A hydrogel composition containing aconitine, its preparation method, and its application.

Abstract

This invention discloses a hydrogel composition containing aconitine, its preparation method, and its applications, relating to the field of pharmaceutical manufacturing technology. By mass percentage, it comprises the following components: 0.01%–0.05% aconitine; 2.0%–5.0% hydroxypropyl-β-cyclodextrin; 65%–75% citrate-sodium citrate buffer; 0.4%–0.8% carbomer 974P; 0.8%–1.5% hydroxypropyl methylcellulose; 15%–20% a composition of glycerol and 1,2-propanediol; 0.5%–1.0% laurocapram; 0.1%–0.2% sodium bisulfite; 0.05%–0.1% EDTA-2Na; and the balance being water for injection. This invention overcomes industry technical biases and simultaneously resolves two core contradictions: the stability and gel-forming properties of aconitine, and the drug electromigration efficiency and gel conductivity, achieving the clinical translation of aconitine iontophoresis drug delivery.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation manufacturing technology, and in particular to a hydrogel composition containing aconitine, its preparation method, and its application. Background Technology

[0002] Aconitum carmichaelii is a diterpenoid diester alkaloid isolated from Aconitum yunnanensis, a plant belonging to the Ranunculaceae family. It has both central and peripheral analgesic and anti-inflammatory effects, with an analgesic potency 1.75 to 65.5 times that of morphine. It is non-addictive and does not cause analgesia tolerance. Clinically, it is widely used to treat chronic pain diseases such as osteoarthritis, rheumatoid arthritis, postherpetic neuralgia, and soft tissue injuries.

[0003] Currently available aconitine formulations are all available in oral and intramuscular injection forms, which present unavoidable clinical challenges: ① Oral formulations have a first-pass effect in the liver, resulting in large fluctuations in blood drug concentrations, while aconitine has a very narrow therapeutic window, which can easily cause systemic adverse reactions such as cardiotoxicity and gastrointestinal irritation; ② Intramuscular injection formulations are highly irritating locally, and the injection site is prone to prolonged and severe pain, resulting in extremely poor patient compliance.

[0004] Iontoosmotic drug delivery is a non-invasive drug delivery technology that utilizes a gentle DC / pulsed electric field to drive charged drug molecules to break through the skin's stratum corneum barrier via electromigration. It allows for precise control of drug delivery dosage and is particularly suitable for low-dose, potent drugs with a narrow therapeutic window. However, currently, there is no mature and commercially viable iontoosmotic formulation compatible with aconitine. The core obstacle lies in the fact that existing technologies cannot solve two contradictory core technical problems, and there is a widespread industry bias regarding technology: 1. The core contradiction between the stability and gel-forming properties of aconitine: The molecular structure of aconitine contains diester bonds at the C8 and C14 positions, making it stable only in acidic environments with a pH of 4.0–6.0. ​​Under alkaline conditions, it rapidly hydrolyzes and becomes ineffective. The most commonly used carbomer gel matrix in iontophoresis formulations typically employs alkaline neutralizing agents such as triethanolamine and sodium hydroxide to adjust the pH to above 6.0 to form a stable three-dimensional gel network. In existing technologies, aconitine hydrogels either use alkaline neutralizing agents, leading to continuous degradation of the drug during preparation and storage, resulting in severe exceedances of related substances; or they abandon the carbomer matrix and use other gel-forming materials, but the conductivity, skin adhesion, and mechanical strength of the gel cannot meet the requirements for iontophoresis drug delivery.

[0005] 2. The core contradiction between drug electromigration efficiency and gel conductivity: Aconitum carmichaelii is a strongly basic tertiary amine alkaloid that protonates to form a positively charged cation in an acidic environment of pH 4.0–6.0, requiring anodic iontophoresis for transdermal delivery. Another common technical solution in the industry is to add inorganic electrolytes such as sodium chloride and potassium chloride to the iontophoresis gel to improve the system's conductivity and ensure electric field transmission efficiency. However, the Na⁺ and K⁺ cations introduced by inorganic salts fiercely compete with the positively charged Aconitum carmichaelii for electromigration channels, leading to a significant decrease in transdermal drug efficiency and failing to achieve clinically effective therapeutic doses. Currently, no solution addresses the cationic characteristics of Aconitum carmichaelii to resolve this core contradiction.

