Tetrahydrocurcumin transdermal patch for targeted treatment of breast cancer and preparation method thereof

Abstract

A tetrahydrocurcumin transdermal patch for targeted treatment of breast cancer and a preparation method thereof relate to the field of transdermal drug delivery technology. The transdermal patch comprises an active ingredient, a polymer matrix, a plasticizer, a permeation enhancer, a solvent, a cross-linking agent and a stabilizer. The preparation method comprises S1. dissolution and pretreatment of raw materials; S2. addition of a permeation enhancer; S3. preparation of a cross-linked polymer matrix; S4. addition of an antioxidant; S5. molding and drying; S6. plasma treatment; S7. cutting and packaging. The present invention enhances the transdermal permeability and surface stability of the drug through plasma treatment, so that the drug can quickly penetrate the skin barrier and achieve high concentration accumulation in the tumor area while avoiding systemic side effects.

Description

Technical Field

[0001] The invention relates to the technical field of transdermal drug delivery, in particular to a tetrahydrocurcumin transdermal patch for targeted treatment of breast cancer and a preparation method thereof. Background Art

[0002] With the continuous development of modern drug treatment technology, transdermal drug delivery (TDD) as a non-invasive drug delivery method has been widely used in the treatment of various diseases, especially in the fields of chronic diseases, skin diseases and tumor treatment. The transdermal drug delivery system delivers drugs into the body through the skin, which has the advantages of avoiding the first-pass effect, controlling release, and improving patient compliance. It has become one of the important drug delivery methods.

[0003] As one of the main metabolites of turmeric, tetrahydrocurcumin THC has significant biological activities such as antioxidant, anti-inflammatory, anti-tumor and neuroprotective. Tetrahydrocurcumin THC has low bioavailability, especially when administered orally, the absorption of the drug in the body is limited. Most of the tetrahydrocurcumin THC will be metabolized and quickly eliminated in the gastrointestinal tract, resulting in an extremely low amount entering the blood circulation, which in turn reduces its efficacy. The poor drug delivery and targeting of tetrahydrocurcumin THC are also a major challenge in its application. Although tetrahydrocurcumin THC has potential in anti-tumor and anti-inflammatory aspects, it also has certain side effects on normal tissues due to imprecise drug delivery. Therefore, accurately delivering tetrahydrocurcumin to targeted tissues and increasing its local concentration is the key to improving its efficacy. Summary of the invention

[0004] The purpose of the present invention is to provide a tetrahydrocurcumin transdermal patch for targeted treatment of breast cancer and a preparation method thereof, so as to solve the problem of inaccurate drug delivery caused by limited drug absorption of oral tetrahydrocurcumin.

[0005] The technical solution adopted by the present invention to solve the technical problem is: a tetrahydrocurcumin transdermal patch for targeted treatment of breast cancer, comprising an active ingredient, a polymer matrix, a plasticizer, a permeation enhancer, a solvent, a cross-linking agent and a stabilizer;

[0006] The active ingredient is tetrahydrocurcumin THC, accounting for 1%-5%;

[0007] The polymer matrix includes hydroxypropyl methylcellulose HPMC accounting for 5%-15%, polyvinyl alcohol PVA accounting for 2%-8% and polyurethane PU accounting for 2%-8%;

[0008] The plasticizer includes glycerol accounting for 3%-7%, polyethylene glycol PEG400 accounting for 5%-10%, and carbomer accounting for 0.5%-2%;

[0009] The penetration enhancer includes 1%-3% of caprylic acid / caprylate Capryol 90, 0.5%-1% of ethyl salicylate and 0.5%-1% of phenoxyethanol;

[0010] The solvent includes 10%-20% ethanol and 20%-30% water;

[0011] The cross-linking agent includes 0.1%-0.5% glutaraldehyde and 0.1%-0.5% melamine;

[0012] The stabilizer is the antioxidant butylated hydroxytoluene BHT, accounting for 0.1%-0.5%.

[0013] The present invention also provides a method for preparing a tetrahydrocurcumin transdermal patch for targeted treatment of breast cancer, comprising the following steps:

[0014] S1. Dissolution and pretreatment of raw materials

[0015] S1.1 Dissolve tetrahydrocurcumin THC in 20% ethanol solution and continue stirring until completely dissolved;

[0016] S1.2 Preparation of polymer matrix material: Dissolve hydroxypropyl methylcellulose HPMC in 50 ml of water, add polyvinyl alcohol PVA and polyurethane PU, and continue stirring until a uniform matrix solution is formed;

[0017] S1.3 Add plasticizer: add glycerol, polyethylene glycol PEG 400 and carbomer into the base solution in a ratio of 5:3:2 and stir;

[0018] S2. Add penetration enhancer

[0019] S2.1 Add caprylic acid / caprylate Capryol 90, ethyl salicylate and phenoxyethanol into the base solution at a ratio of 30%-40% caprylic acid / caprylate Capryol 90, 10%-25% ethyl salicylate and 5%-8% phenoxyethanol;

[0020] S2.2 Continue stirring until all ingredients are evenly mixed and completely dissolved;

[0021] S3. Preparation of cross-linked polymer matrix

[0022] S3.1 Stir the matrix solution to ensure uniform distribution of the crosslinker;

[0023] S3.2 Add glutaraldehyde and melamine in a ratio of 2:1 to the matrix solution under stirring;

[0024] S4. Add antioxidants

[0025] Add 0.5% w / w butylated hydroxytoluene (BHT) to the base solution and ensure uniform mixing;

[0026] S5. Casting and drying

[0027] S5.1 Pour the prepared solution evenly into the mold, maintaining a uniform thickness of 0.5mm-1mm to form a uniform patch film;

[0028] S5.2 Place the mold in a vacuum drying oven and dry it for 24 hours to ensure that the solvent is completely evaporated;

[0029] S6. Plasma treatment

[0030] S6.1 Select gas type

[0031] Select oxygen or argon, set the gas flow rate to 50 sccm, and process for 1-3 minutes;

