0064] Borneol (synthetic borneol): Using ultrafine grinding technology (particle size ≤ 10μm), pre-mixed with menthol at a mass ratio of 3:2, added with 1% polyethylene glycol 400 as a dispersion stabilizer, melt blended at 60°C and then rapidly cooled and solidified to form eutectic infiltration-promoting micropowder.

[0065] 2. Preparation of Lipid-soluble Targeting Components

[0066] Liposomal Curcumin:

[0067] Formula: Curcumin-soy lecithin-cholesterol (molar ratio 1:4:0.5).

[0068] Process: The lipid material was dissolved in chloroform by thin film dispersion method, and a thin film was formed by rotary evaporation. Then, phosphate buffer (pH 6.8) was added for hydration. Nanoliposomes (particle size 80-120 nm, PDI ≤ 0.2) were obtained by high-pressure homogenization (800 bar, 3 cycles).

[0069] Frankincense AKBA Purification:

[0070] Frankincense resin was extracted with 95% ethanol by ultrasonic wave (40kHz, 60°C), purified by silica gel column chromatography (eluent: n-hexane-ethyl acetate = 4:1), and the purity was ≥95% after HPLC detection.

[0071] Process characteristics:

[0072] (1) Through the process innovation of "co-extrusion processing + high-pressure homogenization", the differentiated drug loading of liposomes and lipid microspheres is achieved (liposome encapsulation rate ≥ 90%, lipid microsphere burst release rate ≤ 15%);

[0073] (2) Laboratory studies have found that when the high shear rate is lower than 8000 rpm, the transdermal efficiency of the prepared patch is relatively low by more than 10%. Therefore, when the high shear rate is 8000 rpm and the ratio of phospholipid to drug is 3:1, the transdermal efficiency is optimal;

[0074] (3) Synergistic relationship of components: the mass ratio of the immediate-release layer to the sustained-release layer is 1:1.2-1.5 (in vitro release conforms to the Higuchi model, R 2 >0.991).

[0075] (II) Vector system construction process

[0076] 1. Panax notoginseng total saponin lipid microspheres

[0077] Formula: Notoginseng saponin-glyceryl monostearate-poloxamer 188 (mass ratio 1:3:0.5).

[0078] Process: melt emulsification method, melt lipid phase at 75℃, emulsify with high-speed shear (12000rpm) and then suddenly cool to 4℃, sterilize with 0.22μm filter membrane to obtain drug-loaded lipid microspheres with a particle size of 150-200nm.

[0079] 2. Glycyrrhetinic acid β-cyclodextrin inclusion complex

[0080] Saturated aqueous solution method: the molar ratio of glycyrrhetinic acid to β-CD is 1:2, magnetic stirring is carried out at 45°C for 48 hours, the precipitate is collected by centrifugation, vacuum dried and crushed to pass through a 200-mesh sieve, and the inclusion rate is ≥85%.

[0081] (III) Composite patch molding process

[0082] 1. Preparation of three-layer delivery system

[0083]

[0084] 2. Coating and packaging

[0085] A multi-channel extrusion coating machine (temperature controlled at 45±2°C) was used to coat the medical non-woven fabric substrate in the order of quick-release layer → sustained-release layer → reservoir layer;

[0086] Covered with a silicone anti-sticking layer, cut into 8cm×12cm patches, and sealed with aluminum-plastic composite film (humidity ≤ 30% RH).

[0087] (IV) Control of key process parameters

[0088]

[0089] (V) Quality inspection methods

[0090] 1. Vector Characterization

[0091] Dynamic light scattering (DLS) to measure particle size / Zeta potential;

[0092] Transmission electron microscopy (TEM) was used to observe the morphology of liposomes.

[0093] 2. Content Determination

[0094] HPLC method for simultaneous determination of 5 active ingredients:

[0095] Chromatographic conditions: C18 column (4.6×250 mm), acetonitrile-0.1% phosphoric acid gradient elution, flow rate 1.0 mL / min, detection wavelength 280 nm.

[0096] 3. Transdermal performance verification

[0097] In vitro rat skin model (Franz diffusion cell), 37℃ circulating water bath, HPLC-MS quantitative analysis of skin retention and systemic permeation at different time points.

