Methyl methacrylate-butyl methacrylate copolymers and methods for their preparation

Abstract

The application belongs to the technical field of pharmaceutical excipients, and particularly relates to a methyl methacrylate-butyl methacrylate copolymer and a preparation method thereof; the monomer molar ratio of methyl methacrylate to butyl methacrylate in the copolymer is about 1:2.5-1:3.4, and the butyl methacrylate-methyl methacrylate copolymer has the following structure. The butyl methacrylate-methyl methacrylate copolymer with better adhesion and higher stability is prepared by limiting the monomer ratio, molecular weight and viscosity of the copolymer; and the preparation method of the butyl methacrylate-methyl methacrylate copolymer has the comprehensive advantages of high heat dissipation efficiency, excellent product form and simple post-treatment.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical excipients technology, and specifically relates to a methyl methacrylate-butyl methacrylate copolymer and its preparation method. Background Technology

[0002] Methacrylate copolymers are a class of polymeric materials polymerized from monomers of different methacrylic acids, acrylic acids, or their esters. In the field of pharmaceutical excipients, they are often referred to as acrylic resins or eutectic polymers. These copolymers possess the following key characteristics: good biocompatibility, being non-toxic and non-irritating in vivo, not absorbed by the gastrointestinal tract, and ultimately excreted intact; excellent film-forming properties, capable of forming robust and continuous films, making them ideal materials for coating processes; and high stability, relatively stable to light, heat, and moisture, suitable for most drugs.

[0003] Butyl methacrylate-methyl methacrylate (BMA-MMA) copolymer is also a type of methacrylate copolymer, formed by copolymerizing hydrophobic butyl methacrylate and relatively hydrophilic methyl methacrylate in a certain ratio (commonly 1:2 or 1:1). It exhibits good permeability and film-forming properties and is often used as a coating or matrix material in solid dosage forms, such as Eudragit. Furthermore, due to its designable viscoelasticity and three-dimensional network structure, BMA-MMA copolymer can also be used as a matrix thickener in patches, providing suitable adhesion properties.

[0004] As one of the three major drug delivery systems, patches deliver medication to the skin by loading it into a special matrix or reservoir system, securing it to a soft backing material, and then adhering it to the intact skin surface. This allows the medication to penetrate the skin and enter the systemic circulation at a controlled rate, achieving local or systemic long-lasting treatment. In this field, BMA-MMA copolymer, as a key matrix thickener material, provides cohesion and adhesion to the patch matrix due to its viscoelasticity and network structure, resulting in continuously growing market demand. However, currently available copolymer products of this type still have some significant drawbacks: the chemical structure of commercially available products, especially the monomer ratio of BMA to MMA, is usually limited in its selection range, making it difficult to finely and broadly adjust their adhesion, cohesive strength, and drug release rate according to the differentiated needs of different types of patches; with the addition of functional excipients such as transdermal penetration enhancers and plasticizers, some BMA-MMA copolymers have poor compatibility with these excipients, which may lead to decreased formulation stability, drift in adhesion performance, or drug crystallization, affecting product quality; the synthesis and purification processes are complex. In existing technologies, BMA-MMA copolymers are mostly synthesized using bulk polymerization and solution polymerization. Bulk polymerization is difficult to dissipate heat, prone to explosive polymerization, and has a complex process, while solution polymerization requires solvent recovery and has high energy consumption.

[0005] Therefore, there is an urgent need in the field to provide a butyl methacrylate-methyl methacrylate copolymer that can improve the adhesion performance of patches, has high stability, and has a simple preparation process. Summary of the Invention

[0006] The purpose of this invention is to provide a butyl methacrylate-methyl methacrylate copolymer and its preparation method that can improve the adhesion performance of patches, have high stability, and have a simple preparation process.

[0007] To achieve the above objectives, the present invention adopts the following technical solution: This invention provides a butyl methacrylate-methyl methacrylate copolymer, wherein the monomer molar ratio of methyl methacrylate to butyl methacrylate in the copolymer is approximately 1:2.5 to 1:3.4; and the structure of the butyl methacrylate-methyl methacrylate copolymer is shown below: .

[0008] In some embodiments, the molecular weight of the copolymer is 100,000 to 160,000 Da.