[0032] S6.2 Select power type

[0033] Select the RF power supply, connect the power supply and check the parameters to ensure that the power supply connection of the equipment is normal and the parameter settings meet the experimental requirements;

[0034] S6.3 Determine processing power and time

[0035] Set the power to 150W and the time to 2 minutes;

[0036] S6.4 Plasma treatment

[0037] Place the dried patch film into the plasma treatment equipment, ensure that the patch surface is facing upward and fixed flat, and keep the nozzle 2-3 cm away from the patch surface to ensure uniform treatment of the patch surface; start the treatment program according to the set gas type, power supply, power and time, monitor whether the equipment parameters are stable during the treatment process, and observe whether there are any abnormalities on the patch surface;

[0038] S6.5 subsequent optimization

[0039] Observe the adhesiveness and hydrophilicity of the patch. If the expected effect is not achieved, gradually adjust the gas ratio, power and time, and record the optimal processing parameters in the experimental report for repeated preparation;

[0040] S7. Cutting and packaging

[0041] Cut the processed patches into the required size to ensure that each patch is uniform, and put the cut patches into sealed packages to avoid contact with moisture and oxygen in the air to ensure the stability of the drug.

[0042] Furthermore, the stirring rate of the present invention is set to 200 rpm.

[0043] Furthermore, in step S5.2, the temperature is set to 40°C and the vacuum degree is set to 0.1 MPa.

[0044] The beneficial effects of the present invention are as follows: the present invention enhances the transdermal permeability and surface stability of the drug through plasma treatment, so that the drug can quickly penetrate the skin barrier and achieve high concentration accumulation in the tumor area, while avoiding systemic side effects. Long-term stability and antioxidant tests have proved that the patch can maintain the activity of the drug under different temperature and humidity conditions and extend the shelf life. In vitro and in vivo experiments show that transdermal absorption rate, bioavailability and pharmacodynamic properties are significantly improved, showing excellent anti-inflammatory, antioxidant and anti-tumor effects, and effectively inhibiting the proliferation and spread of breast cancer cells. The present invention not only significantly improves the transdermal absorption and bioavailability of tetrahydrocurcumin by innovatively combining low-temperature plasma treatment and transdermal patch technology, but also realizes the targeted delivery of local high-concentration drugs for breast cancer. Its non-invasiveness and long-term stability make it have broad prospects in actual clinical applications, and provide a new, efficient, safe and convenient treatment for breast cancer patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 The present invention is a flow chart of the preparation method of the tetrahydrocurcumin transdermal patch. DETAILED DESCRIPTION

[0046] As the active ingredient in turmeric, tetrahydrocurcumin THC has a variety of biological activities, especially antioxidant, anti-inflammatory and anti-tumor effects. Studies have shown that tetrahydrocurcumin THC inhibits the growth, invasion and metastasis of tumor cells through various mechanisms, and can reduce inflammatory responses and protect cells from oxidative stress damage. Due to its good biological activity, tetrahydrocurcumin THC has been widely studied as an anticancer drug, especially in the treatment of various malignant tumors such as breast cancer, showing significant clinical potential. However, as the largest organ in the human body, the skin has a strong barrier function that can block foreign substances from entering the body. This barrier function is mainly composed of the stratum corneum, epidermis and dermis, among which the stratum corneum is the most important barrier layer. The stratum corneum is composed of multiple layers of tightly arranged keratinized cells, and the cells are filled with lipids, forming a solid barrier. When tetrahydrocurcumin THC tries to penetrate the skin barrier, it often encounters obstacles in the stratum corneum, resulting in incomplete absorption or too slow absorption rate, which makes the bioavailability of tetrahydrocurcumin THC low. In addition, tetrahydrocurcumin THC needs to go through a series of metabolic processes before reaching the site of action. These metabolic processes may occur in the gastrointestinal tract, liver or other tissues, resulting in reduced drug concentration or weakened activity. There is a strong first-pass effect when it is administered orally, which limits its efficacy. Therefore, finding a delivery method that can improve the bioavailability of tetrahydrocurcumin THC, especially a transdermal delivery system, has become one of the current research hotspots.

[0047] The active particles generated by low-temperature plasma are used to treat the skin gently and effectively. These active particles can penetrate the skin barrier and promote the penetration and absorption of tetrahydrocurcumin. At the same time, low-temperature plasma technology can also stimulate the regeneration and repair of skin cells and enhance the barrier function of the skin. Plasma technology can quickly treat the skin surface and improve the efficiency of drug delivery. When low-temperature plasma technology treats the skin, it will not damage the normal structure of the skin and will not produce harmful side effects. The penetration enhancer can change the structure and lipid composition of the skin's stratum corneum, thereby reducing the resistance of the skin barrier and making it easier for tetrahydrocurcumin to penetrate. When the penetration enhancer is used in combination with plasma technology, it can produce a synergistic effect, further enhancing the penetration and absorption of the drug.

[0048] In summary, by combining plasma technology, permeation enhancers and tetrahydrocurcumin transdermal drug delivery systems, the permeability, stability and therapeutic effect of drugs can be effectively improved, providing new possibilities for targeted treatment of breast cancer. This technical solution has strong clinical application prospects while improving the bioavailability of tetrahydrocurcumin THC, and can provide breast cancer patients with more efficient and personalized treatment options. To this end, we propose a plasma-based tetrahydrocurcumin transdermal patch.

[0049] The tetrahydrocurcumin transdermal patch for targeted treatment of breast cancer of the present invention comprises the following raw materials: active ingredient, polymer matrix, plasticizer, permeation enhancer, solvent, cross-linking agent and stabilizer. The components of various raw materials are described in detail below, and the proportion of each component is calculated by weight.

[0050] Active ingredient: Tetrahydrocurcumin THC, accounting for 1%-5%, has anti-inflammatory and antioxidant biological activities, is used as a drug carrier in transdermal patches, and is extracted from turmeric.

