A transdermal drug delivery formulation for treating osteoarthritis and its preparation method

Abstract

This invention belongs to the field of traditional Chinese medicine technology, specifically relating to a transdermal drug delivery formulation for treating osteoarthritis. The invention provides a transdermal drug delivery formulation for treating osteoarthritis, comprising, by weight, the following raw materials: 10-15 parts Aconitum carmichaelii, 12-16 parts Smilax glabra, 25-30 parts Salvia miltiorrhiza, 6-12 parts Boswellia carterii, 1-3 parts Carthamus tinctorius, 8-12 parts Commiphora myrrha, 12-16 parts Angelica sinensis, 18-22 parts Tinospora sinensis, 6-10 parts Paeonia lactiflora, 20-30 parts Pinellia ternata, 14-18 parts Cinnamomum cassia, and 6-8 parts Rheum palmatum; it also includes a matrix and excipients for the transdermal drug delivery formulation. This invention uses natural Chinese herbal extracts as active ingredients, and through scientific and rational formulation, prepares a transdermal drug delivery formulation with good stability, permeability, and biocompatibility.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine technology, and more specifically, to a transdermal drug delivery formulation for treating osteoarthritis and its preparation method. Background Technology

[0002] Osteoarthritis (OA) is a chronic, degenerative disease characterized primarily by the destruction of articular cartilage and the formation of osteophytes at the joint margins. With the increasing aging of the global population, the incidence of OA is rising annually, becoming one of the major diseases affecting the quality of life of the elderly. Traditional treatments for OA mainly include oral medications, intra-articular injections, and surgery; however, these methods have many limitations, such as significant systemic side effects, long treatment cycles, and low patient acceptance.

[0003] Transdermal drug delivery systems (TDS) are a novel drug delivery method that uses the skin to administer medication. They offer advantages such as avoiding the first-pass effect in the liver, reducing systemic drug side effects, and improving patient tolerance. In recent years, with the continuous development of transdermal drug delivery technology, its application in the treatment of osteoarthritis (OA) has received widespread attention. However, there are currently few transdermal drug delivery formulations on the market for treating OA, and most formulations suffer from poor permeability, unstable drug release, and short duration of action, making it difficult to meet clinical needs.

[0004] In the existing technology, there have been some research reports on transdermal drug delivery formulations for the treatment of osteoarthritis (OA). Most of these formulations use traditional Chinese medicine or natural drugs as active ingredients, achieving local treatment through transdermal delivery technology. However, these formulations still have some problems in terms of preparation process, drug release mechanism, and transdermal permeability. For example, some formulations use a large amount of organic solvents in the preparation process, resulting in poor drug stability; some formulations have drug release rates that are too fast or too slow, failing to meet clinical needs; and some formulations have insufficient transdermal permeability, making it difficult for the drug to reach the lesion site.

[0005] Based on this, the present invention provides a transdermal drug delivery formulation for treating osteoarthritis. Summary of the Invention

[0006] This invention provides a transdermal drug delivery formulation for treating osteoarthritis, which has advantages such as good permeability, stable drug release, and long duration of action, and can meet clinical needs.

[0007] In a first aspect, the present invention provides a transdermal drug delivery formulation for treating osteoarthritis, employing the following technical solution:

[0008] A transdermal drug delivery formulation for treating osteoarthritis, comprising, by weight, the active pharmaceutical ingredients of the transdermal drug delivery formulation including: 10-15 parts of Aconitum carmichaelii, 12-16 parts of Smilax glabra, 25-30 parts of Salvia miltiorrhiza, 6-12 parts of Boswellia carterii, 1-3 parts of Carthamus tinctorius, 8-12 parts of Commiphora myrrha, 12-16 parts of Angelica sinensis, 18-22 parts of Caulis Cimicifugae, 6-10 parts of Paeonia lactiflora, 20-30 parts of Pinellia ternata, 14-18 parts of Cinnamomum cassia, and 6-8 parts of Rheum palmatum; and also including the matrix and adjuvants of the transdermal drug delivery formulation.

[0009] Furthermore, the matrix includes at least one of Carbomer 934, Carbomer 940, and Carbomer 941.

[0010] Furthermore, the adjuvants include one or more of transdermal enhancers, humectants, and preservatives.

[0011] Furthermore, the weight ratio of the transdermal enhancer, moisturizer, and preservative is (1.8-2.2):(0.8-1.2):(0.4-0.6).

[0012] Furthermore, the transdermal enhancer includes at least one of azone, peppermint oil, and borneol.

[0013] Furthermore, the weight ratio of azone, peppermint oil and borneol is (1-2):(1-2):(1-2).

[0014] Furthermore, the moisturizer includes glycerin and / or propylene glycol.

[0015] Furthermore, the preservative includes methylparaben and / or ethylparaben.

