Coated slow-release borneol and preparation method thereof
By encapsulating borneol with biodegradable polymer materials containing carbonate groups, a sustained-release system was constructed, which solved the problems of high volatility and poor stability of borneol, and achieved continuous release of borneol and improved safety.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- 湖南医药学院
- Filing Date
- 2026-01-21
- Publication Date
- 2026-04-10
AI Technical Summary
Neoborneol is highly volatile, has poor stability, and a short duration of efficacy. Existing sustained-release technologies suffer from problems such as low encapsulation efficiency, inaccurate release curves, and highly acidic and irritating degradation products.
A coating-type sustained-release system was constructed using biodegradable polymer materials with carbonate groups. Borneol was coated with cross-linked polymers, and the controlled degradation characteristics of carbonate materials were used to achieve the continuous release of borneol.
It improves the stability and duration of efficacy of borneol, enhances the encapsulation rate, and ensures skin health and environmental friendliness.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of slow-release materials, in particular to a coated slow-release borneol and a preparation method thereof. BACKGROUND
[0002] Xinhuang borneol is derived from the unique Borneol camphor tree in Xinhuang County, Hunan Province, and is a national geographical indication product. The cultivation area of Xinhuang borneol camphor tree exceeds 25,000 mu. Relying on the unique geographical environment, climate conditions and plant community advantages in Xinhuang area, Xinhuang borneol has the characteristics of natural composition, pure smell and outstanding biological activity. It shows good anti-inflammatory, analgesic, antibacterial and drug absorption promoting activities. Xinhuang borneol is also a rare Chinese herbal medicine and spice with high medicinal value. The medicinal function of borneol is recorded in historical Chinese medical books and Chinese Pharmacopoeia, and has the effects of refreshing, opening, dispelling and permeating.
[0003] However, similar to conventional natural borneol, Xinhuang borneol also has strong volatility and high fat solubility. In the actual application process, it is easy to volatilize quickly or penetrate and diffuse excessively into the deep layer of the skin, resulting in insufficient effective retention time in the action site, and thus causing problems such as short drug effect duration, high drug administration frequency and enhanced local irritation. At the same time, Xinhuang borneol is also easy to oxidize or degrade during contact with air, light and heat environment, affecting its physicochemical stability and use effect.
[0004] The existing slow-release technology often constructs a drug carrier system through high molecular materials, including microcapsules, nanoparticles, film or gel embedding and the like. Among them, degradable polymers are widely studied because of their excellent biocompatibility, adjustable degradation rate, and the ability to achieve long-term drug release. The currently used degradable polymers include polylactic acid (PLA), poly (lactic-co-glycolic acid) (PLGA) and the like. However, the degradation products of such polyester materials are mainly acidic components, which can easily cause local microenvironment acidification, affecting the safety of wound repair and sensitive skin use. In addition, its combination capacity with small molecule aromatic active substances is limited, the encapsulation efficiency is low, and the release curve lacks precise control.
[0005] In contrast, degradable materials containing carbonate groups, such as aliphatic polycarbonates and carbonate copolymers, have better biocompatibility and near-neutral degradation characteristics. Their degradation products have low tissue irritation and good flexibility and film-forming properties, which can be used to construct skin-adhesive drug delivery systems. In recent years, polyol cross-linked polymers based on carbonate structures, as well as carbonate-functionalized natural high molecular materials, have shown development potential in the field of slow-release carriers due to their strong structure designability and easy-to-control degradation rate. However, there is still a lack of special controlled-release systems for volatile small molecules such as borneol, especially carbonate-based degradable coating structures that can have high encapsulation efficiency, environmental stability and skin use safety.