[0009] In some embodiments, the degree of polymerization of the copolymer is n=190~304, m=570~912.

[0010] In some embodiments, the viscosity of the copolymer is 3-8 mPa·s.

[0011] It is understandable that when the monomer molar ratio of methyl methacrylate to butyl methacrylate is approximately 1:2.5 to 1:3.4, the resulting copolymer has a molecular weight of 100,000 to 160,000 Da, a degree of polymerization of n = 190 to 304, m = 570 to 912, and a viscosity of 3-8 mPa·s, this copolymer, as a matrix thickener, can meet the process requirements for patch production. Its viscosity is suitable for processing operations such as stirring and coating, providing appropriate cohesion for the patch, thereby improving its application performance and comfort. Simultaneously, this copolymer can effectively delay the drug release rate, achieving a sustained-release effect.

[0012] On the other hand, the present invention also provides a method for preparing butyl methacrylate-methyl methacrylate copolymer, comprising the following steps: Step 1: Add purified water and polyvinyl alcohol to the reaction vessel and mix. Step 2: Mix methyl methacrylate, butyl methacrylate and dodecyl peroxide, and add the mixture into the reaction vessel in 3-5 portions. After the reaction is complete, a copolymer is obtained.

[0013] In some embodiments, the mixture in step one is heated to 85-90°C under stirring to dissolve completely, and then kept at that temperature for temporary storage.

[0014] In some embodiments, the reaction temperature in step two is 85~92℃ and the reaction time is 7~24h.

[0015] In some embodiments, the weight ratio of purified water in step one to the sum of methyl methacrylate and butyl methacrylate in step two is greater than 3:1, the weight ratio of polyvinyl alcohol in step one to the sum of methyl methacrylate and butyl methacrylate in step two is 0.01:1 to 0.05:1, and the weight ratio of dodecyl peroxide to methyl methacrylate in step two is 0.14:1 to 0.30:1.

[0016] In some embodiments, the reactants in step two are added as follows: methyl methacrylate, butyl methacrylate, and dodecyl peroxide are divided into 3-5 portions, mixed in 3-5 batches, and then added to the reaction vessel in 3-5 batches.

[0017] It is understandable that the purpose of staged mixing is to prevent self-aggregation of the mixture after preparation, thereby reducing the risk during storage. In actual production, staged processing is recommended, mainly to further reduce the risk of material self-aggregation during large-scale production and ensure process safety and stability.

[0018] In some embodiments, after each addition of the mixture of methyl methacrylate, butyl methacrylate, and dodecyl peroxide in step two, the reaction system is observed to cool down to the temperature before the addition is carried out, and then the next addition is performed.

[0019] It is understandable that the addition of a mixture of methyl methacrylate, butyl methacrylate, and dodecyl peroxide will trigger a polymerization reaction. This reaction is exothermic, leading to an increase in system temperature. If the next addition is carried out directly at a high temperature, it may cause the reaction to run away from control, trigger explosive polymerization, or affect the molecular weight distribution of the products, thus hindering the normal progress of the reaction. Therefore, to ensure a stable and controllable reaction, it is necessary to wait for the system to cool naturally to near its initial temperature (i.e., the temperature before addition) before proceeding with a new round of material addition.

[0020] In some embodiments, the preparation method further includes the following post-processing steps: after the reaction is complete, the reaction solution is cooled, filtered, the filter cake is rinsed multiple times with purified water, and the filter cake is dried.

[0021] In some embodiments, the post-processing step involves cooling the reaction solution to 10-30°C.

[0022] In some embodiments, the drying method in the post-processing step is vacuum drying.

[0023] It is understandable that if forced air drying is used, the oxygen or moisture contained in the hot air may cause the product to undergo degradation reactions such as oxidation or hydrolysis, affecting the purity and stability of the product.

[0024] In some embodiments, in the post-processing step, the material is dried until it passes the HPLC monitoring (the sum of methyl methacrylate and butyl methacrylate does not exceed 0.10%), at which point it can be collected to obtain the methyl methacrylate-butyl methacrylate copolymer.