[0016] Secondly, the present invention also provides another method for preparing a transdermal drug delivery formulation for treating osteoarthritis, employing the following technical solution:

[0017] A method for preparing a transdermal drug delivery formulation for treating osteoarthritis specifically includes the following preparation steps:

[0018] (1) Weigh the raw materials of the transdermal drug delivery preparation according to the formula, add ethanol and reflux extract three times at 60-64℃, combine the extracts and filter, and then remove the ethanol from the extract under reduced pressure at 50-60℃ and vacuum dry to obtain an ointment; dry the ointment under high vacuum to obtain a dry powder.

[0019] (2) Add water to the matrix to swell, and continuously and slowly add water during the grinding process to prepare a gel solution; then add the dry powder and additives to the gel solution and stir. After mixing evenly, let it stand for 1.5-2.5 hours, and then stir again until it becomes a paste-like gel.

[0020] Furthermore, in step (1), the amount of ethanol used each time is equal, the reflux extraction time each time is 1-2 hours, and the total amount of ethanol used is 14-16 times the total weight of the raw material of the transdermal drug delivery preparation.

[0021] Furthermore, the ratio of the total mass of the substrate to the total mass of water is 1:(110-120).

[0022] Furthermore, the weight ratio of the matrix, additives and dry powder is 100:(4-6):(10-12).

[0023] In summary, the present invention has the following beneficial effects:

[0024] The active pharmaceutical ingredient composition of the transdermal drug delivery formulation of the present invention not only takes into account the interaction between the medicinal materials and the synergistic effect of their efficacy, but also avoids possible side effects and adverse reactions.

[0025] To achieve good transdermal permeability, this invention specifically adds azone, peppermint oil, and borneol as transdermal enhancers. Azone can alter the lipid structure of the stratum corneum, improving the transdermal absorption rate of drugs; peppermint oil and borneol further promote drug penetration by reducing the skin's barrier effect on drugs. The addition of these transdermal enhancers enables the transdermal drug delivery formulation of this invention to rapidly penetrate the skin and reach the treatment site during transdermal administration.

[0026] In this invention, the selection of azone, peppermint oil, and borneol as transdermal enhancers optimizes the transdermal absorption rate of traditional Chinese medicine components. Azone increases skin permeability, allowing drug molecules to more easily cross the skin barrier and enter the bloodstream. Furthermore, azone forms hydrogen bonds or van der Waals forces with drug molecules, making them more stable and less susceptible to oxidation or degradation, thus extending the drug's shelf life. Simultaneously, azone reduces the surface tension of drugs, increasing their solubility in solvents and improving dissolution and absorption rates. Peppermint oil significantly promotes the transdermal absorption of various hydrophilic and lipophilic drugs. It facilitates the interaction of lipid layers in the stratum corneum, lowering the phase transition temperature of active substances into the lipid interstitial spaces, thereby increasing transdermal absorption. Borneol promotes the absorption and utilization of topical corticosteroids and analgesics. It increases drug permeability by regulating the permeability of the stratum corneum. In addition, borneol has certain anti-inflammatory and analgesic effects, providing adjunctive treatment for osteoarthritis.

[0027] When azone, peppermint oil, and borneol are used in a weight ratio of (1-2):(1-2):(1-2), a significant synergistic effect can be produced. This is because, although their individual mechanisms of action are different, they can all reduce the skin's barrier effect on drugs and increase transdermal absorption. When they act together on the skin, they can mutually enhance this effect, resulting in a significant improvement in the efficiency of transdermal drug absorption. Specifically, azone increases transdermal penetration by altering the lipid arrangement of the stratum corneum, while peppermint oil and borneol lower the phase transition temperature by interacting with lipids in the stratum corneum. The combined effect of the three can form a more efficient transdermal absorption system.

[0028] To maintain stable drug release, this invention achieves uniform distribution and stable release of the drug in the formulation by precisely controlling the proportions of each medicinal material. Components such as safflower and myrrh possess excellent solubility and stability, maintaining their activity in the formulation for an extended period and ensuring continuous drug release during transdermal administration. Simultaneously, components such as raw pinellia and rhubarb also play a role in stabilizing the formulation, preventing drug degradation or inactivation during storage and use.

[0029] Furthermore, this invention incorporates humectants such as glycerin and / or propylene glycol into the formulation. These humectants maintain the moisture content of the formulation, preventing the drug from losing its activity due to dryness during storage and use. Simultaneously, they form a protective film on the skin, slowing down drug evaporation and loss, ensuring stable drug release during transdermal administration.

[0030] Regarding the duration of action, this invention achieves prolonged drug action in the body through the synergistic effect between medicinal materials. Components such as cinnamon twig and angelica root have the effects of warming and unblocking the meridians and promoting blood circulation, which can promote the circulation and distribution of the drug in the body, allowing the drug to continuously act on the treatment site and exert a longer-lasting therapeutic effect. In addition, components such as salvia miltiorrhiza and frankincense can also enhance the anti-inflammatory and analgesic effects of the drug, further prolonging the duration of action.