[0006] Existing technologies have failed to simultaneously resolve the two core contradictions mentioned above. They cannot balance the chemical stability of aconitine with the gelling properties of the gel, nor can they balance the conductivity of the gel with the electromigration efficiency of the drug. As a result, the clinical translation of aconitine iontophoresis delivery has been consistently hindered.

[0007] Therefore, a hydrogel composition containing aconitine, its preparation method, and its application were developed to solve the above problems. Summary of the Invention

[0008] This invention proposes a hydrogel composition containing aconitine, its preparation method, and its application, in order to solve the problem that existing technologies cannot simultaneously achieve the chemical stability of aconitine and the gelling properties of the gel, nor can they simultaneously achieve the conductivity of the gel and the electromigration efficiency of the drug.

[0009] The present invention achieves the above objectives through the following technical solutions: The present invention also provides a hydrogel composition containing aconitine, comprising, by weight percentage: 0.01%–0.05% aconitine; 2.0%–5.0% hydroxypropyl-β-cyclodextrin; 65%–75% citrate-sodium citrate buffer; 0.4%–0.8% carbomer 974P; 0.8%–1.5% hydroxypropyl methylcellulose; 15%–20% a composition of glycerol and 1,2-propanediol; 0.5%–1.0% laurocapram; 0.1%–0.2% sodium bisulfite; 0.05%–0.1% EDTA-2Na; with the balance being water for injection.

[0010] Furthermore, the concentration of the citrate-sodium citrate buffer solution is 0.1–0.2 mol / L.

[0011] Furthermore, the pH of the citrate-sodium citrate buffer solution is 4.2–4.8.

[0012] Furthermore, in the composition of glycerol and 1,2-propanediol, the mass ratio of glycerol to 1,2-propanediol is 3:5.

[0013] Furthermore, the hydrogel composition has a pH of 4.2 to 4.8 and an electrical conductivity of ≥5 mS / cm at 25°C.

[0014] The present invention also provides a method for preparing the aforementioned hydrogel composition containing aconitine, comprising the following steps: S1: Buffer preparation: Weigh out citric acid and sodium citrate according to the prescription amount, prepare citric acid-sodium citrate buffer solution with water for injection, stir until completely dissolved, filter through a filter membrane, and seal for use in the dark. S2: Preparation of drug inclusion solution: Weigh hydroxypropyl-β-cyclodextrin according to the prescription amount, add 1 / 2 of the citrate-sodium citrate buffer prepared in step S1, and stir until completely dissolved; then weigh aconitine according to the prescription amount, slowly add it to the hydroxypropyl-β-cyclodextrin solution, stir in the dark to completely encapsulate and dissolve aconitine, and obtain a clear drug inclusion solution, which is then stored in the dark for later use. S3: Preparation of excipient solution: Weigh sodium bisulfite and EDTA-2Na according to the prescription amount, add the remaining 1 / 2 of the citrate-sodium citrate buffer prepared in step S1, and stir until completely dissolved; then add the combination of glycerol and 1,2-propanediol and laurocapram according to the prescription amount, stir evenly, filter through a filter membrane to obtain the excipient solution, and store in the dark. S4: Gel matrix dispersion. Combine the drug inclusion solution prepared in step S2 with the excipient solution prepared in step S3 and stir evenly. Under high-speed stirring, slowly add the prescribed amount of carbomer 974P and hydroxypropyl methylcellulose, and continue stirring to completely disperse the powder without clumping, thus obtaining the gel premix. S5: Vacuum degassing and swelling. The gel premix prepared in step S4 is placed in a vacuum degassing machine and degassed in the dark to completely remove air bubbles. Then, it is left to stand in the dark to allow the matrix to fully swell and form a uniform, delicate, bubble-free hydrogel composition, which is the finished hydrogel composition containing aconitine.

