Manchurian wildginger-containing slow-release transdermal arthralgia-relieving traditional Chinese medicine ointment and preparation method thereof

Abstract

The invention discloses a herba asari-containing slow-release transdermal arthralgia-relieving traditional Chinese medicine ointment and a preparation method thereof. The active ingredients of the ointment are prepared by extracting a plurality of traditional Chinese medicines such as clove, asarum, pepper, saffron crocus, ginseng, radix clematidis, eucommia ulmoides, ligusticum wallichii and pseudo-ginseng through a specific process. The auxiliary materials comprise olive oil emulsifying wax, alkyl polyglucoside and purified water. According to the invention, the O / W type cream is prepared through scientific formula compatibility and fusion of a modern cream preparation technology. The ointment has the effects of expelling wind and removing cold, promoting blood circulation to remove blood stasis and activating meridians to stop pain, and can effectively relieve various arthralgia. An adopted auxiliary material system is mild, safe, free of hormones and preservatives and suitable for sensitive skin. The unique cream structure can wrap medicine components, and slow-release transdermal absorption of the medicine is realized by utilizing the permeation enhancing effect of the alkyl polyglucoside, so that the purpose of long-acting analgesia is achieved. The preparation process is stable, the product quality is controllable, and the preparation method has a wide clinical application prospect.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine preparation technology, specifically to a traditional Chinese medicine ointment for relieving joint pain and its preparation method, particularly an ointment containing Asarum and having sustained-release transdermal function. Background Technology

[0002] Joint pain is a common symptom of various diseases such as rheumatoid arthritis, osteoarthritis, and others, severely impacting patients' quality of life. Currently, treatments for joint pain mainly include oral nonsteroidal anti-inflammatory drugs (NSAIDs) and topical analgesic plasters. Oral medications often have side effects such as gastrointestinal irritation and liver and kidney damage; while traditional topical plasters (such as rubber plasters and poultices) generally suffer from low transdermal absorption, short duration of action, and a tendency to cause skin allergies (e.g., due to residual adhesive, added chemical penetration enhancers, or preservatives).

[0003] Asarum, a traditional Chinese medicine, has the effects of dispelling wind and cold, clearing the meridians and relieving pain. It is a commonly used medicine for treating wind-cold-dampness arthralgia and joint pain. However, the active ingredients in Asarum (such as volatile oils) are volatile and unstable, and traditional ointments have difficulty controlling their release rate, resulting in a short duration of efficacy and the need for frequent use.

[0004] Therefore, developing a topical Chinese medicine preparation that can stabilize drug components, achieve sustained-release transdermal absorption, provide long-lasting relief of joint pain, and is gentle and non-irritating to the skin has significant clinical importance and market value. Summary of the Invention

[0005] One of the objectives of this invention is to provide a sustained-release transdermal herbal ointment containing Asarum. This ointment, through scientific formulation and modern pharmaceutical technology, can provide long-lasting and stable relief of joint pain, and is highly safe and suitable for sensitive skin.

[0006] The second objective of this invention is to provide a method for preparing the above-mentioned ointment, which has a stable process, can effectively retain the active ingredients of traditional Chinese medicine, and form a stable sustained-release transdermal system.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] A sustained-release transdermal herbal ointment for relieving joint pain containing Asarum, made from active ingredients and excipients, wherein the active ingredients consist of the following parts by weight of extracts from traditional Chinese medicinal materials:

[0009] Cloves 5-15 parts; Asarum 3-10 parts; Sichuan pepper 5-12 parts; Saffron 1-5 parts; Ginseng 3-8 parts; Clematis chinensis 8-18 parts; Eucommia ulmoides 6-15 parts; Ligusticum chuanxiong 8-20 parts; Panax notoginseng 5-15 parts

[0010] The excipients comprise the following components by weight percentage:

[0011] Olive oil emulsifying wax 5%-15%; alkyl polysaccharide 1%-5%; purified water balance

[0012] Preferably, the active ingredient is composed of the following parts by weight of Chinese herbal raw material extracts: 10 parts clove, 5 parts asarum, 8 parts Sichuan pepper, 3 parts saffron, 5 parts ginseng, 12 parts clematis, 10 parts eucommia, 15 parts chuanxiong, and 10 parts notoginseng.

[0013] Preferably, the ointment is an O / W (oil-in-water) type cream.

[0014] The present invention also provides a method for preparing the above-mentioned ointment, comprising the following steps:

[0015] Preparation of extracts from Chinese medicinal herbs:

[0016] a. Mix the four medicinal materials of clove, asarum, Sichuan pepper and chuanxiong in the above proportions, extract the volatile oil by steam distillation, collect the volatile oil for later use, and obtain the residue A and the distillate.

