Dexketoprofen tromethamine patch and preparation method thereof

Abstract

This invention provides a dextro-ketoprofen tromethamine patch and its preparation method. The preparation method includes: S100, using raw materials including dextro-ketoprofen tromethamine, first polyacrylic acid, poly-N-isopropylacrylamide, chitosan, and titanium dioxide, preparing ketoprofen nanofibers by electrospinning; S200, using raw materials including ropivacaine, L-phenylalanine, second polyacrylic acid, and tetraethyl orthosilicate, preparing a matrix sol by a sol-gel method; S300, mixing the ketoprofen nanofibers and the matrix sol, and performing a gelation treatment to prepare the dextro-ketoprofen tromethamine patch. The dextro-ketoprofen tromethamine patch obtained by this invention has good photostability and a good sustained-release effect.

Description

Technical Field

[0001] This invention relates to the technical field of pharmaceutical chemistry, and more specifically, to a dextromethorphan tromethamine plaster and its preparation method. Background Technology

[0002] Ketoprofen is a nonsteroidal anti-inflammatory drug (NSAID), also known as ibuprofenone. Its main indication is the relief of mild to moderate pain, including headaches, toothaches, joint pain, and muscle pain. Prostaglandins can sensitize nerve endings, leading to pain. Ketoprofen reduces prostaglandin synthesis, thus alleviating pain. Ketoprofen can also reduce discomfort caused by inflammation and is suitable for inflammatory diseases such as arthritis and rheumatoid arthritis. Ketoprofen exerts its anti-inflammatory effect by inhibiting the activity of cyclooxygenase (COX), a key enzyme involved in the conversion of arachidonic acid to prostaglandins. Prostaglandins are pro-inflammatory mediators involved in the inflammatory response; ketoprofen inhibits COX activity, thereby reducing inflammatory symptoms. Ketoprofen also has a hypothermic effect and is suitable for discomfort caused by fever. During fever, leukocytes release prostaglandins, which cause body temperature to rise by affecting the hypothalamic thermoregulation center. Ketoprofen reduces the stimulation of the hypothalamic thermoregulation center by inhibiting the synthesis of prostaglandins, thereby alleviating the symptoms of fever.

[0003] Ketoprofen gel or patch is a topical medication with promising applications in recent years. Ketoprofen gel uses ketoprofen as its main active ingredient and is applied directly to the skin surface and local tissues through application and massage. It penetrates the skin and releases ketoprofen at the site of inflammation for local treatment of pain and inflammation. Ketoprofen gel utilizes transdermal drug delivery, a non-invasive route of drug delivery through the skin. Unlike traditional direct drug delivery, transdermal delivery does not require needle injection or involve the gastrointestinal tract. Small molecule drugs can typically cross the stratum corneum of the epidermis via intracellular pathways, thus avoiding first-pass metabolism and drug loss. Furthermore, the drug can be delivered without interference from pH, enzymes, or intestinal bacteria.

[0004] A series of existing technologies with publication numbers CN118526444A, CN116747208A, CN103156803A, and CN110693860A are dedicated to providing ketoprofen drugs for external use.

[0005] However, these existing technologies have the problem that the active ingredient of ketoprofen is unstable and easily decomposed under light. For ketoprofen used as a patch, improving its photostability is particularly important. Summary of the Invention

[0006] One of the problems solved by this invention is how to provide a dextro-ketoprofen patch with better photostability.

[0007] To solve at least one of the above problems, the present invention provides a method for preparing a dextromethorphan tromethamine plaster, the method comprising:

[0008] S100 uses raw materials including dextro-ketoprofen tromethamine, first polyacrylic acid, poly-N-isopropylacrylamide, chitosan and titanium dioxide to prepare ketoprofen nanofibers by electrospinning.

[0009] S200 uses raw materials including ropivacaine, L-phenylalanine, second polyacrylic acid and tetraethyl orthosilicate to prepare a matrix sol through the sol-gel method;

[0010] S300: Ketoprofen nanofibers and matrix sol are mixed and gelled to prepare dextro-ketoprofen tromethamine plaster.