[0015] Furthermore, a stirring speed of 150–200 rpm is used in S2, and a high-speed stirring speed of 300–500 rpm is used in S4.

[0016] The present invention also provides the application of the aforementioned hydrogel composition containing aconitine in the preparation of analgesic and anti-inflammatory drugs for transdermal iontophoresis.

[0017] Furthermore, the analgesic and anti-inflammatory drug is used to treat osteoarthritis, rheumatoid arthritis, frozen shoulder, lumbar muscle strain, soft tissue contusion, postherpetic neuralgia, and postoperative incision pain.

[0018] Furthermore, the transdermal iontophoresis drug delivery method is as follows: the hydrogel composition containing aconitine is used as the anode drug-loaded layer, and arranged with a drug-free cathode conductive gel layer at a physical interval of ≥5 mm on the same light-shielding backing layer to form an iontophoresis patch; in use, the anode drug-loaded layer is applied to the patient's affected skin, and the cathode conductive gel layer is applied to the intact skin near the affected area, connected to a wearable iontophoresis device, and the anode drug delivery mode is adopted. In specific applications, the current density is set to 0.1-0.3 mA / cm², the single administration time is 4-8 hours, and the daily aconitine delivery dose is 0.2-1.2 mg.

[0019] The beneficial effects of this invention are as follows: The present invention proposes a hydrogel composition containing aconitine and its preparation method and application, which breaks through the industry's technical prejudices and solves the two core contradictions of aconitine stability and gel-forming properties, and drug electromigration efficiency and gel conductivity, thus realizing the clinical translation of aconitine iontophoresis drug delivery. Detailed Implementation

[0020] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.

[0021] Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without inventive effort are within the scope of protection of this invention.

[0022] Example 1 The hydrogel composition containing aconitine in this embodiment has the following formulation based on a total mass of 1000g: Aconitum carmichaelii 0.2g (i.e., 0.02% by mass); Hydroxypropyl-β-cyclodextrin 30g (i.e., 3.0% by mass); 720g of 0.2mol / L citrate-sodium citrate buffer (i.e., 72% by mass), with a pH of 4.5; Carbomer 974P 6g (i.e., 0.6% by mass); 10g of hydroxypropyl methylcellulose (i.e., 1.0% by weight); 60g of glycerin (i.e., 6.0% by mass); 1,2-Propanediol 100g (i.e., 10.0% by mass); 8g of laurocapram (i.e., 0.8% by mass); 1.5g of sodium bisulfite (i.e., 0.15% by mass); EDTA-2Na 0.8g (i.e., 0.08% by mass); The remainder is water for injection.

[0023] The preparation method is carried out entirely in a Class D cleanroom, protected from light, and at a normal temperature of 22°C, and includes the following steps: S1: Buffer preparation: Weigh citric acid and sodium citrate according to the prescription, prepare 0.2 mol / L, pH 4.5 citric acid-sodium citrate buffer solution with water for injection, stir until completely dissolved, filter through a 0.45 μm filter membrane, and store in a light-proof, sealed container for later use. S2: Preparation of drug inclusion solution: Weigh hydroxypropyl-β-cyclodextrin according to the prescription amount, add 360g of the buffer solution prepared in step S1, and stir at 180rpm until completely dissolved; then weigh aconitine and slowly add it to the hydroxypropyl-β-cyclodextrin solution, stir at 200rpm in the dark for 2.5h to obtain a clear drug inclusion solution, which is then stored in the dark for later use. S3: Preparation of excipient solution: Weigh out sodium bisulfite and EDTA-2Na according to the prescription amount, add the remaining 360g of buffer solution prepared in step S1, and stir until completely dissolved; then add glycerol, 1,2-propanediol and laurocapram, stir evenly, filter through a 0.45μm filter membrane to obtain excipient solution, and store in the dark for later use. S4: Gel matrix dispersion. Combine the drug inclusion solution from step S2 with the excipient solution from step S3 and stir until homogeneous. Under high-speed stirring at 400 rpm, slowly add carbomer 974P and hydroxypropyl methylcellulose and continue stirring for 30 min to ensure complete dispersion of the powder without clumping, thus obtaining the gel premix. S5: Vacuum degassing and swelling. The gel premix was placed in a vacuum degassing machine and degassed under -0.08 MPa in the dark for 20 min to completely remove air bubbles. Then, it was allowed to stand at 22°C in the dark for 12 h to allow the matrix to fully swell, resulting in a uniform, delicate, and bubble-free hydrogel composition.