[0006] In summary, developing a sustained-release system using borneol as the core material and a biodegradable polymer with carbonate groups as the coating material can not only inhibit the rapid volatilization and diffusion of borneol and improve its stability, but also achieve the continuous release of borneol through the controllable degradation behavior of carbonate materials. This is expected to improve its efficacy and safety in clinical and daily use, and has important research value and application prospects. Summary of the Invention
[0007] Purpose of the Invention: The purpose of this invention is to address the problems of high volatility, poor stability, and short duration of efficacy in existing borneol applications by providing a sustained-release borneol material and its preparation method. This invention uses borneol as the core material and a biodegradable polymer with carbonate groups as the coating material. By constructing a stable coating structure, the rapid volatilization and migration of borneol are inhibited. Simultaneously, the controllable degradation properties of carbonate polymers are utilized to achieve continuous and stable release of borneol.
[0008] The technical solution of this invention: In a first aspect, the present invention provides a coated sustained-release borneol comprising a core material and a sustained-release coating film covering the core material; the sustained-release coating film is a cross-linked polymer; the polymer monomers include 3-methoxybenzaldehyde, O-acetylethanolamine and citric acid.
[0009] In some embodiments, the core material includes borneol.
[0010] In some embodiments, the molar ratio of 3-methoxybenzaldehyde, O-acetylethanolamine, and citric acid is 10:11-15:5-10.
[0011] In some embodiments, the crosslinked polymer has a structure comprising carbonate groups.
[0012] In a second aspect, the present invention provides a method for preparing the above-mentioned coated sustained-release borneol, specifically comprising the following steps: S1: 3-Methoxybenzaldehyde was added to a solvent and stirred until homogeneous. O-acetylethanolamine was added and stirred until dissolved. The pH was adjusted to a weakly acidic state. The catalyst was slowly added and the reaction was carried out at room temperature. After the reaction was completed, product 1 was obtained through post-treatment. S2: Citric acid was added to the solvent, and product 1 was added at room temperature. After the reaction was completed by stirring, the mixture of cross-linked polymers was obtained. S3: Add borneol to the above mixture and ultrasonically stir until it is evenly dispersed to obtain an organic phase; add emulsifier to deionized water to obtain an aqueous phase; add the organic phase dropwise to the aqueous phase, shear and stir, evaporate the solvent, and generate microparticles; recover the microparticles, wash and freeze-dry to obtain coated sustained-release borneol.
[0013] In some implementations, the pH of S1 is 6-7.
[0014] In some embodiments, the catalyst in S1 is NaBH(OAc)3, and the amount added is 1.2-1.5 times the molar amount of 3-methoxybenzaldehyde; the reaction time is 2-4 hours.
[0015] In some embodiments, the reaction temperature of the reaction described in S2 is 20-30°C, and the reaction time is 2-4 hours.
[0016] In some embodiments, the solvent in S2 is one or more combinations of chloroform (dichloromethane) and ethyl acetate.
[0017] In some embodiments, the molar ratio of borneol to 3-methoxybenzaldehyde in S3 is 1:2-8; the volume ratio of the organic phase to the water phase is 1:10-20.
[0018] In some embodiments, the emulsifier in S3 is PVA, and the amount of the emulsifier added is 1%-2% (w / v) of the volume of the aqueous solvent.
[0019] Beneficial effects: By encapsulating borneol within a carbonic acid cross-linked polymer structure, particularly using a citric acid cross-linked polymer with controllable degradation properties, the volatilization rate of borneol can be effectively reduced, its residence time on the skin surface can be prolonged, and slow hydrolysis can be achieved to gradually release the active ingredients of borneol, thus achieving a sustained-release effect. This technology not only improves the encapsulation rate but also significantly enhances the stability and duration of efficacy of borneol; furthermore, the use of natural, biodegradable cross-linked polymers improves the product's environmental friendliness, ensuring the user's skin health and long-term safety. Detailed Implementation
[0020] The present invention will be described below with reference to specific embodiments. It should be noted that the following embodiments are examples of the present invention and are used only to illustrate the invention, not to limit it. Other combinations and various modifications within the scope of the present invention can be made without departing from its spirit or scope.
[0021] Unless otherwise specified, all chemical reagents used in this invention are commercially available analytical grade reagents.
[0022] PVA was purchased from Shanghai Maclean Biochemical Technology Co., Ltd., and was polyvinyl alcohol (Mw13000, 98% hydrolyzed).
