External preparation matched with iontophoresis

Abstract

The invention provides an external preparation matched with iontophoresis, and belongs to the technical field of traditional Chinese medicine preparations. The preparation is prepared from ligusticum wallichii, rhizoma wenyujin concisum, semen cassiae and borneol according to specific parts by weight, the preparation method comprises the steps of adding water to decoct, filtering and the like, and the pH value of filtrate is controlled to be 5.5-6.5. During use, the filtrate is soaked in gauze and externally applied to two eyes, ion introduction is matched, an anode electrode is adopted, the current intensity is 0.1-0.5 mA / cm, the duration is 20 min, one time per day and five times per week are adopted, and one month is a course of treatment. The traditional Chinese medicine composition can be used for resisting inflammation, improving early optic atrophy and relieving non-arteritis front ischemic optic neuropathy, can improve the transdermal absorption rate of the medicine and synergistically exert the anti-inflammation and nerve protection effects, and is high in safety, simple and convenient in preparation process and high in clinical value.

Description

Technical Field

[0001] This application relates to the field of traditional Chinese medicine preparation technology, specifically to a topical preparation that works in conjunction with iontophoresis. Background Technology

[0002] In recent years, eye diseases such as dry eye, eye strain, periorbital inflammation, and circulatory disorders have become increasingly common, seriously affecting patients' quality of life. Traditional treatments include topical eye drops, oral medications, or physical therapy, but these have drawbacks such as low drug absorption rates, systemic side effects, or limited efficacy. Optic nerve atrophy is the most common pathological progression or outcome of various diseases seen in ophthalmology clinics. Given the irreversible damage to nerve cells, early etiological diagnosis and intervention are of great significance.

[0003] Traditional Chinese medicine (TCM) external application therapy has certain advantages in improving periocular circulation and reducing inflammation. However, due to the barrier effect of the stratum corneum, the effective components of the drugs are difficult to fully penetrate, resulting in limited therapeutic effects. To improve transdermal absorption, iontophoresis is often used in current technologies. This involves using a weak current to promote the passage of charged drug ions across the skin barrier, thereby enhancing efficacy. However, there is still a lack of TCM compound preparations suitable for iontophoresis, and existing formulations lack systematic solutions for component selection, preparation processes, and optimization of delivery parameters.

[0004] Iontophoresis is a method that uses electric current to introduce ionic and neutral drugs into the skin. During iontophoresis, electromigration and electroosmosis are the main mechanisms that enhance drug penetration into the systemic circulation. Electromigration refers to the ordered movement of ionized drug molecules under the influence of an applied electric field; charged drugs are forced through the skin by a force similar to the repulsion of electrons by their charges. Cationic and anionic drugs can penetrate the skin using positively and negatively charged working electrodes, respectively. Electroosmosis is the movement of a liquid in a specific direction under the influence of an electric field, forming an electroosmotic flow that drives the movement of hydrated ions. When neutral particles pass through the skin, the electroosmotic flow plays a dominant role.

[0005] Furthermore, in vitro iontophoresis studies have shown that promoting changes in skin barrier function, such as enlarging or creating new pores, is also one of the mechanisms for enhancing skin permeability. Recent studies have demonstrated the contribution of drug iontophoresis to improving visual function in optic nerve diseases. Summary of the Invention

[0006] To address the issues of low transdermal absorption, high risk of systemic side effects, and insufficient early intervention methods for optic nerve atrophy in traditional ocular drug treatments, this paper proposes a topical preparation combined with iontophoresis. This preparation scientifically combines traditional Chinese medicines such as Ligusticum chuanxiong, Curcuma longa, Cassia tora, and Borneol. Optimized decoction processes and precise control of the pH value of the decoction ensure the activity and stability of the drug components. Simultaneously, iontophoresis technology significantly enhances transdermal drug delivery efficiency through electromigration and electroosmosis. This not only improves treatment adherence but also provides a highly efficient and targeted new local treatment strategy for anti-inflammatory and early optic nerve atrophy treatment.

[0007] This application provides a topical preparation for use with iontophoresis, which is made from the following raw materials in parts by weight: 15-25 parts of Ligusticum chuanxiong, 15-25 parts of Curcuma longa, 5-15 parts of Cassia tora, and 0.5-2 parts of Borneol.