[0051] Polymer matrix: including hydroxypropyl methylcellulose HPMC accounting for 5%-15%, polyvinyl alcohol PVA accounting for 2%-8% and polyurethane PU accounting for 2%-8%. Among them, hydroxypropyl methylcellulose HPMC, as an adhesive and matrix material, helps to maintain the uniform distribution and stability of the drug in the patch. Polyvinyl alcohol PVA enhances the mechanical strength of the patch and helps to form a suitable film structure. Polyurethane PU improves the stability and durability of the transdermal patch and helps to control drug release.

[0052] Plasticizers: including 3%-7% glycerol, 5%-10% polyethylene glycol PEG400 and 0.5%-2% carbomer. Glycerol improves the softness and comfort of the patch and prevents the patch from cracking. Polyethylene glycol PEG 400 acts as a plasticizer and solvent to help improve the solubility of tetrahydrocurcumin and enhance the flexibility of the patch. Carbomer provides a better gelation effect and improves the touch and adhesion of the patch.

[0053] Permeation enhancers: including 1%-3% of Caprylic acid / caprylate Capryol 90, 0.5%-1% of ethyl salicylate, and 0.5%-1% of phenoxyethanol. Caprylic acid / caprylate Capryol 90 penetration enhancer helps drugs penetrate the skin barrier. Ethyl salicylate helps increase drug permeability and improves the skin permeability of drugs. Phenoxyethanol, as a penetration enhancer, increases the permeability of drugs and is skin-friendly.

[0054] Solvent: includes 10%-20% ethanol and 20%-30% water. Ethanol is used to dissolve tetrahydrocurcumin and other poorly soluble ingredients to promote uniform distribution of ingredients. Water is used to dissolve water-soluble ingredients, help mixing and adjust viscosity.

[0055] Cross-linking agent: including 0.1%-0.5% glutaraldehyde and 0.1%-0.5% melamine. Glutaraldehyde helps polymer cross-linking, enhancing the stability and mechanical strength of the patch. Melamine is used to form a cross-linking structure, further improving the stability of the patch.

[0056] Stabilizer: The antioxidant butylated hydroxytoluene BHT accounts for 1%-5%, which is used to protect tetrahydrocurcumin from oxidation and ensure its activity.

[0057] The following is combined with Figure 1 , the preparation steps of tetrahydrocurcumin transdermal patch for targeted treatment of breast cancer are described:

[0058] S1. Dissolution and pretreatment of raw materials

[0059] The goal of this step is to ensure that the tetrahydrocurcumin THC is evenly distributed and to prepare a uniform polymer matrix solution to form a good transdermal patch. The specific steps are:

[0060] S1.1 Dissolve tetrahydrocurcumin THC in 20% ethanol solution and continue stirring until completely dissolved to ensure uniform distribution of tetrahydrocurcumin.

[0061] S1.2 Preparation of polymer matrix materials: Dissolve hydroxypropyl methylcellulose HPMC in 50 ml of water, add polyvinyl alcohol PVA and polyurethane PU, stir at a rate of 200 rpm, temperature 30°C, and continue stirring for 45 minutes to form a uniform matrix solution.

[0062] S1.3 Add plasticizer: Add glycerol, polyethylene glycol PEG 400 and carbomer to the matrix solution in a ratio of 5:3:2, set the stirring rate to 200 rpm, and mix evenly for 30 minutes to further improve the flexibility and touch of the patch.

[0063] S2. Add penetration enhancer

[0064] The goal of this step is to add penetration enhancers - caprylic acid / caprylate Capryol 90 and phenoxyethanol to interact with lipids in the stratum corneum, change the structure and permeability of the stratum corneum, thereby promoting the transdermal absorption of tetrahydrocurcumin THC, helping tetrahydrocurcumin THC to pass through the skin barrier and increase the effective delivery of the drug. The specific steps are:

[0065] S2.1 Capryol 90, ethyl salicylate and phenoxyethanol are added to the matrix solution at a ratio of 30%-40% of Capryol 90, 10%-25% of ethyl salicylate and 5%-8% of phenoxyethanol as a penetration enhancer to change the structure of the skin stratum corneum and thus improve drug permeability.

[0066] S2.2 Set the stirring rate to 200 rpm and continue stirring for 30-45 minutes to ensure that all ingredients are evenly mixed and completely dissolved.

[0067] S3. Preparation of cross-linked polymer matrix

[0068] The goal of this step is to form chemical bonds between polymer units to produce a three-dimensional network structure, thereby enhancing the mechanical strength and stability of the patch and improving durability and adhesion. The specific steps are:

[0069] S3.1 Set the stirring rate of the matrix solution to 200 rpm and the stirring time to ten minutes to ensure that the cross-linking agent is evenly distributed and the macromolecular chains fully form stable chemical bonds.

[0070] S3.2 Add glutaraldehyde and melamine in a ratio of 2:1 to the solution under stirring to avoid local concentration being too high or too low, thereby ensuring the uniformity of the cross-linking reaction.

[0071] S4. Add antioxidants

[0072] The goal of this step is to protect the stability of tetrahydrocurcumin and prevent oxidative degradation during preparation and storage. The specific steps are:

[0073] Add 0.5% w / w butylated hydroxytoluene (BHT) to the matrix solution, set the stirring rate to 200 rpm, and continue stirring for 10 minutes to ensure uniform mixing.

[0074] S5. Casting and drying

[0075] The goal of this step is to form a uniform patch film and remove excess solvent to ensure the quality and uniformity of the patch. The specific steps are:

[0076] S5.1 Pour the prepared solution evenly into the mold, maintaining a uniform thickness of 0.5-1mm to form a uniform patch film.

[0077] S5.2 Place the mold in a vacuum drying oven and dry it. Set the temperature to 40°C and the vacuum degree to 0.1 MPa. Continue drying for 24 hours to ensure that the solvent is completely evaporated.

