Transdermal promotion type traditional Chinese medicine sustained-release plaster and preparation method thereof

Abstract

The invention provides a transdermal promotion type traditional Chinese medicine sustained-release plaster and a preparation method thereof, the transdermal promotion type traditional Chinese medicine sustained-release plaster comprises a backing layer and an ointment-containing body coated on the surface of the backing layer, and the surface of the ointment-containing body is covered with a release layer; the ointment-containing body comprises a traditional Chinese medicine extract, a hydrogel matrix, a slow release agent and a composite transdermal enhancer; the hydrogel matrix comprises isopropyl acrylamide, acrylamide, a metal organic framework material, cellulose nanofibers, an initiator, a cross-linking agent, a humectant, a binder, a skin feeling regulator and deionized water; the composite transdermal enhancer comprises menthol, azone, propylene glycol and oleic acid. According to the invention, the drug sustained-release effect is realized by utilizing the temperature-sensitive characteristic of the hydrogel matrix and combining with the sustained-release agent, and the percutaneous penetration effect on the complex-component traditional Chinese medicine extract is improved by compounding a plurality of transdermal promoters; the patch has the advantages of moisture retention, breathability, repeated uncovering and pasting, low skin irritation and allergy risk, long drug effect exertion time, few drug use times, good treatment effect and the like.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine plaster technology, and relates to a transdermal-promoting sustained-release traditional Chinese medicine plaster and its preparation method. Background Technology

[0002] Arthritis is a comprehensive joint disease involving structural changes in the hyaline articular cartilage, subchondral bone, ligaments, joint capsule, synovium, and surrounding muscles. Due to a global aging population, rising obesity rates, and increasing joint injuries, arthritis has become a common and serious disease, impacting individuals, healthcare systems, and socioeconomic costs, and several other syndromes are on the rise.

[0003] Knee synovitis refers to a non-infectious inflammatory reaction caused by synovial membrane damage or rupture due to acute trauma or chronic strain, leading to functional abnormalities and the inability of synovial fluid to be properly produced and absorbed, resulting in hemorrhage or effusion within the knee joint cavity. Knee synovial lesions are an important factor in the development of knee osteoarthritis and often serve as a signal for its prevention and treatment. Studies have shown that inflammation in the synovium or effusion is the main cause of pain in knee osteoarthritis.

[0004] Currently, common treatments for arthritis include oral acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), or intra-articular injections. However, acetaminophen has a very small effect compared to a placebo, and coupled with safety concerns, it is practically useless as a single-drug treatment for arthritis. Long-term use of NSAIDs can lead to adverse reactions such as peptic ulcers and bleeding, while intra-articular injections can easily cause infections.

[0005] Traditional Chinese medicine plasters can effectively relieve the pain caused by arthritis, and they do not produce the adverse reactions associated with other treatments such as oral acetaminophen, nonsteroidal anti-inflammatory drugs, or intra-articular injections.

[0006] Traditional Chinese medicine plasters have a long history of application in my country. They are made by boiling medicinal herbs in vegetable or animal oil to create a gel-like substance, which is then applied to one side of cloth, paper, or leather and left on the affected area for an extended period. The medicinal properties of the plaster are directly applied to acupoints on the body surface, penetrating the skin and subcutaneous tissues. This creates a relatively high local drug concentration and, through the flow of Qi and blood through the meridians, reaches the affected area where the internal organs and Qi are imbalanced, maximizing the systemic pharmacological effect. Traditional injections and oral medications damage nerves, blood vessels, and muscles, making them difficult for patients to tolerate. Furthermore, these methods tend to disperse the drug throughout the body via the bloodstream, resulting in less drug actually reaching the affected area, requiring large doses but with poor efficacy. Traditional Chinese medicine plasters avoid the toxic side effects of oral medications, while acting directly on the affected area, resulting in high efficacy, noticeable effects, and low risk of drug resistance. They are particularly effective for rheumatic pain and sprains.

[0007] However, existing Chinese herbal plasters still have problems such as low transdermal absorption rate, easy volatility of active ingredients leading to reduced efficacy, slow onset of action, and long treatment cycle. Therefore, there is an urgent need to design a Chinese herbal plaster that can promote transdermal absorption and slow release of drug efficacy. Summary of the Invention

[0008] To address the shortcomings of existing technologies, the present invention aims to provide a transdermal-enhancing sustained-release traditional Chinese medicine patch and its preparation method. The sustained-release traditional Chinese medicine patch provided by the present invention is a gel-type patch. It utilizes the thermosensitive properties of the hydrogel matrix combined with a sustained-release agent to achieve a sustained-release effect. By compounding various transdermal enhancers with different properties, the transdermal penetration effect of complex component traditional Chinese medicine extracts is improved. It has advantages such as moisturizing, breathability, high compliance, good adhesion, reusability, low risk of skin irritation and allergies, long duration of efficacy, fewer applications, and good therapeutic effect.

[0009] To achieve this objective, the present invention adopts the following technical solution:

[0010] In a first aspect, the present invention provides a transdermal promoting sustained-release traditional Chinese medicine patch, the transdermal promoting sustained-release traditional Chinese medicine patch comprising a backing layer and a medicated paste coated on the surface of the backing layer, the surface of the medicated paste being covered with a release layer;

[0011] The medicated ointment includes traditional Chinese medicine extracts, a hydrogel matrix, a sustained-release agent, and a complex transdermal penetration enhancer.

[0012] The hydrogel matrix includes isopropylacrylamide, acrylamide, metal-organic framework materials, cellulose nanofibers, initiators, crosslinking agents, humectants, binders, skin feel modifiers, and deionized water.

[0013] The composite transdermal penetration enhancer includes menthol, azone, propylene glycol, and oleic acid.

[0014] The herbal sustained-release patch provided by this invention is a gel-type patch. It is made by mixing herbal extracts, sustained-release agents, and composite transdermal penetration enhancers with a hydrogel matrix and then coating the mixture onto the surface of a backing layer. The sustained-release effect of the drug is achieved by utilizing the thermosensitive properties of the hydrogel matrix in combination with the sustained-release agent. By compounding various transdermal penetration enhancers with different properties, the transdermal penetration effect of complex herbal extracts is improved. Compared with ordinary pharmaceutical preparations, the herbal sustained-release patch provided by this invention has advantages such as moisturizing, breathability, high compliance, good adhesion, reusability, low risk of skin irritation and allergies, long duration of drug efficacy, fewer applications, and better therapeutic effect. It can avoid the first-pass effect of the liver and gastrointestinal inactivation. The temperature sensitivity of the thermosensitive hydrogel matrix enables the sustained-release effect of the drug, thereby controlling the drug to enter the human circulation at a constant rate and for a long time, fully exerting the drug efficacy, and reducing adverse drug reactions.

[0015] The water solubility of most polymers increases with increasing temperature. However, the polymer hydrogel matrix provided by this invention has temperature-sensitive properties, and its water solubility decreases with increasing temperature. The hydrogel matrix prepared from this type of polymer undergoes volume shrinkage and dehydration when the temperature rises, allowing the active ingredients of the embedded traditional Chinese medicine extract to flow out from the hydrogel matrix through dynamic water exchange and penetrate transdermally into the human bloodstream to exert their medicinal effects. Conversely, when the temperature decreases, the hydrogel matrix expands and absorbs water. Dynamic water molecules carrying the active ingredients of the traditional Chinese medicine extract are reabsorbed into the hydrogel matrix, achieving the recovery of the active ingredients and preventing the volatilization of the active ingredients in the sustained-release patch when not in use. Furthermore, because the temperature-sensitive properties of the hydrogel matrix provided by this invention are reversible, the traditional Chinese medicine sustained-release patch can be reused repeatedly until the active ingredients of the traditional Chinese medicine extract are completely absorbed by the human body.