[0025] In another aspect, the present invention provides the application of butyl methacrylate-methyl methacrylate copolymer in the preparation of patches, wherein the copolymer is compounded with pressure-sensitive adhesive to improve the adhesion performance of the patch.

[0026] This invention has the following advantages: 1. This invention prepares a butyl methacrylate-methyl methacrylate copolymer with better adhesion and higher stability by limiting the copolymer monomer ratio, molecular weight and viscosity; 2. The preparation method of butyl methacrylate-methyl methacrylate copolymer provided by the present invention has the comprehensive advantages of efficient heat dissipation, excellent product morphology, and simple post-processing. Specifically: (1) The polymerization process is controllable, which is conducive to maintaining the stability of the reaction system and improving the uniformity of the molecular weight distribution of the product; (2) Solid products are obtained directly, eliminating the complex solvent removal and recovery steps required by traditional solution polymerization; (3) The overall post-processing process is relatively simple, and the energy consumption and operating costs are significantly reduced; and the method innovatively uses a water-soluble polymeric dispersant (polyvinyl alcohol), which not only further simplifies the process flow, but also effectively reduces the use and emission of organic solvents. Attached Figure Description

[0027] Figure 1 Release curves of formulations 1-5 in Example 1 and the commercially available formulation; Figure 2 The patch prepared according to prescription 7 in Example 3 is shown in the patch status diagram at 0h (left), 48h (middle) and 7 days (right) after application to the subjects; Figure 3 The patch prepared according to prescription 8 in Example 3 shows the patch status at 0h (left), 48h (middle), and 7 days (right) after application to the subjects. Detailed Implementation

[0028] This invention is not limited to the specific embodiments listed below. Those skilled in the art can implement this invention using various other specific embodiments based on the content disclosed herein. Any modifications or alterations made to the design structure and concept of this invention fall within the protection scope of this invention. It should be noted that, unless otherwise specified, the embodiments and features described in this invention can be combined with each other.

[0029] Methods for determining molecular weight and molecular weight distribution: (1) Instruments, reagents, and standards Instruments: 1 / 1,000,000 balance, high performance liquid chromatograph (differential detector); Reagent: Tetrahydrofuran; Reference standards: Polystyrene standards of different molecular weights (Mw).

[0030] Test methods Determined by size exclusion chromatography (Chinese Pharmacopoeia 2025, Part IV, General Chapter 0514).

[0031] Solution preparation Mobile phase: tetrahydrofuran; Blank solvent: tetrahydrofuran; Reference solution: Weigh appropriate amounts of polystyrene reference standards of different molecular weights, dissolve and dilute them in tetrahydrofuran to prepare a solution containing approximately 3 mg of polystyrene per 1 mL as the reference solution; Test solution: Take about 40 mg of the test sample, place it in a 10 mL volumetric flask, dissolve and dilute with tetrahydrofuran to the mark, mix well, and the solution is ready.

[0032] Viscosity measurement methods: (1) Instruments and reagents Instrument: Electronic balance; Reagents: Ultrapure water, water bath.

[0033] (2) Detection method: according to the third method of General Chapter 0633 of Part IV of Chinese Pharmacopoeia 2025.

[0034] (3) Solution preparation Test solution: Weigh approximately 2.0 g of the test sample accurately and place it in a 20 mL volumetric flask. Add 15 mL of ethyl acetate to the volumetric flask, sonicate until dissolved, and dilute to the mark with ethyl acetate.

[0035] Operating instructions: Adjust the viscometer and graduated cylinder adjustment seat to be level, ensuring the connecting screw is centered in the graduated cylinder. Screw the selected rotor into the connecting screw, connect the temperature control device, and set the temperature. Input the selected rotor number; when the screen displays the selected rotor number, the input is complete. Set the rotation speed and measurement time to 1 minute, taking the average median value from a single point. Take an appropriate amount of the test solution, place it on the graduated cylinder adjustment seat, and secure it with screws. Rotate the lifting frame knob to slowly lower the viscometer, gradually immersing the rotor into the liquid being measured until the liquid level covers the rotor. Press the measurement button to obtain the viscosity value at the current rotor and rotation speed. Perform three parallel measurements.