[0023] Example 1 S1: 10 mmol of 3-methoxybenzaldehyde was added to 80 ml of dry dichloromethane and stirred at 0 °C until homogeneous. 11 mmol of O-acetylethanolamine was added and stirred until dissolved. The pH was adjusted to 6 with acetic acid. 12 mmol of NaBH(OAc)3 was slowly added and reacted at room temperature (25 °C) for 3 h. After the reaction was completed, the mixture was neutralized with saturated NaHCO3. The organic phase was extracted with ethyl acetate, washed with water until neutral, dried, filtered, and concentrated to obtain product 1. Infrared spectral data of product 1: 3400 cm -1 Stretching vibrations of alcohol and amino groups; 2950 cm⁻¹ -1 CH stretching vibrations of methyl and imine groups; 1600 cm⁻¹ -1 C–H bending vibration of the benzene ring; 1300 cm -1 CN stretching vibration (amine group) and CO stretching vibration of alcohol group. It was confirmed that the aldehyde group (-CHO) of 3-methoxybenzaldehyde is reduced to an imine group (-CH2-NH2) via an amino reduction reaction, which reacts with 5-amino-1-pentanol to generate the corresponding amino alcohol.
[0024] S2: Add 5 mmol of citric acid to 80 ml of dry dichloromethane, add product 1 at room temperature (25°C), stir the reaction for 3 h, add 20 ml of deionized water to quench, transfer to a separatory funnel, neutralize with saturated NaHCO3, extract, recrystallize, filter and dry to obtain cross-linked polymer. S3: The cross-linked polymer was added to 80 ml of dry dichloromethane and ultrasonically stirred until it was evenly dispersed. Then, 5 mmol of borneol was added and evenly dispersed to obtain the organic phase. PVA was added to 800 ml of deionized water to prepare a 2% (w / v) aqueous phase. The organic phase was added dropwise to the aqueous phase, sheared and stirred at 10,000 rpm, and the solvent was slowly evaporated at 35°C until microparticles were generated. The microparticles were recovered, washed, and freeze-dried to obtain coated sustained-release borneol #1.
[0025] Example 2 The preparation steps were basically the same as in Example 1, except that the amount of borneol added was 2 mmol and the amount of citric acid added was 8 mmol, thus preparing the coated sustained-release borneol #2.
[0026] Example 3 The preparation steps were basically the same as in Example 1, except that the amount of borneol added was 1.25 mmol and the amount of citric acid added was 10 mmol, thus preparing coated sustained-release borneol #3.
[0027] Comparative Example 1 S1: 10 mmol of 3-methoxybenzaldehyde was added to 80 ml of dry dichloromethane and stirred at 0 °C until homogeneous. 11 mmol of O-acetylethanolamine was added, and the pH was adjusted to 6 with acetic acid. 12 mmol of NaBH(OAc)3 was slowly added and the reaction was carried out at room temperature (25 °C) for 3 h. After the reaction was completed, the mixture was neutralized with saturated NaHCO3, and the organic phase was extracted with ethyl acetate. The mixture was washed with water until neutral, dried, filtered, and concentrated to obtain product 1. S2: Product 1 was added to 80 ml of dry dichloromethane, and 11 mmol of N'N-carbonyldiimidazole was added dropwise. The mixture was stirred at 0 °C for 60 min. After the reaction was completed, the temperature was lowered to room temperature (25 °C), and 5 mmol of citric acid and 1 mmol of DMAP were added. The mixture was stirred at 40 °C for 10 h. After the reaction was completed, 20 ml of deionized water was added to quench the reaction. The mixture was then transferred to a separatory funnel, neutralized with saturated NaHCO3, extracted, recrystallized, filtered, and dried to obtain the crosslinked polymer. S3: Add the crosslinked polymer to 80 ml of dry dichloromethane, sonicate and stir until uniformly dispersed, then add 5 mmol of borneol and disperse evenly to obtain the organic phase; add PVA to 800 ml of deionized water to prepare a 2% (w / v) aqueous phase; add the organic phase dropwise to the aqueous phase, shear and stir at 10000 rpm, slowly evaporate the solvent at 35℃ until microparticles are generated; recover the microparticles, wash and freeze-dry to obtain coated sustained-release borneol #4.