[0016] The polymer hydrogel matrix provided by this invention uses a polymer containing hydrophilic molecular chains (acrylamide) and protophilic molecular chains (isopropylacrylamide). In a low-temperature environment, the hydrogen bonding between the hydrophilic molecular chains and water molecules in the polymer molecular chains is dominant, which makes the polymer molecular chains extend and improves the water solubility of the hydrogel matrix. The dynamic water molecules in the hydrogel matrix can carry the traditional Chinese medicine extract and disperse it uniformly in the network structure of the polymer to form a gel state. When the herbal sustained-release patch is applied to the skin, the temperature of the hydrogel matrix increases with the increase of the body surface temperature. This leads to enhanced protonic interactions of the protonic molecular chains in the polymer chains and weakened hydrogen bonding. As a result, the network structure of the polymer chain-associated hydrogel shrinks, reducing its water solubility. When the temperature rises to the critical solution temperature, the hydrogel matrix begins to shrink and dehydrate, causing dynamic water molecules within it to carry the herbal extracts out and release them onto the skin surface. The active ingredients in the herbal extracts are then absorbed transdermally into the bloodstream under the action of a composite transdermal penetration enhancer, thus exerting their effects. As the body surface temperature continues to rise, the volume shrinkage rate of the hydrogel matrix gradually increases, and the drug release effect gradually intensifies.

[0017] This invention incorporates metal-organic framework (MOF) materials during the preparation of the hydrogel matrix. MOF materials possess a porous structure with a large specific surface area and high porosity, exhibiting excellent drug loading capacity and serving as a suitable carrier for traditional Chinese medicine extracts. Furthermore, MOF materials are composed of metal ions and organic ligands, with most metal ions (such as Ag) being... + Zn 2+ and Cu 2+ MOF materials possess excellent antibacterial activity, and some organic ligands also exhibit good antibacterial activity and biocompatibility. However, MOF materials are prone to aggregation, and their degradation can cause certain toxic effects on the human body. Therefore, this invention incorporates cellulose nanofibers into the hydrogel matrix. On the one hand, this reduces the likelihood of MOF material aggregation, resulting in higher porosity and specific surface area, thereby improving drug loading capacity while reducing the potential toxic effects of MOF material degradation on the human body. On the other hand, MOF materials can form strong hydrogen bonds and physical entanglements with cellulose nanofibers, allowing the prepared hydrogel matrix to withstand greater tensile stress.

[0018] Compared to single-component transdermal penetration enhancers, the use of compound transdermal penetration enhancers can further improve the transdermal penetration effect of drugs. Furthermore, the traditional Chinese medicine extracts used in this invention are refined from various herbs, and compared to single drugs, their component characteristics are more complex, containing both water-soluble and lipid-soluble components; ionic and molecular components; and cationic and anionic components. Single-component transdermal penetration enhancers often only promote the transdermal penetration of one type of active component and cannot cover different types of active components. Therefore, using single-component transdermal penetration enhancers cannot achieve the desired penetration-enhancing effect. To address this, this invention uses a compound transdermal penetration enhancer formed by combining menthol, azone, propylene glycol, and oleic acid, which can significantly improve the transdermal absorption effect of active ingredients in traditional Chinese medicine extracts.

[0019] Ammone can alter the density of the lipid bilayer, increasing lipid fluidity and thus disrupting the lipid film formed on the skin surface without causing toxic side effects to skin cells. Simultaneously, it expands the intercellular pores in the stratum corneum, allowing the active ingredients of traditional Chinese medicine extracts to be stored within the stratum corneum, thereby significantly increasing the permeability of water-soluble components in the extracts. However, its effect on promoting the penetration of lipid-soluble components is relatively weak. Therefore, this invention adds propylene glycol to ammone, utilizing propylene glycol to dissolve lipid-soluble drugs. The lipid-soluble components dissolved in propylene glycol can then easily penetrate the skin through ammone.

[0020] Menthol and oleic acid have similar permeation-enhancing effects to azone, altering the arrangement of lipid molecules between stratum corneum cells, increasing lipid fluidity, and thus enhancing skin permeability. Furthermore, menthol and oleic acid possess other advantages: menthol stimulates blood circulation in subcutaneous capillaries and can be absorbed transdermally; its synergistic effect with azone can promote the transdermal absorption of traditional Chinese medicine extracts. Oleic acid, on the other hand, can promote the transdermal penetration of cationic, anionic, and molecularly-based drugs, thus producing a synergistic effect with azone.

[0021] As a preferred embodiment of the present invention, the ointment comprises the following components in parts by weight:

[0022]

[0023]

[0024] The weight parts of the traditional Chinese medicine composition can be 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 parts; the weight parts of the hydrogel matrix can be 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 parts; the weight parts of the sustained-release agent can be 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 parts; and the weight parts of the composite transdermal penetration enhancer can be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 parts, but are not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0025] As a preferred embodiment of the present invention, the herbal extract is obtained by extracting from a herbal composition composed of several kinds of Chinese medicinal materials, wherein the herbal composition includes the following types of Chinese medicinal materials in the indicated mass fractions:

[0026] Cuscuta chinensis 5–15 wt%, Eupatorium fortunei 2–10 wt%, Smilax glabra 5–10 wt%, Plantago asiatica 10–12 wt%, Clematis chinensis 5–9 wt%, Angelica sinensis 11–14 wt%, Achyranthes bidentata 5–10 wt%, Saposhnikovia divaricata 10–15 wt%, Angelica pubescens 8–12 wt%, Carthamus tinctorius 5–15 wt%, Spatholobus suberectus 5–15 wt%, and Paeonia lactiflora 5–10 wt%.

[0027] The mass fraction of Cuscuta chinensis can be 5wt%, 6wt%, 7wt%, 8wt%, 9wt%, 10wt%, 11wt%, 12wt%, 13wt%, 14wt%, or 15wt%; the mass fraction of Eupatorium fortunei can be 2wt%, 3wt%, 4wt%, 5wt%, 6wt%, 7wt%, 8wt%, 9wt%, or 10wt%; the mass fraction of Smilax glabra can be 5.0wt%, 5.5wt%, 6.0wt%, 6.5wt%, 7.0wt%, 7.5wt%, 8.0wt%, 8.5wt%, 9.0wt%, 9.5wt%, or 10.0wt%; and the mass fraction of Plantago asiatica can be 10wt%, 10.2wt%, or 10wt%. The mass fractions of *Clematis chinensis* can be 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 7.5 wt%, 8.0 wt%, 8.5 wt%, or 9.0 wt%; the mass fractions of *Angelica sinensis* can be 11.0 wt%, 11.5 wt%, 12.0 wt%, 12.5 wt%, 13.0 wt%, 13.5 wt%, or 14.0 wt%; the mass fractions of *Symplocos rubra* can be 5.0 wt%, 5.5 wt%, 6.0 wt%, t%, 10.4 wt%, 10.6 wt%, 10.8 wt%, 11.2 wt%, 11.4 wt%, 11.6 wt%, 11.8 wt%, or 12 wt%; the mass fractions of *Clematis chinensis* can be 5.0 wt%, 5.5 wt%, 6.0 wt%; the mass fractions of *Angelica sinensis* can be 11.0 wt%, 11.5 wt%, 12.0 wt%, 12.5 wt%, 13.0 wt%, 13.5 wt%, or 14.0 wt%; the mass fractions of *Symplocos rubra* can be 5.0 wt%, 5.5 wt%, 6.0 wt%. The mass fractions of the following ingredients can be 6.5 wt%, 7.0 wt%, 7.5 wt%, 8.0 wt%, 8.5 wt%, 9.0 wt%, 9.5 wt%, or 10.0 wt%; the mass fractions of Saposhnikovia divaricata can be 10 wt%, 10.5 wt%, 11 wt%, 11.5 wt%, 12 wt%, 12.5 wt%, 13 wt%, 13.5 wt%, 14 wt%, 14.5 wt%, or 15 wt%; the mass fractions of Angelica pubescens can be 8.0 wt%, 8.5 wt%, 9.0 wt%, 9.5 wt%, 10.0 wt%, 10.5 wt%, 11.0 wt%, 11.5 wt%, or 12.0 wt%; the mass fractions of Carthamus tinctorius can be 5 wt%, 6 wt%, 6 wt%, 6 wt%, 7.0 wt%, 7.5 wt%, 8.0 wt%, 8.5 wt%, 9.0 wt%, 10.0 wt%, 10.5 wt%, 11.0 wt%, 11.5 wt%, or 12.0 wt%; the mass fractions of Carthamus tinctorius can be 5 wt%, 6 wt%, 6 wt%, 7.0 wt%, 7.5 wt%, 8.0 wt%, 8.5 wt%, 9.0 wt%, 9.5 wt%, 10.0 wt%, 10.5 wt%, 11.0 wt%, 11.5 wt%, or 12.0 wt%; the mass fractions of Carthamus tinctorius can be 5 wt%, 6 wt%, 6 wt%, 7.0 wt%, 7.5 7wt%, 8wt%, 9wt%, 10wt%, 11wt%, 12wt%, 13wt%, 14wt%, or 15wt%; the mass fraction of *Spatholobus suberectus* can be 5wt%, 6wt%, 7wt%, 8wt%, 9wt%, 10wt%, 11wt%, 12wt%, 13wt%, 14wt%, or 15wt%; the mass fraction of *Paeonia lactiflora* can be 5.0wt%, 5.5wt%, 6.0wt%, 6.5wt%, 7.0wt%, 7.5wt%, 8.0wt%, 8.5wt%, 9.0wt%, 9.5wt%, or 10.0wt%, but is not limited to the listed values; other unlisted values ​​within this range also apply.