[0011] In any of the above technical solutions, S100 specifically includes:

[0012] S110: The core spinning solution is prepared by mixing raw materials including dextromethorphan tromethamine, first polyacrylic acid, polyvinylpyrrolidone, ethanol, polyvinyl alcohol and water.

[0013] S120: A shell spinning solution is prepared by mixing raw materials including titanium dioxide, chitosan, poly-N-isopropylacrylamide, methylcellulose, polylactic acid, water and hexafluoroisopropanol.

[0014] S130. Inject the core spinning solution and the shell spinning solution into a coaxial electrospinning device, and obtain ketoprofen nanofibers by electrospinning.

[0015] The core of the ketoprofen nanofiber contains dextro-ketoprofen tromethamine, while the outer wall contains poly(N-isopropylacrylamide) and titanium dioxide.

[0016] In any of the above technical solutions, S110 specifically includes: according to the mass ratio of dextromethorphan tromethorphan: first polyacrylic acid: polyvinylpyrrolidone: ethanol: polyvinyl alcohol: water = (0.2-0.4): (8-12): (8-12): (16-20): (16-20): 100, firstly, polyvinyl alcohol and half of the water are mixed in a first container, then the uniform mixture of dextromethorphan tromethorphan and ethanol is added to the first container and mixed, and finally, the first polyacrylic acid and polyvinylpyrrolidone are swollen in the other half of the water and added to the first container and mixed, magnetically stirred for 8 to 10 hours, and allowed to stand for 1.5 to 2 hours to degas, to obtain the core spinning solution.

[0017] In any of the above technical solutions, S120 specifically includes: according to the mass ratio of titanium dioxide: chitosan: poly-N-isopropylacrylamide: methylcellulose: polylactic acid: water: hexafluoroisopropanol = (0.2-0.6): (4-6): (8-12): (8-12): (14-18): (40-50): 100, first mix methylcellulose, polylactic acid and hexafluoroisopropanol in a second container, then add a uniform mixture of titanium dioxide, chitosan, poly-N-isopropylacrylamide and water to the second container and mix, magnetically stir for 2 to 4 hours, and let stand for 0.5 to 2 hours to degas, to obtain a shell spinning solution;

[0018] In any of the above technical solutions, S130 specifically includes: injecting the core spinning solution and the shell spinning solution into a coaxial electrospinning device, controlling the injection flow rate of the core spinning solution to be 0.7 mL / h to 0.8 mL / h, controlling the injection flow rate of the shell spinning solution to be 0.3 mL / h to 0.4 mL / h, performing electrospinning under a voltage condition of 12 kV to 14 kV, receiving the solution with tin foil at a receiving distance of 18 cm to 20 cm, and vacuum drying at room temperature for 18 h to 24 h after receiving to obtain ketoprofen nanofibers.

[0019] In any of the above technical solutions, S200 specifically includes:

[0020] S210 uses raw materials including ropivacaine, L-phenylalanine, second polyacrylic acid, tetraethyl orthosilicate, ethanol and water, and hydrochloric acid as a catalyst to obtain a matrix sol through a sol-gel reaction.

[0021] In any of the above technical solutions, S210 specifically includes: according to the mass ratio of ropivacaine: L-phenylalanine: second polyacrylic acid: tetraethyl orthosilicate: ethanol: water = (1-1.5): (2-3): (6-8): (8-10): (30-35): 100, first mix ropivacaine, tetraethyl orthosilicate and ethanol evenly in a third container, then add the uniform mixture of L-phenylalanine, second polyacrylic acid and water to the third container and mix, add an aqueous solution of hydrochloric acid dropwise to adjust the pH value to 4 to 5, and stir magnetically for 3 to 4 hours to obtain the matrix sol.

[0022] In any of the above technical solutions, S300 specifically includes:

[0023] S310. Mix and disperse ketoprofen nanofibers evenly in a matrix sol to obtain ketoprofen sol;

[0024] S320. Soak the ketoprofen sol in anhydrous ethanol for 30 to 36 hours, then remove, wash, and dry to obtain dextro-ketoprofen tromethamine plaster.

[0025] In any of the above technical solutions, in S310, the mass ratio of ketoprofen nanofibers to matrix sol is (40-60):100.