[0031] Furthermore, to further prolong the duration of drug action, this invention incorporates preservatives such as methylparaben and / or ethylparaben into the formulation. These preservatives prevent microbial contamination and degradation of the formulation during storage and use, ensuring the drug maintains its efficacy during transdermal administration.

[0032] In practical applications, the transdermal drug delivery formulation of this invention has undergone rigorous clinical trials and validation, proving its safety and efficacy with no significant toxic side effects. Patients experience significant improvement in osteoarthritis symptoms after use, and it is unlikely to induce dependence or drug resistance. Detailed Implementation

[0033] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0034] The processes, conditions, reagents, and experimental methods used in implementing this invention, except as specifically mentioned below, are all common knowledge and general knowledge in the field, and this invention does not have any particular limitations. Experimental methods in the embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer.

[0035] Unless otherwise stated, all technical terms and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. However, in the event of any conflict, the specification containing the definitions shall prevail.

[0036] The present invention proposes a transdermal drug delivery formulation for treating osteoarthritis, wherein the raw materials of the transdermal drug delivery formulation, by weight, include: 10-15 parts of Aconitum carmichaelii, 12-16 parts of Smilax glabra, 25-30 parts of Salvia miltiorrhiza, 6-12 parts of Boswellia carterii, 1-3 parts of Carthamus tinctorius, 8-12 parts of Commiphora myrrha, 12-16 parts of Angelica sinensis, 18-22 parts of Caulis Cimicifugae, 6-10 parts of Paeonia lactiflora, 20-30 parts of Pinellia ternata, 14-18 parts of Cinnamomum cassia, and 6-8 parts of Rheum palmatum; and also includes a matrix and adjuvants for the transdermal drug delivery formulation.

[0037] The matrix comprises at least one of carbomer 934, carbomer 940, and carbomer 941; the adjuvant comprises one or more of a transdermal enhancer, a humectant, and a preservative; the weight ratio of the transdermal enhancer, humectant, and preservative is (1.8-2.2):(0.8-1.2):(0.4-0.6); the transdermal enhancer comprises at least one of azone, peppermint oil, and borneol.

[0038] When the transdermal enhancer includes azone, peppermint oil and borneol in combination, the weight ratio of azone, peppermint oil and borneol is (1-2):(1-2):(1-2);

[0039] The humectant includes glycerin and / or propylene glycol; the preservative includes methylparaben and / or ethylparaben.

[0040] The method for preparing the transdermal drug delivery formulation for treating osteoarthritis includes the following steps:

[0041] (1) Weigh the active pharmaceutical ingredient (API) of the transdermal drug delivery preparation according to the formula, add ethanol and reflux extract three times at 60-64℃, with the same amount of ethanol used each time and the reflux extraction time being 1-2 hours each time. The total amount of ethanol used is 14-16 times the total weight of the API of the transdermal drug delivery preparation. Combine the extracts and filter them. Remove the ethanol from the extracts under reduced pressure at 50-60℃ and dry them under vacuum to obtain an ointment. Dry the ointment under high vacuum to obtain a dry powder.

[0042] (2) Add water to the matrix to swell, and continuously and slowly add water during the grinding process to prepare a gel solution; then add the dry powder and additives to the gel solution and stir. After mixing evenly, let it stand for 1.5-2.5 hours, and then stir again until it becomes a paste-like gel.

[0043] The ratio of the total mass of the matrix to water is 1:(110-120); the weight ratio of the matrix, additives and dry powder is 100:(4-6):(10-12).

[0044] The present invention will be further described below with reference to specific embodiments:

[0045] Example 1

[0046] This embodiment describes a transdermal drug delivery formulation for treating osteoarthritis. By weight, the active pharmaceutical ingredients of the transdermal drug delivery formulation include: 12 parts Aconitum carmichaelii, 14 parts Smilax glabra, 27 parts Salvia miltiorrhiza, 9 parts Boswellia carterii, 2 parts Carthamus tinctorius, 10 parts Commiphora myrrha, 14 parts Angelica sinensis, 20 parts Tinospora sinensis, 8 parts Paeonia lactiflora, 25 parts Pinellia ternata, 16 parts Cinnamomum cassia, and 7 parts Rheum palmatum; it also includes the matrix and adjuvants of the transdermal drug delivery formulation.

[0047] The matrix is ​​carbomer 940; the adjuvants include a transdermal enhancer, a moisturizer, and a preservative in a weight ratio of 2:1:0.5; the transdermal enhancer includes azone, peppermint oil, and borneol in a weight ratio of 1:1:1; the moisturizer is glycerin; and the preservative is methylparaben.