[0028] The herbal sustained-release plaster provided by this invention is a compound of various Chinese herbal medicines, exhibiting good stability and resistance to deterioration. It meets pharmaceutical requirements, is safe, effective, and non-irritating, and can be used for pain caused by non-articular inflammations such as rheumatoid arthritis, adhesive spondylitis, non-inflammatory joint pain, arthritis, and non-articular rheumatism, as well as various types of neuralgia, cancer pain, post-traumatic pain, and fever caused by various inflammations. The herbal sustained-release plaster has a high drug loading capacity, high water content, strong moisturizing properties, high transdermal rate, and good long-lasting sustained-release effect, which can greatly reduce toxic side effects and achieve a systemic health-preserving therapeutic effect by unblocking meridians and internal organs.

[0029] As a preferred embodiment of the present invention, the sustained-release agent includes any one or a combination of at least two of ethyl cellulose, α-cyclodextrin, or hydroxypropyl-β-cyclodextrin.

[0030] Based on a mass fraction of 100 wt% for the composite transdermal penetration enhancer, the composite transdermal penetration enhancer comprises the following components by mass fraction:

[0031]

[0032]

[0033] The menthol content can be 20wt%, 21wt%, 22wt%, 23wt%, 24wt%, 25wt%, 26wt%, 27wt%, 28wt%, 29wt%, or 30wt%; the azone content can be 40wt%, 41wt%, 42wt%, 43wt%, 44wt%, 45wt%, 46wt%, 47wt%, 48wt%, 49wt%, or 50wt%; and the propylene glycol content can be 15wt%, 15.5wt%, or 15wt%. 16wt%, 16.5wt%, 17wt%, 17.5wt%, 18wt%, 18.5wt%, 19wt%, 19.5wt%, or 20wt%; the mass fraction of oleic acid may be 8.0wt%, 8.2wt%, 8.4wt%, 8.6wt%, 8.8wt%, 9.0wt%, 9.2wt%, 9.4wt%, 9.6wt%, 9.8wt%, or 10.0wt%, but is not limited to the listed values; other unlisted values ​​within this range also apply.

[0034] This invention specifically limits the mass fraction of azone to 40-50 wt%. When the mass fraction of azone exceeds 50 wt%, it affects the formability of the hydrogel matrix, making it impossible to form the hydrogel matrix after incorporation. Furthermore, this invention also specifically limits the mass fraction of propylene glycol to 15-20 wt%. When the mass fraction of propylene glycol exceeds 20 wt%, it leads to an increase in the viscosity of the composite transdermal penetration enhancer, which in turn hinders drug diffusion.

[0035] As a preferred embodiment of the present invention, based on a mass fraction of 100 wt% for the hydrogel matrix, the hydrogel matrix comprises the following components by mass fraction:

[0036]

[0037]

[0038] The mass fraction of isopropylacrylamide can be 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, or 20 wt%; the mass fraction of acrylamide can be 0.5 wt%, 0.55 wt%, 0.6 wt%, 0.65 wt%, 0.7 wt%, 0.75 wt%, or 0.8 wt%; and the mass fraction of the metal-organic framework material can be 8.0 wt%, 8.2 wt%, 8.4 wt%, 8.6 wt%, 8.8 wt%. The mass fraction of cellulose nanofibers can be 3.0 wt%, 3.2 wt%, 3.4 wt%, 3.6 wt%, 3.8 wt%, 4.0 wt%, 4.2 wt%, 4.4 wt%, 4.6 wt%, 4.8 wt%, or 5.0 wt%; the mass fraction of initiator can be 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, or 3.5 wt%. The mass fraction of the crosslinking agent can be 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, or 5.0 wt%; the mass fraction of the humectant can be 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, or 10 wt%; the mass fraction of the binder can be 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, or 9 wt%. Or 10 wt%; the mass fraction of the skin feel modifier may be 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, or 5.0 wt%; the mass fraction of deionized water may be 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, or 50 wt%, but is not limited to the listed values, and other unlisted values ​​within this range also apply.

[0039] It should be noted that the higher the content of protonic components in the polymer chain segments, the lower the critical solution temperature of the hydrogel matrix; conversely, the higher the content of hydrophilic components, the higher the critical solution temperature of the hydrogel matrix. Since the traditional Chinese medicine sustained-release patch provided by this invention is applied to the surface of human skin, the critical solution temperature of the hydrogel matrix should be close to or slightly higher than the surface temperature of human skin. This allows for the control of drug release using body surface temperature. When the hydrogel matrix reaches the body surface temperature, its volume shrinks, releasing the drug; when the hydrogel matrix is ​​below the body surface temperature, its volume expands, stopping drug release.

[0040] In order to obtain a hydrogel matrix with a critical solution temperature that is the same as or similar to the human body surface temperature, the present invention specifically limits the mass fraction of isopropylacrylamide and acrylamide. The critical solution temperature of the hydrogel matrix formed within this temperature range is in the range of 36 to 40°C, which is similar to the human body surface temperature. The water solubility of the hydrogel matrix can be controlled by human skin temperature, thereby controlling the release of active pharmaceutical ingredients and achieving a sustained-release effect where the drug is released when the patch is applied to the human skin and stops being released when the patch is removed from the human skin.

[0041] As a preferred embodiment of the present invention, the initiator includes any one or a combination of at least two of ammonium persulfate, potassium persulfate, or sodium persulfate.

[0042] The crosslinking agent includes any one or a combination of at least two of N,N'-methylenebisacrylamide, N,N'-methylenebisacrylamide, or N,N'-methylenebisacrylamide.

[0043] The moisturizer includes any one or a combination of at least two of glycerin, sorbitol, butylene glycol, or polyethylene glycol.

[0044] The adhesive comprises any one or a combination of at least two of polyvinyl alcohol, carboxymethyl cellulose, sodium carboxymethyl cellulose, or polyvinylpyrrolidone.

[0045] The skin feel modifier includes any one or a combination of at least two of hyaluronic acid, sodium hyaluronate, dimethyl silicone oil, aryl silicone oil, or amino silicone oil.

[0046] Secondly, the present invention provides a method for preparing the transdermal-enhancing sustained-release traditional Chinese medicine plaster described in the first aspect, the preparation method comprising:

[0047] (I) Freeze-dry and pulverize various Chinese medicinal materials, mix the pulverized Chinese medicinal materials in proportion to obtain a Chinese medicine composition; extract the Chinese medicine composition by supercritical carbon dioxide extraction to obtain a Chinese medicine extract, extract the active ingredients of the Chinese medicine extract with ethanol, and then concentrate the supernatant by centrifugation to obtain a Chinese medicine extract.