[0036] Release rate testing method: The experiment was conducted using a rotary drum method with a LOGAN dissolution apparatus. The patch was fixed in the center of a large paddle dish with the ointment side facing upwards. 500 ml of 0.9% sodium chloride solution was used as the release medium at a temperature of 32℃±0.5℃ and a rotation speed of 50 rpm. Samples were taken after 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 7 hours, 9 hours, and 12 hours. The drug content was determined by HPLC, and the average release rate was calculated to obtain a graph showing the change in release rate over time.

[0037] Methods for testing the adhesion of the patch: according to the Chinese Pharmacopoeia 2025 edition 0952 Adhesion Determination Method: Method 1 (Determination of initial tack) and Method 2 (Determination of holding power).

[0038] Transdermal assay method: The diffusion device used in the transdermal assay was a vertical Franz diffusion cell with a diameter of 1.5 cm and a receiving cell volume of 12 mL. The receiving solution was 0.9% physiological saline. During the experiment, a 0.45 μm aqueous microporous membrane was sonicated in the receiving solution for 10 min and then soaked for 30 min. After removing surface moisture, it was placed on the diffusion cell, covered with a metering ring, and fixed. Fresh, isolated Bama miniature pig back skin was fixed in the center of the Franz diffusion cell with the stratum corneum facing upwards. Patches were applied to the surface of the stratum corneum. The receiving solution, after degassing, filled the receiving cell. The transdermal apparatus was turned on at 600 rpm and a temperature of 32.0℃ ± 0.5℃. The receiving solution was collected at specified times. After filtering the receiving solution through a 0.22 μm pore size membrane, samples were taken to measure the concentration of bisoprolol in the receiving medium at each time point. The drug permeation rate for each sample was calculated, and the permeation rate was calculated as the drug permeation rate / drug loading.

[0039] Example 1: Investigation of the molar ratio of copolymer monomers According to the different monomer weights in Table 1, methyl methacrylate, butyl methacrylate, and 1.53 g of dodecyl peroxide were added to the reaction vessel and dissolved at room temperature to obtain mixture 1.

[0040] Add 338.40g of purified water and 0.68g of polyvinyl alcohol to a three-necked flask, heat to 87℃ and stir to dissolve. Then add the mixture 1 dropwise in three portions. After the addition is complete, keep the temperature at 87℃ and react for 16 hours. Cool down to about 20℃, filter, wash the filter cake twice with water, and dry under vacuum at 55℃ to obtain the target copolymer.

[0041] Table 1. Feed ratio of methyl methacrylate and butyl methacrylate monomers .

[0042] Table 2 Results of the investigation of different monomer feed ratios .

[0043] Conclusion: Based on 1 According to H NMR data, when the feed ratio of methyl methacrylate to butyl methacrylate is 1:2.50 to 1:3.10 eq, the resulting copolymers have a methyl methacrylate:butyl methacrylate composition ratio between 1:2.5 and 1:3.4, a molecular weight between 100,000 and 160,000 Da, a viscosity between 3 and 8 mPa·s, and a degree of polymerization between n=190-304 and m=570-912.

[0044] Table 3 Prescription Tables for Prescriptions 1-5 .

[0045] Preparation method: After mixing acrylate pressure-sensitive adhesive with ethyl acetate, butyl methacrylate-methyl methacrylate copolymer (... 1 The ¹H NMR molar ratio (methyl methacrylate: butyl methacrylate) was 1:2.41, 1:2.58, 1:2.95, 1:3.39, and 1:3.55, respectively. The mixture was stirred until completely dissolved, tocopherol was added, and the mixture was stirred evenly. Then, lidismin active pharmaceutical ingredient was added and stirred until evenly mixed (stirring in an ice bath throughout the process). The mixture was allowed to stand to defoam. The drug solution was coated onto a polyester release liner (release film) and dried in a drying oven at 80°C until the solvent was removed. The mixture was then covered and laminated with a polyester lining foil (backing film) and cut and packaged.

[0046] Release requirements: To achieve a release rate close to that of the commercially available formulation (Exelon), the average release rate over 12 hours must be between 80% and 90%; according to Figure 1 As can be seen, the release rate of the patches prepared according to prescriptions 2-4 meets the requirements and is closer to that of commercially available formulations.