[0026] The present invention also provides a dextro-ketoprofen tromethamine patch, which is obtained by the preparation method of any of the above technical solutions.

[0027] Beneficial effects

[0028] The preparation method of this invention first uses raw materials including dextro-ketoprofen tromethamine, first polyacrylic acid, poly-N-isopropylacrylamide, chitosan, and titanium dioxide to prepare ketoprofen nanofibers through electrospinning. Then, using raw materials including ropivacaine, L-phenylalanine, second polyacrylic acid, and tetraethyl orthosilicate, a matrix sol is prepared via a sol-gel method. Finally, the ketoprofen nanofibers and the matrix sol are mixed and gelled to prepare a dextro-ketoprofen tromethamine patch.

[0029] Dextromethorphan tromethamine is an over-the-counter medication used to treat joint swelling and pain caused by rheumatoid arthritis, osteoarthritis, and other conditions. Its patch formulation facilitates drug release at the affected area and is suitable for long-term administration.

[0030] Compared to existing gel-based ketoprofen patches, this invention prepares dextro-ketoprofen tromethamine drug-loaded nanofibers through electrospinning and uses titanium dioxide as a light-shielding agent to protect the dextro-ketoprofen tromethamine.

[0031] Ropivacaine can shorten the analgesic onset time of dextromethorphan tromethorphan plaster, and L-phenylalanine can protect dextromethorphan tromethorphan, further improving its storage stability.

[0032] Furthermore, compared to water-soluble polymeric gels in existing technologies, this invention employs an inorganic gel system based on silica, which has higher mechanical strength, thermal stability, and chemical stability, effectively protecting the internal dextro-ketoprofen tromethamine drug-loaded nanofibers. Detailed Implementation

[0033] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, a detailed description of specific embodiments of the present invention will be provided below.

[0034] Unless otherwise specified, all reagents and raw materials used in this invention are commercially available. Experimental methods in the following examples that do not specify particular conditions should be performed according to conventional methods and conditions, or as selected in the product instructions.

[0035] The preparation method of the dextromethorphan tromethamine plaster of the present invention includes:

[0036] S100 uses raw materials including dextro-ketoprofen tromethamine, first polyacrylic acid, poly-N-isopropylacrylamide, chitosan and titanium dioxide to prepare ketoprofen nanofibers by electrospinning.

[0037] S200 uses raw materials including ropivacaine, L-phenylalanine, second polyacrylic acid and tetraethyl orthosilicate to prepare a matrix sol through the sol-gel method;

[0038] S300: Ketoprofen nanofibers and matrix sol are mixed and gelled to prepare dextro-ketoprofen tromethamine plaster.

[0039] Dextrorotatory ketoprofen is the dextrorotatory form of ketoprofen and is the active ingredient in the racemic mixture of ketoprofen. Its effect is equivalent to twice that of the same dose of ketoprofen. Using dextrorotatory ketoprofen can reduce the toxic side effects caused by the levorotatory form (ineffective ingredient) of ketoprofen. Dextrorotatory ketoprofen is usually used as tromethamine salt.

[0040] Although dextrorotatory ketoprofen has a high content of the active ingredient tromethamine, its photostability is poor. Ketoprofen drugs can undergo rapid photolysis under sunlight. This is because the carbonyl group in the ketoprofen molecule is linked to two benzene rings, resulting in high conjugation between the carbonyl group and the two benzene rings. This leads to a very low n-π transition energy, easily generating a highly reactive triplet state, thus initiating the photolysis reaction. For ketoprofen patches used as transdermal preparations, improving their photostability is particularly important.

[0041] To improve the photostability of ketoprofen, this invention adds titanium dioxide as a light-blocking agent. Titanium dioxide particles typically range in size from 10 nanometers to 1 micrometer, corresponding to the wavelength of visible light. When light encounters titanium dioxide particles, it undergoes multiple scatterings on the particle surface. This scattering effect complicates the light's propagation path within the medium, making it difficult to penetrate and effectively reducing light transmittance. Furthermore, titanium dioxide has a certain absorption capacity in the ultraviolet region. It can absorb ultraviolet light and convert it into heat energy. This absorption prevents ultraviolet light from entering the blocked object. Finally, titanium dioxide has a relatively high refractive index. When light enters titanium dioxide from a medium with a low refractive index, refraction occurs, changing the direction of light propagation. This refraction effect also helps reduce light transmittance, thereby enhancing the light-blocking effect. Therefore, this invention utilizes the above-mentioned properties of titanium dioxide to improve the photostability of dextro-ketoprofen tromethamine.