[0008] Preferably, the preparation method of the topical preparation is as follows: (1) Weigh out 15-25 parts of Ligusticum chuanxiong, 15-25 parts of Curcuma longa, 5-15 parts of Cassia tora, and 0.5-2 parts of Borneol by weight. (2) Decoction: Mix the weighed Chinese herbs and decoct them in water until concentrated; (3) Collection of medicinal liquid: Continue to decoct until the remaining amount of medicinal liquid is 100mL, then stop decoction, filter to remove the dregs, and the filtrate obtained is the external preparation.

[0009] Preferably, the method of using the formulation is iontophoresis.

[0010] Preferably, the ion-importing electrode is an anode.

[0011] Preferably, the current intensity of the iontophoresis is 0.1-0.5 mA / cm2.

[0012] Preferably, the iontophoresis duration is 20 minutes, once a day, five times a week, and one course of treatment is one month.

[0013] Preferably, the formulation is used for anti-inflammatory purposes and to improve early optic nerve atrophy.

[0014] Preferably, the amount of water added during the decoction process is 8-10 times the total weight of the medicinal materials, the decoction temperature is 90-100℃, and the decoction time is 1.5-2 hours.

[0015] Preferably, the filtration process employs a 200-300 mesh filter for two-stage filtration, resulting in a filtrate with a pH value of 5.5-6.5.

[0016] Preferably, the filtrate is used to soak gauze and then applied externally to the eyes in conjunction with iontophoresis treatment.

[0017] The beneficial effects of the embodiments in this application are as follows: (1) Significantly improve the transdermal absorption rate of drugs: By combining iontophoresis technology (current intensity 0.1-0.5mA / cm²) with optimized traditional Chinese medicine preparations, the transdermal absorption rate of active ingredients such as ligustrazine and curcumin is increased by more than 50% through electromigration and electroosmosis, and the drugs are targeted to the periorbital tissues and optic nerve.

[0018] (2) Synergistic anti-inflammatory and neuroprotective effects: The combination of Ligusticum chuanxiong and borneol can inhibit pro-inflammatory factors such as TNF-α and IL-6, and reduce periorbital inflammatory response; Curcumin in turmeric can reduce oxidative damage to the optic nerve by regulating the NF-κB pathway; Cassia seed can enhance local microcirculation, improve blood supply to the optic nerve, delay the atrophy process, and achieve targeted therapy.

[0019] (3) Optimized treatment parameters and high safety: The iontophoresis parameters have been optimized by the system to ensure that the drug efficacy is fully exerted and to avoid skin irritation caused by excessive current. The safety is high and the patient compliance is good. At the same time, the use of local application combined with iontophoresis reduces the systemic exposure of the drug and reduces the risk of systemic side effects caused by oral or injection administration.

[0020] (4) Clear scope of application and high clinical value: The formulation is specifically designed for anti-inflammatory and early optic nerve atrophy treatment, providing a highly efficient and convenient new local treatment strategy for eye diseases (such as periorbital inflammation and early intervention for optic nerve atrophy). Compared with traditional eye drops and oral medications, it combines the gentleness of traditional Chinese medicine with the high efficiency of iontophoresis, filling the gap in the field of traditional Chinese medicine compound preparations suitable for iontophoresis and possessing significant clinical application value.

[0021] (5) The preparation process is simple and easy to promote: the preparation process only requires steps such as adding water to boil and filtering. The process is simple and controllable, without the need for complex equipment, and the cost is low. It is suitable for primary medical institutions and clinical promotion and use, which is conducive to the technology benefiting patients on a larger scale. Attached Figure Description

[0022] Figure 1 This is a flowchart illustrating the preparation process of the topical formulation in Example 3 of this application. Detailed Implementation

[0023] The technical solutions of this application will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments in this application, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of this application.

[0024] The reagents and equipment used in the embodiments of this disclosure are all conventional and commercially available.

[0025] Example 1 A topical preparation (1) Raw material preparation: Weigh out 15 parts of Ligusticum chuanxiong, 15 parts of turmeric, 5 parts of cassia seed, and 0.5 parts of borneol.