[0047] Table 4 Results of adhesion tests on patches prepared from formulations 1-5 .

[0048] To achieve better adhesion performance, the holding power requirement is not less than 10 min; the initial tack requirement is not less than a ball size 10. As shown in Table 4, the holding power of the patch prepared by Formula 1 does not meet the requirements. The holding power and initial tack of the patches prepared by Formulas 2 to 4 are closer to those of commercially available formulations, which meet the requirements of the Chinese Pharmacopoeia and related guidelines for the adhesive properties of generic patches.

[0049] Example 2: Screening of parameters for copolymer preparation method 1. Investigation of the reaction temperature in step two 7.00 g of methyl methacrylate, 26.84 g of butyl methacrylate, and 1.53 g of dodecyl peroxide were added to the reaction vessel and dissolved at room temperature to obtain mixture 1.

[0050] Add 338.40g of purified water and 0.68g of polyvinyl alcohol to a three-necked flask. Heat the mixture to 85℃, 87℃, 90℃, and 92℃ respectively, and stir to dissolve. Then, add the mixture 1 dropwise in three batches. After the addition is complete, keep the mixture at the temperature at which the polyvinyl alcohol was dissolved and react for 16 hours. Cool the mixture to about 20℃, filter the mixture, wash the filter cake twice with water, and dry it under vacuum at 55℃ to obtain the target copolymer.

[0051] Table 5 Results of reaction temperature investigation .

[0052] Conclusion: The molecular weight of the product decreases significantly with increasing polymerization temperature. To obtain a polymer that combines suitable drug release properties with good adhesion properties, the reaction temperature should ideally be controlled within the range of 85–92 °C. The polymer prepared under these conditions has a molecular weight that simultaneously meets the requirements of the patch for both release rate and adhesive strength.

[0053] 2. Investigation into the weight ratio of purified water in step one to methyl methacrylate and butyl methacrylate in step two. 7.00 g of methyl methacrylate, 26.84 g of butyl methacrylate, and 1.53 g of dodecyl peroxide were added to the reaction vessel and dissolved at room temperature to obtain mixture 1.

[0054] Add 67.68g, 101.52g, 169.20g, 338.40g, and 406.08g of purified water and 0.68g of polyvinyl alcohol to a three-necked flask, respectively. Heat to 86℃ and stir to dissolve. Then, add the mixture 1 dropwise in three batches. After the addition is complete, keep the temperature at 86℃ for 16 hours. Cool down to about 20℃, filter, wash the filter cake twice with water, and dry under vacuum at 55℃ to obtain the target copolymer.

[0055] Table 6 Results of the study on purified water usage .

[0056] Conclusion: Based on the changes in heat released during the reaction, it is evident that the total heat of reaction released gradually decreases with increasing purified water dosage. Simultaneously, system temperature significantly impacts the polymerization process and molecular weight distribution. Increased temperature not only increases the difficulty of process operation but also poses potential risks, particularly in large reactors, due to slow heat dissipation. To avoid problems such as reaction runaway, explosive polymerization, or broadening of product molecular weight distribution caused by increased system temperature, and to ensure a stable and controllable reaction process, the final determined purified water dosage is a ratio of methyl methacrylate to butyl methacrylate by weight greater than 3:1.

[0057] 3. Investigation into the feed ratio of polyvinyl alcohol in step one to the sum of the weights of methyl methacrylate and butyl methacrylate in step two. 7.00 g of methyl methacrylate, 26.84 g of butyl methacrylate, and 1.53 g of dodecyl peroxide were added to the reaction vessel and dissolved at room temperature to obtain mixture 1.

[0058] Add 338.40g of purified water to a three-necked flask, then add 0.17g, 0.34g, 1.02g, 1.69g, and 2.37g of polyvinyl alcohol respectively. Heat to 88℃ and stir to dissolve. Add the mixture 1 dropwise in three batches. After the addition is complete, keep the temperature at 88℃ for 16 hours. Cool down to about 20℃, filter, wash the filter cake twice with water, and dry under vacuum at 55℃ to obtain the target copolymer.

[0059] Table 7 Results of the investigation on polyvinyl alcohol dosage .