[0017] b. Combine the dregs A obtained in step a with the three medicinal materials Clematis chinensis, Eucommia ulmoides and Panax notoginseng, add 8-12 times the amount of 60%-80% ethanol, heat and reflux to extract 1-3 times, 1-2 hours each time, combine the ethanol extracts, filter, recover the ethanol and concentrate to a fragrant paste A with a relative density of 1.10-1.25 (60℃) for later use.

[0018] c. Mix ginseng and saffron, decoct them with 6-10 times the amount of purified water 1-3 times, 1-2 hours each time, combine the water extracts, filter, and concentrate to a fragrant paste B with a relative density of 1.10-1.25 (60℃) for later use.

[0019] d. Mix the volatile oil collected in step a with the fragrance paste A obtained in step b and the fragrance paste B obtained in step c evenly to obtain a compound Chinese medicine extract for later use.

[0020] Oil phase preparation: Heat olive oil emulsified wax to 70-80℃ and stir until it is completely melted to obtain a clear oil phase.

[0021] Aqueous phase preparation: Dissolve the alkyl polysaccharide in the prescribed amount of purified water, heat to 70-80℃, and stir until completely dissolved to obtain the aqueous phase.

[0022] Emulsification and compounding: Under continuous stirring, the oil phase obtained in step 2 is slowly added to the aqueous phase obtained in step 3, while maintaining the temperature at 70-80℃. High-speed shear emulsification is carried out at a speed of 1000-3000 rpm for 5-15 minutes to form a uniform cream matrix.

[0023] Drug loading and cooling: The compound herbal extract prepared in step 1d is slowly added to the cream matrix obtained in step 4 under stirring, maintaining the temperature at 40-50℃, and stirring continuously until the extract and matrix are evenly mixed. Then, it is slowly cooled to room temperature to obtain the sustained-release transdermal herbal ointment.

[0024] The beneficial effects of this invention are as follows:

[0025] 1. Scientifically formulated with synergistic effects: Asarum is the principal ingredient, dispelling wind and cold, clearing the channels and relieving pain. Clematis chinensis, Sichuan pepper, and cloves are added to enhance the effects of dispelling wind and dampness, warming the channels and clearing the channels. Ligusticum chuanxiong, a "qi-regulating herb in the blood," invigorates blood and qi, and together with Panax notoginseng and saffron, which invigorate blood and remove blood stasis, they act as assistant ingredients, effectively improving local blood circulation and promoting the absorption of inflammation. Ginseng and Eucommia ulmoides are added to replenish qi and blood, strengthen muscles and bones, and support the body's resistance to expel pathogens. The entire formula works synergistically to dispel wind and cold, invigorate blood and remove blood stasis, clear the channels and relieve pain, and tonify the liver and kidneys. It targets multiple aspects of the pathogenesis of joint pain (wind, cold, dampness, blood stasis, and deficiency), resulting in significant effects.

[0026] 2. Advanced Formulation, Sustained-Release Transdermal: Utilizing an O / W type cream as a carrier, it exhibits good skin affinity, excellent spreadability, and does not stain clothing. Olive oil emulsifying wax and alkyl polysaccharide glycosides are selected as excipients. The olive oil emulsifying wax forms a fine cream structure that effectively encapsulates the volatile oils and extracts of traditional Chinese medicine, reducing volatilization and oxidation, thus achieving initial sustained-release. Alkyl polysaccharide glycosides are plant-derived green surfactants that not only possess strong emulsifying power but also have a mild penetration-enhancing effect, promoting the penetration of drug components through the stratum corneum, improving bioavailability, and avoiding skin irritation caused by chemical penetration enhancers. By "encapsulating" the drug components within the oil-phase microparticles or interfacial film of the cream, a drug reservoir is formed. When applied to the skin, the drug needs to be slowly released from the reservoir and penetrate the skin, thereby achieving a long-lasting sustained-release effect.

[0027] 3. Safe and gentle: The formula is explicitly free of hormones and preservatives. All excipients are selected as mild and low-irritant ingredients, especially alkyl polysaccharides and olive oil derivatives, which have been proven to be friendly to sensitive skin and have high safety through skin irritation tests.

[0028] The preparation process is rational: Distillation, alcohol extraction, and water extraction are employed according to the characteristics of the medicinal materials to maximize the extraction and retention of effective components of different polarities (such as the volatile oil of Asarum and the saponins of Panax notoginseng), ensuring efficacy. Combining the extract with modern cream preparation technology results in good product stability and controllable quality. Attached Figure Description

[0029] Figure 1 Release curves of methyl eugenol and ginsenosides in the ointment of this invention.