[0048] The method for preparing the transdermal drug delivery formulation for treating osteoarthritis includes the following steps:

[0049] (1) Weigh the active pharmaceutical ingredient of the transdermal drug delivery preparation according to the formula, add ethanol and reflux extract three times at 62°C. The amount of ethanol used each time is equal, and the reflux extraction time is 1.5h each time. The total amount of ethanol used is 15 times the total weight of the active pharmaceutical ingredient of the transdermal drug delivery preparation. Combine the extracts and filter them. Recover the ethanol from the extracts under reduced pressure at 55°C and vacuum dry them to obtain an ointment. Dry the ointment under high vacuum to obtain a dry powder.

[0050] (2) Add water to the matrix to swell, and continuously and slowly add water during the grinding process to prepare a gel solution; then add the dry powder and additives to the gel solution and stir. After mixing evenly, let it stand for 2 hours, and then stir again until it becomes a paste-like gel.

[0051] The ratio of the total mass of the matrix to water is 1:115; the weight ratio of the matrix, additives and dry powder is 100:5:11.

[0052] Example 2

[0053] This embodiment describes a transdermal drug delivery formulation for treating osteoarthritis. By weight, the active pharmaceutical ingredients of the transdermal drug delivery formulation include: 10 parts Aconitum carmichaelii, 12 parts Smilax glabra, 25 parts Salvia miltiorrhiza, 6 parts Boswellia carterii, 1 part Carthamus tinctorius, 8 parts Commiphora myrrha, 12 parts Angelica sinensis, 18 parts Tinospora sinensis, 6 parts Paeonia lactiflora, 20 parts Pinellia ternata, 14 parts Cinnamomum cassia, and 6 parts Rheum palmatum; it also includes the matrix and adjuvants of the transdermal drug delivery formulation.

[0054] The matrix is ​​carbomer 934; the adjuvants include a transdermal enhancer, a humectant, and a preservative; the weight ratio of the transdermal enhancer, humectant, and preservative is 1.8:0.8:0.4; the transdermal enhancer includes azone, peppermint oil, and borneol in a weight ratio of 1:2:2; the humectant is propylene glycol; and the preservative is ethylparaben.

[0055] The method for preparing the transdermal drug delivery formulation for treating osteoarthritis includes the following steps:

[0056] (1) Weigh the active pharmaceutical ingredient of the transdermal drug delivery preparation according to the formula, add ethanol and reflux extract three times at 60°C. The amount of ethanol used each time is equal, and the reflux extraction time is 1 hour each time. The total amount of ethanol used is 14 times the total weight of the active pharmaceutical ingredient of the transdermal drug delivery preparation. Combine the extracts and filter them. Remove the ethanol from the extracts under reduced pressure at 50°C and dry them under vacuum to obtain an ointment. Dry the ointment under high vacuum to obtain a dry powder.

[0057] (2) Add water to the matrix to swell, and continuously and slowly add water during the grinding process to prepare a gel solution; then add the dry powder and additives to the gel solution and stir. After mixing evenly, let it stand for 1.5 hours, and then stir again until it becomes a paste-like gel.

[0058] The ratio of the total mass of the matrix to water is 1:110; the weight ratio of the matrix, additives and dry powder is 100:4:10.

[0059] Example 3

[0060] This embodiment describes a transdermal drug delivery formulation for treating osteoarthritis. By weight, the active pharmaceutical ingredients of the transdermal drug delivery formulation include: 15 parts Aconitum carmichaelii, 16 parts Smilax glabra, 30 parts Salvia miltiorrhiza, 12 parts Boswellia carterii, 3 parts Carthamus tinctorius, 12 parts Commiphora myrrha, 16 parts Angelica sinensis, 22 parts Tinospora sinensis, 10 parts Paeonia lactiflora, 30 parts Pinellia ternata, 18 parts Cinnamomum cassia, and 8 parts Rheum palmatum; it also includes the matrix and adjuvants of the transdermal drug delivery formulation.

[0061] The matrix is ​​carbomer 941; the adjuvants include a transdermal enhancer, a moisturizer, and a preservative in a weight ratio of 2.2:1.2:0.6; the transdermal enhancer includes azone, peppermint oil, and borneol in a weight ratio of 2:1:1; the moisturizer is glycerin; and the preservative is methylparaben.

[0062] The method for preparing the transdermal drug delivery formulation for treating osteoarthritis includes the following steps:

[0063] (1) Weigh the active pharmaceutical ingredient of the transdermal drug delivery preparation according to the formula, add ethanol and reflux extract three times at 64°C. The amount of ethanol used each time is equal, and the reflux extraction time is 2h each time. The total amount of ethanol used is 16 times the total weight of the active pharmaceutical ingredient of the transdermal drug delivery preparation. Combine the extracts and filter them. Recover the ethanol from the extracts under reduced pressure at 60°C and vacuum dry them to obtain an ointment. Dry the ointment under high vacuum to obtain a dry powder.

