Polymer / calcium carbonate oligomer core-shell structure double-release drug delivery system and preparation method

Abstract

The present application relates to a kind of polymer / calcium carbonate oligomer core-shell structure double sustained-release drug delivery system and preparation method, first the prepared calcium carbonate oligomer is mixed with drug stirring, in the stirring process, the transformation of calcium carbonate oligomer to crystal calcium carbonate is regulated, so as to embed drug in crystal calcium carbonate.The drug-loaded crystal calcium carbonate is coated by polymer by solvent evaporation method, so as to form polymer / calcium carbonate oligomer core-shell structure double sustained-release drug delivery system.Result shows, the drug delivery system drug release is stable, there is no burst release phenomenon, the sustained-release time of the drug loaded is 3-5 times of the calcium carbonate loaded with drug alone and the polymer coated drug alone, the present application is first by regulating crystal growth to regulate drug loading, and then the drug loaded is further coated by polymer, forms core-shell structure double sustained-release drug delivery system, overcomes the burst release problem of polymer coated drug, has good popularization prospect.

Description

Technical Field

[0001] This invention belongs to the field of sustained-release drug delivery materials, and relates to a polymer / calcium carbonate oligomer core-shell structure dual sustained-release drug delivery system and its preparation method. Background Technology

[0002] Drug sustained-release technology utilizes specialized formulation processes to release drugs slowly and uniformly within the body, thereby enhancing therapeutic efficacy and the user experience. Currently, cutting-edge drug sustained-release systems include hydrogel systems, functionalized nanomaterial drug delivery systems, device-based sustained-release systems, and polymer-encapsulated drug systems (Pharmaceutics 2025, 17, 143; ACS Nano 2025, 19, 28342). 28352; Langmuir 2014, 30, 6151 6161; ACS Biomaterials. Science&Engineering 2021, 7, 2548 (2557). For hydrogel systems, there are issues such as poor stability, potentially uneven drug release, and early clinical application; more safety data are needed. For functionalized nanomaterial drug delivery systems, preparation is complex and costly, toxicity may be introduced, clinical translation is difficult, and long-term safety requires further research. For device-based sustained release, implantation is required, causing patient discomfort. Polymer-coated drug systems are simple to prepare and relatively inexpensive, showing promise for clinical translation; however, release stability is an issue, and sudden release may occur. Summary of the Invention

[0003] Technical problems to be solved To overcome the shortcomings of existing technologies, this invention proposes a polymer / calcium carbonate oligomer core-shell structure dual sustained-release drug delivery system and its preparation method. First, the prepared calcium carbonate oligomers are mixed and stirred with a drug. During stirring, the transformation of the calcium carbonate oligomers into crystalline calcium carbonate is regulated, thereby encapsulating the drug within the crystalline calcium carbonate. The drug-loaded crystalline calcium carbonate is then coated with a polymer using a solvent evaporation method, thus forming the polymer / calcium carbonate oligomer core-shell structure dual sustained-release drug delivery system.

[0004] Technical solution A method for preparing a polymer / calcium carbonate oligomer core-shell structure dual sustained-release drug delivery system is characterized by the following steps: mixing and stirring calcium carbonate oligomers with a drug, controlling the transformation of the calcium carbonate oligomers into crystalline calcium carbonate during stirring, thereby embedding the drug in the crystalline calcium carbonate; and coating the drug-loaded crystalline calcium carbonate with a polymer by solvent evaporation, thereby forming a polymer / calcium carbonate oligomer core-shell structure dual sustained-release drug delivery system.

[0005] The calcium carbonate oligomer was dissolved in methanol solution at a mass ratio of 500:1-300:1 when it was mixed with the drug. Then water was added, stirred, centrifuged, washed, and dried to obtain drug-loaded calcium carbonate.

[0006] The amount of water added during the stirring process is 2-5 mL. After stirring for 5-10 minutes, the mixture is centrifuged, washed, and dried to obtain drug-loaded calcium carbonate.