[0024] Process parameter selection criteria: Step S2 uses a stirring speed of 150-200 rpm: Preliminary experiments have verified that when the speed is below 150 rpm, hydroxypropyl-β-cyclodextrin is not completely dissolved and the inclusion efficiency decreases; when the speed is above 200 rpm, a large number of bubbles will be generated, which will easily cause the solution to splash, and at the same time prolong the subsequent vacuum degassing time and increase the risk of drug light exposure. Therefore, 150-200 rpm is determined to be the optimal stirring range.

[0025] Step S4 uses a high-speed stirring speed of 300-500 rpm: Preliminary experiments have verified that when the speed is below 300 rpm, carbomer and HPMC powder are prone to agglomeration and cannot be evenly dispersed, resulting in particles and unevenness after gel formation; when the speed is above 500 rpm, a large amount of air will be entrained, generating microbubbles that are difficult to remove, which will destroy the uniform conductivity of the gel. At the same time, high-speed shearing will destroy the long chain structure of carbomer and affect the gel formation. Therefore, 300-500 rpm is determined to be the optimal stirring range.

[0026] Example 2 The hydrogel composition containing aconitine in this embodiment has the following formulation based on a total mass of 1000g: Aconitum carmichaelii 0.1g (i.e., 0.01% by mass); Hydroxypropyl-β-cyclodextrin 20g (i.e., 2.0% by mass); 750g of 0.15mol / L citrate-sodium citrate buffer (i.e., 75% by mass), pH 4.8; Carbomer 974P 4g (i.e., 0.4% by mass); 8g of hydroxypropyl methylcellulose (i.e., 0.8% by weight); 45g of glycerin (i.e., 4.5% by weight); 1,2-Propanediol 105g (i.e., 10.5% by mass); 5g of laurocapram (i.e., 0.5% by mass); Sodium bisulfite 1.0g (i.e., 0.1% by mass); EDTA-2Na 0.5g (i.e., 0.05% by mass); The remainder is water for injection.

[0027] The preparation method is completely consistent with that in Example 1.

[0028] Example 3 The hydrogel composition containing aconitine in this embodiment has the following formulation based on a total mass of 1000g: Aconitum carmichaelii 0.5g (i.e., 0.05% by mass); Hydroxypropyl-β-cyclodextrin 50g (i.e., 5.0% by mass); 650g of 0.2mol / L citrate-sodium citrate buffer (i.e., 65% by mass), pH 4.2; Carbomer 974P 8g (i.e., 0.8% by mass); 15g of hydroxypropyl methylcellulose (i.e., 1.5% by weight); 75g of glycerin (i.e., 7.5% by weight); 1,2-Propanediol 125g (i.e., 12.5% ​​by mass); 10g of laurocapram (i.e., 1.0% by mass); Sodium bisulfite 2.0g (i.e., 0.2% by mass); EDTA-2Na 1.0g (i.e., 0.1% by mass); The remainder is water for injection.

[0029] The preparation method is completely consistent with that in Example 1.

[0030] Comparative Example 1: Comparison with conventional alkaline neutralization processes in existing technologies.

[0031] This comparative example reproduces the conventional preparation process of aconitine hydrogel in the prior art. The only difference from Example 1 is that hydroxypropyl methylcellulose is removed, the amount of carbomer 974P is adjusted to 16g, and triethanolamine is used as an alkaline neutralizing agent to adjust the pH of the system to 6.5. All other components, preparation environment, and operation steps are completely consistent with Example 1.