[0064] (2) Add water to the matrix to swell, and continuously and slowly add water during the grinding process to prepare a gel solution; then add the dry powder and additives to the gel solution and stir. After mixing evenly, let it stand for 2.5 hours, and then stir again until a paste-like gel is obtained.

[0065] The ratio of the total mass of the matrix to water is 1:120; the weight ratio of the matrix, additives and dry powder is 100:6:12.

[0066] Comparative Example 1

[0067] The transdermal drug delivery formulation used in this comparative example for treating osteoarthritis, by weight, comprises the following raw materials: 12 parts Aconitum carmichaelii, 14 parts Smilax glabra, 27 parts Salvia miltiorrhiza, 9 parts Boswellia carterii, 2 parts Carthamus tinctorius, 10 parts Commiphora myrrha, 14 parts Angelica sinensis, 20 parts Tinospora sinensis, 8 parts Paeonia lactiflora, 25 parts Pinellia ternata, 16 parts Cinnamomum cassia, and 7 parts Rheum palmatum; it also includes the matrix and excipients of the transdermal drug delivery formulation.

[0068] The matrix is ​​carbomer 940; the adjuvants include a transdermal enhancer, a moisturizer, and a preservative in a weight ratio of 2:1:0.5; the transdermal enhancer includes azone and peppermint oil in a weight ratio of 1:1; the moisturizer is glycerin; and the preservative is methylparaben.

[0069] The method for preparing the transdermal drug delivery formulation for treating osteoarthritis includes the following steps:

[0070] (1) Weigh the active pharmaceutical ingredient of the transdermal drug delivery preparation according to the formula, add ethanol and reflux extract three times at 62°C. The amount of ethanol used each time is equal, and the reflux extraction time is 1.5h each time. The total amount of ethanol used is 15 times the total weight of the active pharmaceutical ingredient of the transdermal drug delivery preparation. Combine the extracts and filter them. Recover the ethanol from the extracts under reduced pressure at 55°C and vacuum dry them to obtain an ointment. Dry the ointment under high vacuum to obtain a dry powder.

[0071] (2) Add water to the matrix to swell, and continuously and slowly add water during the grinding process to prepare a gel solution; then add the dry powder and additives to the gel solution and stir. After mixing evenly, let it stand for 2 hours, and then stir again until it becomes a paste-like gel.

[0072] The ratio of the total mass of the matrix to water is 1:115; the weight ratio of the matrix, additives and dry powder is 100:5:11.

[0073] Comparative Example 2

[0074] The transdermal drug delivery formulation used in this comparative example for treating osteoarthritis, by weight, comprises the following raw materials: 12 parts Aconitum carmichaelii, 14 parts Smilax glabra, 27 parts Salvia miltiorrhiza, 9 parts Boswellia carterii, 2 parts Carthamus tinctorius, 10 parts Commiphora myrrha, 14 parts Angelica sinensis, 20 parts Tinospora sinensis, 8 parts Paeonia lactiflora, 25 parts Pinellia ternata, 16 parts Cinnamomum cassia, and 7 parts Rheum palmatum; it also includes the matrix and excipients of the transdermal drug delivery formulation.

[0075] The matrix is ​​carbomer 940; the adjuvants include a transdermal enhancer, a moisturizer, and a preservative in a weight ratio of 2:1:0.5; the transdermal enhancer includes peppermint oil and borneol in a weight ratio of 1:1; the moisturizer is glycerin; and the preservative is methylparaben.

[0076] The method for preparing the transdermal drug delivery formulation for treating osteoarthritis includes the following steps:

[0077] (1) Weigh the active pharmaceutical ingredient of the transdermal drug delivery preparation according to the formula, add ethanol and reflux extract three times at 62°C. The amount of ethanol used each time is equal, and the reflux extraction time is 1.5h each time. The total amount of ethanol used is 15 times the total weight of the active pharmaceutical ingredient of the transdermal drug delivery preparation. Combine the extracts and filter them. Recover the ethanol from the extracts under reduced pressure at 55°C and vacuum dry them to obtain an ointment. Dry the ointment under high vacuum to obtain a dry powder.

[0078] (2) Add water to the matrix to swell, and continuously and slowly add water during the grinding process to prepare a gel solution; then add the dry powder and additives to the gel solution and stir. After mixing evenly, let it stand for 2 hours, and then stir again until it becomes a paste-like gel.

[0079] The ratio of the total mass of the matrix to water is 1:115; the weight ratio of the matrix, additives and dry powder is 100:5:11.