[0007] The drug-loaded crystalline calcium carbonate is coated with a polymer via solvent evaporation, resulting in a drug-loaded calcium carbonate aqueous solution dispersed in water. This solution is then mixed with a mixture of hexane and chloroform at a mass ratio of 1:5-1:10 to prepare a mixture of the drug-loaded calcium carbonate aqueous solution, hexane, and chloroform. After thorough stirring, polymethyl methacrylate (PMMA) is added, with PMMA comprising 3%-5% of the total solution mass. Following stirring and centrifugation and washing, a polymer / calcium carbonate oligomer core-shell structured dual sustained-release drug delivery system is obtained.

[0008] The mass fraction of drug-loaded calcium carbonate in the drug-loaded calcium carbonate aqueous solution is 0.5%.

[0009] The dispersion is performed by ultrasonic dispersion in water.

[0010] The mass ratio of n-hexane to chloroform in the mixture is 1:2.

[0011] After adding polymethyl methacrylate, stir for 12-24 h, then centrifuge and wash.

[0012] The calcium carbonate oligomer is prepared as follows: prepare an ethanol solution of calcium chloride with a mass fraction of 2%-5%, take 10 mL and add 8-10 mL of triethylamine to it, stir evenly, and then introduce carbon dioxide gas into the mixture for 10-30 min at a gas flow rate of 50 mL / min; after the gas is introduced, continue stirring for 30 min, and after stirring is completed, centrifuge and wash to obtain the calcium carbonate oligomer.

[0013] A polymer / calcium carbonate oligomer core-shell structure dual sustained-release drug delivery system obtained by the preparation method described above is characterized in that: the drug is loaded onto the calcium carbonate oligomer as the core, and the outside of the core is a polymer shell, thus forming a polymer / calcium carbonate oligomer core-shell structure dual sustained-release drug delivery system; the sustained-release time of the loaded drug is 3-5 times that of calcium carbonate alone loaded with drug and polymer alone coated with drug.

[0014] Beneficial effects This invention proposes a polymer / calcium carbonate oligomer core-shell structure dual sustained-release drug delivery system and its preparation method. First, the prepared calcium carbonate oligomers are mixed and stirred with a drug. During stirring, the transformation of the calcium carbonate oligomers into crystalline calcium carbonate is regulated, thereby encapsulating the drug within the crystalline calcium carbonate. The drug-loaded crystalline calcium carbonate is then coated with a polymer using a solvent evaporation method, thus forming a polymer / calcium carbonate oligomer core-shell structure dual sustained-release drug delivery system. Results show that this drug delivery system exhibits stable drug release without burst release. The sustained-release time of the loaded drug is 3-5 times that of drug-loaded calcium carbonate alone and drug-coated polymer alone. This invention first regulates drug loading by controlling crystal growth, and then further encapsulates the loaded drug with a polymer to form a core-shell structure dual sustained-release drug delivery system, overcoming the burst release problem inherent in polymer-coated drugs and demonstrating promising application prospects.

[0015] Compared with existing technologies, the polymer / calcium carbonate oligomer core-shell dual sustained-release drug delivery system provided by this invention first constructs a first sustained-release barrier by transforming calcium carbonate crystals to load the drug, and then uses a polymer to encapsulate the drug-loaded calcium carbonate, thereby constructing a second sustained-release barrier, ultimately forming a polymer / calcium carbonate oligomer core-shell dual sustained-release drug delivery system. In terms of drug release time, this drug delivery system is 3-5 times longer than that of calcium carbonate alone loaded with the drug or the polymer alone coated with the drug. Furthermore, this system does not exhibit the burst release phenomenon seen in either the drug-loaded calcium carbonate or the polymer-coated drug. This material shows great promise for the development of sustained-release drugs. Detailed Implementation

[0016] The present invention will now be further described with reference to the embodiments: The polymer / calcium carbonate oligomer core-shell structured dual sustained-release drug delivery system and its preparation method are prepared by the following steps: Step 1, Preparation of calcium carbonate oligomers (according to existing reports): Prepare a 2%-5% (w / w) calcium chloride ethanol solution. Take 10 mL of the solution and add 8-10 mL of triethylamine. Stir until homogeneous, then introduce carbon dioxide gas (at a flow rate of 50 mL / min) into the mixture for 10-30 min. After the gas is introduced, continue stirring for 30 min. After stirring is complete, centrifuge and wash to obtain the calcium carbonate oligomers.