[0098] (VI) Process characteristics: Low-temperature co-extrusion technology is used, and liposomes and lipid microspheres are co-extruded at 45°C to avoid drug degradation caused by high temperature (traditional processes mostly use above 60°C); infrared-hot air combined drying (40°C→30°C gradient cooling) is used to reduce the loss of volatile components;

[0099] Example 2: Experiment on optimizing the mass ratio of curcumin liposomes to Panax notoginseng lipid microspheres

[0100] The effects of different mass ratios of curcumin liposomes (component A) and notoginseng saponin lipid microspheres (component B) on transdermal efficiency and anti-inflammatory effects were tested, and the proportions of other components were fixed as follows: borneol 1.2%, menthol 0.8%, AKBA 0.5%, and tetrahydropalmatine 2%.

[0101] According to the "Technical Guidelines for Pharmaceutical Research of Chemical Drug Transdermal Patches", the following indicators are tested:

[0102] Skin penetration rate: Franz diffusion cell (ex vivo rat skin) and HPLC method (test conditions are shown in the table below) were used to determine the cumulative penetration of curcumin and notoginseng saponins.

[0103] Anti-inflammatory indicators: LPS induced RAW264.7 macrophage model, and ELISA was used to detect PGE2 (COX-2) and LTB4 (5-LOX) levels.

[0104] 1. Experimental Materials and Equipment

[0105] 1. Skin sample: ex vivo rat abdominal skin (after depilation, thickness 0.6-0.8 mm, stored at -20°C for future use);

[0106] Diffusion cell system: Franz vertical diffusion cell (effective diffusion area 1.77cm 2 , receiving cell volume 7 mL).

[0107] 2. Test samples:

[0108] Curcumin liposome solution (concentration 1 mg / mL, encapsulation efficiency ≥ 90%);

[0109] Notoginseng saponin lipid microsphere suspension (concentration 2 mg / mL, particle size 150-200 nm).

[0110] 3. Receiving liquid:

[0111] Curcumin: pH 7.4 phosphate buffer containing 40% ethanol (to enhance the solubility of fat-soluble components);

[0112] Notoginsenosides: Normal saline (simulating body fluid environment).

[0113] 4. Detection instrument: High performance liquid chromatography (HPLC, equipped with ultraviolet detector).

[0114] 2. Experimental steps

[0115] 1. Skin pretreatment: After thawing the frozen skin, clean the surface with physiological saline, remove the subcutaneous fat tissue, and place it between the supply tank and the receiving tank of the diffusion tank with the stratum corneum facing up.

[0116] 2. Sample loading and diffusion cell assembly: 0.5 mL of curcumin liposome solution (or notoginseng saponin lipid microsphere suspension) was evenly applied on the skin surface (supply cell side). The receiving cell was injected with preheated receiving solution (37±0.5℃), and sealed after removing bubbles. The magnetic stirring rate was 300rpm24.

[0117] 3. Sampling and refilling: At 0.5, 1, 2, 4, 8, 12, and 24 hours, take 0.5 mL of sample from the receiving pool and immediately add isothermal and equal volume of fresh receiving solution. After filtering the sample through a 0.22 μm filter membrane, store it at -20°C for testing.

[0118] 4.HPLC detection conditions, see the table below:

[0119]

[0120] 3. Experimental Results

[0121] The experimental results are shown in the following table:

[0122]

[0123] IV. Conclusion:

[0124] When the mass ratio is 1:1.2 (A:B), the liposomes and lipid microspheres enhance the targeting of the inflammatory site through the charge complementation effect (liposome ζ = -25mV, lipid microsphere ζ = +8mV), the transdermal rate is increased by 11.4%, and the COX-2 / 5-LOX dual inhibition rate reaches the optimal value. The mass ratio of curcumin to notoginseng saponin is 1:1.2, which is the penetration-anti-inflammatory balance point. A ratio higher than this leads to carrier overload (encapsulation efficiency <85%), and a ratio lower than this leads to insufficient anti-inflammatory activity.

[0125] 5. We further carried out the following comparative experiments:

[0126] (1) Characterization of carrier structure: Transmission electron microscopy (TEM) showed that the liposome-lipid microspheres of Example 2-2 formed a stable core-shell structure (particle size 150±20 nm), while the control example 2 showed aggregation.

[0127] (2) Temperature response: The release rate of the liposome-lipid microspheres of Example 2-2 increased by 40% at 35-37°C, and the phase transition temperature was in line with the microenvironment of the inflammatory site.

[0128] (3) Efficacy verification: The rat adjuvant arthritis model showed that the paw swelling inhibition rate (72.3%) of Example 2-2 group was significantly higher than that of Control Example 2 (58.1%), and the analgesic onset time was shortened to 12 minutes.

[0129] Example 3: Verification of the synergistic penetration ratio of borneol and menthol

[0130] 1. Experimental design: Adjust the ratio of borneol (component C) and menthol (component D) to test their differential effects on the transdermal rates of corydalis ethyl (fat-soluble) and notoginseng saponins (water-soluble).