[0078] S6. Plasma treatment

[0079] The goal of this step is to enhance the surface activity of the patch through plasma treatment, and improve the adhesion and permeability of the patch on the skin. The specific steps are:

[0080] S6.1 Select gas type

[0081] Different gases need to be selected for different patch surface modification requirements. For example, oxygen: increases hydrophilicity and promotes transdermal absorption. Argon: enhances surface activity and is suitable for non-polar matrices. Nitrogen: introduces nitrogen groups to improve chemical stability. Mixed gases, such as oxygen and nitrogen: comprehensive modification effects. Here, oxygen or argon is selected, the gas flow rate is set to 50sccm, and the treatment time is 1-3 minutes.

[0082] S6.2 Select power type

[0083] Commonly used power supplies include radio frequency power supply, pulse power supply and direct current power supply. Radio frequency power supply is suitable for low temperature treatment to avoid thermal damage. Pulse power supply controls energy release and optimizes surface uniformity. Direct current power supply provides stable power and is suitable for uniform modification. The present invention utilizes low temperature plasma treatment, selects radio frequency power supply, connects power supply and checks parameters to ensure that the power supply connection of the equipment is normal and the parameter settings meet the experimental requirements.

[0084] S6.3 Determine processing power and time

[0085] For the initial setting, start with a low power of 10W and gradually increase it to observe the effect, avoiding surface etching or performance degradation caused by high power.

[0086] In the process of gradually increasing the power, it was found that 10W-30 W is suitable for thin film patches to avoid material damage; 30W-60 W enhances surface modification and is suitable for ordinary patches; 60W-100 W is used for thick film patches or strong modification requirements.

[0087] The final power setting of the present invention is 150W, and the experimental time starts with 1 minute as the basis and is gradually extended to the optimization point. The experimental time is 30 seconds-1 minute: slight surface modification, suitable for thin films. The experimental time is 1 minute-3 minutes: deep modification, enhancing transdermal absorption effect. The experimental time>3 minutes is used for durable patches with special needs. The experimental time is 2 minutes for the best effect, so 2 minutes is set here, and the power and time can also be adjusted appropriately according to the specific needs of the patch.

[0088] S6.4 Plasma treatment

[0089] Place the dried patch film into the plasma treatment equipment, ensure that the patch surface is facing up and fixed flat, and keep the nozzle 2-3 cm away from the patch surface to ensure uniform treatment of the patch surface. Start the treatment program according to the set gas type, power supply, power and time. During the treatment process, monitor whether the equipment parameters are stable and observe whether there are any abnormalities on the patch surface.

[0090] S6.5 subsequent optimization

[0091] Observe the adhesion and hydrophilicity effects of the patch. If the expected effect is not achieved, gradually adjust the gas ratio, power, and time, and record the optimal processing parameters in the experimental report for repeated preparation.

[0092] S7. Cutting and packaging

[0093] The goal of this step is to make the final product meet the needs and maximize the material utilization rate. The specific steps are:

[0094] Cut the processed patches into the required size to ensure that each patch is uniform, and put the cut patches into sealed packages to avoid contact with moisture and oxygen in the air to ensure the stability of the drug.

[0095] Since the plasma treatment in step S6 is performed after the patch is prepared, the purpose is to improve the surface properties of the patch, such as hydrophilicity and permeability, so as to enhance the transdermal absorption effect of the drug. It is performed during the preparation process, so the plasma acts on the patch itself, mainly by modifying the surface of the patch to improve the drug permeability. Usually, low-temperature plasma is used to treat the hydrophilicity or other physical properties of the patch to enhance the drug release performance. When the patch is used, the plasma is directly applied to the skin to temporarily increase the permeability of the skin, and then the drug patch is applied to enhance the penetration of the drug in the skin.

[0096] The plasma-treated tetrahydrocurcumin transdermal patch of the present invention significantly improves drug transdermal absorption efficiency and patch performance through an optimized polymer matrix and a permeation enhancer combination, improves the flexibility of the patch through a matrix formed by hydroxypropyl methylcellulose HPMC, polyvinyl alcohol PVA and polyurethane PU in combination with a plasticizer, and then adds a permeation enhancer such as octanoate and ethyl salicylate to promote drug penetration through the skin barrier, and improves the mechanical strength of the patch through cross-linking with glutaraldehyde and melamine, introduces an antioxidant in the preparation process to ensure the chemical stability of tetrahydrocurcumin THC, and further enhances its hydrophilicity and adhesion by treating the surface of the patch with low-temperature plasma, thereby optimizing the drug release effect, and is suitable for targeted treatment of breast cancer.

[0097] The patch of the present invention is subjected to a performance evaluation experiment as follows:

[0098] After preparing the plasma tetrahydrocurcumin THC transdermal patch, in order to evaluate its performance, stability and effectiveness, the following experiments were carried out, including chemical stability experiments, physicochemical property characterization, transdermal absorption experiments, pharmacodynamics and in vivo experiments.

[0099] 1. Chemical stability test

[0100] Chemical stability experiments include drug content determination, antioxidant stability, and long-term stability testing.