[0048] (II) Isopropylacrylamide and metal-organic framework materials are dispersed in deionized water to form a dispersion. Cellulose nanofibers are added to the dispersion and soaked for a period of time to allow the cellulose nanofibers to fully swell and obtain a suspension. Acrylamide, initiator and crosslinking agent are added to the suspension, stirred evenly and heated to initiate monomer polymerization. After the reaction is completed, humectant, binder and skin feel modifier are added to the reactants and mixed evenly to obtain a hydrogel matrix.

[0049] (III) Add the sustained-release agent, the composite transdermal activator and the Chinese herbal extract obtained in step (I) to the hydrogel matrix obtained in step (II), mix evenly and then degas by ultrasonication to obtain a medicated ointment. Coat the medicated ointment on the surface of the backing layer and cover it with a release layer to obtain the transdermal activating Chinese herbal sustained-release patch.

[0050] As a preferred technical solution of the present invention, in step (I), the freeze-drying temperature is -60 to -50°C, for example, it can be -60°C, -59°C, -58°C, -57°C, -56°C, -55°C, -54°C, -53°C, -52°C, -51°C or -50°C, but it is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0051] The pressure for supercritical carbon dioxide extraction is 30–40 MPa, for example, it can be 30 MPa, 31 MPa, 32 MPa, 33 MPa, 34 MPa, 35 MPa, 36 MPa, 37 MPa, 38 MPa, 39 MPa or 40 MPa, but is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0052] The temperature for supercritical carbon dioxide extraction is 40–50°C, for example, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, or 50°C, but is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0053] The supercritical carbon dioxide extraction time is 1 to 3 hours, for example, it can be 1.0 hours, 1.2 hours, 1.4 hours, 1.6 hours, 1.8 hours, 2.0 hours, 2.2 hours, 2.4 hours, 2.6 hours, 2.8 hours or 3.0 hours, but it is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0054] The CO2 flow rate of the supercritical carbon dioxide extraction is 20-30 kg / h, for example, it can be 20 kg / h, 21 kg / h, 22 kg / h, 23 kg / h, 24 kg / h, 25 kg / h, 26 kg / h, 27 kg / h, 28 kg / h, 29 kg / h or 30 kg / h, but it is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0055] The centrifugal separation speed is 5000-6000 rpm, for example, it can be 5000 rpm, 5100 rpm, 5200 rpm, 5300 rpm, 5400 rpm, 5500 rpm, 5600 rpm, 5700 rpm, 5800 rpm, 5900 rpm or 6000 rpm, but is not limited to the listed values, other unlisted values ​​within this range are also applicable.

[0056] The centrifugation time is 5 to 10 minutes, for example, it can be 5.0 minutes, 5.5 minutes, 6.0 minutes, 6.5 minutes, 7.0 minutes, 7.5 minutes, 8.0 minutes, 8.5 minutes, 9.0 minutes, 9.5 minutes or 10.0 minutes, but it is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0057] The vacuum degree of the vacuum concentration is 0.09 to 0.1 MPa, for example, it can be 0.09 MPa, 0.091 MPa, 0.092 MPa, 0.093 MPa, 0.094 MPa, 0.095 MPa, 0.096 MPa, 0.097 MPa, 0.098 MPa, 0.099 MPa or 0.1 MPa, but is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0058] As a preferred technical solution of the present invention, in step (II), the soaking temperature of the cellulose nanofibers is 80-90℃, for example, it can be 80℃, 81℃, 82℃, 83℃, 84℃, 85℃, 86℃, 87℃, 88℃, 89℃ or 90℃, but it is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0059] The soaking time for the cellulose nanofibers is 1 to 2 hours, for example, 1.0 hours, 1.2 hours, 1.3 hours, 1.4 hours, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours or 2.0 hours, but is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0060] The reaction temperature for the monomer polymerization reaction is 60–70°C, for example, it can be 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C or 70°C, but it is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0061] The reaction time for the monomer polymerization reaction is 3 to 4 hours, for example, 3.0 hours, 3.1 hours, 3.2 hours, 3.3 hours, 3.4 hours, 3.5 hours, 3.6 hours, 3.7 hours, 3.8 hours, 3.9 hours, or 4.0 hours, but is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0062] As a preferred technical solution of the present invention, in step (III), the mixing temperature is 50-60°C, for example, it can be 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C or 60°C, but it is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0063] The mixing time is 1 to 2 hours, for example, it can be 1.0h, 1.1h, 1.2h, 1.3h, 1.4h, 1.5h, 1.6h, 1.7h, 1.8h, 1.9h or 2.0h, but it is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0064] The coating thickness containing the ointment is 0.5 to 0.6 mm, for example, it can be 0.50 mm, 0.51 mm, 0.52 mm, 0.53 mm, 0.54 mm, 0.55 mm, 0.56 mm, 0.57 mm, 0.58 mm, 0.59 mm or 0.6 mm, but is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0065] This invention provides a method for preparing a transdermal-enhancing sustained-release traditional Chinese medicine plaster, the preparation method specifically including the following steps:

[0066] (1) Weigh out the following types of Chinese medicinal materials in the following quantities, based on a mass fraction of 100 wt% for the Chinese medicinal composition:

[0067] Cuscuta chinensis 5-15 wt%, Eupatorium fortunei 2-10 wt%, Smilax glabra 5-10 wt%, Plantago asiatica 10-12 wt%, Clematis chinensis 5-9 wt%, Angelica sinensis 11-14 wt%, Achyranthes bidentata 5-10 wt%, Saposhnikovia divaricata 10-15 wt%, Angelica pubescens 8-12 wt%, Carthamus tinctorius 5-15 wt%, Spatholobus suberectus 5-15 wt%, and Paeonia lactiflora 5-10 wt%.

[0068] (2) The above-mentioned Chinese medicinal materials were freeze-dried and pulverized at -60 to -50℃. The pulverized Chinese medicinal materials were mixed in proportion to obtain a Chinese medicine composition. The Chinese medicine composition was subjected to supercritical carbon dioxide extraction for 1 to 3 hours under a pressure of 30 to 40 MPa and a temperature of 40 to 50℃ to obtain a Chinese medicine extract. The CO2 flow rate used for supercritical carbon dioxide extraction was 20 to 30 kg / h. The active ingredients of the Chinese medicine extract were extracted with ethanol. Then, the extract was centrifuged at 5000 to 6000 rpm for 5 to 10 minutes. After centrifugation, the supernatant was concentrated under vacuum at 0.09 to 0.1 MPa to obtain a Chinese medicine extract.

[0069] (3) Based on the mass fraction of the final prepared hydrogel matrix as 100wt%, 10-20wt% of isopropylacrylamide and 8-10wt% of metal-organic framework material are dispersed in 40-50wt% of deionized water to form a dispersion. 3-5wt% of cellulose nanofibers are added to the dispersion and soaked at 80-90℃ for 1-2h to allow the cellulose nanofibers to fully swell and obtain a suspension. 0.5-0.8wt% of acrylamide, 1-5wt% of initiator and 1-5wt% of crosslinking agent are added to the suspension. After stirring evenly, the mixture is heated to 60-70℃ for monomer polymerization reaction for 3-4h. After the reaction is completed, 3-10wt% of humectant, 3-10wt% of binder and 1-5wt% of skin feel modifier are added to the reactants and mixed evenly to obtain the hydrogel matrix.

[0070] (4) Taking 100 parts by weight of the final prepared medicated ointment, 5-15 parts of sustained-release agent, 10-20 parts of composite transdermal activator (based on a mass fraction of 100wt% of composite transdermal activator, including 20-30wt% menthol, 40-50wt% azone, 15-20wt% propylene glycol and 8-10wt% oleic acid) and 20-30 parts of traditional Chinese medicine extract are added to 40-50 parts of hydrogel matrix and mixed at 50-60℃ for 1-2 hours. Then, the mixture is degassed by ultrasonication to obtain the medicated ointment. The medicated ointment is coated on the surface of the backing layer with a coating thickness of 0.5-0.6 mm. A release layer is then covered on the surface of the medicated ointment to obtain the transdermal activating traditional Chinese medicine sustained-release patch.