[0131] 2. Test method:

[0132] 1. Transdermal kinetics experiment: Franz diffusion cell was used to measure the drug permeation within 0-6 hours, and the rate was calculated by fitting the first-order kinetic equation.

[0133] In vitro skin model: SD rat abdominal skin (thickness 0.6-0.8 mm, pre-treated after depilation) was selected and Franz vertical diffusion cell (effective diffusion area 2.0 cm 2 , receiving solution pH 7.4 PBS), the epidermal temperature was maintained at 32±1℃ (simulating the surface temperature of human skin).

[0134] Detection index: curcumin, notoginsenoside (same as Example 2);

[0135] Tetrahydropalmatine: isotope labeled 3H tracer method (quantitative determination by liquid scintillation counter).

[0136] 2. Irritation test: Single patch test on New Zealand rabbit skin (OECD 404 standard), with comprehensive evaluation of erythema / edema score.

[0137] 3. Experimental results (see the table below):

[0138]

[0139]

[0140] IV. Conclusion:

[0141] At a 1:1 ratio, borneol preferentially promotes the passage of fat-soluble components (corydalis) through the stratum corneum lipid barrier, while menthol opens aquaporin (AQP3) to enhance the penetration of water-soluble components (notoginseng saponins), forming a bidirectional synergistic penetration enhancement with minimal irritation.

[0142] Furthermore, a guinea pig GPMT test was conducted, and the results showed that the skin sensitization rate of Example 3-2 was only 3.2%, which was significantly lower than the commercially available diclofenac patch (12.5%), and had good safety.

[0143] Example 4: Effect Example of the Aromatic Double-Effect External Pain Relief Patch of the Present Invention

[0144] 1. Prepare the aromatic dual-effect external analgesic patch of the present invention by referring to the formula and preparation method described in Example 1.

[0145] 1. The specific formula is:

[0146]

[0147] 2. Key preparation process parameters:

[0148] (1) Liposome-lipid microsphere co-extrusion process: temperature: 45±2°C, shear rate: 10000 rpm, phospholipid to drug mass ratio: 3:1 (soy lecithin: curcumin).

[0149] (2) Inclusion technology: β-cyclodextrin: glycyrrhetinic acid molar ratio 1:1, ultrasonic treatment for 30 min (40 kHz)

[0150] (3) Patch molding: coating thickness: 200±20 μm, drying conditions: vacuum drying at 40°C for 2 h.

[0151] 2. Experimental Verification

[0152] (I) Transdermal dynamics:

[0153] 1. In vitro skin model

[0154] Sample preparation: The abdominal skin of SD rats (after depilation, thickness 0.8±0.1 mm) was obtained, washed with 0.9% NaCl solution, and stored at -20°C for later use.

[0155] Franz diffusion cell system: effective diffusion area 1.77cm 2 The receiving cell has a volume of 7 mL and the receiving solution is a pH 7.4 PBS buffer (containing 30% ethanol to improve solubility).

[0156] 2. Experimental Grouping

[0157]

[0158] 3. Transdermal process:

[0159] The skin sample was fixed in the diffusion cell with the stratum corneum facing the donor chamber. 2 The drug) was evenly applied. A constant temperature water bath was maintained at 37±0.5℃ and the magnetic stirring speed was 300rpm. 0.5mL of the receiving solution was sampled at 0.5, 1, 2, 4, 8, 12, and 24h, and an equal amount of fresh receiving solution was added at the same temperature.

[0160] 4. Detection method (same as above)

[0161] 5. Data Processing

[0162] (1) Cumulative penetration (Q_n):

[0163]

[0164] (V = 7 mL, A = 1.77 cm 2 )

[0165] (2) Transdermal rate (J): Slope of the Qt curve in the steady state

[0166] (3) Lag time (t_lag): The intersection of the curve and the time axis

[0167] 6. Experimental results:

[0168] (1) Transdermal kinetics curve

[0169]

[0170] Transdermal rate comparison:

[0171] Curcumin: test group (i.e., the patch of the present invention) 2.45 μg / (cm 2 ·h) vs control group 2 0.79μg / (cm 2 h) (increased by 3.1 times);

[0172] Notoginsenosides: experimental group 1.77μg / (cm 2 ·h) vs control group 2 0.52μg / (cm 2 h) (increased by 3.4 times).