[0028] Comparative Example 2 S1: Add 10 mmol of terephthalic acid and 10 mmol of ethylene glycol to a dry reactor, then add 2 drops of concentrated sulfuric acid, heat to 180°C and react for 3 hours. After the reaction is complete, cool to room temperature, filter, wash and dry to obtain the crosslinked polymer. S2: The cross-linked polymer was added to 80 ml of dry dichloromethane and ultrasonically stirred until it was evenly dispersed. Then, 5 mmol of borneol was added and evenly dispersed to obtain the organic phase. PVA was added to 800 ml of deionized water to prepare a 2% (w / v) aqueous phase. The organic phase was added dropwise to the aqueous phase, sheared and stirred at 10,000 rpm, and the solvent was slowly evaporated at 35°C until microparticles were generated. The microparticles were recovered, washed, and freeze-dried to obtain coated sustained-release borneol #5.
[0029] Comparative Example 3 10 mmol of 3-methoxybenzaldehyde, 11 mmol of O-acetylethanolamine, 5 mmol of citric acid and 5 mmol of borneol were added to 80 ml of dry dichloromethane and mixed thoroughly. The mixture was sheared and stirred at 10,000 rpm, and the solvent was slowly evaporated at 35 °C until microparticles were generated. The microparticles were recovered, washed and freeze-dried to obtain the borneol mixture.
[0030] Performance testing 1. Borneol sustained-release test: 5g of the borneol material prepared above was mixed with 10g of glycerin until homogeneous to obtain a paste; Healthy mice were euthanized by removing hair with 8% Na2S solution and cervical dislocation. Skin from the back was harvested, subcutaneous fat and adhesions were scraped off, and the skin was rinsed with distilled water and soaked in physiological saline for 30 minutes to obtain spare skin. Using an in vitro intelligent transdermal assay apparatus, the spare skin was fixed between the supply and receiving chambers of the diffusion cell, with the stratum corneum facing the supply chamber. 0.1g of an ointment was accurately weighed and placed in the supply chamber, spread evenly, and brought into contact with the skin. The mixture was kept at 37℃ and magnetically stirred at a constant speed of 100 r / min. 1ml samples were taken at 1h, 8h, and 24h, and an equal volume of receiving solution was added simultaneously. The borneol content was determined by GC / MS, and the cumulative release per unit area was calculated as follows, then the percentage of release was calculated by comparing this percentage with the total amount of borneol coated.
[0031]
[0032] Cn is the mass concentration at the nth sampling point, Ci is the mass concentration at the ith sampling point, V0 is the volume of the receiving cell, V is the sampling volume, and S is the diffusion area.
[0033] 2. Skin allergy test: Take 30 healthy DHA-supplemented guinea pigs, half male and half female, weighing 250-300g, and remove approximately 3*3cm of hair from each side of the spine on the back. 2 Twenty-four hours later, the animals were randomly divided into three groups: a test ointment group, a negative control group (saline), and a positive control group (2,4-dinitrochlorophenylacetone), with 10 animals in each group. The corresponding ointment was applied to the left-sided hair-removing area. The negative control group received saline, and the positive control group received 1% 2,4-dinitrochlorophenylacetone solution. The test substance was washed off with warm water six hours after administration. Sensitization was repeated once each on days 7 and 14. Fourteen days after the last administration, the corresponding drug was applied to the right-sided hair-removing area for stimulation. The negative control group received saline, and the positive control group received 0.1% 2,4-dinitrochlorophenylacetone solution. The test substance was washed off with warm water six hours after stimulation. Skin allergic reactions were observed two hours later, and allergic reaction symptoms were scored according to the scoring criteria in the "Technical Guidelines for Drug Irritation, Allergy, and Hemolysis Studies," and the average value was calculated.