[0017] Step 2, Preparation of drug-loaded calcium carbonate: Dissolve calcium carbonate oligomers and epirubicin hydrochloride in methanol solution at a mass ratio of 500:1-300:1, then slowly add 2-5 mL of water and stir for 5-10 min. After centrifugation, washing and drying, obtain drug-loaded calcium carbonate.

[0018] Step 3: Preparation of the polymer / calcium carbonate oligomer core-shell dual sustained-release drug delivery system: Drug-loaded calcium carbonate is ultrasonically dispersed in water to form a 0.5% (w / w) drug-loaded calcium carbonate aqueous solution. The drug-loaded calcium carbonate aqueous solution is then mixed with a mixture of n-hexane and chloroform (mass ratio 1:2) at a ratio of 1:5-1:10 to prepare a mixed solution of drug-loaded calcium carbonate aqueous solution, n-hexane, and chloroform. After thorough stirring, polymethyl methacrylate (PMMA) is added, with PMMA comprising 3%-5% of the total solution mass. After stirring for 12-24 h, centrifugation and washing yield the polymer / calcium carbonate oligomer core-shell dual sustained-release drug delivery system.

[0019] Example 1: Prepare a 2% (w / w) calcium chloride ethanol solution. Take 10 mL of the solution and add 8 mL of triethylamine. Stir well and then purge the mixture with carbon dioxide gas (50 mL / min) for 10 min. After the gas is completely passed through, continue stirring for 30 min. After stirring, centrifuge and wash to obtain calcium carbonate oligomers. Dissolve the calcium carbonate oligomers and epirubicin hydrochloride in methanol at a mass ratio of 500:1. Then slowly add 2 mL of water and stir for 5 min. Centrifuge, wash, and dry to obtain drug-loaded calcium carbonate. Sonicately disperse the drug-loaded calcium carbonate in water to form a 0.5% (w / w) drug-loaded calcium carbonate aqueous solution. Mix the drug-loaded calcium carbonate aqueous solution with a mixture of n-hexane and chloroform (mass ratio of n-hexane to chloroform is 1:2) at a mass ratio of 1:5 to prepare a mixed solution of drug-loaded calcium carbonate aqueous solution, n-hexane, and chloroform. After stirring well, add polymethyl methacrylate (PMMA), with PMMA accounting for 3% of the total solution mass. After stirring for 12 h, centrifugation and washing yielded a polymer / calcium carbonate oligomer core-shell structured dual sustained-release drug delivery system.

[0020] Test results showed that the drug release times of the polymer / calcium carbonate oligomer core-shell dual sustained-release drug delivery system at pH 5, 7, and 9 were 6.5, 7.1, and 7.6 days, respectively, with a stable release rate and no burst release phenomenon. In contrast, the drug release times of the drug-loaded calcium carbonate at pH 5, 7, and 9 were 1.5, 1.6, and 2.1 days, respectively; while the drug release times of the polymer-coated system at pH 5, 7, and 9 were 1.2, 1.4, and 1.7 days, respectively. Both the drug-loaded calcium carbonate and the polymer-coated system exhibited burst release behavior, with more than 60% of the drug released within 2 hours.

[0021] Example 2: Prepare a 3% (w / w) calcium chloride ethanol solution. Take 10 mL of the solution and add 9 mL of triethylamine. Stir well and then purge the mixture with carbon dioxide gas (flow rate 50 mL / min) for 15 min. After the gas is completely passed through, continue stirring for 30 min. After stirring, centrifuge and wash to obtain calcium carbonate oligomers. Dissolve the calcium carbonate oligomers and epirubicin hydrochloride in methanol solution at a mass ratio of 400:1. Then slowly add 3 mL of water and stir for 7 min. Centrifuge, wash, and dry to obtain drug-loaded calcium carbonate. Sonicately disperse the drug-loaded calcium carbonate in water to form a 0.5% (w / w) drug-loaded calcium carbonate aqueous solution. Mix the drug-loaded calcium carbonate aqueous solution with a mixture of n-hexane and chloroform (mass ratio of n-hexane to chloroform 1:2) at a mass ratio of 1:6 to prepare a mixed solution of drug-loaded calcium carbonate aqueous solution, n-hexane, and chloroform. After stirring well, add polymethyl methacrylate (PMMA), with PMMA accounting for 4% of the total solution mass. After stirring for 15 h, centrifugation and washing yielded a polymer / calcium carbonate oligomer core-shell structured dual sustained-release drug delivery system.