[0032] Comparative Example 2: Comparison of existing conventional inorganic salt addition processes.

[0033] This comparative example replicates the conventional addition process of existing iontophoresis gels. The only difference from Example 1 is the addition of 0.9% sodium chloride as an inorganic salt electrolyte. All other components and preparation methods are completely consistent with Example 1.

[0034] Comparative Example 3: Control without HPMC composite matrix.

[0035] This comparative example verifies the necessity of the composite matrix. The only difference from Example 1 is that hydroxypropyl methylcellulose is removed, and the amount of carbomer 974P is adjusted to 16g. All other components, preparation methods, and buffer pH are completely consistent with Example 1.

[0036] Comparative Example 4: Hydroxypropyl-β-cyclodextrin-free inclusion complex control.

[0037] This comparative example verifies the necessity of inclusion with hydroxypropyl-β-cyclodextrin. The only difference from Example 1 is that hydroxypropyl-β-cyclodextrin is removed, while all other components and preparation methods are completely consistent with Example 1.

[0038] Effect verification experiment: All tests used standardized testing instruments, methods, and environments, with three parallel replicates. The results were averaged to ensure the accuracy and comparability of the data.

[0039] Experiment 1: Gel formation and basic performance testing.

[0040] The gelling properties, pH, and conductivity of the gels from Examples 1-3 and Comparative Example 3 were tested, and the results are shown in Table 1 below: Table 1

[0041] The results show that the carbomer + HPMC composite matrix of the present invention can form a stable elastic gel under acidic conditions of pH 4.2 to 4.8, which fully meets the requirements of iontophoresis drug delivery; while the single carbomer matrix without HPMC cannot form a gel under the same acidic conditions, which verifies the necessity of the composite matrix design of the present invention.

[0042] Experiment 2: Accelerated stability test.

[0043] The samples from Example 1, Comparative Example 1, and Comparative Example 4 were placed in a dark, sealed environment at 40°C and 75% relative humidity for 6 months. The content of aconitine and total related substances was determined by high performance liquid chromatography (HPLC). The appearance of the samples was also observed. The results are shown in Table 2 below: Table 2

[0044] The results showed that: ① The hydrogel composition of the present invention had a drug degradation rate of only 1.7% in the accelerated test after 6 months, which was much lower than that of Comparative Example 1 using the conventional alkaline neutralization process in the prior art, and the stability was improved by more than 10 times; ② Comparative Example 4, which removed hydroxypropyl-β-cyclodextrin, showed problems of drug precipitation and a significantly increased degradation rate, which verified the necessity of hydroxypropyl-β-cyclodextrin for drug solubilization and stabilization in this system.

[0045] Experiment 3: In vitro transdermal performance test.

[0046] A Franz diffusion cell was used, with intact rat skin as the transdermal barrier. The receiving solution was a pH 4.5 citrate-sodium citrate buffer solution. The experimental temperature was 32 ± 0.5℃, and the stirring speed was 300 rpm. In Examples 1, 2, and 4, anodic iontophoresis was performed using a direct current of 0.2 mA / cm². Samples were taken at 2 h, 4 h, 8 h, and 12 h, and the drug concentration was determined by HPLC. The cumulative transdermal dose was calculated, and the results are shown in Table 3 below. Table 3

[0047] The results showed that: ① The inorganic salt-free formulation of the present invention had a cumulative transdermal absorption rate of 2.3 times that of Comparative Example 2 with added sodium chloride after 12 hours, which completely solved the problem of low transdermal efficiency caused by cation competitive electromigration; ② Comparative Example 4 without hydroxypropyl-β-cyclodextrin showed a significant decrease in transdermal efficiency due to insufficient drug solubility and precipitation, verifying the necessity of hydroxypropyl-β-cyclodextrin in ensuring drug electromigration efficiency; ③ The transdermal rate of the present invention showed a good linear relationship with time, enabling precise controlled release dependent on current.

[0048] Experiment 4: Skin irritation test on rabbits.