[0071] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0072] The herbal sustained-release patch provided by this invention is a gel-type patch. It is made by mixing herbal extracts, sustained-release agents, and composite transdermal penetration enhancers with a hydrogel matrix and then coating the mixture onto the surface of a backing layer. The sustained-release effect of the drug is achieved by utilizing the thermosensitive properties of the hydrogel matrix in combination with the sustained-release agent. By compounding various transdermal penetration enhancers with different properties, the transdermal penetration effect of complex herbal extracts is improved. Compared with ordinary pharmaceutical preparations, the herbal sustained-release patch provided by this invention has advantages such as moisturizing, breathability, high compliance, good adhesion, reusability, low risk of skin irritation and allergies, long duration of drug efficacy, fewer applications, and better therapeutic effect. It can avoid the first-pass effect of the liver and gastrointestinal inactivation. The temperature sensitivity of the thermosensitive hydrogel matrix enables the sustained-release effect of the drug, thereby controlling the drug to enter the human circulation at a constant rate and for a long time, fully exerting the drug efficacy, and reducing adverse drug reactions.

[0073] The water solubility of most polymers increases with increasing temperature. However, the polymer hydrogel matrix provided by this invention has temperature-sensitive properties, and its water solubility decreases with increasing temperature. The hydrogel matrix prepared from this type of polymer undergoes volume shrinkage and dehydration when the temperature rises, allowing the active ingredients of the embedded traditional Chinese medicine extract to flow out from the hydrogel matrix through dynamic water exchange and penetrate transdermally into the human bloodstream to exert their medicinal effects. Conversely, when the temperature decreases, the hydrogel matrix expands and absorbs water. Dynamic water molecules carrying the active ingredients of the traditional Chinese medicine extract are reabsorbed into the hydrogel matrix, achieving the recovery of the active ingredients and preventing the volatilization of the active ingredients in the sustained-release patch when not in use. Furthermore, because the temperature-sensitive properties of the hydrogel matrix provided by this invention are reversible, the traditional Chinese medicine sustained-release patch can be reused repeatedly until the active ingredients of the traditional Chinese medicine extract are completely absorbed by the human body.

[0074] The polymer hydrogel matrix provided by this invention uses a polymer containing hydrophilic molecular chains (acrylamide) and protophilic molecular chains (isopropylacrylamide). In a low-temperature environment, the hydrogen bonding between the hydrophilic molecular chains and water molecules in the polymer molecular chains is dominant, which makes the polymer molecular chains extend and improves the water solubility of the hydrogel matrix. The dynamic water molecules in the hydrogel matrix can carry the traditional Chinese medicine extract and disperse it uniformly in the network structure of the polymer to form a gel state. When the herbal sustained-release patch is applied to the skin, the temperature of the hydrogel matrix increases with the increase of the body surface temperature. This leads to enhanced protonic interactions of the protonic molecular chains in the polymer chains and weakened hydrogen bonding. As a result, the network structure of the polymer chain-associated hydrogel shrinks, reducing its water solubility. When the temperature rises to the critical solution temperature, the hydrogel matrix begins to shrink and dehydrate, causing dynamic water molecules within it to carry the herbal extracts out and release them onto the skin surface. The active ingredients in the herbal extracts are then absorbed transdermally into the bloodstream under the action of a composite transdermal penetration enhancer, thus exerting their effects. As the body surface temperature continues to rise, the volume shrinkage rate of the hydrogel matrix gradually increases, and the drug release effect gradually intensifies.

[0075] This invention incorporates metal-organic framework (MOF) materials during the preparation of the hydrogel matrix. MOF materials possess a porous structure with a large specific surface area and high porosity, exhibiting excellent drug loading capacity and serving as a suitable carrier for traditional Chinese medicine extracts. Furthermore, MOF materials are composed of metal ions and organic ligands, with most metal ions (such as Ag) being... + Zn 2+ and Cu 2+ MOF materials possess excellent antibacterial activity, and some organic ligands also exhibit good antibacterial activity and biocompatibility. However, MOF materials are prone to aggregation, and their degradation can cause certain toxic effects on the human body. Therefore, this invention incorporates cellulose nanofibers into the hydrogel matrix. On the one hand, this reduces the likelihood of MOF material aggregation, resulting in higher porosity and specific surface area, thereby improving drug loading capacity while reducing the potential toxic effects of MOF material degradation on the human body. On the other hand, MOF materials can form strong hydrogen bonds and physical entanglements with cellulose nanofibers, allowing the prepared hydrogel matrix to withstand greater tensile stress.

[0076] Compared to single-component transdermal penetration enhancers, the use of compound transdermal penetration enhancers can further improve the transdermal penetration effect of drugs. Furthermore, the traditional Chinese medicine extracts used in this invention are refined from various herbs, and compared to single drugs, their component characteristics are more complex, containing both water-soluble and lipid-soluble components; ionic and molecular components; and cationic and anionic components. Single-component transdermal penetration enhancers often only promote the transdermal penetration of one type of active component and cannot cover different types of active components. Therefore, using single-component transdermal penetration enhancers cannot achieve the desired penetration-enhancing effect. To address this, this invention uses a compound transdermal penetration enhancer formed by combining menthol, azone, propylene glycol, and oleic acid, which can significantly improve the transdermal absorption effect of active ingredients in traditional Chinese medicine extracts.

[0077] Ammone can alter the density of the lipid bilayer, increasing lipid fluidity and thus disrupting the lipid film formed on the skin surface without causing toxic side effects to skin cells. Simultaneously, it expands the intercellular pores in the stratum corneum, allowing the active ingredients of traditional Chinese medicine extracts to be stored within the stratum corneum, thereby significantly increasing the permeability of water-soluble components in the extracts. However, its effect on promoting the penetration of lipid-soluble components is relatively weak. Therefore, this invention adds propylene glycol to ammone, utilizing propylene glycol to dissolve lipid-soluble drugs. The lipid-soluble components dissolved in propylene glycol can then easily penetrate the skin through ammone.

[0078] Menthol and oleic acid have similar permeation-enhancing effects to azone, altering the arrangement of lipid molecules between stratum corneum cells, increasing lipid fluidity, and thus enhancing skin permeability. Furthermore, menthol and oleic acid possess other advantages: menthol stimulates blood circulation in subcutaneous capillaries and can be absorbed transdermally; its synergistic effect with azone can promote the transdermal absorption of traditional Chinese medicine extracts. Oleic acid, on the other hand, can promote the transdermal penetration of cationic, anionic, and molecularly-based drugs, thus producing a synergistic effect with azone. Attached Figure Description

[0079] Figure 1 The following is a flowchart of the preparation process of the transdermal-enhancing sustained-release traditional Chinese medicine plasters prepared in Examples 1-5 of this invention;

[0080] Figure 2 This is a comparison chart of the cumulative permeation of the transdermal-enhancing sustained-release traditional Chinese medicine plasters prepared in Examples 1-5 of this invention in in vitro transdermal experiments. Detailed Implementation

[0081] The technical solutions of the present invention will be described in detail below with reference to specific embodiments and accompanying drawings. The embodiments described herein are specific implementations of the present invention, used to illustrate the concept of the present invention; these descriptions are explanatory and exemplary, and should not be construed as limiting the implementation methods or the scope of protection of the present invention. In addition to the embodiments described herein, those skilled in the art can employ other obvious technical solutions based on the content disclosed in the claims and specification of this application. These technical solutions include those that make any obvious substitutions and modifications to the embodiments described herein.