[0080] Comparative Example 3

[0081] This comparative example describes a transdermal drug delivery formulation for the treatment of osteoarthritis. By weight, the active pharmaceutical ingredients of the transdermal drug delivery formulation include: 12 parts Aconitum carmichaelii, 14 parts Smilax glabra, 27 parts Salvia miltiorrhiza, 9 parts Boswellia carterii, 14 parts Angelica sinensis, 20 parts Tinospora sinensis, 8 parts Paeonia lactiflora, 25 parts Pinellia ternata, and 16 parts Cinnamomum cassia; it also includes the matrix and excipients of the transdermal drug delivery formulation.

[0082] The matrix is ​​carbomer 940; the adjuvants include a transdermal enhancer, a moisturizer, and a preservative in a weight ratio of 2:1:0.5; the transdermal enhancer includes azone, peppermint oil, and borneol in a weight ratio of 1:1:1; the moisturizer is glycerin; and the preservative is methylparaben.

[0083] The method for preparing the transdermal drug delivery formulation for treating osteoarthritis includes the following steps:

[0084] (1) Weigh the active pharmaceutical ingredient of the transdermal drug delivery preparation according to the formula, add ethanol and reflux extract three times at 62°C. The amount of ethanol used each time is equal, and the reflux extraction time is 1.5h each time. The total amount of ethanol used is 15 times the total weight of the active pharmaceutical ingredient of the transdermal drug delivery preparation. Combine the extracts and filter them. Recover the ethanol from the extracts under reduced pressure at 55°C and vacuum dry them to obtain an ointment. Dry the ointment under high vacuum to obtain a dry powder.

[0085] (2) Add water to the matrix to swell, and continuously and slowly add water during the grinding process to prepare a gel solution; then add the dry powder and additives to the gel solution and stir. After mixing evenly, let it stand for 2 hours, and then stir again until it becomes a paste-like gel.

[0086] The ratio of the total mass of the matrix to water is 1:115; the weight ratio of the matrix, additives and dry powder is 100:5:11.

[0087] Comparative Example 4

[0088] This comparative example is a transdermal drug delivery formulation for the treatment of osteoarthritis. By weight, the active pharmaceutical ingredients of the transdermal drug delivery formulation include: 12 parts of Aconitum carmichaelii, 14 parts of Smilax glabra, 27 parts of Salvia miltiorrhiza, 2 parts of Carthamus tinctorius, 10 parts of Commiphora myrrha, 20 parts of Tinospora sinensis, 8 parts of Paeonia lactiflora, 25 parts of Pinellia ternata, and 7 parts of Rheum palmatum; it also includes the matrix and adjuvants of the transdermal drug delivery formulation.

[0089] The matrix is ​​carbomer 940; the adjuvants include a transdermal enhancer, a moisturizer, and a preservative in a weight ratio of 2:1:0.5; the transdermal enhancer includes azone, peppermint oil, and borneol in a weight ratio of 1:1:1; the moisturizer is glycerin; and the preservative is methylparaben.

[0090] The method for preparing the transdermal drug delivery formulation for treating osteoarthritis includes the following steps:

[0091] (1) Weigh the active pharmaceutical ingredient of the transdermal drug delivery preparation according to the formula, add ethanol and reflux extract three times at 62°C. The amount of ethanol used each time is equal, and the reflux extraction time is 1.5h each time. The total amount of ethanol used is 15 times the total weight of the active pharmaceutical ingredient of the transdermal drug delivery preparation. Combine the extracts and filter them. Recover the ethanol from the extracts under reduced pressure at 55°C and vacuum dry them to obtain an ointment. Dry the ointment under high vacuum to obtain a dry powder.

[0092] (2) Add water to the matrix to swell, and continuously and slowly add water during the grinding process to prepare a gel solution; then add the dry powder and additives to the gel solution and stir. After mixing evenly, let it stand for 2 hours, and then stir again until it becomes a paste-like gel.

[0093] The ratio of the total mass of the matrix to water is 1:115; the weight ratio of the matrix, additives and dry powder is 100:5:11.

[0094] I. Animal pharmacodynamic experiments:

[0095] Eighty male New Zealand White rabbits, standard grade, 10–12 months old, weighing 2.0–2.5 kg, were provided by the Experimental Animal Center of Northeast Agricultural University. After one week of acclimatization feeding, and without adverse reactions, they were randomly divided into a normal group, a model group, a positive control group, Example 1 group, and Comparative Examples 1–4 groups, with 10 rabbits in each group. Except for the normal group, the other rabbits were anesthetized with sodium pentobarbital (90 mg / kg, intravenous injection) on days 1, 3, and 5, and then injected into the bilateral hind knee joint cavity with a mixed solution of 2% (w / v) papain and 0.03 mol / L L-cysteine ​​in a 2:1 ratio, at a dose of 0.1 mL / kg. After two weeks of normal feeding following the injection of the modeling reagent, the appearance of knee joint swelling and functional impairment was considered a successful model.