[0060] Conclusion: Polyvinyl alcohol (PVA), as a water-soluble dispersant in the polymerization system, affects particle size depending on its dosage. With increasing PVA dosage, the average particle size of the copolymer particles under a microscope tends to decrease, but the particle size distribution difference remains relatively stable, with the difference between large and small particle sizes consistently around 300 μm. However, higher PVA dosage results in finer particle sizes and more foam generated during stirring. Excessive foam necessitates the addition of defoamers to avoid affecting operation and reaction uniformity. Experiments show that when the PVA dosage is 0.07Q, the amount of foam generated during preparation significantly increases, which is detrimental to stirring and process stability. Therefore, it is recommended that the weight ratio of PVA to the sum of methyl methacrylate and butyl methacrylate be set at 0.01:1~0.05:1 to achieve a balance between controlling particle size and reducing the impact of foam.

[0061] 4. Investigation of the weight ratio of dodecyl peroxide to methyl methacrylate in step two. 7.00 g of methyl methacrylate and 26.84 g of butyl methacrylate were added to the reaction vessel, followed by 4.74 g, 6.09 g, 6.77 g, 8.12 g, and 10.15 g of dodecyl peroxide, respectively. The mixture was dissolved at room temperature to obtain mixture 1.

[0062] Add 338.40g of purified water and 0.68g of polyvinyl alcohol to a reaction flask, heat to 88℃ and stir to dissolve. Then add the mixture 1 dropwise in three portions. After the addition is complete, keep the temperature at 88℃ for 16 hours. Cool down to about 20℃, filter, wash the filter cake twice with water, and dry under vacuum at 55℃ to obtain the target copolymer.

[0063] Table 8 Results of the investigation on initiator dosage .

[0064] Conclusion: As the amount of initiator increases, the molecular weight of the polymer increases. When the weight ratio of initiator to methyl methacrylate is below 0.14 or above 0.35, the resulting polymer has a small or large molecular weight, which does not meet the formulation requirements. Therefore, a weight ratio of initiator to methyl methacrylate of 0.14 to 0.30 is acceptable.

[0065] 5. Examination of the feeding method in step two The research revealed that the method of monomer addition significantly impacts the stability of the polymerization reaction and the distribution of key parameters such as molecular weight and viscosity of the product during scale-up or industrial production. Experiment ①, using a single monomer addition method, resulted in concentrated exothermic reaction and higher temperature control risks. Experiment ②, with a further increase in the feed amount, showed a tendency for self-polymerization in the monomer mixture during the feeding period, affecting reaction uniformity. Experiments ③ and ④, by optimizing the feeding method, achieved stable reaction processes without significant abnormalities, and the resulting butyl methacrylate-methyl methacrylate copolymer met the required molecular weight and viscosity. Furthermore, excessive addition of materials significantly prolongs the reaction cycle, hindering efficiency and cost control in industrial production.

[0066] ①Without batch addition: Add 7.00g methyl methacrylate, 26.84g butyl methacrylate, and 1.53g dodecyl peroxide to the reaction vessel and dissolve at room temperature to obtain mixture 1.

[0067] Add 338.40 g of purified water and 0.68 g of polyvinyl alcohol to a three-necked flask, heat to 88 °C and stir to dissolve. Then start adding mixture 1 dropwise. After the addition is complete, a significant temperature rise is observed, reaching a maximum of 94 °C, which exceeds the control standard.

[0068] ② The monomer mixture was prepared in one batch and planned to be added to the reaction system in three stages: 140.00g of methyl methacrylate, 536.87g of butyl methacrylate, and 30.66g of dodecyl peroxide were added to the reaction vessel and stirred at room temperature to dissolve, resulting in mixture 1. After standing for 1.5 hours, a white solid settled. After standing at room temperature for another 6 hours, the monomer mixture was completely polymerized. Increasing the feed rate poses a risk of self-polymerization in the monomer mixture.