[0082] Example 1

[0083] This embodiment provides a method for preparing a transdermal-enhancing sustained-release traditional Chinese medicine plaster, the preparation method as follows: Figure 1 As shown, the specific steps include the following:

[0084] (1) Weigh out the following types of Chinese medicinal materials in the following quantities, based on a mass fraction of 100 wt% for the Chinese medicinal composition:

[0085] Cuscuta chinensis 5wt%, Eupatorium fortunei 8wt%, Smilax glabra 6wt%, Plantago asiatica 10wt%, Clematis chinensis 8wt%, Angelica sinensis 12wt%, Achyranthes bidentata 7wt%, Saposhnikovia divaricata 10wt%, Angelica pubescens 9wt%, Carthamus tinctorius 15wt%, Spatholobus suberectus 5wt%, and Paeonia lactiflora 5wt%.

[0086] (2) The above-mentioned Chinese medicinal materials were freeze-dried and pulverized at -60℃. The pulverized Chinese medicinal materials were mixed in proportion to obtain a Chinese medicine composition. The Chinese medicine composition was subjected to supercritical carbon dioxide extraction at 30MPa and 40℃ for 3h to obtain a Chinese medicine extract. The CO2 flow rate used for supercritical carbon dioxide extraction was 20kg / h. The active ingredients of the Chinese medicine extract were extracted with ethanol. Then, the extract was centrifuged at 5000rpm for 10min. After centrifugation, the supernatant was concentrated under vacuum at 0.09MPa to obtain the Chinese medicine extract.

[0087] (3) Taking the final hydrogel matrix as 100wt%, 10wt% of isopropylacrylamide and 8wt% of metal-organic framework material are dispersed in 45wt% of deionized water to form a dispersion. 4wt% of cellulose nanofibers are added to the dispersion and soaked at 80℃ for 2h to allow the cellulose nanofibers to fully swell and obtain a suspension. 0.6wt% of acrylamide, 2.4wt% of ammonium persulfate and 5wt% of N,N'-methylenebisacrylamide are added to the suspension. After stirring evenly, the mixture is heated to 60℃ for monomer polymerization reaction for 4h. After the reaction is completed, 10wt% of glycerol, 10wt% of polyvinyl alcohol and 5wt% of hyaluronic acid are added to the reactants and mixed evenly to obtain the hydrogel matrix.

[0088] (4) Taking the weight of the final prepared medicated ointment as 100 parts, 5 parts of ethyl cellulose, 15 parts of composite transdermal activator (based on the mass fraction of the composite transdermal activator as 100 wt%, including 20 wt% menthol, 50 wt% azone, 20 wt% propylene glycol and 10 wt% oleic acid) and 30 parts of traditional Chinese medicine extract are added to 50 parts of hydrogel matrix and mixed at 50°C for 2 h. Then, the mixture is degassed by ultrasonication to obtain the medicated ointment. The medicated ointment is coated on the surface of the backing layer with a coating thickness of 0.5 mm. A release layer is then covered on the surface of the medicated ointment to obtain the transdermal activating traditional Chinese medicine sustained-release patch.

[0089] Example 2

[0090] This embodiment provides a method for preparing a transdermal-enhancing sustained-release traditional Chinese medicine plaster, the preparation method as follows: Figure 1 As shown, the specific steps include the following:

[0091] (1) Weigh out the following types of Chinese medicinal materials in the following quantities, based on a mass fraction of 100 wt% for the Chinese medicinal composition:

[0092] Cuscuta chinensis 9wt%, Eupatorium fortunei 3wt%, Smilax glabra 5wt%, Plantago asiatica 10wt%, Clematis chinensis 5wt%, Angelica sinensis 11wt%, Achyranthes bidentata 5wt%, Saposhnikovia divaricata 10wt%, Angelica pubescens 12wt%, Carthamus tinctorius 10wt%, Spatholobus suberectus 15wt%, and Paeonia lactiflora 5wt%.

[0093] (2) The above-mentioned Chinese medicinal materials were freeze-dried and pulverized at -58℃. The pulverized Chinese medicinal materials were mixed in proportion to obtain a Chinese medicine composition. The Chinese medicine composition was subjected to supercritical carbon dioxide extraction at 32MPa and 42℃ for 2.5h to obtain the Chinese medicine extract. The CO2 flow rate used for supercritical carbon dioxide extraction was 23kg / h. The active ingredients of the Chinese medicine extract were extracted with ethanol. Then, the extract was centrifuged at 5200rpm for 9min. After centrifugation, the supernatant was concentrated under vacuum at 0.092MPa to obtain the Chinese medicine extract.

[0094] (3) Taking the final hydrogel matrix as 100wt%, 15wt% of isopropylacrylamide and 10wt% of metal-organic framework material were dispersed in 40wt% of deionized water to form a dispersion. 3wt% of cellulose nanofibers were added to the dispersion and soaked at 82℃ for 1.8h to allow the cellulose nanofibers to fully swell and obtain a suspension. 0.8wt% of acrylamide, 3.2wt% of ammonium persulfate and 5wt% of N,N'-methylenebisacrylamide were added to the suspension. After stirring evenly, the mixture was heated to 62℃ for monomer polymerization reaction for 3.8h. After the reaction was completed, 8wt% of sorbitol, 10wt% of polyvinyl alcohol and 5wt% of hyaluronic acid were added to the reactants and mixed evenly to obtain the hydrogel matrix.

[0095] (4) Taking the weight of the final prepared medicated ointment as 100 parts, 15 parts of α-cyclodextrin, 15 parts of the composite transdermal penetration enhancer (based on the mass fraction of the composite transdermal penetration enhancer as 100wt%, including 22wt% menthol, 50wt% azone, 20wt% propylene glycol and 8wt% oleic acid) and 30 parts of traditional Chinese medicine extract are added to 40 parts of hydrogel matrix and mixed at 53℃ for 1.8h. Then, the mixture is degassed by ultrasound to obtain the medicated ointment. The medicated ointment is coated on the surface of the backing layer with a coating thickness of 0.52mm. A release layer is then covered on the surface of the medicated ointment to obtain the transdermal-promoting traditional Chinese medicine sustained-release patch.

[0096] Example 3

[0097] This embodiment provides a method for preparing a transdermal-enhancing sustained-release traditional Chinese medicine plaster, the preparation method as follows: Figure 1 As shown, the specific steps include the following:

[0098] (1) Weigh out the following types of Chinese medicinal materials in the following quantities, based on a mass fraction of 100 wt% for the Chinese medicinal composition:

[0099] Cuscuta chinensis 8wt%, Eupatorium fortunei 2wt%, Smilax glabra 5wt%, Plantago asiatica 10wt%, Clematis chinensis 5wt%, Angelica sinensis 14wt%, Achyranthes bidentata 10wt%, Saposhnikovia divaricata 15wt%, Angelica pubescens 8wt%, Carthamus tinctorius 7wt%, Spatholobus suberectus 10wt%, and Paeonia lactiflora 6wt%.

[0100] (2) The above-mentioned Chinese medicinal materials were freeze-dried and pulverized at -55℃. The pulverized Chinese medicinal materials were mixed in proportion to obtain a Chinese medicine composition. The Chinese medicine composition was subjected to supercritical carbon dioxide extraction at 35MPa and 45℃ for 2h to obtain a Chinese medicine extract. The CO2 flow rate used for supercritical carbon dioxide extraction was 25kg / h. The active ingredients of the Chinese medicine extract were extracted with ethanol. Then, the extract was centrifuged at 5500rpm for 8min. After centrifugation, the supernatant was concentrated under vacuum at 0.095MPa to obtain the Chinese medicine extract.

[0101] (3) Taking the final hydrogel matrix as 100wt%, 13wt% of isopropylacrylamide and 8wt% of metal-organic framework material were dispersed in 48wt% of deionized water to form a dispersion. 5wt% of cellulose nanofibers were added to the dispersion and soaked at 85℃ for 1.5h to allow the cellulose nanofibers to fully swell and obtain a suspension. 0.7wt% of acrylamide, 1wt% of potassium persulfate and 1wt% of N,N'-methylenebismethylacrylamide were added to the suspension. After stirring evenly, the mixture was heated to 65℃ for monomer polymerization reaction for 3.5h. After the reaction was completed, 8.3wt% of butanediol, 10wt% of carboxymethyl cellulose and 5wt% of aryl silicone oil were added to the reactants and mixed evenly to obtain the hydrogel matrix.