[0042] Formulating ketoprofen into a gel system using water-soluble polymers, solvents, and other excipients is a common method for preparing ketoprofen patches in the prior art. However, ketoprofen has a relatively short half-life, and its drug release rate fluctuates significantly, making it difficult to guarantee stable efficacy. While the active ingredient in a single gel system of ketoprofen patches is easily absorbed, its rapid release results in an unsatisfactory sustained-release effect. Therefore, this invention prepares a drug-loaded fiber from dextro-ketoprofen tromethamine through electrospinning, and then mixes the drug-loaded fiber into the gel system to ensure a more stable release of dextro-ketoprofen tromethamine.

[0043] The onset time of oral ketoprofen is usually 0.5 to 2 hours after administration. Due to the long onset time of ketoprofen's analgesic effect, existing technologies have solutions to coordinate its effects by adding local anesthetic drugs (such as prilocaine, tetracaine, bupivacaine, etc.).

[0044] Among numerous local anesthetics, ropivacaine is one of the most commonly used long-acting local anesthetics in clinical practice. It has a rapid onset of action, a long duration of action, relatively low neurotoxicity, and a high safety profile. In addition to its anesthetic effect, ropivacaine also has analgesic effects, especially when used in small doses, where it can provide local analgesia.

[0045] Therefore, this invention employs a combination of ropivacaine and dextromethorphan tromethamine. Ropivacaine utilizes the principle that it produces an anesthetic effect by reversibly blocking the inflow of sodium ions into the nerve fiber cell membrane, thereby inhibiting impulse conduction along the nerve fiber. This works synergistically with ketoprofen. Ropivacaine has an onset time of approximately 10 minutes and is added to the gel matrix to ensure rapid release and action upon application. Thus, this invention, by combining ropivacaine and ketoprofen, allows the resulting ketoprofen to exert a better analgesic effect in treating pain such as arthritis, compensating for the slow onset of analgesia of ketoprofen itself.

[0046] In some embodiments of the present invention, S100 specifically includes:

[0047] S110: The core spinning solution is prepared by mixing raw materials including dextromethorphan tromethamine, first polyacrylic acid, polyvinylpyrrolidone, ethanol, polyvinyl alcohol and water.

[0048] S120: A shell spinning solution is prepared by mixing raw materials including titanium dioxide, chitosan, poly-N-isopropylacrylamide, methylcellulose, polylactic acid, water and hexafluoroisopropanol.

[0049] S130. Inject the core spinning solution and the shell spinning solution into a coaxial electrospinning device, and obtain ketoprofen nanofibers by electrospinning.

[0050] The core of the ketoprofen nanofiber contains dextro-ketoprofen tromethamine, while the outer wall contains poly(N-isopropylacrylamide) and titanium dioxide.

[0051] The purpose of the above steps is to prepare a bilayer composite fiber with dextro-ketoprofen tromethamine as the inner core and titanium dioxide and poly(N-isopropylacrylamide) as the outer protective walls through coaxial electrospinning. This allows titanium dioxide to be uniformly coated around the outer periphery of the ketoprofen nanofiber core, thus better reducing the impact of light on dextro-ketoprofen tromethamine.