[0173] (2) Analysis of time lag effect

[0174]

[0175] (II) Clinical efficacy (n=120):

[0176] 1. Research Methods

[0177] (1) Experimental design: A single-center, randomized, double-blind, placebo-controlled trial was conducted. The experimental group (n=80, active ingredient patch) vs. the control group (n=40, matrix patch without drug) were given once a day for 14 consecutive days and followed up to 28 days. The hospital ethics approval certificate is: 202205070023.

[0178] (2) Inclusion criteria: subjects aged 18–75 years, diagnosed with osteoarthritis or chronic low back pain (VAS ≥ 4 points), and those with skin damage, allergic constitution, or those who had received intra-articular injection within 3 months were excluded.

[0179] (3) Evaluation indicators

[0180]

[0181] (4) Statistical methods: Intention-to-treat (ITT) and per-protocol set (PPS) data sets were used. Continuous variables were analyzed using ANOVA, and categorical variables were analyzed using the chi-square test (α=0.05).

[0182] 2. Experimental Data

[0183] (1) Primary efficacy data (Day 14)

[0184]

[0185] (2) Subgroup analysis (osteoarthritis patients n = 60)

[0186]

[0187] (3) Safety data

[0188]

[0189] 3. Experimental results

[0190] (1) Verification of rapid onset mechanism:

[0191] Borneol / menthol synergistically allows the drug to penetrate the stratum corneum within 15 minutes (HPLC detected that the skin retention of curcumin reached 1.2 μg / cm 2 ),

[0192] The blood concentration of tetrahydropalmatine reaches its peak at 30 minutes (Cmax=12.3 ng / mL), which coincides with the onset of analgesia.

[0193] (2) Multi-pathway anti-inflammatory effects:

[0194] The serum PGE2 level in the experimental group decreased by 67% (vs 21% in the control group, p<0.01).

[0195] The inhibition rate of 5-LOX activity in synovial tissue reached 72% (verified by immunohistochemistry).

[0196] (3) Advantages of the vector system:

[0197] The drug concentration of the liposome / lipomicrosphere group in the inflammatory area was 6.3 times higher than that in the non-inflammatory area (near infrared imaging), and the 72-hour sustained release rate was: curcumin 82% vs. notoginseng saponin 91% (in vitro release experiment).

[0198] 4. Research Conclusion

[0199] (1) Clinical effectiveness: Significantly shortened the onset time to 12.3 minutes (conventional patches ≥ 30 minutes), and increased the VAS improvement rate by 2.25 times

[0200] The recovery of joint function in patients with osteoarthritis was accelerated (the improvement rate of WOMAC score was 37% higher than that in the control group);

[0201] (2) Safety: The incidence of skin irritation is ≤3.75%, which is significantly lower than that of diclofenac patch (11.3% reported in the literature), and there are no systemic toxic and side effects (changes in liver and kidney indicators are all within the normal range).

[0202] (3) Technological innovation: The fragrance-to-skin dual-effect technology breaks through the bottleneck of traditional transdermal efficiency (the transdermal rate is increased by 3.2 times), and the COX-2 / 5-LOX / D2 receptor multi-target synergistic mechanism fills the market gap.

[0203] (III) Stability investigation

[0204] (1) Experimental conditions (according to ICH Q1A(R2) guidelines):

[0205] Accelerated test: 40℃±2℃ / 75%RH±5%RH, 6 months

[0206] Long-term test: 25℃±2℃ / 60%RH±5%RH, 24 months

[0207] (2) Detection indicators

[0208]

[0209] (3) Experimental results

[0210] After 24 months of long-term use and 6 months of accelerated use, the paste prepared by the present invention was uniform and free of crystal precipitation, and the content of main components, related substances and transdermal penetration rate all met the quality standard requirements (part of the key data is shown in the table below):

[0211]

[0212] 3. Summary:

[0213] 1. Innovation of ingredient combination:

[0214] Triple delivery system: curcumin liposomes (to improve bioavailability), Panax notoginseng lipid microspheres (to prolong the duration of action), and glycyrrhizic acid inclusion complex (anti-allergic and sustained release) to form a synergistic transdermal system.

[0215] Dual pathway inhibition mechanism: The first combined application of frankincense extract AKBA (5-LOX inhibitor) and tetrahydropalmatine (COX-2 / D2 receptor antagonist) covers the dual pathways of inflammation and neuropathic pain.

[0216] 2. Preparation technology innovation

[0217] Differentiated carrier design: curcumin liposomes (particle size 80-120nm, targeting MMP-9 at inflammatory sites), Panax notoginseng lipid microspheres (150-200nm, improving microcirculation);

[0218] Borneol / menthol synergistically promotes penetration: synthetic borneol destroys the structure of the stratum corneum, and menthol activates the TRPM8 receptor, increasing the transdermal efficiency by 3.2 times.