[0049] Six healthy New Zealand white rabbits (half male and half female), weighing 2.0–2.5 kg, were used. 24 hours prior to the experiment, the hair on both sides of the spine on the back was removed, with a hair removal area of ​​approximately 3 cm × 3 cm per side. The skin was examined for any damage, erythema, or edema. Self-controls were used, with 1 g of the gel from Example 1 applied to intact skin on the left side of the back, and 1 g of a blank matrix applied to intact skin on the right side of the back. The blank matrix was a gel with aconitine removed; all other components, proportions, and preparation methods were identical to those in Example 1. The dressing was secured with sterile gauze and medical tape. The dressing was removed 24 hours after a single application, and the application site was cleaned with warm water. Skin erythema and edema were observed at 1 hour, 24 hours, 48 ​​hours, and 72 hours after dressing removal, and skin irritation intensity was scored according to the "Cosmetic Safety Technical Specifications".

[0050] The results showed that at all observation time points, there was no erythema or edema on the skin of both the treatment side and the control side of the rabbits, and the irritation score was 0, which met the standard of "non-irritating" topical preparation. This verified that the weakly acidic gel system of pH 4.2 to 4.8 of this invention is non-irritating to intact skin and fully meets the safety requirements for clinical topical administration.

[0051] Compared with existing technologies, this invention overcomes common technical biases in the industry, resolves core contradictions that existing technologies cannot overcome, and achieves synergistic and beneficial effects that are unpredictable to those skilled in the art, as detailed below: 1. It breaks through the technical bias in existing technologies that "carbomer must be neutralized by alkali to form a gel", and solves the stability problem of aconitine from the root.

[0052] This invention uses a composite matrix of carbomer 974P and hydroxypropyl methylcellulose, combined with a citrate-sodium citrate buffer, to form a stable three-dimensional gel network under acidic conditions without any alkaline neutralizing agent, thus completely avoiding the hydrolysis of the diester bonds of aconitine caused by an alkaline environment.

[0053] Accelerated stability testing of this application verified that the hydrogel composition of the present invention, after being placed at 40°C and 75% relative humidity for 6 months, showed a degradation rate of only 1.7% for aconitine; while the hydrogel of Comparative Example 1, prepared using conventional alkaline neutralization process of existing technology, showed a degradation rate of 20.5% for aconitine during the same period. The drug storage stability of the present invention is improved by more than 10 times.

[0054] Meanwhile, Comparative Example 3 of this application verifies that a single carbomer matrix without HPMC cannot form an elastic three-dimensional gel under the same acidic conditions, proving that the composite matrix design of this invention is a core and necessary technical means to achieve gelation under acidic conditions.

[0055] 2. It breaks through the technical prejudice in the existing technology that "inorganic salts must be added to iontophoresis gels to improve conductivity", and completely solves the common industry problem of cation competitive electromigration.

[0056] This invention is the first to discover that for positively charged aconitine, the addition of inorganic salts such as sodium chloride can only slightly improve the conductivity of the system, but the transdermal efficiency of the drug will be greatly reduced due to cation competition. The negative impact is far greater than the gain of improved conductivity.

[0057] Based on this discovery, the present invention uses only the citrate-sodium citrate buffer pair as the sole source of conductivity in the system, without any added sodium chloride or potassium chloride inorganic salt electrolytes. This ensures that the system conductivity is ≥5mS / cm, fully meeting the electric field transfer requirements for iontophoresis drug delivery, while retaining only the minimum concentration of Na⁺ required to maintain pH stability, thus completely avoiding competition between additional free Na⁺ and aconitine for electromigration channels.

[0058] The in vitro transdermal control test of this application verified that: the hydrogel composition of Example 1 of this invention achieved a cumulative transdermal transdermal amount of 62.4% of the labeled amount in intact skin after 12 hours at a current density of 0.2 mA / cm²; while the hydrogel of Comparative Example 2 with the same formulation and 0.9% sodium chloride added only achieved a cumulative transdermal transdermal amount of 27.1% during the same period. The transdermal transdermal efficiency of this invention is improved by 2.3 times, which completely solves the core problem of low transdermal efficiency in the prior art.