[0052] Furthermore, poly(N-isopropylacrylamide) is a thermosensitive polymer. The thermosensitivity of poly(N-isopropylacrylamide) stems from the simultaneous presence of hydrophilic amide groups and hydrophobic isopropyl groups on its macromolecular chain. At low temperatures, hydrogen bonds form between the amide groups and water molecules, making poly(N-isopropylacrylamide) exhibit a hydrophilic and homogeneous system. However, as the temperature increases, these hydrogen bonds break, and the interactions between the hydrophobic isopropyl groups strengthen, leading to a phase transition in poly(N-isopropylacrylamide), transforming it into a hydrophobic and heterogeneous system. Therefore, when poly(N-isopropylacrylamide) in an aqueous system is heated to approximately 36°C, it will transform from a homogeneous system to a heterogeneous system. This invention utilizes the thermosensitive properties of poly(N-isopropylacrylamide) to co-coat the surface of the ketoprofen nanofiber core with N-isopropylacrylamide and titanium dioxide, forming a dense protective film. This prevents the release of the active ingredient, dextromethorphan tromethorphan, into the gel system protecting the drug-carrying fibers under low-temperature storage conditions. When the patch is used, it comes into contact with the human body and the temperature rises. As the poly(N-isopropylacrylamide) transforms from a homogeneous to a heterogeneous system, it shrinks. The outer shell of the ketoprofen nanofiber core gradually develops pores and fails, allowing the dextromethorphan tromethorphan to be released gradually.

[0053] More preferably, S110 specifically comprises: according to the mass ratio of dextromethorphan tromethorphan: first polyacrylic acid: polyvinylpyrrolidone: ethanol: polyvinyl alcohol: water = (0.2-0.4): (8-12): (8-12): (16-20): (16-20): 100, firstly, polyvinyl alcohol and half of the water are mixed in a first container, then the homogeneous mixture of dextromethorphan tromethorphan and ethanol is added to the first container and mixed, and finally, the first polyacrylic acid and polyvinylpyrrolidone are swollen in the other half of the water and added to the first container and mixed. The mixture is magnetically stirred for 8 to 10 hours and allowed to stand for 1.5 to 2 hours to degas, thereby obtaining the core spinning solution.

[0054] More preferably, S120 specifically comprises: according to the mass ratio of titanium dioxide: chitosan: poly-N-isopropylacrylamide: methylcellulose: polylactic acid: water: hexafluoroisopropanol = (0.2-0.6): (4-6): (8-12): (8-12): (14-18): (40-50): 100, first mixing methylcellulose, polylactic acid and hexafluoroisopropanol in a second container, then adding a uniform mixture of titanium dioxide, chitosan, poly-N-isopropylacrylamide and water to the second container and mixing, magnetically stirring for 2 to 4 hours, and standing for 0.5 to 2 hours to degas, to obtain a shell spinning solution.

[0055] More preferably, S130 specifically includes: injecting the core spinning solution and the shell spinning solution into a coaxial electrospinning device, controlling the injection flow rate of the core spinning solution to be 0.7 mL / h to 0.8 mL / h, controlling the injection flow rate of the shell spinning solution to be 0.3 mL / h to 0.4 mL / h, performing electrospinning under a voltage condition of 12 kV to 14 kV, receiving the solution with tin foil at a receiving distance of 18 cm to 20 cm, and vacuum drying at room temperature for 18 h to 24 h after receiving to obtain ketoprofen nanofibers.

[0056] In some embodiments of the present invention, S200 specifically includes:

[0057] S210 uses raw materials including ropivacaine, L-phenylalanine, second polyacrylic acid, tetraethyl orthosilicate, ethanol and water, and hydrochloric acid as a catalyst to obtain a matrix sol through a sol-gel reaction.

[0058] More preferably, S210 specifically includes: ropivacaine: L-phenylalanine: second polyacrylic acid: tetraethyl orthosilicate: ethanol: water = (1-1.5): (2-3): (6-8): (8-10): (30-35): 100. First, ropivacaine, tetraethyl orthosilicate, and ethanol are mixed evenly in a third container. Then, a uniform mixture of L-phenylalanine, second polyacrylic acid, and water is added to the third container and mixed. An aqueous solution of hydrochloric acid is added dropwise to adjust the pH value to 4 to 5. The mixture is magnetically stirred for 3 to 4 hours to obtain a matrix sol.

[0059] It should be noted that the gel system used in this invention is a silica inorganic gel. Accordingly, this invention mixes ropivacaine, L-phenylalanine, and tetraethyl orthosilicate in an aqueous alcohol system under the action of an acidic catalyst to prepare a sol containing ropivacaine and L-phenylalanine.