[0026] (2) Preparation method: 1) Add water and decoct: Mix the weighed Chinese herbs, add water equal to 8 times the total weight of the herbs, put them in an electric slow cooker with temperature control function, set the temperature to 95℃, decoct for 1.5 hours; 2) Decoction Collection: Continue decocting until the remaining decoction volume is 100mL, then stop decocting. A two-stage filtration system is used: the first stage is a 200-mesh filtration (75μm pore size): removing plant tissue residues >50μm, with the filtration flux maintained at 50mL / min; the second stage is a 300-mesh filtration (48μm pore size): retaining colloidal particles and starchy substances. Cross-flow filtration is used to reduce membrane clogging. The pH is tested using a pH meter and adjusted to 5.5, which is the pH of the topical preparation.

[0027] (3) Usage steps: Soak gauze with the prepared filtrate, then apply the gauze soaked in the medicine to the eyes, and use a medical iontophoresis device for iontophoresis treatment. The iontophoresis parameters are: use an anode electrode, current intensity 0.1mA / cm², set the iontophoresis duration to 20min, once a day, 5 times a week, and 1 month as one course of treatment.

[0028] Example 2 A topical preparation (1) Raw material preparation: Weigh 25 parts of Ligusticum chuanxiong, 25 parts of turmeric, 15 parts of cassia seed, and 2 parts of borneol.

[0029] (2) Preparation method: 1) Add water and decoct: Mix the weighed Chinese herbs, add water 9 times the total weight of the herbs, put them in an electric slow cooker with temperature control function, set the temperature to 95℃, decoct for 1.5 hours. 2) Decoction Collection: Continue decocting until the remaining decoction volume is 100mL, then stop decocting. A two-stage filtration system is used: the first stage is a 200-mesh filtration (75μm pore size): removing plant tissue residues >50μm, with the filtration flux maintained at 50mL / min; the second stage is a 300-mesh filtration (48μm pore size): retaining colloidal particles and starchy substances. Cross-flow filtration is used to reduce membrane clogging. A pH meter is used for testing, and the pH value is adjusted to 6.5, which is the final product for external use.

[0030] (3) Usage steps: Soak gauze with the prepared filtrate, then apply the soaked gauze to the eyes, and use a medical iontophoresis device for iontophoresis treatment. The iontophoresis parameters are: use an anode electrode, current intensity 0.5mA / cm², set the iontophoresis duration to 20min, once a day, 5 times a week, and 1 month as one course of treatment.

[0031] Example 3 A topical preparation (1) Raw material preparation: Weigh 20 parts of Ligusticum chuanxiong, 20 parts of turmeric, 10 parts of cassia seed, and 1 part of borneol.

[0032] (2) Preparation method: 1) Add water and decoct: Mix the weighed Chinese herbs, add water 10 times the total weight of the herbs, put them in an electric slow cooker with temperature control function, set the temperature to 100℃, decoct for 2 hours. 2) Decoction Collection: Continue decocting until the remaining decoction volume is 100 mL, then stop decocting. A two-stage filtration system is used: the first stage is a 200-mesh filtration (75 μm pore size): removing plant tissue residues >50 μm, with the filtration flux maintained at 50 mL / min; the second stage is a 300-mesh filtration (48 μm pore size): retaining colloidal particles and starchy substances. Cross-flow filtration is used to reduce membrane clogging. A pH meter is used for testing, and the pH value is adjusted to 6.0. This is the preparation of the external preparation. The preparation process is shown in Figure 1.

[0033] (3) Usage steps: Soak gauze with the prepared filtrate, then apply the soaked gauze to the eyes, and use a medical iontophoresis device for iontophoresis treatment. The iontophoresis parameters are: use an anode electrode, current intensity 0.3mA / cm², set the iontophoresis duration to 20min, once a day, 5 times a week, and 1 month as one course of treatment.

[0034] Comparative Example 1 A topical formulation (without iontophoresis) (1) Raw material preparation: Same as in Example 3.

[0035] (2) Preparation method: Same as in Example 3.

[0036] (3) Usage steps: Soak gauze with the prepared filtrate, then apply the soaked gauze to the eyes once a day, five times a week, for one month as one course of treatment.

[0037] Comparative Example 2 A topical preparation (primary filtration) (1) Raw material preparation: Same as in Example 3.

[0038] (2) Preparation method: 1) Add water and decoct: Mix the weighed Chinese herbs, add water equal to 8 times the total weight of the herbs, put them in an electric slow cooker with temperature control function, set the temperature to 100℃, decoct for 2 hours. 2) Collection of decoction: Continue decocting until the remaining decoction volume is 100mL, then stop decocting. Use a 200-mesh filter (75μm pore size) to remove plant tissue residue >50μm. Maintain the filtration flux at 50mL / min, test with a pH meter, and adjust the pH value to 6.0. This is the external preparation.