[0102] (4) Taking the weight of the final prepared medicated ointment as 100 parts, 12 parts of hydroxypropyl-β-cyclodextrin, 18 parts of the composite transdermal penetration enhancer (based on the mass fraction of the composite transdermal penetration enhancer as 100wt%, including 28wt% menthol, 48wt% azone, 15wt% propylene glycol and 9wt% oleic acid) and 25 parts of traditional Chinese medicine extract are added to 45 parts of hydrogel matrix and mixed at 55℃ for 1.5h. Then, the mixture is degassed by ultrasound to obtain the medicated ointment. The medicated ointment is coated on the surface of the backing layer with a coating thickness of 0.55mm. A release layer is then covered on the surface of the medicated ointment to obtain the transdermal-promoting traditional Chinese medicine sustained-release patch.

[0103] Example 4

[0104] This embodiment provides a method for preparing a transdermal-enhancing sustained-release traditional Chinese medicine plaster, the preparation method as follows: Figure 1 As shown, the specific steps include the following:

[0105] (1) Weigh out the following types of Chinese medicinal materials in the following quantities, based on a mass fraction of 100 wt% for the Chinese medicinal composition:

[0106] Cuscuta chinensis 15wt%, Eupatorium fortunei 2wt%, Smilax glabra 6wt%, Plantago asiatica 12wt%, Clematis chinensis 9wt%, Angelica sinensis 11wt%, Achyranthes bidentata 10wt%, Saposhnikovia divaricata 12wt%, Angelica pubescens 8wt%, Carthamus tinctorius 5wt%, Spatholobus suberectus 5wt%, and Paeonia lactiflora 5wt%.

[0107] (2) The above-mentioned Chinese medicinal materials were freeze-dried and pulverized at -52℃. The pulverized Chinese medicinal materials were mixed in proportion to obtain a Chinese medicine composition. The Chinese medicine composition was subjected to supercritical carbon dioxide extraction at 38MPa and 48℃ for 1.5h to obtain the Chinese medicine extract. The CO2 flow rate used for supercritical carbon dioxide extraction was 28kg / h. The active ingredients of the Chinese medicine extract were extracted with ethanol. Then, the extract was centrifuged at 5800rpm for 6min. After centrifugation, the supernatant was concentrated under vacuum at 0.098MPa to obtain the Chinese medicine extract.

[0108] (3) Taking the final hydrogel matrix as 100wt%, 14wt% of isopropylacrylamide and 10wt% of metal-organic framework material were dispersed in 50wt% of deionized water to form a dispersion. 4wt% of cellulose nanofibers were added to the dispersion and soaked at 88℃ for 1.3h to allow the cellulose nanofibers to fully swell and obtain a suspension. 0.6wt% of acrylamide, 4wt% of sodium persulfate and 1.2wt% of N,N'-methylenebismethylacrylamide were added to the suspension. After stirring evenly, the mixture was heated to 68℃ for monomer polymerization reaction for 3.2h. After the reaction was completed, 3wt% of polyethylene glycol, 9wt% of sodium carboxymethyl cellulose and 4.2wt% of sodium hyaluronate were added to the reactants and mixed evenly to obtain the hydrogel matrix.

[0109] (4) Taking the weight of the final prepared medicated ointment as 100 parts, 12 parts of hydroxypropyl-β-cyclodextrin, 20 parts of the composite transdermal penetration enhancer (based on the mass fraction of the composite transdermal penetration enhancer as 100wt%, including 30wt% menthol, 40wt% azone, 20wt% propylene glycol and 10wt% oleic acid) and 20 parts of traditional Chinese medicine extract are added to 48 parts of hydrogel matrix and mixed at 58℃ for 1.2h. Then, the mixture is degassed by ultrasound to obtain the medicated ointment. The medicated ointment is coated on the surface of the backing layer with a coating thickness of 0.58mm. A release layer is then covered on the surface of the medicated ointment to obtain the transdermal-promoting traditional Chinese medicine sustained-release patch.

[0110] Example 5

[0111] This embodiment provides a method for preparing a transdermal-enhancing sustained-release traditional Chinese medicine plaster, the preparation method as follows: Figure 1 As shown, the specific steps include the following:

[0112] (1) Weigh out the following types of Chinese medicinal materials in the following quantities, based on a mass fraction of 100 wt% for the Chinese medicinal composition:

[0113] Cuscuta chinensis 6wt%, Eupatorium fortunei 10wt%, Smilax glabra 10wt%, Plantago asiatica 11wt%, Clematis chinensis 6wt%, Angelica sinensis 11wt%, Achyranthes bidentata 5wt%, Saposhnikovia divaricata 11wt%, Angelica pubescens 8wt%, Carthamus tinctorius 6wt%, Spatholobus suberectus 6wt%, and Paeonia lactiflora 10wt%.

[0114] (2) The above-mentioned Chinese medicinal materials were freeze-dried and pulverized at -50℃. The pulverized Chinese medicinal materials were mixed in proportion to obtain a Chinese medicine composition. The Chinese medicine composition was subjected to supercritical carbon dioxide extraction for 1 h under a pressure of 40 MPa and a temperature of 50℃ to obtain a Chinese medicine extract. The CO2 flow rate used for supercritical carbon dioxide extraction was 30 kg / h. The active ingredients of the Chinese medicine extract were extracted with ethanol. Then, the extract was centrifuged at 6000 rpm for 5 min. After centrifugation, the supernatant was concentrated under vacuum at 0.1 MPa to obtain the Chinese medicine extract.

[0115] (3) Taking the final hydrogel matrix as 100wt%, 20wt% of isopropylacrylamide and 9wt% of metal-organic framework material were dispersed in 50wt% of deionized water to form a dispersion. 3wt% of cellulose nanofibers were added to the dispersion and soaked at 90℃ for 1h to allow the cellulose nanofibers to fully swell and obtain a suspension. 0.5wt% of acrylamide, 5wt% of sodium persulfate and 5wt% of N,N'-methylenebismethylacrylamide were added to the suspension. After stirring evenly, the mixture was heated to 70℃ for monomer polymerization reaction for 3h. After the reaction was completed, 3.5wt% of glycerol, 3wt% of polyvinylpyrrolidone and 1wt% of dimethyl silicone oil were added to the reactants and mixed evenly to obtain the hydrogel matrix.

[0116] (4) Taking the weight of the final prepared medicated ointment as 100 parts, 10 parts of ethyl cellulose, 11 parts of the composite transdermal activator (based on the mass fraction of the composite transdermal activator as 100 wt%, including 30 wt% menthol, 42 wt% azone, 18 wt% propylene glycol and 10 wt% oleic acid) and 29 parts of traditional Chinese medicine extract are added to 50 parts of hydrogel matrix and mixed at 60°C for 1 h. Then, the mixture is degassed by ultrasonication to obtain the medicated ointment. The medicated ointment is coated on the surface of the backing layer with a coating thickness of 0.6 mm. A release layer is then covered on the surface of the medicated ointment to obtain the transdermal activating traditional Chinese medicine sustained-release patch.

[0117] In vitro transdermal absorption experiments were conducted on the traditional Chinese medicine sustained-release plasters prepared in Examples 1-5. The specific testing procedures are as follows:

[0118] (1) Skin preparation: Take the abdominal skin of SD rats, remove hair with depilatory agent, wash the skin surface with water, feed for 24 hours and then kill by neck dislocation, cut off the abdominal skin, peel off the subcutaneous fat and mucous tissue, wash repeatedly with distilled water, then rinse with physiological saline and soak in physiological saline for short-term storage at 4℃.