[0060] In some embodiments of the present invention, S300 specifically includes:

[0061] S310. Mix and disperse ketoprofen nanofibers evenly in a matrix sol to obtain ketoprofen sol;

[0062] S320. Soak the ketoprofen sol in anhydrous ethanol for 30 to 36 hours, then remove, wash, and dry to obtain dextro-ketoprofen tromethamine plaster.

[0063] More preferably, in S310, the mass ratio of ketoprofen nanofibers to matrix sol is (40-60):100.

[0064] After obtaining ketoprofen nanofibers and a matrix sol, this invention disperses the ketoprofen nanofibers in the matrix sol and ages the sol containing the active ingredient ketoprofen into a gel. Finally, the gel is cut, sterilized, and packaged to obtain the plaster.

[0065] The matrix sol of this invention also contains a certain amount of polyacrylic acid. Polyacrylic acid is a water-soluble polymer compound. When polyacrylic acid molecules dissolve in water, their side carboxyl groups partially ionize into carboxylate ions, thus acquiring a negative charge. In this invention, the shell of the ketoprofen nanofibers contains positively charged chitosan. Therefore, in the aqueous gel system containing polyacrylic acid, the ketoprofen nanofibers are effectively encapsulated by the aqueous gel system due to the electrostatic interaction between the positive and negative charges, resulting in the uniform and stable dispersion of the ketoprofen nanofibers in the aqueous gel system composed of silica and polyacrylic acid.

[0066] Furthermore, the raw materials for polylactic acid (PLA) fibers mainly come from starchy agricultural products such as corn, wheat, and sugar beets, which possess excellent hydrophilicity. Therefore, ketoprofen nanofibers with PLA added to the shell are more easily and stably dispersed in aqueous gel systems.

[0067] Compared to aqueous polymeric compound gel systems, the silica-based inorganic gel system used in this invention not only has higher mechanical strength, thermal stability, and chemical stability, but also has poor compatibility with organic ketoprofen nanofibers. This allows the gel system of this invention to effectively protect the internal dextro-ketoprofen tromethamine drug-loaded nanofibers, preventing the release of the dextro-ketoprofen tromethamine active ingredient before use.

[0068] Example 1

[0069] This embodiment provides a series of dextromethorphan tromethamine plaster samples, the raw material ratios of which are detailed in Table 1.

[0070] Table 1

[0071]

[0072] The process steps adopted are as follows:

[0073] S1. Dissolve dextromethorphan tromethorphan in ethanol at room temperature by stirring until completely dissolved; mix the first polyacrylic acid and polyvinylpyrrolidone in half the mass of water by stirring until completely swollen; mix polyvinyl alcohol and the remaining half the mass of water in a beaker, then add the homogeneous mixture of dextromethorphan tromethorphan and ethanol to the first container and mix; finally, add the swollen first polyacrylic acid and polyvinylpyrrolidone to the first container and mix; after mixing, turn on the magnetic stirrer and stir at 800 rpm / min for 8 hours to ensure that the raw materials are completely and evenly mixed, let stand for 2 hours to degas, and obtain the core spinning solution;

[0074] S2. Mix titanium dioxide, chitosan, poly-N-isopropylacrylamide, and water evenly; mix methylcellulose, polylactic acid, and hexafluoroisopropanol in a beaker, then add the homogeneous mixture of titanium dioxide, chitosan, poly-N-isopropylacrylamide, and water to the beaker and mix; after mixing, turn on magnetic stirring and stir at 600 rpm / min for 2 hours, then let it stand for 0.5 hours to degas and obtain the shell spinning solution;

[0075] S3. Inject the core spinning solution and the shell spinning solution into a coaxial electrospinning device. Control the injection flow rate of the core spinning solution to 0.7 mL / h and the injection flow rate of the shell spinning solution to 0.35 mL / h. Perform electrospinning under a voltage of 12 kV, control the spinning temperature to 25 ± 0.5℃ and the humidity to 50 ± 5%. Receive the solution with tin foil at a receiving distance of 20 cm. After receiving, vacuum dry at room temperature for 24 h to obtain ketoprofen nanofibers.