[0022] Test results showed that the drug release times of the polymer / calcium carbonate oligomer core-shell dual sustained-release drug delivery system at pH 5, 7, and 9 were 6.6, 7.5, and 7.7 days, respectively, with a stable release rate and no burst release phenomenon. In contrast, the drug release times of the drug-loaded calcium carbonate at pH 5, 7, and 9 were 1.7, 1.7, and 2 days, respectively; while the drug release times of the polymer-coated system at pH 5, 7, and 9 were 1.3, 1.5, and 2 days, respectively. Both the drug-loaded calcium carbonate and the polymer-coated system exhibited burst release behavior, with more than 65% of the drug released within 2 hours.

[0023] Example 3: Prepare a 4% (w / w) calcium chloride ethanol solution. Take 10 mL of the solution and add 10 mL of triethylamine. Stir well and then purge the mixture with carbon dioxide gas (50 mL / min) for 20 min. After purging, continue stirring for 30 min. After stirring, centrifuge and wash to obtain calcium carbonate oligomers. Dissolve the calcium carbonate oligomers and epirubicin hydrochloride in methanol at a mass ratio of 300:1. Then slowly add 4 mL of water and stir for 8 min. Centrifuge, wash, and dry to obtain drug-loaded calcium carbonate. Sonicately disperse the drug-loaded calcium carbonate in water to form a 0.5% (w / w) drug-loaded calcium carbonate aqueous solution. Mix the drug-loaded calcium carbonate aqueous solution with a mixture of n-hexane and chloroform (mass ratio of n-hexane to chloroform is 1:2) at a mass ratio of 1:8 to prepare a mixture of drug-loaded calcium carbonate aqueous solution, n-hexane, and chloroform. After stirring well, add polymethyl methacrylate (PMMA), with PMMA accounting for 5% of the total solution mass. After stirring for 20 h, centrifugation and washing yielded a polymer / calcium carbonate oligomer core-shell structured dual sustained-release drug delivery system.

[0024] Test results showed that the drug release times of the polymer / calcium carbonate oligomer core-shell dual sustained-release drug delivery system at pH 5, 7, and 9 were 6.5, 7.6, and 8 days, respectively, with a stable release rate and no burst release phenomenon. In contrast, the drug release times of the drug-loaded calcium carbonate at pH 5, 7, and 9 were 1.5, 1.5, and 1.7 days, respectively; while the drug release times of the polymer-coated system at pH 5, 7, and 9 were 1.5, 1.4, and 1.7 days, respectively. Both the drug-loaded calcium carbonate and the polymer-coated system exhibited burst release behavior, with more than 60% of the drug released within 2 hours.

[0025] Example 4: Prepare a 5% (w / w) calcium chloride ethanol solution. Take 10 mL of the solution and add 10 mL of triethylamine. Stir until homogeneous, then purge the mixture with carbon dioxide gas (50 mL / min) for 30 min. After the gas is completely passed through, continue stirring for another 30 min. After stirring, centrifuge and wash to obtain calcium carbonate oligomers. Dissolve the calcium carbonate oligomers and epirubicin hydrochloride in methanol at a mass ratio of 300:1. Then slowly add 5 mL of water and stir for 10 min. Centrifuge, wash, and dry to obtain drug-loaded calcium carbonate. Sonicately disperse the drug-loaded calcium carbonate in water to form a 0.5% (w / w) drug-loaded calcium carbonate aqueous solution. Mix the drug-loaded calcium carbonate aqueous solution with a mixture of n-hexane and chloroform (mass ratio of n-hexane to chloroform is 1:2) at a mass ratio of 1:10 to prepare a mixture of drug-loaded calcium carbonate aqueous solution, n-hexane, and chloroform. After stirring until homogeneous, add polymethyl methacrylate (PMMA), with PMMA accounting for 4% of the total solution mass. After stirring for 24 h, centrifugation and washing yielded a polymer / calcium carbonate oligomer core-shell structured dual sustained-release drug delivery system.