[0219] The present invention successfully prepares a fragrant and penetrating double-effect external analgesic patch. After stability inspection, the effective period of the fragrant and penetrating double-effect external analgesic patch prepared by the present invention can be set to 24 months.

[0220] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. An external analgesic patch with a double effect of fragrance and penetration, characterized in that It includes: aromatic penetration-enhancing group, lipid-soluble targeted group, synergistic analgesic group, anti-allergic sustained-release group, and the rest is excipient matrix; The aromatic penetration-promoting group is borneol and menthol; The lipid-soluble targeting group is curcumin liposome and frankincense AKBA; The synergistic analgesic group is tetrahydropalmatine and notoginseng saponin lipid microspheres; The anti-allergic sustained-release group is β-cyclodextrin inclusion glycyrrhetinic acid; The auxiliary material matrix is ​​one or more of a pressure-sensitive adhesive matrix, a temperature-sensitive gel, or a pH-responsive hydrogel.

2. The external analgesic patch with aromatic and penetrating effects according to claim 1, characterized in that: Calculated by weight ratio (w / w), a) Aromatherapy penetration enhancing group: 0.5-2% borneol, 0.3-1.5% menthol; b) Lipid-soluble targeted group: 1-5% curcumin liposomes (encapsulation efficiency ≥ 90%), 0.2-1% frankincense AKBA (purity ≥ 95%); c) Synergistic analgesia group: 0.5-3% tetrahydropalmatine, 1-4% notoginseng saponin lipid microspheres; d) Anti-allergic sustained-release group: 0.1-0.5% β-cyclodextrin inclusion glycyrrhetinic acid.

3. The external analgesic patch with aromatic and penetrating effects according to claim 1, characterized in that: Calculated by weight ratio (w / w), the pressure-sensitive adhesive matrix is ​​polyacrylate: 60% to 80%.

4. The external analgesic patch with aromatic and penetrating effects according to claim 1, characterized in that: Calculated by weight ratio (w / w), the thermosensitive gel is poloxamer 407: 5% to 10%.

5. The external analgesic patch with aromatic and penetrating effects according to claim 1, characterized in that: Calculated by weight ratio (w / w), the pH responsive hydrogel is dimethylaminoethyl methacrylate: 5% to 10%.

6. The external analgesic patch with aromatic and penetrating effects according to claim 2, characterized in that: The particle size of Panax notoginseng total saponin lipid microspheres is 150-200nm.

7. The external analgesic patch with aromatic and penetrating effects according to claim 2, characterized in that: Calculated by weight ratio (w / w), borneol 1.2%, menthol 0.8%, curcumin liposome 3.0%, frankincense AKBA 0.5%, tetrahydropalmatine 2.0%, notoginseng saponin lipid microspheres 2.5%, glycyrrhetinic acid inclusion complex 0.3%, and the balance is polyacrylate or poloxamer 407 or dimethylaminoethyl methacrylate.

8. The external analgesic patch with both aromatic and penetrating effects according to claim 2, characterized in that: Calculated by weight ratio (w / w), the mass ratio of corydaline to notoginseng saponin is 1:1.

5.

9. A method for preparing an external analgesic patch with both aromatic and penetrating effects, comprising the following steps: (1) Preparation of liposoluble targeting group: Curcumin and phospholipids were dissolved in an organic solvent at a mass ratio of 1:3-5, and curcumin liposomes were formed by a thin film dispersion method, and then mixed with frankincense extract AKBA, and co-extruded at a controlled shear rate of 8000-12000 rpm and a temperature of 45±2°C; (2) Synergistic analgesic group loading: Tetrahydropalmatine was dissolved in a fat-soluble matrix, and Panax notoginseng total saponins were dissolved in an aqueous phase. The lipid microsphere carrier was prepared by a high-pressure homogenization method. The particle size of the Panax notoginseng total saponins lipid microsphere was controlled at 150-200 nm; (3) Composite matrix molding: Synthetic borneol and menthol are dissolved in ethanol as a quick-release layer, and β-cyclodextrin encapsulated glycyrrhetinic acid is used as a sustained-release layer. The mixture is mixed with the components obtained in steps (1) and (2) at a mass ratio of 1:1.2-1.5, coated on a non-woven fabric substrate, and dried and cut into patches.

10. Use of the pain-relieving patch according to any one of claims 1 to 8 or the pain-relieving patch prepared by the preparation method according to claim 9 in preparing a drug for treating osteoarthritis, neuropathic pain or sports injuries.

Images