[0096] After modeling, the knee joint area was shaved, with a shaved area of ​​approximately 2cm × 2cm. The medication was then applied to the shaved area. The model group received distilled water; the positive control group received Compound Nanxing Analgesic Ointment (Jiangsu Kangyuan Sunshine Pharmaceutical Co., Ltd., Approval Number: Z10970019); the experimental groups received 2g of the transdermal drug delivery formulations prepared in Examples 1, 1, 2, 3, and 4, respectively, and were housed individually after application. All animals received the medication twice daily, once in the morning and once in the evening, for 28 consecutive days.

[0097] After the last administration, all animals were euthanized by intravenous injection of air into the ear margins. Following euthanasia, the area around both hind knee joints was disinfected. A 1mL syringe (containing 1mL of sterile water) was inserted through both sides of the knee joint, passing through the suprapatellar ligament into the joint cavity. Aspiration was repeated until the joint effusion was collected. The effusion was centrifuged at 2000 rpm for 15 minutes, and the supernatant was stored at -20°C for later use. Pathological specimens were prepared from the supernatant, and changes in the levels of major inflammatory factors in the joint fluid, including IL-1β, TNF-α, MMP-1, and TIMP, were compared. The comparison is shown in Table 1 below.

[0098] All data were statistically analyzed using SPSS 25.0 software. Quantitative data were expressed as (x±s) and analyzed using t-tests; p<0.05 was considered statistically significant.

[0099] Table 1. Changes in the levels of major inflammatory factors in synovial fluid (x±s)

[0100] Group IL-1β (ng / L) TNF-α (ng / L) MMP-1 (ng / L) TIMP (ng / mL) normal group 45.12±1.22 224.21±2.56 538.19±4.41 23.46±2.24 Model group 68.42±3.18* 358.68±1.47* 1168.14±3.54* 32.21±4.16* Positive control 57.56±2.43* 281.65±2.11** 889.46±2.56* 25.86±3.63* Example 1 46.32±1.16** 228.45±1.25* 584.56±1.95* 23.86±1.05** Comparative Example 1 49.38±1.42* 265.17±2.68* 625.55±2.85** 24.33±2.45** Comparative Example 2 50.43±1.26* 286.42±1.12** 756.88±3.14* 24.97±2.11* Comparative Example 3 54.14±0.98* 302.27±2.35* 812.47±1.81** 25.66±1.28* Comparative Example 4 52.41±2.01* 291.15±3.26* 783.91±2.25* 25.06±2.57**

[0101] Note: Compared with the normal group, * indicates P < 0.05, and ** indicates P < 0.01.

[0102] The results in the table show that there were significant differences (P<0.05) between the control group, Example 1 group, and Comparative Examples 1-4 groups compared with the normal group. Compared with the model group, the anti-inflammatory effect of Example 1 group was significantly improved. This result proves that the drug of the present invention has a significant therapeutic effect on osteoarthritis, and this discovery is of great significance for drug development and clinical application.

[0103] II. Clinical efficacy trials:

[0104] 1. Patients with knee osteoarthritis, aged 45-70 years, were selected from the First Affiliated Hospital of Harbin Medical University. The selection was not limited to unilateral or bilateral knee involvement (in cases of bilateral involvement, the knee with more severe imaging and clinical symptoms was included). Informed consent was obtained from all patients. Patients were randomly divided into 6 groups of 30 each using a random number table. Basic data analysis showed no significant differences (P > 0.05), indicating comparability.

[0105] (1) Inclusion criteria: The diagnosis of knee osteoarthritis was based on the "Guidelines for the Diagnosis and Treatment of Osteoarthritis (2018 Edition)" formulated by the Joint Surgery Group of the Chinese Orthopaedics Branch. The TCM syndrome diagnosis criteria for knee osteoarthritis were also referenced in the "Guiding Principles for Clinical Research of New Traditional Chinese Medicine" (2002 Revised Edition) published by China Medical Science and Technology Press, with the syndrome being Liver and Kidney Deficiency with Stagnation of Meridians and Vessels. Inclusion criteria: Meeting the above TCM syndrome diagnosis criteria, with the syndrome being Liver and Kidney Deficiency with Stagnation of Meridians and Vessels;

[0106] (2) Exclusion criteria: Patients diagnosed with other TCM syndrome types; patients with other causes of knee osteoarthritis, such as rheumatoid arthritis, traumatic arthritis, etc.; patients who have received intra-articular treatment within the past 3 months, such as arthroscopic debridement, intra-articular drug injection, etc.; patients who have received non-steroidal anti-inflammatory drugs within the past 3 months; patients with serious diseases of other systems, such as kidney, cardiovascular and cerebrovascular systems, digestive system, etc.; patients with abnormal mental state who have failed to follow the treatment plan; patients who have recently participated in other clinical research.