[0026] Test results showed that the drug release times of the polymer / calcium carbonate oligomer core-shell dual sustained-release drug delivery system at pH 5, 7, and 9 were 6.8, 7.5, and 8.2 days, respectively, with a stable release rate and no burst release phenomenon. In contrast, the drug release times of the drug-loaded calcium carbonate at pH 5, 7, and 9 were 1.6, 1.5, and 1.6 days, respectively; while the drug release times of the polymer-coated system at pH 5, 7, and 9 were 1.4, 1.5, and 1.7 days, respectively. Both the drug-loaded calcium carbonate and the polymer-coated system exhibited burst release behavior, with more than 58% of the drug released within 2 hours.

[0027] Although the present invention has been described in detail through the preferred embodiments above, it should be understood that the above description should not be considered as a limitation of the present invention. Various modifications and substitutions to the present invention will be apparent to those skilled in the art after reading the above description. Therefore, the scope of protection of the present invention should be defined by the appended claims.

Claims

1. A method for preparing a polymer / calcium carbonate oligomer core-shell structured dual sustained-release drug delivery system, characterized in that... The steps are as follows: calcium carbonate oligomers are mixed and stirred with drugs. During the stirring process, the transformation of calcium carbonate oligomers into crystalline calcium carbonate is controlled, thereby embedding the drug in the crystalline calcium carbonate. The drug-loaded crystalline calcium carbonate is coated with polymer by solvent evaporation, thereby forming a polymer / calcium carbonate oligomer core-shell structure dual sustained-release drug delivery system.

2. The preparation method according to claim 1, characterized in that: The calcium carbonate oligomer was dissolved in methanol solution at a mass ratio of 500:1-300:1 when it was mixed with the drug. Then water was added, stirred, centrifuged, washed, and dried to obtain drug-loaded calcium carbonate.

3. The preparation method according to claim 2, characterized in that: The amount of water added during stirring is 2-5 mL. After stirring for 5-10 minutes, the mixture is centrifuged, washed, and dried to obtain drug-loaded calcium carbonate.

4. The preparation method according to claim 1, characterized in that: The drug-loaded crystalline calcium carbonate is coated with a polymer via solvent evaporation, resulting in a drug-loaded calcium carbonate aqueous solution dispersed in water. This solution is then mixed with a mixture of hexane and chloroform at a mass ratio of 1:5-1:10 to prepare a mixture of the drug-loaded calcium carbonate aqueous solution, hexane, and chloroform. After thorough stirring, polymethyl methacrylate (PMMA) is added, with PMMA comprising 3%-5% of the total solution mass. Following stirring and centrifugation and washing, a polymer / calcium carbonate oligomer core-shell structured dual sustained-release drug delivery system is obtained.

5. The preparation method according to claim 4, characterized in that: The mass fraction of drug-loaded calcium carbonate in the drug-loaded calcium carbonate aqueous solution is 0.5%.

6. The preparation method according to claim 4, characterized in that: The dispersion is performed by ultrasonic dispersion in water.

7. The preparation method according to claim 4, characterized in that: The mass ratio of n-hexane to chloroform in the mixture is 1:

2.

8. The preparation method according to claim 4, characterized in that: After adding polymethyl methacrylate, stir for 12-24 hours, then centrifuge and wash.

9. The preparation method according to claim 1, characterized in that: The calcium carbonate oligomer is prepared as follows: prepare an ethanol solution of calcium chloride with a mass fraction of 2%-5%, take 10 mL and add 8-10 mL of triethylamine to it, stir evenly, and then introduce carbon dioxide gas into the mixture for 10-30 min at a gas flow rate of 50 mL / min; after the gas is introduced, continue stirring for 30 min, and after stirring is completed, centrifuge and wash to obtain the calcium carbonate oligomer.

10. A polymer / calcium carbonate oligomer core-shell structured dual sustained-release drug delivery system obtained by the preparation method according to any one of claims 1 to 9, characterized in that: The drug is loaded onto calcium carbonate oligomers as the core, and the core is surrounded by a polymer shell, forming a polymer / calcium carbonate oligomer core-shell dual sustained-release drug delivery system; the sustained-release time of the loaded drug is 3-5 times that of calcium carbonate alone loaded with drug and polymer alone coated with drug.