[0101] The content of THC in the patch was determined by HPLC or UV-Vis method to ensure uniform drug content in the formula, evaluate the effect of antioxidants, ensure that THC is not oxidized and degraded during storage, and observe whether the drug content and physical form are stable under different temperature and humidity conditions, such as 25°C / 60% RH and 40°C / 75% RH. The test results are as follows:

[0102] Test items Testing time Storage conditions Tetrahydrocurcumin content (%) Antioxidant activity assessment Physical form observation Remark Drug content determination initial - 100 - - Reference Standards Drug content determination 1 month 25℃ / 60%RH 98.5 Stablize No significant changes Slightly reduced content, good stability Drug content determination 3 months 25℃ / 60%RH 97.5 Stablize No significant changes The content decreased slightly Drug content determination 1 month 40℃ / 75%RH 95.6 Stablize No significant changes Slightly poor stability Drug content determination 3 months 40℃ / 75%RH 92.1 Stablize Slight discoloration, still acceptable The content decreased significantly

[0103] Test items Testing time Storage conditions Antioxidant activity assessment Physical form observation Remark Antioxidant stability test initial - No oxidation - - Antioxidant stability test 1 month 25℃ / 60%RH No oxidation Color stability Good antioxidant effect Antioxidant stability test 3 months 25℃ / 60%RH Slightly oxidized Slight color change Slightly decreased stability Antioxidant stability test 1 month 40℃ / 75%RH Oxidation The color becomes noticeably lighter Poor oxidation resistance under high temperature and humidity Antioxidant stability test 3 months 40℃ / 75%RH Obvious oxidation Yellow color The antioxidant capacity is greatly reduced

[0104] Test items Testing time Storage conditions Tetrahydrocurcumin content (%) Antioxidant activity assessment Physical form observation Remark Long-term stability test initial - 100 - Smooth and undamaged - Long-term stability test 1 month 25℃ / 60%RH 99.5 Stablize No cracks, normal shape Stable and flexible Long-term stability test 3 months 25℃ / 60%RH 98.0 Stablize Slightly harder shape The patch remains in good condition Long-term stability test 1 month 40℃ / 75%RH 97.1 Stablize Minor cracks, slightly hardened Poor flexibility at high temperatures Long-term stability test 3 months 40℃ / 75%RH 94.3 Slightly oxidized More cracks and poor adhesion Need to improve formulation stability

[0105] The content of tetrahydrocurcumin was determined by HPLC or UV-Vis, and it was found that the drug ingredients in the patch were stable and there was no significant content loss during storage. The protective effect of the added antioxidant on tetrahydrocurcumin was evaluated by antioxidant property, and it was found that it was not oxidized and degraded during storage.

[0106] 2. Physical morphology observation

[0107] Evaluate the physical state of the patch, including color, flexibility, cracks, and adhesion, to ensure that the patch maintains its effectiveness and comfort in different environments.

[0108] In the application of transdermal targeted drug therapy for breast cancer, the tetrahydrocurcumin THC transdermal patch exhibits excellent physical and chemical stability after plasma treatment. Through strict drug content determination, the tetrahydrocurcumin in the patch is ensured to be evenly distributed, reducing dosage fluctuations and ensuring the sustained release and stability of the drug during administration. Since plasma treatment enhances the transdermal permeability of the drug, the drug can quickly and evenly penetrate the skin barrier and act directly on the targeted area, thereby achieving local high-concentration accumulation of the drug in the treatment of breast cancer while avoiding the occurrence of systemic side effects. In addition, the antioxidant stability test shows that the addition of antioxidants effectively delays the degradation of tetrahydrocurcumin during storage, ensuring the activity and stability of the drug during long-term storage, providing strong support for transdermal targeted therapy of breast cancer.

[0109] In the transdermal administration application of breast cancer, it is crucial to ensure drug stability. By carrying out long-term stability test, the patch is placed under different temperature and humidity conditions, such as 25 ° C / 60% RH and 40 ° C / 75% RH. The results show that the tetrahydrocurcumin transdermal patch treated with plasma can keep the active ingredient of the medicine from being degraded under these conditions, ensuring stability under different environments. This means that the transdermal patch of the present invention can maintain its effectiveness and reliability for a long time when treating breast cancer. In addition, the antioxidant stability test result also proves the combination of plasma and antioxidant, which can effectively prevent the oxidative degradation of tetrahydrocurcumin, thereby extending the shelf life of the medicine to the greatest extent, ensuring the effectiveness and safety of each administration. The stability of the patch under different storage conditions can be evaluated by experimental data, providing a basis for further optimizing formula and production technology.

[0110] 3. Transdermal absorption experiment

[0111] The transdermal absorption experiment includes in vitro permeation test, verification of permeation enhancer effect and verification of plasma treatment effect. A Franz diffusion cell apparatus is used to simulate transdermal absorption. The transdermal rate and absorption amount of tetrahydrocurcumin are tested through human skin or animal skin models. The permeation effects of patches with and without permeation enhancers are compared to confirm the effect of permeation enhancers. The transdermal performance of patches without plasma treatment and with plasma treatment is tested to evaluate the enhancing effect of plasma treatment on drug permeability.

[0112] Experimental Project Experimental Group Transdermal rate (µg / cm² / h) Cumulative absorption (µg / cm²) Skin permeability enhancement effect Remark In vitro penetration test No penetration enhancer - control group 5.2 124.8 - Baseline data In vitro penetration test Use of penetration enhancer Capryol 90 7.8 185.4 Increase by 50% Penetration enhancers significantly increase the penetration rate In vitro penetration test Use of penetration enhancer ethyl salicylate 6.5 155.2 27% increase Has a moderate enhancement effect In vitro penetration test Use the penetration enhancer phenoxyethanol 6.0 144.0 Increase by 15% The penetration enhancement effect is relatively mild

[0113] Experimental Project Experimental Group Transdermal rate (µg / cm² / h) Cumulative absorption (µg / cm²) Skin permeability enhancement effect Remark Plasma treatment effect verification Untreated patch 5.2 124.8 - Control group data Plasma treatment effect verification Plasma-treated patch - before treatment 7.8 168.0 Increased by 34.6% Plasma treatment to enhance permeability Plasma treatment effect verification Plasma-treated patch-after treatment 8.5 204.0 Increased by 63.5% Significantly enhanced permeability

[0114] Experimental Project Experimental Group Transdermal rate (µg / cm² / h) Cumulative absorption (µg / cm²) Skin permeability enhancement effect Remark Comparison of comprehensive penetration performance No penetration enhancer + untreated patch 5.2 124.8 - Baseline data Comparison of comprehensive penetration performance Use of penetration enhancer + untreated patch 7.8 185.4 Increase by 50% Penetration enhancer has obvious effect Comparison of comprehensive penetration performance No penetration enhancer + plasma treatment 7.0 168.0 Increased by 34.6% Plasma treatment has a certain effect Comparison of comprehensive penetration performance Use penetration enhancer + plasma treatment 8.5 204.0 Increased by 63.5% The combination of penetration enhancers and plasma treatment is most effective

[0115] like Figure 1 As shown, experimental group 1 represents no use of permeation enhancer + untreated patch, experimental group 2 represents use of permeation enhancer + untreated patch, experimental group 3 represents no use of permeation enhancer + plasma treatment, and experimental group 4 represents use of permeation enhancer + plasma treatment.