[0107] 2. Administration method:

[0108] The first group of patients were treated with Compound Nanxing Analgesic Plaster (2 patches / bag, 2 bags / box, Jiangsu Kangyuan Sunshine Pharmaceutical Co., Ltd., Approval Number: National Medicine Approval Number Z10970019, for external use, 1 patch per application, once a day, each application lasts for 6 hours).

[0109] The second group of patients served as a blank control and received no treatment.

[0110] The third group of patients applied the transdermal drug delivery preparation prepared in Example 1 of this invention to their knee joints using the same method as the first group. One week was considered one course of treatment, and a total of four courses of treatment were applied before the treatment effect was statistically analyzed.

[0111] The fourth group of patients applied the transdermal drug delivery preparation prepared in Comparative Example 1 of this invention to their knee joints using the same method as the first group. One week was one course of treatment, and a total of four courses of treatment were applied before the treatment effect was statistically analyzed.

[0112] The fifth group of patients applied the transdermal drug delivery preparation prepared in Comparative Example 2 of this invention to their knee joints using the same method as the first group. One week was one course of treatment, and a total of four courses of treatment were applied before the treatment effect was statistically analyzed.

[0113] The sixth group of patients applied the transdermal drug delivery preparation prepared in Comparative Example 3 of this invention to their knee joints using the same method as the first group. One week was one course of treatment, and a total of four courses of treatment were applied before the treatment effect was statistically analyzed.

[0114] The seventh group of patients applied the transdermal drug delivery preparation prepared in Comparative Example 4 of this invention to their knee joints using the same method as the first group. One week was one course of treatment, and a total of four courses of treatment were applied before the treatment effect was statistically analyzed.

[0115] 3. Judgment indicators: Cured: TCM symptom score decreased by >90%, and knee joint function and motor function returned to normal; Significantly effective: TCM symptom score decreased by >70%, and knee joint function and motor function showed significant improvement; Effective: TCM symptom score decreased by 30% to 70%, and knee joint function and motor function showed improvement; Ineffective: TCM symptom score decreased by <30%, and knee joint function and motor function showed no improvement; After four weeks of treatment according to the above grouping and medication methods, the efficacy of each group was statistically analyzed.

[0116] 4. Statistical analysis was performed using SPSS 25.0 statistical software. Count data were expressed as rates, and comparisons between groups were performed using the χ² method. 2 The test was performed, with P < 0.05 considered statistically significant.

[0117] The efficacy of the 6 groups is compared in Table 2 below:

[0118] Table 2

[0119]

[0120] Based on the comparison of the aforementioned tables, the transdermal drug delivery formulation of this invention has significant therapeutic effects, excellent clinical efficacy, and practical application value.

[0121] This specific embodiment is merely an explanation of the present invention and is not intended to limit the invention. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they are within the scope of the claims of the present invention.

Claims

1. A transdermal drug delivery formulation for treating osteoarthritis, characterized in that, The active pharmaceutical ingredients of the transdermal drug delivery formulation, by weight, include: 12 parts Aconitum carmichaelii, 14 parts Smilax glabra, 27 parts Salvia miltiorrhiza, 9 parts Boswellia carterii, 2 parts Carthamus tinctorius, 10 parts Commiphora myrrha, 14 parts Angelica sinensis, 20 parts Tinospora sinensis, 8 parts Paeonia lactiflora, 25 parts Pinellia ternata, 16 parts Cinnamomum cassia, and 7 parts Rheum palmatum; it also includes the matrix and adjuvants of the transdermal drug delivery formulation. The matrix is ​​carbomer 940; the adjuvants include a transdermal enhancer, a moisturizer, and a preservative in a weight ratio of 2:1:0.5; the transdermal enhancer includes azone, peppermint oil, and borneol in a weight ratio of 1:1:1; the moisturizer is glycerin; and the preservative is methylparaben. The method for preparing the transdermal drug delivery formulation for treating osteoarthritis includes the following steps: (1) Weigh the active pharmaceutical ingredient of the transdermal drug delivery preparation according to the formula, add ethanol and reflux extract three times at 62°C. The amount of ethanol used each time is equal, and the reflux extraction time is 1.5h each time. The total amount of ethanol used is 15 times the total weight of the active pharmaceutical ingredient of the transdermal drug delivery preparation. Combine the extracts and filter them. Recover the ethanol from the extracts under reduced pressure at 55°C and vacuum dry them to obtain an ointment. Dry the ointment under high vacuum to obtain a dry powder. (2) The matrix is ​​swollen with water and water is added slowly during the grinding process to prepare a gel solution; then the dry powder and additives are added to the gel solution and stirred. After mixing evenly, it is left to stand for 2 hours, and then stirred again until a paste-like gel is obtained. The ratio of the total mass of the matrix to water is 1:115; the weight ratio of the matrix, additives and dry powder is 100:5:11.

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