[0034] 3. Stability Testing: The microparticles prepared above were placed in an environment with a temperature of 25°C and a relative humidity of 60% for 48 hours. Samples were taken and the borneol content of the microparticles was measured. The stability of the microparticles was determined by calculating the borneol release rate.
[0035] The test results are shown in Table 1.
[0036] Table 1 Test Results
[0037] The test data above show that the coated sustained-release borneol material provided by this invention is non-irritating to the human body and skin, and the tested samples did not produce allergic reactions, making it safe and reliable. Furthermore, in the sustained-release test, it is clearly evident that the carbonate-bonded microparticles provided in the examples possess the characteristic of slowly releasing borneol. Hydrolysis in a physiological saline environment releases borneol, and the sustained-release effect is significant and the quality is stable. In contrast, the ester groups prepared in Comparative Examples 1 and 2 cannot be hydrolyzed, failing to release all the borneol and failing to achieve the sustained-release effect.
[0038] Stability results showed that the borneol in Comparative Example 3, being uncoated, evaporated and was lost over time. The stability of the example samples was significantly better than that of Comparative Example 3 without coating, indicating that the coated sustained-release borneol has a stable structure at room temperature and does not alter the properties of the borneol.
[0039] This invention can also be implemented in various other ways. Without departing from the spirit and essence of this invention, those skilled in the art can make various corresponding changes and modifications according to this invention, but these corresponding changes and modifications should all fall within the protection scope of the appended claims.
Claims
1. A type of coated sustained-release borneol, characterized in that, The coated sustained-release borneol comprises a core material and a sustained-release coating film covering the core material; the sustained-release coating film is a cross-linked polymer; the polymer monomers include 3-methoxybenzaldehyde, O-acetylethanolamine and citric acid.
2. The coated sustained-release borneol according to claim 1, characterized in that, The core material includes borneol.
3. The coated sustained-release borneol according to claim 1, characterized in that, The molar ratio of 3-methoxybenzaldehyde, O-acetylethanolamine and citric acid is 10:11-15:5-10.
4. The coated sustained-release borneol according to claim 1, characterized in that, The crosslinked polymer has a structure including carbonate groups.
5. The method for preparing the coated sustained-release borneol according to any one of claims 1-4, characterized in that, Includes the following steps: S1: 3-Methoxybenzaldehyde was added to a solvent and stirred until homogeneous. O-acetylethanolamine was added and stirred until dissolved. The pH was adjusted to a weakly acidic state. The catalyst was slowly added and the reaction was carried out at room temperature. After the reaction was completed, product 1 was obtained through post-treatment. S2: Citric acid was added to the solvent, and product 1 was added at room temperature. After the reaction was completed by stirring, the mixture of cross-linked polymers was obtained. S3: Add borneol to the above mixture and ultrasonically stir until evenly dispersed to obtain the organic phase; add emulsifier to deionized water to obtain the aqueous phase; add the organic phase dropwise to the aqueous phase, shear and stir, evaporate the solvent, and generate microparticles; The microparticles were recovered, washed, and freeze-dried to obtain coated sustained-release borneol.
6. The method for preparing the coated sustained-release borneol according to claim 5, characterized in that, The catalyst in S1 is NaBH(OAc)3, and the amount added is 1.2-1.5 times the molar amount of 3-methoxybenzaldehyde; the reaction time is 2-4 hours.
7. The method for preparing the coated sustained-release borneol according to claim 5, characterized in that, The reaction temperature of S2 is 20-30℃, and the reaction time is 2-4h.
8. The method for preparing the coated sustained-release borneol according to claim 5, characterized in that, The solvent mentioned in S2 is one or more combinations of chloroform and ethyl acetate.
9. The method for preparing the coated sustained-release borneol according to claim 5, characterized in that, The molar ratio of borneol to 3-methoxybenzaldehyde in S3 is 1:2-8; the volume ratio of the organic phase to the water phase is 1:10-20.
10. The preparation method of the coated sustained-release borneol according to claim 5, wherein the emulsifier in S3 is PVA, and the amount of emulsifier added is 1%-2% (w / v) of the volume of the aqueous solvent.