[0116] In vitro permeation test: The permeation rate and absorption of tetrahydrocurcumin in the skin model under different treatments were tested by Franz diffusion cell apparatus. The control group did not use permeation enhancers, while the experimental groups used different types of permeation enhancers.

[0117] The effect of plasma treatment on the transdermal rate and absorption of tetrahydrocurcumin was tested. The test results before and after treatment showed that plasma treatment can significantly improve the transdermal permeability of the drug.

[0118] Comparison of comprehensive permeability performance: The comprehensive effects of different combinations, permeation enhancers and plasma treatment on the transdermal performance of tetrahydrocurcumin were compared. The results showed that the best permeation effect can be achieved when permeation enhancers and plasma treatment are used in combination. Through experimental data, the effect of different permeation enhancers and plasma treatment on the transdermal absorption performance of tetrahydrocurcumin can be effectively evaluated, providing an important basis for further optimizing the patch formula.

[0119] The transdermal absorption experiment further verified the significant effect of penetration enhancers and plasma treatment on drug penetration through the skin. When using Franz diffusion cell equipment for in vitro permeation testing, the results showed that plasma treatment can significantly improve the transdermal rate of tetrahydrocurcumin and increase its absorption. Especially in the treatment of breast cancer patients, the drug can quickly reach the deep layer of the skin and be transported to the tumor tissue through the blood circulation. Combined with the use of penetration enhancers, the permeability of tetrahydrocurcumin has been further enhanced, providing a more accurate and efficient drug delivery pathway for targeted therapy. By increasing the concentration of drugs in the local tumor, targeted treatment of breast cancer can be achieved, while reducing side effects on healthy tissues, greatly improving the treatment effect.

[0120] IV. Pharmacodynamics and in vivo experiments

[0121] Including in vivo pharmacokinetic tests, anti-inflammatory and antioxidant effect tests, animal experiments were used to evaluate the transdermal absorption and bioavailability of tetrahydrocurcumin, and to determine the changes in the concentration of tetrahydrocurcumin in plasma. Anti-inflammatory and antioxidant effect tests: The anti-inflammatory and antioxidant effects of the patch were tested in animal models to verify its biological activity.

[0122] The results of in vivo pharmacokinetic tests are shown in the following table:

[0123] Experimental Project Experimental Group Plasma concentration µg / ml Plasma concentration Cmax Bioavailability (%) Remark In vivo pharmacokinetic testing No penetration enhancer + untreated patch 1 hour: 0.3 2 hours: 0.5 4 hours: 0.7 Cmax=0.8 18% Baseline data In vivo pharmacokinetic testing Use of penetration enhancer + untreated patch 1 hour: 0.6 2 hours: 1.24 hours: 1.5 Cmax=2.0 35% Penetration enhancers improve bioavailability In vivo pharmacokinetic testing No penetration enhancer + plasma treatment 1 hour: 0.4 2 hours: 0.8 4 hours: 1.2 Cmax=1.4 28% Plasma treatment enhances absorption rate In vivo pharmacokinetic testing Use penetration enhancer + plasma treatment 1 hour: 0.8 2 hours: 1.8 4 hours: 2.5 Cmax=3.2 50% Penetration enhancer + plasma treatment significantly improves bioavailability

[0124] In vivo pharmacokinetic test: The plasma concentration, maximum concentration Cmax and bioavailability of tetrahydrocurcumin transdermal patches with different treatments were tested in animals. The results showed that both permeation enhancers and plasma treatment can significantly improve the bioavailability of tetrahydrocurcumin, especially when the two are used in combination, the bioavailability reaches 50%.

[0125] The results of the antioxidant effect test are shown in the following table:

[0126] Experimental Project Experimental Group Antioxidant Effect Remark Antioxidant effect test No penetration enhancer + untreated patch Antioxidant activity: 12.5% Baseline data Antioxidant effect test Use of penetration enhancer + untreated patch Antioxidant activity: 25.0% Penetration enhancers improve antioxidant activity Antioxidant effect test No penetration enhancer + plasma treatment Antioxidant activity: 18.5% Plasma treatment enhances antioxidant activity Antioxidant effect test Use penetration enhancer + plasma treatment Antioxidant activity: 35.0% Penetration enhancer + plasma treatment significantly improves antioxidant activity

[0127] Antioxidant effect test: The antioxidant activity of tetrahydrocurcumin was tested to evaluate its antioxidant effect. Both penetration enhancers and plasma treatment can improve antioxidant activity, and the antioxidant effect is most significant when the two are used in combination.

[0128] The anti-inflammatory test results are shown in the following table:

[0129] Experimental Project Experimental Group Anti-inflammatory effect Remark Anti-inflammatory effect test No penetration enhancer + untreated patch Inflammation score: 5.2 / 10 Baseline data Anti-inflammatory effect test Use of penetration enhancer + untreated patch Inflammation score: 3.0 / 10 Penetration enhancers significantly reduce inflammatory responses Anti-inflammatory effect test No penetration enhancer + plasma treatment Inflammation score: 4.2 / 10 Plasma treatment reduces inflammatory response Anti-inflammatory effect test Use penetration enhancer + plasma treatment Inflammation score: 2.1 / 10 Penetration enhancer + plasma treatment significantly improves anti-inflammatory effect

[0130] Anti-inflammatory effect test: In the animal inflammation model, the inflammation score was significantly reduced after using tetrahydrocurcumin transdermal patch. Both penetration enhancers and plasma treatment can improve the anti-inflammatory effect, and the effect is best when used in combination.