[0039] (3) Usage steps: Same as in Example 3.

[0040] Comparative Example 3 A topical preparation (without cassia seeds) (1) Raw material preparation: Weigh 20 parts of Ligusticum chuanxiong, 20 parts of turmeric slices, and 1 part of borneol.

[0041] (2) Preparation method: Same as in Example 3.

[0042] (3) Usage steps: Same as in Example 3.

[0043] Experimental Example 1 In vitro transdermal absorption experiment (1) Experimental materials: topical formulations of the examples and comparative examples of this application, Franz diffusion cell system (effective diffusion area 1.77 cm²), UPLC-MS / MS system, and intelligent iontophoresis instrument; (2) Experimental animals: 30 SPF-grade miniature pigs were purchased from the Experimental Animal Center of Dalian Medical University. Half were male and half were female, weighing between 8 and 10 kg and 12 weeks old. They were divided into 6 groups of 5 pigs each, half were male and half were female. (3) Experimental grouping: Example 1 (low-dose group) +0.1mA / cm 2 Example 2 (High-dose group) +0.5mA / cm 2 Example 3 (Medium-dose group) +0.3mA / cm 2 Comparative Example 1 (no iontophoresis), Comparative Example 2 (first-stage filtration) +0.3mA / cm 2 Comparative Example 3 (without cassia seeds) + 0.3 mA / cm 2 Blank control group (physiological saline); (4) Experimental protocol: Before the experiment, miniature pigs were raised in a standard animal house with a temperature of 22±3℃ and a humidity of 40%~60%. They were kept under 12-hour light / dark cycles and allowed free access to water and food. They were allowed to adapt to the environment for 3~5 days. The experimental period was 28 days. A 5×10cm area was selected behind the left ear of the miniature pig for hair removal. The area was disinfected with iodine solution. The gauze was soaked in the solution and applied externally once a day for 20 minutes each time, 5 times a week. One month was one course of treatment. The transdermal absorption rate was tested using the UPLC-MS / MS system for a total of 6 hours of external application.

[0044] (5) Experimental data: Transdermal transdermal data are shown in Table 1: Table 1 Comparison of transdermal absorption rates of active ingredients (n=5)

[0045] (6) Experimental results: All examples were significantly better than the comparative examples: Example 1 (low dose) improved by 41.5% compared with passive osmosis (comparative example 1) (tetramethylpyrazine); Example 3 (medium dose) improved by 19.7% compared with primary filtration (comparative example 2) (total flavonoids).

[0046] Experimental Example 2 Comparison of optic nerve protection effects (1) Model mice and grouping: Rabbit optic nerve compression injury model was purchased from Jiangsu Hanjiang Biotechnology Co., Ltd., and the mice were randomly grouped (n=10) at 6-8 weeks old. (2) Detection indicators: After administration according to the method corresponding to the example, the survival rate (%) of retinal ganglion cells (RGC) was measured 4 weeks later. (3) Experimental data: The survival rate (%) of retinal ganglion cells (RGC) after 4 weeks is shown in Table 2: Table 2. RGC survival rate of each group

[0047] (4) Experimental results: The survival rate of RGC in Example 3 was increased by 46.2% compared with Comparative Example 2 (first-level filtration), and the survival rate of RGC in Example 2 was increased by 16.0% compared with Comparative Example 3 (without cassia seeds). Comparative Example 1 (without introduction) had the worst effect.

[0048] Experimental Example 3 Comparison of relief for non-arteritis anterior ischemic optic neuropathy (NAION) (1) Model mice and grouping: Jiangsu Hanjiang Biotechnology Co., Ltd. purchased NAION mouse models and selected 8-week-old C57BL / 6J male mice. The model group was randomly divided into 3 groups (n=12) and the normal group was 1 group (n=12).

[0049] (2) Grouping: Normal group: No modeling was performed, and the contralateral eye served as the self-control; Model group: No treatment was given after modeling; Example 3 group: After modeling, the preparation of Example 3 was used in combination with iontophoresis treatment; Comparative Example 1: After modeling, the formulation of Example 3 was used but without iontophoresis treatment.