[0076] S4. Mix L-phenylalanine, second polyacrylic acid and water evenly; mix ropivacaine, tetraethyl orthosilicate and ethanol evenly in a beaker, then add the uniform mixture of L-phenylalanine, second polyacrylic acid and water to the beaker and mix. Add 4wt% hydrochloric acid aqueous solution dropwise and stir to adjust the pH to 5. After the addition is complete, stir magnetically at 300 rpm / min for 4 hours to obtain the matrix sol.

[0077] S5. Ketoprofen nanofibers were sheared and crushed into short fibers of 0.1 mm to 0.15 mm. The ketoprofen nanofibers were mixed in a matrix sol and ultrasonically dispersed evenly to obtain ketoprofen sol. The ketoprofen sol was soaked in anhydrous ethanol for 36 h for aging. After being removed, it was washed twice with water and dried to obtain a dextrorotatory ketoprofen tromethamine plaster sample.

[0078] Comparative Example 1

[0079] This comparative example provides a series of dextromethorphan tromethamine plaster samples, the raw material ratios of which are detailed in Table 2.

[0080] Table 2

[0081]

[0082]

[0083] The process steps adopted are as follows:

[0084] S1. Same as in Example 1, obtain the core spinning solution;

[0085] S2. Mix chitosan, poly-N-isopropylacrylamide, and water evenly; mix methylcellulose, polylactic acid, and hexafluoroisopropanol in a beaker, then add the homogeneous mixture of chitosan, poly-N-isopropylacrylamide, and water to the beaker and mix; after mixing, turn on the magnetic stirrer and stir at 600 rpm / min for 2 hours, then let it stand for 0.5 hours to remove bubbles and obtain the shell spinning solution;

[0086] S3. Same as in Example 1, obtain ketoprofen nanofibers;

[0087] S4. Mix titanium dioxide, ropivacaine, L-phenylalanine, second polyacrylic acid, sorbitol polyethylene glycol, gum arabic and N-methylpyrrolidone evenly, and magnetically stir at 300 rpm / min for 2 hours to obtain the matrix sol.

[0088] S5. Ketoprofen nanofibers are sheared and crushed into short fibers of 0.1 mm to 0.15 mm. The ketoprofen nanofibers are mixed in the matrix sol and ultrasonically dispersed evenly to obtain a dextrorotatory ketoprofen tromethamine plaster sample.

[0089] Performance testing

[0090] Samples 1 to 6 of the ointment-like dextromethorphan tromethamine plaster were cut into 4cm × 4cm pieces with a thickness of 0.3cm for in vitro transdermal testing using SD rat ex vivo skin. Intact and undamaged ex vivo skin samples were obtained from rats, washed with solvent and buffer to remove residues, and fixed in the permeation device. Samples 1 to 6 were then fed into the supply device, ensuring contact between the sample and the ex vivo skin. The temperature was set at 36℃ to simulate the in vivo environment. The test results are shown in Table 3.

[0091] Table 3

[0092]

[0093]

[0094] Samples 1 to 6 of the dextromethorphan tromethamine plaster were cut into 10cm × 10cm pieces with a thickness of 0.5cm. They were then irradiated for 96 hours in a light chamber at a temperature of 45±1℃ and a humidity of 80±5% using a 1500W white light source. The rate of change in ketoprofen content after irradiation compared to the initial concentration was measured, and the results are shown in Table 4.

[0095] Table 4

[0096] Serial Number Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 Sample 6 Relative content 98.65％ 98.46％ 98.31％ 98.57％ 92.62％ 93.34％

[0097] While the present invention has been disclosed above, it is not limited thereto. Any person skilled in the art can make various modifications and alterations without departing from the spirit and scope of the invention; therefore, the scope of protection of the present invention should be determined by the scope defined in the claims.