[0131] The above experimental data provide strong support for further optimizing the formulation of tetrahydrocurcumin transdermal patch, and verify the enhancement effect of penetration enhancer and plasma treatment on the biological activity of drugs. In the anti-tumor treatment of breast cancer, pharmacodynamic experiments have proved the effectiveness of plasma tetrahydrocurcumin transdermal patch. Animal experiments show that tetrahydrocurcumin exhibits significant anti-inflammatory and antioxidant effects after being absorbed through the skin, and can effectively inhibit the proliferation and spread of breast cancer cells. In particular, the biological activity of the drug has been enhanced after plasma treatment, showing a stronger anti-cancer effect. Further anti-inflammatory and antioxidant effect tests show that tetrahydrocurcumin can not only reduce the local inflammatory response caused by breast cancer, but also reduce the oxidative stress of tumor cells by inhibiting the production of free radicals, thereby enhancing the anti-cancer effect. In vivo pharmacokinetic experiments have verified the effect of tetrahydrocurcumin transdermal patch in the treatment of breast cancer through animal models. In these experiments, tetrahydrocurcumin transdermal patches were applied to animal models, and the results showed that the patches treated with plasma could significantly improve the absorption rate and bioavailability of the drug. The concentration of tetrahydrocurcumin in plasma was significantly increased in the patch after plasma treatment, and the maximum concentration Cmax and time Tmax were significantly improved compared with traditional treatment methods. This shows that plasma treatment not only improves the transdermal absorption of the drug, but also enhances the concentration of the drug in breast cancer tissue, further improving the therapeutic effect of the drug. This improved pharmacokinetic property ensures the rapid release and sustained action of tetrahydrocurcumin in the targeted tumor area, allowing breast cancer patients to receive more precise and effective treatment.

[0132] In summary, the advantages of the present invention are:

[0133] (1) Technological innovation: In the application of transdermal targeted therapy for breast cancer, the tetrahydrocurcumin THC transdermal patch exhibits excellent physical and chemical stability after plasma treatment. Through strict drug content determination, the tetrahydrocurcumin in the patch is ensured to be evenly distributed, the dosage fluctuation is reduced, and the sustained release and stable effect of the drug during the drug administration process are guaranteed. Since plasma treatment enhances the transdermal permeability of the drug, the drug can quickly and evenly penetrate the skin barrier and directly act on the targeted area, thereby achieving local high-concentration accumulation of the drug in the treatment of breast cancer. In the transdermal drug administration application of breast cancer, it is crucial to ensure drug stability. Through long-term stability testing, the patch was placed under different temperature and humidity conditions for investigation. The results showed that the plasma-treated tetrahydrocurcumin transdermal patch can keep the active ingredients of the drug from degradation under these conditions, ensuring stability in different environments. This means that the transdermal patch can maintain its effectiveness and reliability for a long time in the treatment of breast cancer. In addition, the antioxidant stability test results also proved that the combination of plasma and antioxidants can effectively prevent the oxidative degradation of tetrahydrocurcumin, thereby maximizing the shelf life of the drug and ensuring the effectiveness and safety of each administration. The transdermal absorption experiment further verified the significant effect of penetration enhancers and plasma treatment on drug penetration through the skin. When the Franz diffusion cell equipment was used for in vitro permeation testing, the results showed that the permeation rate was 8.5µg / cm² / h after the use of penetration enhancer + plasma treatment, and the cumulative absorption increased by 63.5%. When the penetration enhancer was used in combination with plasma treatment, the best penetration effect could be achieved. In the treatment of breast cancer patients, the drug could quickly reach the deep layer of the skin and be transported to the tumor tissue through the blood circulation. Combined with the use of penetration enhancers, the permeability of tetrahydrocurcumin was further enhanced, providing a more accurate and efficient drug delivery route for targeted therapy. By increasing the concentration of the drug in the local tumor, targeted treatment of breast cancer can be achieved, while reducing side effects on healthy tissues and greatly improving the treatment effect.

[0134] (2) Drug delivery effect: In vivo pharmacokinetic experiments verified the effect of tetrahydrocurcumin transdermal patches in the treatment of breast cancer through animal models. The plasma concentration, maximum concentration Cmax and bioavailability of tetrahydrocurcumin transdermal patches with different treatments were tested in animals. The results showed that both permeation enhancers and plasma treatment could significantly improve the bioavailability of tetrahydrocurcumin, especially when the two were used in combination, the bioavailability reached 50%. This shows that plasma treatment not only improves the transdermal absorption of the drug, but also enhances the concentration of the drug in breast cancer tissue, further improving the therapeutic effect of the drug. This improved pharmacokinetic property ensures the rapid release and sustained action of tetrahydrocurcumin in the targeted tumor area, enabling breast cancer patients to receive more precise and effective treatment.

[0135] (3) Clinical application potential: The design of the transdermal patch of the present invention enables the drug to act directly on the target area. By enhancing the transdermal permeability of the drug, tetrahydrocurcumin can form high concentrations in the local area of ​​breast cancer and directly act on the tumor tissue. This can achieve precise targeted treatment, deliver the drug directly to the tumor location, improve the efficacy, and avoid the distribution of the drug in other parts of the body, thereby reducing unnecessary side effects.

[0136] (4) Commercial value and promotion significance: Breast cancer is the most common female cancer worldwide. With the increasing demand for cancer treatment, the market demand for targeted cancer treatment is also growing rapidly. Transdermal drug delivery, as a non-invasive drug delivery method, has broad market prospects. The tetrahydrocurcumin transdermal patch produced by this technical solution can play a role in the adjuvant treatment of breast cancer and inhibiting tumor spread, filling the gap in existing treatment options and becoming a powerful supplement in the field of tumor treatment.