[0059] 3. Hydroxypropyl-β-cyclodextrin directional inclusion technology achieves a triple synergistic effect of solubilization, drug stabilization, and retention of electromigration efficiency.

[0060] This invention utilizes hydroxypropyl-β-cyclodextrin to directionally encapsulate the hydrophobic core and ester bond degradation sites of aconitine, achieving a triple synergistic effect, which has been fully verified by the control experiments in this application. ① Solubilizing effect: It increases the water solubility of aconitine by more than 120 times, avoiding drug crystallization during storage (comparative example 4 showed obvious drug crystallization in the accelerated test after 6 months after the removal of hydroxypropyl-β-cyclodextrin). ② Drug stabilization effect: Further inhibits ester bond hydrolysis, and the degradation rate of the accelerated drug in the 6-month test decreased from 6.6% in Comparative Example 4 to 1.7%, with stability improved by more than 3 times; ③ Electrophoretic migration efficiency: This inclusion method does not affect the protonation of the tertiary amine group in the aconitine molecule, and completely preserves the positive charge of the drug. The cumulative transdermal amount after 12 hours increased from 34.2% in Comparative Example 4 to 62.4%, and the transdermal efficiency was improved by 82%.

[0061] The aforementioned triple synergistic effect is something that cannot be predicted when hydroxypropyl-β-cyclodextrin is used only for conventional solubilization in existing technologies.

[0062] 4. The above three core technical features form a synergistic closed loop, perfectly matching the drug delivery requirements of aconitine with a narrow therapeutic window.

[0063] The three core technical features of this invention are not simply superimposed, but rather form a synergistic closed loop that supports each other and is indispensable: "Acidic composite gel molding" provides a stable pH environment for drugs, while also providing a uniform conductive medium for electromigration; "No added inorganic salts" ensures conductivity while maximizing the efficiency of drug electromigration. "Hydroxypropyl-β-cyclodextrin directional inclusion" achieves stable solubilization of drugs in acidic environments without destroying the charged properties of the drugs.

[0064] Comparative Examples 1-4 of this application verify that the four core objectives of "stability, gelation, conductivity, and high transdermal efficiency" cannot be achieved simultaneously without any of the core features.

[0065] Ultimately, the hydrogel composition of this invention can achieve current-dependent zero-order controlled release, with a good linear relationship between transdermal rate and current intensity (R²≥0.99). The drug delivery dose can be precisely controlled by the current magnitude and administration time. At the same time, it can achieve local targeted drug delivery, with drug concentration at the lesion site being more than 8 times that of oral formulations, and systemic blood drug concentration being only 1 / 3 of that of oral formulations. The therapeutic window is expanded by 2.5 times, significantly reducing the risk of systemic adverse reactions such as cardiotoxicity and gastrointestinal irritation. The non-invasive drug delivery method also significantly improves patients' long-term medication compliance.

[0066] It is worth noting that although there are some existing documents in the field of non-ionic electroosmosis that disclose the technology of preparing mucosal adhesion gels by compounding carbomer and hydroxypropyl methylcellulose under acidic conditions, they only solve the problem of mucosal adhesion and have never involved the scenario of iontophoresis drug delivery, let alone provided a solution to the specific problem of diester bond hydrolysis of aconitine.

[0067] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the technical principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A l-tetrahydropalmatine-containing hydrogel composition, characterized in that, By weight percentage, it consists of the following components: 0.01%–0.05% aconitine; 2.0%–5.0% hydroxypropyl-β-cyclodextrin; 65%–75% citrate-sodium citrate buffer; 0.4%–0.8% carbomer 974P; 0.8%–1.5% hydroxypropyl methylcellulose; 15%–20% a combination of glycerol and 1,2-propanediol; 0.5%–1.0% laurocapram; 0.1%–0.2% sodium bisulfite; 0.05%–0.1% EDTA-2Na; the balance being water for injection.

2. The lappaconitine-containing hydrogel composition according to claim 1, characterized in that, The concentration of the citrate-sodium citrate buffer solution is 0.1–0.2 mol / L.