[0069] ③ Prepare the monomer solution in three separate batches and add it to the reaction system in three separate batches: Add 6768.58g of purified water and 13.54g of polyvinyl alcohol to the reaction vessel, heat to 88℃ and stir to dissolve. Then, add the mixture in three separate batches (before each batch, take 46.67g of methyl methacrylate, 178.96g of butyl methacrylate, and 10.22g of dodecyl peroxide, stir and dissolve at room temperature to obtain the mixture). Allow the system to cool naturally to 88℃ before adding the next batch of materials. After the addition is complete, maintain the reaction temperature at 88℃ for 16 hours, cool to about 20℃, filter, wash the filter cake twice with water, and vacuum dry at 55℃ to obtain the target copolymer.

[0070] ④ Prepare the monomer solution in five separate batches and add it to the reaction system in five separate batches: Add 6768.58g of purified water and 13.54g of polyvinyl alcohol to the reaction vessel, heat to 88℃ and stir to dissolve. Then, add the mixture dropwise in five separate batches (before each addition, take 28g of methyl methacrylate, 107.37g of butyl methacrylate, and 6.13g of dodecyl peroxide, stir and dissolve at room temperature to obtain the mixture). Allow the system to cool naturally to 88℃ before adding the next batch of materials. After the addition is complete, maintain the reaction temperature at 88℃ for 16 hours, cool to approximately 20℃, filter, wash the filter cake twice with water, and vacuum dry at 55℃ to obtain the target copolymer.

[0071] ⑤ Prepare the monomer solution in three batches and add it to the reaction system in three separate batches, without waiting for the system to cool down before each addition: Add 6768.58g of purified water and 13.54g of polyvinyl alcohol to the reaction vessel, heat to 88℃ and stir to dissolve. Then add the mixture in three batches (before each addition, take 46.67g of methyl methacrylate, 178.96g of butyl methacrylate, and 10.22g of dodecyl peroxide, stir to dissolve at room temperature to obtain the mixture). There is no need to wait for the system to cool down naturally to 88℃ before adding the next batch of materials. After the addition is complete, a significant temperature rise is observed, exceeding the control standard.

[0072] Example 3 Application of copolymers in formulations Table 9 Prescription 6 Prescription Table .

[0073] Preparation method: Weigh bisoprolol, isopropyl myristate, methyl methacrylate-butyl methacrylate copolymer (1 The ¹H NMR molar ratio (methyl methacrylate: butyl methacrylate) is 1:2.95. Acrylic pressure-sensitive adhesive and ethyl acetate are added to a beaker and stirred for 1 hour until homogeneous to obtain an adhesive solution. The adhesive solution is then coated onto a release film. After coating, the film is transferred to an oven to dry. The PET backing film is then applied to the dried substrate and cut for packaging.

[0074] Table 10 Results of adhesion test of the patch prepared from Formula 6 .

[0075] As shown in Table 10, the patch prepared by Formula 6 is close to the results of commercially available formulations in terms of key adhesive properties (holding power and initial tack), which meets the requirements of the Chinese Pharmacopoeia and related guidelines for the adhesive properties of generic patch drugs.

[0076] Table 11 Results of drug permeation of the patch prepared from Formula 6 .

[0077] The subjects' T / R ratios were within the acceptable range (0.8~1.25), meeting the permeability requirements. Furthermore, the prescription patch exhibited essentially the same residual performance as the commercially available formulation (Bisono Tapes 8mg), with no significant residue, meeting the expected usage.

[0078] Table 12 Prescription 7-9 Prescription Table .

[0079] Preparation method: Weigh the prescribed amounts of estradiol, levonorgestrel, and isopropyl myristate into a container, add a certain amount of ethyl acetate and ethanol, and stir until estradiol and levonorgestrel dissolve. Then, while stirring, add the copolymer (…). 1 The HNMR molar ratio (methyl methacrylate: butyl methacrylate) is 1:2.95. Finally, add the acrylic pressure-sensitive adhesive and continue stirring until there are no insoluble substances and the adhesive solution is homogeneous. Coat the adhesive solution onto the release film. After coating, transfer it to an oven and dry at 70°C for 15 minutes. Lay the backing film on the dried substrate and cut the sample according to the target size.

[0080] During application, the patch prepared by Formula 7 exhibited displacement and cold flow (black ring phenomenon). Compared with the formula without copolymer, the patch prepared by the formula with copolymer showed improved tack and better adhesion.