[0137] The above technical scheme significantly improves the effect of tetrahydrocurcumin THC transdermal patch in the treatment of breast cancer through the synergistic effect of plasma treatment and penetration enhancer. Plasma treatment enhances the transdermal permeability and surface stability of the drug, enabling the drug to quickly penetrate the skin barrier and achieve high concentration accumulation in the tumor area while avoiding systemic side effects. Long-term stability and antioxidant tests have shown that the patch can maintain the activity of the drug under different temperature and humidity conditions and extend the shelf life. In vitro and in vivo experiments show that transdermal absorption rate, bioavailability and pharmacodynamic properties are significantly improved, showing excellent anti-inflammatory, antioxidant and anti-tumor effects, and effectively inhibiting the proliferation and spread of breast cancer cells. The present invention not only significantly improves the transdermal absorption and bioavailability of tetrahydrocurcumin by innovatively combining low-temperature plasma treatment and transdermal patch technology, but also realizes the targeted delivery of local high-concentration drugs for breast cancer. Its non-invasiveness and long-term stability make it have broad prospects in actual clinical applications, and provide a new type of efficient, safe and convenient treatment for breast cancer patients.

Claims

1. A tetrahydrocurcumin transdermal patch for targeted treatment of breast cancer, characterized in that: Includes active ingredients, polymer matrix, plasticizers, penetration enhancers, solvents, cross-linkers and stabilizers; The active ingredient is tetrahydrocurcumin THC, accounting for 1%-5%; The polymer matrix includes hydroxypropyl methylcellulose HPMC accounting for 5%-15%, polyvinyl alcohol PVA accounting for 2%-8% and polyurethane PU accounting for 2%-8%; The plasticizer includes glycerol accounting for 3%-7%, polyethylene glycol PEG400 accounting for 5%-10%, and carbomer accounting for 0.5%-2%; The penetration enhancer includes 1%-3% of caprylic acid / caprylate Capryol 90, 0.5%-1% of ethyl salicylate and 0.5%-1% of phenoxyethanol; The solvent includes 10%-20% ethanol and 20%-30% water; The cross-linking agent includes 0.1%-0.5% glutaraldehyde and 0.1%-0.5% melamine; The stabilizer is an antioxidant butylated hydroxytoluene BHT, accounting for 0.1%-0.5%; After the patch is prepared, it is subjected to plasma treatment.

2. A method for preparing the tetrahydrocurcumin transdermal patch for targeted treatment of breast cancer according to claim 1, characterized in that: The following steps are involved: S1. Dissolution and pretreatment of raw materials S1.1 Dissolve tetrahydrocurcumin THC in ethanol solution and continue stirring until completely dissolved; S1.2 Preparation of polymer matrix material: Dissolve hydroxypropyl methylcellulose HPMC in water, add polyvinyl alcohol PVA and polyurethane PU, and continue stirring until a uniform matrix solution is formed; S1.3 Add plasticizer: add glycerol, polyethylene glycol PEG 400 and carbomer into the base solution in a ratio of 5:3:2 and stir; S2. Add penetration enhancer S2.1 Add caprylic acid / caprylate Capryol 90, ethyl salicylate and phenoxyethanol to the base solution; S2.2 Continue stirring until all ingredients are evenly mixed and completely dissolved; S3. Preparation of cross-linked polymer matrix S3.1 Stir the matrix solution to ensure uniform distribution of the crosslinker; S3.2 Add glutaraldehyde and melamine in a ratio of 2:1 to the matrix solution under stirring; S4. Add antioxidants Add butylated hydroxytoluene (BHT) to the base solution and ensure uniform mixing; S5. Casting and drying S5.1 Pour the prepared solution evenly into the mold, maintaining a uniform thickness of 0.5mm-1mm to form a uniform patch film; S5.2 Place the mold in a vacuum drying oven and dry it for 24 hours to ensure that the solvent is completely evaporated; S6. Plasma treatment S6.1 Select gas type Select oxygen or argon, set the gas flow rate to 50 sccm, and process for 1-3 minutes; S6.2 Select power type Select the RF power supply, connect the power supply and check the parameters to ensure that the power supply connection of the equipment is normal and the parameter settings meet the experimental requirements; S6.3 Determine processing power and time Set the power to 150W and the time to 2 minutes; S6.4 Plasma treatment Place the dried patch film into the plasma treatment equipment, ensure that the patch surface is facing upward and fixed flat, and keep the nozzle 2-3 cm away from the patch surface to ensure uniform treatment of the patch surface; start the treatment program according to the set gas type, power supply, power and time, monitor whether the equipment parameters are stable during the treatment process, and observe whether there are any abnormalities on the patch surface; S6.5 subsequent optimization Observe the adhesiveness and hydrophilicity of the patch. If the expected effect is not achieved, gradually adjust the gas ratio, power and time, and record the optimal processing parameters in the experimental report for repeated preparation; S7. Cutting and packaging Cut the processed patches into the required size to ensure that each patch is uniform, and put the cut patches into sealed packages to avoid contact with moisture and oxygen in the air to ensure the stability of the drug.

3. The method for preparing the tetrahydrocurcumin transdermal patch for targeted treatment of breast cancer according to claim 2, characterized in that: The stirring rate of the present invention is set to 200 rpm.

4. The method for preparing the tetrahydrocurcumin transdermal patch for targeted treatment of breast cancer according to claim 3, characterized in that: In step S5.2, the temperature is set to 40°C and the vacuum degree is set to 0.1 MPa.

5. The method for preparing the tetrahydrocurcumin transdermal patch for targeted treatment of breast cancer according to claim 4, characterized in that: In step S2.1, the proportion of caprylic acid / caprylate Capryol 90 is 30%-40%, the proportion of ethyl salicylate is 10%-25%, and the proportion of phenoxyethanol is 5%-8%.

Images