Claims

1. A method for preparing a dextromethorphan tromethamine plaster, characterized in that, The preparation method includes: S100 uses raw materials including dextro-ketoprofen tromethamine, polyacrylic acid, poly-N-isopropylacrylamide, chitosan and titanium dioxide to prepare ketoprofen nanofibers by electrospinning. S200: A matrix sol is prepared by using raw materials including ropivacaine, L-phenylalanine, polyacrylic acid and tetraethyl orthosilicate via a sol-gel method. S300. The ketoprofen nanofibers and the matrix sol are mixed and gelled to prepare the dextrorotatory ketoprofen tromethamine plaster. S100 specifically includes: S110. The core spinning solution is prepared by mixing raw materials including the dextro-ketoprofen tromethamine, polyacrylic acid, polyvinylpyrrolidone, ethanol, polyvinyl alcohol and water in a mass ratio of (0.2-0.4):(8-12):(8-12):(16-20):(16-20):

100. S120. A shell spinning solution is prepared by mixing raw materials including titanium dioxide, chitosan, poly(N-isopropylacrylamide), methylcellulose, polylactic acid, water, and hexafluoroisopropanol in a mass ratio of (0.2-0.6):(4-6):(8-12):(8-12):(14-18):(40-50):

100. S130. The core spinning solution and the shell spinning solution are injected into a coaxial electrospinning device, and the ketoprofen nanofibers are obtained by electrospinning. S200 specifically includes: The matrix sol is obtained by using raw materials including ropivacaine, L-phenylalanine, polyacrylic acid, tetraethyl orthosilicate, ethanol and water, with hydrochloric acid as a catalyst, in a mass ratio of ropivacaine:L-phenylalanine:polyacrylic acid:tetraethyl orthosilicate:ethanol:water = (1-1.5):(2-3):(6-8):(8-10):(30-35):

100. The S300 specifically includes: S310. The ketoprofen nanofibers are mixed and dispersed evenly in the matrix sol to obtain ketoprofen sol. S320. The ketoprofen sol is soaked and aged in anhydrous ethanol for 30 to 36 hours, then removed, washed, and dried to obtain the dextro-ketoprofen tromethamine plaster.

2. The preparation method according to claim 1, characterized in that, S110 specifically includes: first, mixing the polyvinyl alcohol and half of the water in a first container; then, adding a homogeneous mixture of dextromethorphan tromethamine and ethanol to the first container and mixing; finally, adding the polyacrylic acid and polyvinylpyrrolidone, which have swollen in the other half of the water, to the first container and mixing; magnetically stirring for 8 to 10 hours; and then allowing it to stand for 1.5 to 2 hours to degas, thereby obtaining the core spinning solution.

3. The preparation method according to claim 1, characterized in that, S120 specifically includes: first, mixing the methylcellulose, polylactic acid and hexafluoroisopropanol in a second container; then, adding a homogeneous mixture of titanium dioxide, chitosan, polyN-isopropylacrylamide and water to the second container and mixing; magnetically stirring for 2 to 4 hours; and allowing it to stand for 0.5 to 2 hours to remove bubbles, thereby obtaining the shell spinning solution.

4. The preparation method according to claim 1, characterized in that, S130 specifically includes: injecting the core spinning solution and the shell spinning solution into a coaxial electrospinning device, controlling the injection flow rate of the core spinning solution to be 0.7 mL / h to 0.8 mL / h, controlling the injection flow rate of the shell spinning solution to be 0.3 mL / h to 0.4 mL / h, performing electrospinning under a voltage condition of 12 kV to 14 kV, receiving the solution with tin foil at a receiving distance of 18 cm to 20 cm, and vacuum drying at room temperature for 18 h to 24 h after receiving to obtain the ketoprofen nanofibers.

5. The preparation method according to any one of claims 1 to 4, characterized in that, S200 specifically includes: first, mixing the ropivacaine, the tetraethyl orthosilicate, and the ethanol evenly in a third container; then, adding the uniform mixture of the L-phenylalanine, the polyacrylic acid, and the water into the third container and mixing; adding the aqueous solution of hydrochloric acid dropwise to adjust the pH value to 4 to 5; and stirring magnetically for 3 to 4 hours to obtain the matrix sol.

6. The preparation method according to claim 5, characterized in that, In S310, the mass ratio of ketoprofen nanofibers to matrix sol is (40-60):

100.

7. A dextromethorphan tromethamine plaster, characterized in that, The dextromethorphan tromethamine plaster is obtained by the preparation method as described in any one of claims 1 to 6.

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