3. The lappaconitine-containing hydrogel composition according to claim 1, characterized in that, The pH of the citrate-sodium citrate buffer solution is 4.2–4.

8.

4. The lappaconitine-containing hydrogel composition according to claim 1, characterized in that, In the composition of glycerol and 1,2-propanediol, the mass ratio of glycerol to 1,2-propanediol is 3:

5.

5. The hydrogel composition containing aconitine according to claim 1, characterized in that, The hydrogel composition has a pH of 4.2 to 4.8 and an electrical conductivity of ≥5 mS / cm at 25°C.

6. A method for preparing the l-tetrahydropalmatine-containing hydrogel composition according to any one of claims 1-5, characterized in that, Includes the following steps: S1: Buffer preparation: Weigh out citric acid and sodium citrate according to the prescription amount, prepare citric acid-sodium citrate buffer solution with water for injection, stir until completely dissolved, filter through a filter membrane, and store in a light-proof and sealed container for later use. S2: Preparation of drug inclusion solution: Weigh hydroxypropyl-β-cyclodextrin according to the prescription amount, add 1 / 2 of the citrate-sodium citrate buffer prepared in step S1, and stir until completely dissolved; then weigh aconitine according to the prescription amount, slowly add it to the hydroxypropyl-β-cyclodextrin solution, stir in the dark to completely encapsulate and dissolve aconitine, and obtain a clear drug inclusion solution, which is then stored in the dark for later use. S3: Preparation of excipient solution: Weigh sodium bisulfite and EDTA-2Na according to the prescription amount, add the remaining 1 / 2 of the citrate-sodium citrate buffer prepared in step S1, and stir until completely dissolved; then add the combination of glycerol and 1,2-propanediol and laurocapram according to the prescription amount, stir evenly, filter through a filter membrane to obtain the excipient solution, and store in the dark. S4: Gel matrix dispersion. Combine the drug inclusion solution prepared in step S2 with the excipient solution prepared in step S3 and stir evenly. Under high-speed stirring, slowly add the prescribed amount of carbomer 974P and hydroxypropyl methylcellulose, and continue stirring to completely disperse the powder without clumping, thus obtaining the gel premix. S5: Vacuum degassing and swelling. The gel premix prepared in step S4 is placed in a vacuum degassing machine and degassed in the dark to completely remove air bubbles. Then, it is left to stand in the dark to allow the matrix to fully swell and form a uniform, delicate, bubble-free hydrogel composition, which is the finished hydrogel composition containing aconitine.

7. The method for preparing a hydrogel composition containing aconitine according to claim 6, characterized in that, In S2, a stirring speed of 150-200 rpm is used, and in S4, a high-speed stirring speed of 300-500 rpm is used.

8. The use of the hydrogel composition containing aconitine according to any one of claims 1 to 5 in the preparation of analgesic and anti-inflammatory drugs for transdermal administration via iontophoresis.

9. The use of the lappaconitine-containing hydrogel composition according to claim 8 in the preparation of an analgesic and anti-inflammatory drug for iontophoresis transdermal administration, characterized in that, The analgesic and anti-inflammatory drugs mentioned are used to treat osteoarthritis, rheumatoid arthritis, frozen shoulder, lumbar muscle strain, soft tissue contusion, postherpetic neuralgia, and postoperative incision pain.

10. The use of the hydrogel composition containing aconitine according to claim 8 in the preparation of analgesic and anti-inflammatory drugs for transdermal iontophoresis, characterized in that, The transdermal iontophoresis drug delivery method is as follows: the hydrogel composition containing aconitine is used as the anode drug-carrying layer, and is arranged on the same light-shielding backing layer with a physical interval of ≥5mm with the drug-free cathode conductive gel layer to form an iontophoresis patch; in use, the anode drug-carrying layer is attached to the patient's affected skin, the cathode conductive gel layer is attached to the intact skin near the affected area, and a wearable iontophoresis device is connected to use the anode drug delivery mode.

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