[0030] Figure 2Transdermal absorption curves of methyl eugenol and ginsenosides in the ointment of this invention.

[0031] Figure 3 Skin toxicology test. (A) Body weight. (B) General condition and poisoning symptoms observation record form.

[0032] Figure 4 Mouse analgesia experiment. (A) Pain threshold at different time points after drug administration. (B) Pain threshold increase rate. The calculation formula is as follows: Pain threshold increase rate (%) = [(Pain threshold after drug administration - Pain threshold before drug administration) / Pain threshold before drug administration] × 100%.

[0033] Figure 5 Anti-inflammatory experiment on rat paw edema. (A) Swelling degree of paw at different time points. (B) Swelling inhibition rate. The calculation formula is as follows: Swelling inhibition rate (%) = [(Swelling degree of blank group - Swelling degree of drug-treated group) / Swelling degree of blank group] × 100%.

[0034] Figure 6 Experiment on the prevention and treatment of arthritis in rats. (A) D21 arthritis index score. (B) Histopathological results. Detailed Implementation

[0035] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods. Unless otherwise specified, the materials and reagents used in the following embodiments are commercially available. The substantive content of the present invention is described in detail below with reference to embodiments, but this does not limit the scope of protection of the present invention.

[0036] Example 1. Preparation of Ointment

[0037] 1. Weigh the Chinese medicinal materials according to the following weight parts: 10 parts cloves, 5 parts asarum, 8 parts Sichuan pepper, 3 parts saffron, 5 parts ginseng, 12 parts clematis, 10 parts eucommia, 15 parts chuanxiong, and 10 parts notoginseng.

[0038] 2. Prepare the auxiliary materials according to the following weight percentages: 10% olive oil emulsifying wax, 3% alkyl polysaccharide glycoside, and the remainder purified water.

[0039] 3. Mix cloves, asarum, Sichuan pepper, and chuanxiong, and steam distill for 4 hours, collecting approximately 0.5% (v / w) of volatile oil. Drain the residue A.

[0040] 4. Combine the residue A with Clematis chinensis, Eucommia ulmoides, and Panax notoginseng, add 10 times the amount of 70% ethanol, and reflux extract twice, 1.5 hours each time. Combine the extracts, filter, recover the ethanol under reduced pressure, and concentrate to a fragrant paste A with a relative density of 1.20 at 60℃.

[0041] 5. Mix ginseng and saffron, add 8 times the amount of purified water, and decoct twice, 1 hour each time. Combine the decoctions, filter, and concentrate to a fragrant paste B with a relative density of 1.15 at 60℃.

[0042] 6. Mix the volatile oil, fragrance paste A, and fragrance paste B evenly at 40℃ to obtain a compound Chinese herbal extract.

[0043] 7. Place 10g of olive oil emulsified wax in a beaker, heat in a water bath to 75℃, and stir until melted.

[0044] 8. Dissolve 3g of alkyl polysaccharide in about 77g of purified water, heat to 75℃, and stir to dissolve.

[0045] 9. While stirring in a high-speed homogenizer (2000 rpm), slowly pour the oil phase into the water phase and continue emulsifying for 10 minutes to obtain a white and delicate cream base.

[0046] 10. Add the above compound Chinese herbal extract (equivalent to the total amount of medicinal materials) to the cream base that has been cooled to 45°C under slow stirring. Stir for 30 minutes to mix it evenly, then let it cool naturally to room temperature and fill it to obtain approximately 100g of finished cream.

[0047] Example 2: Release rate determination

[0048] 1. Using the Franz diffusion cell method, 0.5g of drug was added to the donor cell and 15ml of receiving solution was added to the receiver cell. The temperature was set at 32℃ (simulating human skin temperature) and the stirring speed was 500rpm. 5ml samples were taken at 1h, 2h, 4h, 6h, 8h, 12h and 24h, and an equal amount of fresh receiving solution was added at the same time.

[0049] 2. The concentrations of Asarum volatile oil (characteristic component: methyl eugenol) and Panax notoginseng total saponins (characteristic component: ginsenoside Rg1) in the receiving liquid were determined by HPLC, and the cumulative release was calculated.

[0050] Results: The cumulative release of methyl eugenol in the ointment of this invention reached 86.3% over 24 hours, and the release curve conformed to the Higuchi equation (r=0.992), exhibiting good sustained-release characteristics; the cumulative release was 62.1% in the first 8 hours, and the remaining components were slowly released over the next 16 hours. Figure 1 The cumulative release of ginsenoside Rg1 in the ointment of this invention reached 82.5% over 24 hours, and the release curve conformed to the Higuchi equation (r=0.989), exhibiting good sustained-release characteristics; the cumulative release was 57.0% in the first 8 hours, and the remaining components were slowly released over the next 16 hours. Figure 1 ).