[0119] (2) In vitro transdermal test: Prepared mouse skin was cut into three pieces (3.4 cm²) of appropriate size and fixed between the supply and receiving pools of the transdermal tester, with the stratum corneum of the mouse skin facing the supply pool and the dermis of the mouse skin facing the receiving pool. The herbal sustained-release plaster prepared in Examples 1-5 was applied to the stratum corneum of the mouse skin. The receiving pool contained 15 mL of receiving solution (including PEG400, 95% anhydrous ethanol and physiological saline in a volume ratio of 1:3:6). The constant temperature water bath circulation (37±1℃) and magnetic heating stirrer (600 r / min) were started. Timing was started, and air bubbles in the receiving pool were removed at any time. 1 mL samples were taken from the receiving pool at the 2nd, 4th, 6th, 8th, 10th, 12th and 24th hours, and an equal volume of receiving solution at 37℃ was immediately added. The extracted samples were filtered through a 0.45 μm microporous membrane, and the concentration of the herbal extracts was determined by high-performance liquid chromatography (HPLC), which is the cumulative permeation. The test data are shown in Table 1 and... Figure 2 As shown:

[0120] Table 1

[0121]

[0122] Regression analysis was performed on the data in Table 1, and the transdermal rate of the traditional Chinese medicine sustained-release plaster was calculated. The specific calculation process is as follows:

[0123] Plotting time on the x-axis and cumulative permeation on the y-axis in a rectangular coordinate system, and performing regression analysis on each point in the rectangular coordinate system to obtain a linear regression equation, the slope of which is the transdermal rate. The linear regression equations and transdermal rates calculated for each embodiment are shown in Table 2.

[0124] Table 2

[0125] Example Linear regression equation <![CDATA[Transdermal rate (g / cm 2 / h)]]> Example 1 Y = 74.7644x + 107.5072 74.76 Example 2 Y = 76.4496x + 144.4748 76.45 Example 3 Y = 87.0081x + 142.0665 87.01 Example 4 Y = 81.2383x + 218.1817 81.24 Example 5 Y = 79.1259x + 181.8129 79.13

[0126] As can be seen from the test data provided in Tables 1 and 2, the traditional Chinese medicine sustained-release plaster provided by the present invention has a high transdermal rate and a long penetration time.

[0127] The applicant declares that the above description is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention fall within the protection and disclosure scope of the present invention.

Claims

1. A transdermal promoting type traditional Chinese medicine sustained-release plaster, characterized in that, The transdermal penetration promoting type traditional Chinese medicine sustained-release patch includes a backing layer and a drug-containing ointment coated on the surface of the backing layer, and a release layer is coated on the surface of the drug-containing ointment; The drug-containing ointment includes a traditional Chinese medicine extract, a hydrogel matrix, a sustained-release agent and a composite transdermal penetration promoting agent; The hydrogel matrix includes isopropyl acrylamide, acrylamide, a metal organic framework material, cellulose nanofiber, an initiator, a crosslinking agent, a humectant, a binder, a skin feel modifier and deionized water; The composite transdermal penetration promoting agent includes menthol, azone, propylene glycol and oleic acid.

2. The transdermal penetration promoting traditional Chinese medicine sustained-release patch of claim 1, characterized in that, The drug-containing ointment includes the following components by weight:

3. The transdermal penetration promoting traditional Chinese medicine sustained-release patch of claim 1, characterized in that, The traditional Chinese medicine extract is obtained from a traditional Chinese medicine composition composed of several kinds of traditional Chinese medicinal materials, and the traditional Chinese medicine composition includes the following components by mass fraction: Cuscuta chinensis 5-15wt%, Pterocephalus tottoriensis 2-10wt%, Smilax glabra 5-10wt%, Plantago asiatica 10-12wt%, Ophiorrhiza pumila 5-9wt%, Angelica sinensis 11-14wt%, Lysidice rhodostegia 5-10wt%, Saposhnikovia divaricata 10-15wt%, Angelica pubescens 8-12wt%, Carthamus tinctorius 5-15wt%, Spatholobus suberectus 5-15wt% and Radix Paeoniae Rubra 5-10wt%.

4. The transdermal penetration promoting traditional Chinese medicine sustained-release patch of claim 1, characterized in that, The sustained-release agent includes any one or a combination of at least two of ethyl cellulose, alpha-cyclodextrin or hydroxypropyl-beta-cyclodextrin; The composite transdermal penetration promoting agent includes the following components by mass fraction, with the mass fraction of the composite transdermal penetration promoting agent being 100wt%:

5. The transdermal penetration promoting traditional Chinese medicine sustained-release patch of claim 1, characterized in that, The hydrogel matrix includes the following components by mass fraction, with the mass fraction of the hydrogel matrix being 100wt%:

6. The transdermal penetration promoting traditional Chinese medicine sustained-release patch of claim 5, characterized in that, The initiator includes any one or a combination of at least two of ammonium persulfate, potassium persulfate or sodium persulfate; The crosslinking agent includes any one or a combination of at least two of N, N'-methylene bisacrylamide, N, N'-methylene bis-methacrylamide or N, N'-methylene bis-methacrylamide; The humectant includes any one or a combination of at least two of glycerol, sorbitol, butanediol or polyethylene glycol; The binder includes any one or a combination of at least two of polyvinyl alcohol, carboxymethyl cellulose, sodium carboxymethyl cellulose or polyvinyl pyrrolidone; The skin feel modifier includes any one or a combination of at least two of hyaluronic acid, sodium hyaluronate, dimethyl silicone oil, aryl silicone oil or amino silicone oil.

7. A method for preparing the transdermal penetration promoting traditional Chinese medicine sustained-release patch paste according to any one of claims 1 to 6, characterized in that, The preparation method includes: (Ⅰ) freeze-drying and crushing the various kinds of traditional Chinese medicinal materials, mixing the crushed traditional Chinese medicinal materials in proportion to obtain a traditional Chinese medicine composition, supercritical carbon dioxide extraction of the traditional Chinese medicine composition to obtain a traditional Chinese medicine extract, active ingredient extraction of the traditional Chinese medicine extract with ethanol, subsequent centrifugal separation, taking the supernatant and vacuum concentration to obtain a traditional Chinese medicine extract; (II) dispersing isopropyl acrylamide and metal organic framework material in deionized water to form a dispersion, adding cellulose nanofiber to the dispersion, soaking for a period of time to make the cellulose nanofiber fully swollen to obtain a suspension; adding acrylamide, initiator and crosslinking agent to the suspension, stirring uniformly and then heating to initiate monomer polymerization, adding moisturizing agent, adhesive and skin feel modifier to the reaction product after the reaction is completed, mixing uniformly to obtain a hydrogel matrix; (III) adding a sustained-release agent, a composite transdermal enhancer and the traditional Chinese medicine extract obtained in step (I) to the hydrogel matrix obtained in step (II), mixing uniformly, then ultrasonic defoaming to obtain a drug-containing ointment, coating the drug-containing ointment on the surface of the backing layer and covering the release layer to obtain the transdermal enhancer type traditional Chinese medicine sustained-release plaster.

8. The production method according to claim 7, characterized by, In step (I), the temperature of the freeze-drying is -60 to -50℃; The pressure of the supercritical carbon dioxide extraction is 30 to 40 MPa; The temperature of the supercritical carbon dioxide extraction is 40 to 50℃; The time of the supercritical carbon dioxide extraction is 1 to 3 h; The CO2 flow rate of the supercritical carbon dioxide extraction is 20 to 30 kg / h; The rotation speed of the centrifugal separation is 5000 to 6000 rpm; The time of the centrifugal separation is 5 to 10 min; The vacuum degree of the vacuum concentration is 0.09 to 0.1 MPa.

9. The preparation method according to claim 7, characterized in that, In step (II), the soaking temperature of the cellulose nanofiber is 80 to 90℃; The soaking time of the cellulose nanofiber is 1 to 2 h; The reaction temperature of the monomer polymerization is 60 to 70℃; The reaction time of the monomer polymerization is 3 to 4 h.

10. The preparation method according to claim 7, characterized in that, In step (III), the mixing temperature is 50 to 60℃; The mixing time is 1 to 2 h; The coating thickness of the drug-containing ointment is 0.5 to 0.6 mm.

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