[0081] Table 13 Prescription Tables for Prescriptions 10-12 .

[0082] Preparation method: Weigh out the prescribed amounts of osimertin, triethyl glycerol, and copolymer ( 1 The ¹H NMR molar ratio (methyl methacrylate: butyl methacrylate) is 1:2.95. Acrylic pressure-sensitive adhesive is added to a container, and a certain amount of ethyl acetate is added and stirred until there are no insoluble substances and the adhesive solution is homogeneous. The adhesive solution is then coated onto a release film. After coating, it is transferred to an oven and dried at 80°C for 10 minutes. The backing film is then placed on the dried substrate, and the sample is cut to the target size.

[0083] The patch prepared by prescription 10-12 was placed under accelerated conditions (temperature 40℃±2℃, humidity 75%±5%), and its impurities were tested at 0, 3 and 6 months. The results showed that the total impurity content was significantly reduced after the addition of copolymer.

[0084] Related substance detection method: Take an appropriate amount of test sample, add 20 mL of methanol to the test sample, seal, sonicate at room temperature for 1 hour (ultrasonic power: 500 W), then shake for 30 minutes, cool, shake well, filter, inject using HPLC method, detect, and calculate the content of each impurity.

[0085] Table 14 Results of stability studies for prescriptions 10-12 .

[0086] The applicant declares that the present invention is illustrated by the above embodiments, but the present invention is not limited to the above process steps, that is, it does not mean that the present invention must rely on the above process steps to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials used in the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A butyl methacrylate-methyl methacrylate copolymer, characterized in that, The monomer molar ratio of methyl methacrylate to butyl methacrylate in the copolymer is approximately 1:2.5 to 1:3.4, and the structure of the butyl methacrylate-methyl methacrylate copolymer is shown below: .

2. The copolymer according to claim 1, characterized in that, The molecular weight of the copolymer is 100,000 to 160,000 Da.

3. The copolymer according to claim 1, characterized in that, The degree of polymerization of the copolymer is n=190~304, m=570~912.

4. The copolymer according to claim 1, characterized in that, The viscosity of the copolymer is 3-8 mPa·s.

5. A method for preparing the butyl methacrylate-methyl methacrylate copolymer according to any one of claims 1-4, characterized in that, Includes the following steps: Step 1: Add purified water and polyvinyl alcohol to the reaction vessel and mix. Step 2: Mix methyl methacrylate, butyl methacrylate and dodecyl peroxide, and add the mixture into the reaction vessel in 3-5 portions. After the reaction is complete, a copolymer is obtained.

6. The preparation method according to claim 5, characterized in that, The preparation method further includes the following post-processing steps: after the reaction is complete, the reaction solution is cooled, filtered, the filter cake is rinsed multiple times with purified water, and the filter cake is dried.

7. The preparation method according to claim 5, characterized in that, The reactants in step two are added as follows: methyl methacrylate, butyl methacrylate, and dodecyl peroxide are divided into 3-5 portions, mixed in 3-5 batches, and then added to the reaction vessel in 3-5 batches.

8. The preparation method according to claim 5, characterized in that, The reaction temperature in step two is 85~92℃.

9. The preparation method according to claim 5, characterized in that, In step one, the weight ratio of purified water to the sum of methyl methacrylate and butyl methacrylate in step two is greater than 3:1; in step one, the weight ratio of polyvinyl alcohol to the sum of methyl methacrylate and butyl methacrylate in step two is 0.01:1 to 0.05:1; and in step two, the weight ratio of dodecyl peroxide to methyl methacrylate is 0.14:1 to 0.30:

1.

10. The preparation method according to claim 5, characterized in that, In step two, after each addition of the mixture of methyl methacrylate, butyl methacrylate, and dodecyl peroxide, the reaction system is observed to cool down to the temperature before the addition is carried out, and then the next addition is performed.

11. The use of the butyl methacrylate-methyl methacrylate copolymer according to any one of claims 1-4 and the butyl methacrylate-methyl methacrylate copolymer obtained by the preparation method according to any one of claims 5-10 in the preparation of patches, characterized in that, The copolymer is compounded with a pressure-sensitive adhesive to improve the adhesion properties of the patch.

Images