[0051] Example 3: Transdermal Absorption Measurement

[0052] The processed detached pigskin was fixed between the donor and receiver tanks of a Franz diffusion cell. 0.5g of drug was added to the donor tank, and the other conditions were the same as those for the release assay. The concentration of drug components in the receiver liquid was sampled and tested periodically.

[0053] Results: The steady-state transdermal ... Figure 2 The above data indicate that the excipient system of the present invention can effectively promote transdermal drug absorption while achieving a sustained-release effect.

[0054] Example 4: Toxicological Experiments (Safety Verification)

[0055] 1. Acute skin toxicity test

[0056] Grouping: Mice were randomly divided into a blank control group and a test drug group, with 20 mice in each group, half male and half female.

[0057] Methods: 0.5g of the drug was applied to the hairless area on the back of mice in the test drug group, while an equal volume of blank matrix was applied to the blank control group. The mice were observed for 14 consecutive days, and their general condition, weight changes and symptoms of poisoning were recorded.

[0058] Results: Within 14 days, no mice in the test drug group died, their diet and activity were normal, and their weight gain was not significantly different from the blank control group. No symptoms of poisoning such as skin redness, swelling, or ulceration were observed. The calculated median lethal dose (LD50) was >5 g / kg, indicating that the drug has extremely low acute toxicity when administered through the skin. Figure 3 ).

[0059] 2. Skin irritation test

[0060] Grouping: New Zealand rabbits were randomly divided into an intact skin group and a damaged skin group (the epidermis was lightly abraded with sandpaper after hair removal), with 6 rabbits in each group. The left side of the back of each rabbit was the drug administration area, and the right side was the blank control area.

[0061] Methods: Apply 0.2g of the drug to the treatment area daily for 14 consecutive days. After discontinuing the drug, observe for 7 days and evaluate according to the skin irritation reaction scoring standard.

[0062] Results: During and after drug administration, no irritation reactions such as erythema, edema, or exudation were observed in either the intact skin group or the damaged skin group. The irritation score was 0 in both groups, indicating that the drug had no significant irritation to either intact or damaged skin and was suitable for sensitive skin.

[0063] 3. Skin allergy test

[0064] Grouping: 40 guinea pigs were randomly divided into a negative control group (blank matrix), a positive control group (2,4-dinitrochlorobenzene), and a test drug group, with 10 guinea pigs in each group.

[0065] Methods: The Buehler method was used. During the induction period, the drug was applied once every 3 days for a total of 3 times. During the stimulation period, the drug was applied 14 days after the last induction. Skin allergic reactions were observed at 24h and 48h.

[0066] Results: The guinea pigs in the test drug group showed no allergic reactions such as erythema and edema, and the incidence of allergy was 0%, which was significantly lower than that in the positive control group (80% incidence of allergy), indicating that the drug did not cause skin sensitization.

[0067] Example 5: Pharmacodynamic Experiment

[0068] Experimental materials

[0069] Experimental animals: 60 SPF-grade SD rats (weighing 200-220g) and 60 ICR mice (weighing 18-22g), all provided by the animal experiment center.

[0070] Test drug: The traditional Chinese medicine ointment prepared in Example 1 of this invention; Positive control drug: Commercially available ibuprofen cream (containing 10% ibuprofen); Negative control: Blank cream base without traditional Chinese medicine extract.

[0071] 1. Mouse hot plate analgesia test

[0072] Grouping: Mice were randomly divided into a blank matrix group, a positive control group, and low / medium / high dose groups of the test drug (applied doses of 0.1 g / kg, 0.3 g / kg, and 0.5 g / kg, respectively), with 12 mice in each group.

[0073] Methods: The pain threshold of mice was measured before administration. Then, the medication was applied to the right hind paw of the mice according to the dosage. The pain threshold was measured at 1h, 2h, 4h, 6h and 8h after administration, and the pain threshold improvement rate was calculated.

[0074] Results: The pain threshold elevation rate in the medium- and high-dose groups of the test drug was significantly higher than that in the blank matrix group 2 hours after administration (P<0.05). At 8 hours, the pain threshold elevation rate in the high-dose group was still 38.6%, significantly higher than the 25.3% in the positive control group at the same time point, indicating that the analgesic effect of the drug was prolonged. Figure 4 ).

[0075] 2. Anti-inflammatory test of rat paw edema

[0076] Grouping: Rats were randomly divided into blank matrix group, positive control group, and low / medium / high dose of test drug group, with 12 rats in each group.