[0050] (3) Dosing regimen: The prepared filtrate is soaked in gauze and applied to both eyes. In conjunction with iontophoresis, the parameters are as follows: use an anode electrode, current intensity 0.1-0.5mA / cm², duration 20min, once a day, 5 times a week, one month as a course of treatment, a total of 60 days, 2 courses of treatment.

[0051] (4) The detection indicators and results are shown in Table 3: Table 3. Detection data for each group of indicators

[0052] (5) Results: Compared with the normal group, the model group showed significant deterioration in structure (RNFL, vascular density), function (VEP, field of vision) and cell survival (RGC), and inflammation and apoptosis markers were significantly upregulated. Blood routine indicators indicated systemic inflammation. The Example 3 group showed partial recovery in all indicators: RNFL, vascular density, VEP amplitude, and field of vision defects all recovered to about 60-80% of the model group; the upregulation of inflammation and apoptosis markers was significantly inhibited; blood routine indicators also tended to normalize. Although the Comparative Example 1 group also showed improvement, the magnitude was slightly lower than that of the iontophoresis group, indicating that iontophoresis has an additional synergistic effect on drug penetration and efficacy enhancement. The Example 3 group was able to achieve more significant structural, functional and molecular-level protective effects in the NAION mouse model, which was better than that of the Comparative Example 1 group.

[0053] In summary, the topical formulation provided in this application, through the scientific combination of Ligusticum chuanxiong, Curcuma longa, Cassia tora, and Borneol, combined with optimized decoction process and iontophoresis technology, significantly improves the transdermal absorption rate and targeting of the drug. It exhibits a synergistic effect in anti-inflammatory treatment and early optic nerve atrophy therapy, as well as in alleviating non-arteritis anterior ischemic optic neuropathy. Its preparation process is simple and safe, possessing significant clinical application value and promising prospects for widespread application.

[0054] Although embodiments of this application have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of this application. All equivalent changes and improvements made within the scope of this application shall still fall within the patent coverage of this application.

Claims

1. A topical formulation for use with iontophoresis, characterized in that, The topical preparation is made from the following raw materials in parts by weight: 15-25 parts of Ligusticum chuanxiong, 15-25 parts of Curcuma longa, 5-15 parts of Cassia tora, and 0.5-2 parts of Borneol.

2. The topical formulation for iontophoresis as described in claim 1, characterized in that, The preparation method of the topical preparation is as follows: (1) Weigh out 15-25 parts of Ligusticum chuanxiong, 15-25 parts of Curcuma longa, 5-15 parts of Cassia tora, and 0.5-2 parts of Borneol by weight. (2) Decoction: Mix the weighed Chinese herbs and decoct them in water until concentrated; (3) Collection of medicinal liquid: Continue to decoct until the remaining amount of medicinal liquid is 100mL, then stop decoction, filter to remove the dregs, and the filtrate obtained is the external preparation.

3. The topical formulation for use with iontophoresis as described in claim 1, characterized in that, The method of application for the formulation is iontophoresis.

4. The topical formulation for use with iontophoresis as described in claim 3, characterized in that, The ion-importing electrode is an anode.

5. The topical formulation for use with iontophoresis as described in claim 3, characterized in that, The current intensity for iontophoresis is 0.1-0.5 mA / cm. 2 .

6. The topical formulation for use with iontophoresis as described in claim 3, characterized in that, The iontophoresis session lasts 20 minutes, once a day, five times a week, and one course of treatment is one month.

7. The topical formulation for use with iontophoresis as described in claim 1, characterized in that, The formulation is used for anti-inflammatory purposes and to improve early optic nerve atrophy.

8. The topical formulation for use with iontophoresis as described in claim 2, characterized in that, During the concentrated decoction process, the amount of water added is 8-10 times the total weight of the medicinal materials, the decoction temperature is 90-100℃, and the decoction time is 1.5-2 hours.

9. The topical formulation for use with iontophoresis as described in claim 2, characterized in that, The filtration process employs a two-stage filtration using a 200-300 mesh filter, resulting in a filtrate with a pH value of 5.5-6.

5.

10. A topical formulation for use with iontophoresis as described in claim 2, characterized in that, The filtrate is used to soak gauze and then applied externally to the eyes, in conjunction with iontophoresis treatment.

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