[0077] Methods: Rats were subcutaneously injected with 0.1 ml of 1% carrageenan into the right hind paw to induce inflammation. 30 min after inflammation, the test drug was applied according to the dosage. The degree of paw swelling was measured at 1 h, 2 h, 4 h, 6 h and 8 h after inflammation, and the swelling inhibition rate was calculated.

[0078] Results: The high-dose group of the test drug showed a swelling inhibition rate of 42.1% 2 hours after inflammation induction and maintained it at 35.8% 6 hours, significantly better than the positive control group (inhibition rates of 31.5% and 24.7% at the same time), confirming that the drug has a significant anti-inflammatory effect with a long duration. Figure 5 ).

[0079] 3. Rat Arthritis Prevention and Treatment Experiment

[0080] Grouping: Rats were randomly divided into a model control group, a positive control group, and a medium / high dose group of the test drug, with 10 rats in each group. An additional normal control group of 10 rats was also set up.

[0081] Methods: Except for the normal control group, the other rats were injected with 0.1 ml of Freund's complete adjuvant into the right hind paw to induce an arthritis model. After successful modeling, the test drug group was treated with the affected area twice daily for 21 consecutive days, and the degree of joint swelling and arthritis index were measured regularly.

[0082] Results: After 21 days of administration, the joint swelling in the high-dose group was reduced by 58.3% compared with the model control group, and the arthritis index score was significantly reduced (P<0.01). Furthermore, the histopathological sections of the joint tissue showed a significant reduction in inflammatory cell infiltration, indicating that the drug has a significant preventive and therapeutic effect on chronic inflammatory joint pain. Figure 6 ).

Claims

1. A sustained-release transdermal ointment for relieving arthralgia pain containing Szechwan Lovage Root, characterized in that, Is made of active ingredients and adjuvant; the active ingredients are made of following weight parts of traditional Chinese medicinal material extract: clove 5-15 parts, asarum 3-10 parts, zanthoxylum 5-12 parts, saffron 1-5 parts, ginseng 3-8 parts, radix clematidis 8-18 parts, eucommia 6-15 parts, chuanxiong 8-20 parts, panax notoginseng 5-15 parts; the adjuvant includes following weight percentage components: olive oil emulsified wax 5%-15%, alkyl polyglycoside 1%-5%, purified water balance.

2. The traditional Chinese medicine paste according to claim 1, characterized in that, The active ingredients are made of following weight parts of traditional Chinese medicinal material extract: clove 10 parts, asarum 5 parts, zanthoxylum 8 parts, saffron 3 parts, ginseng 5 parts, radix clematidis 12 parts, eucommia 10 parts, chuanxiong 15 parts, panax notoginseng 10 parts.

3. The traditional Chinese medicine paste according to claim 1 or 2, characterized in that, The ointment is an oil-in-water emulsion ointment.

4. A method for preparing the traditional Chinese medicine ointment according to any one of claims 1-3, characterized in that, The method comprises the following steps: a. Preparation of traditional Chinese medicinal material extract: mix clove, asarum, zanthoxylum and chuanxiong to extract volatile oil, collect the volatile oil and dregs A; combine dregs A with radix clematidis, eucommia and panax notoginseng, extract by refluxing with ethanol, and concentrate to obtain fragrance ointment A; extract ginseng and saffron by decocting with water, and concentrate to obtain fragrance ointment B; mix the volatile oil, fragrance ointment A and fragrance ointment B to obtain composite traditional Chinese medicinal extract; b. Preparation of oil phase: melt and dissolve olive oil emulsified wax by heating; c. Preparation of water phase: dissolve alkyl polyglycoside in purified water and heat; d. Emulsification: add the oil phase into the water phase, and emulsify by high-speed shearing to form an emulsion ointment base; e. Drug loading and shaping: add the composite traditional Chinese medicinal extract obtained in step a into the emulsion ointment base, mix uniformly, and cool to room temperature to obtain the ointment.

5. The method of claim 4, wherein, In step a, the volatile oil is extracted by water vapor distillation method; the ethanol reflux extraction uses ethanol with a concentration of 60%-80%, the solid-liquid ratio is 1:8-12, and the extraction is performed 1-3 times; the water decocting extraction uses a solid-liquid ratio of 1:6-10, and the extraction is performed 1-3 times.

6. The method of claim 4, wherein, In step d, the emulsification temperature is 70-80℃, the high-speed shearing speed is 1000-3000 rpm, and the time is 5-15 minutes.

7. The method of claim 4, wherein, In step e, the drug loading temperature is 40-50℃.

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