CN103239727B - Method for preparing material of controlled-release drug - Google Patents

Abstract

The invention relates to a method for preparing a material for controlling drug release, in particular to a method for preparing a drug for controlled drug release that is sensitive to different pH values by wrapping mesoporous _SiO2 with a polymer. Using the principle of free radical polymerization to prepare a double bond-containing silane coupling agent modified pH-sensitive polymer and _SiO2 in a certain proportion, add absolute ethanol, reflux and stir at 70°C for 8-24 hours, filter, wash, and dry Finally, a solid powder of polymer-wrapped mesoporous _SiO2 is obtained. Since this preparation method only has two steps of polymer modification and polymer encapsulation of mesoporous SiO ₂ , the preparation method is simple to operate; in addition, this preparation method only needs to change the amount of polymer and mesoporous SiO ₂ control the results of the invention; at the same time, the present invention does not have the step of synthesizing mesoporous silicon spheres, and there are only two factors affecting the results of the present invention, the addition of polymer and mesoporous _SiO2 . The amount of grafting on the _SiO2 surface.

Description

A kind of preparation method of the material of controlled release drug

technical field

The invention relates to a method for preparing a material for controlling drug release, in particular to a method for preparing a drug for controlled drug release that is sensitive to different pH values by wrapping mesoporous _SiO2 with a polymer.

Background technique

Since Mobil first reported the ordered mesoporous material M41S in 1992 (J.Am.Chem.Soc., 1992, 27(114):10834-10843), the mesoporous SiO ₂ material has a higher specific surface area, better Biocompatibility and non-toxic side effects and other characteristics, modified by organic functional groups have been considered to be one of the most ideal drug sustained release carriers. For example, Chinese patents CN101020058A, CN101337072B, CN200710061610.2 and CN201110052824.X report the application of a pure silicon-based monodisperse spherical mesoporous molecular sieve in drug sustained release. Drug release effect. In US2007/0160639A1, the surface of SiO ₂ mesoporous molecular sieves is oxidized and loaded with drugs, and a good drug sustained release effect is also obtained. The above results show that the controlled release of the drug-loaded system can be achieved by regulating the mesopores and surface modification, but it is still difficult to achieve controlled release in a solution with a certain pH value.

According to reports, the polymer has a certain response function to the pH value according to the different properties of its chain segments, so it can be used as a drug carrier and wrap the drug through chemical, physical, and electrostatic interactions, and can realize the pH-sensitive and controlled release effect of the drug. However, due to its small specific surface area and fewer surface active sites, the drug loading capacity of the polymer is very low, which can only reach about 5% (Modern Chemical Industry, 2007, 27(10):69-74). At present, to solve the above problems, an effective method is to combine the high drug loading of mesoporous SiO ₂ with the pH-stimuli-responsive performance of the polymer, and integrate the stability, high drug loading of silicon-based mesoporous materials and the pH value of the polymer. Responsiveness, constructing a new pH value drug controlled release system, so as to achieve the purpose of drug release sensitive to pH value. Shi et al. (Angew Chem, 2005, 117(32): 5213-5217) (Micropor Mesopor Mater., 2007, 103(1-2): 243-249) utilize the penetration of the hollow core of the mesoporous hollow sphere and the mesoporous shell Pores and polyelectrolytes have the characteristics of responding to the pH value of the environment. Through layer-by-layer self-assembly technology, the polyelectrolyte wrapped in the outer layer of the mesoporous hollow spheres responds to the structural properties of the pH value, thereby acting as a "switch" for the controlled release of drugs. "Effect; however, due to the complex process and cumbersome operation of this method, its application is limited. Zhu et al. (Microporous and Mesoporous Mater. 2005, 85, 75-81) (Angew. Chem. Int. Ed. 2005, 44, 5083-5087) coated the drug-loaded nanospheres with polymers in situ, The release rate of drug molecules is adjusted by using the different solubility of polymers in different pH media; although the operation is simple, the amount of grafting of polymers on the surface of nanospheres is not easy to control and the influencing factors are complicated. Xu et al. (J.Phys.Chem.C.2009, 113, 12753-12758) used the grafting method to wrap a pH-sensitive polymer on the surface of mesoporous silica spheres during the synthesis process of mesoporous silica spheres, and utilize the polymer in the alkaline and The relaxation/contraction in acidic solution achieves the purpose of drug pH-sensitive and controlled release; however, since the encapsulation process is synchronized with the synthesis of mesoporous silica spheres, the research on the synthesis process and the factors affecting the polymer encapsulation performance are complicated .

We have reported a preparation method of drug sustained and controlled release material (CN101337072B), but the prepared drug loading system does not have the characteristics of controlled release sensitive to the environmental pH value. This patented technology is based on the patented technology, combined with the above problems, using the grafting method to prepare pH-sensitive polymer-wrapped mesoporous SiO ₂ , and further reports a polymer-wrapped mesoporous SiO2 for pH-sensitive controlled release drugs _2. The preparation method.

Contents of the invention

Aiming at the deficiencies of the above technologies, the present invention provides a preparation method of a controlled-release drug material with simple operation, easy control of feeding ratio, and few influencing factors. the

A preparation method of a material for controlled drug release, comprising the following steps:

1) Modification of organic compounds containing double bonds and carboxyl groups

Dissolve the silane coupling agent and organic matter containing double bonds and carboxyl groups in absolute ethanol according to the volume ratio of 0-100%, add the initiator after passing nitrogen for two hours, continue to react at 70°C for 4-48 hours, and then pass through n-hexane extraction, obtained polymer, marked as P;

2) The above polymer P was grafted onto mesoporous SiO ₂

Add polymer P and mesoporous _SiO2 into absolute ethanol at a mass ratio of 1-80%, reflux at 70°C for 8-24 hours, finally filter and wash, and dry at 60-80°C for 5-10 hours , to obtain a solid powder of mesoporous _SiO2 coated with polymer P, marked as B.

Preferably, the silane coupling agent is vinyltriethoxysilane, vinyltrimethoxysilane, 3-(methacryloyloxy)propyltrimethoxysilane, 3-(methacryloyloxy) Propyltriethoxysilane. the

Preferably, the organic compound containing double bonds and carboxyl groups is acrylic acid or its derivatives, preferably methacrylic acid and methyl methacrylate. the

Preferably, the initiator is an organic peroxide, azo and inorganic peroxy initiator, the organic peroxide initiator is preferably dibenzoyl peroxide, and the azo initiator is preferably azodiiso Butyronitrile and inorganic peroxygen initiators are preferably persulfates. the

Preferably, the mesoporous SiO ₂ has a dual mesoporous structure, wherein the diameter of the large pores of the dual mesoporous structure is 15-30 nm, the diameter of the small pores is 2-3 nm, and the particle diameter is 20-1000 nm.

Further, the drug loaded on the sample B may be a water-soluble drug such as gentamicin, a slightly soluble drug such as aspirin, or an insoluble drug such as ibuprofen. the

Further, the release system at different pH values after sample B is loaded with drugs can be citric acid buffer system, phosphate buffer system, simulated gastric juice, simulated body fluid, dilute hydrochloric acid, dilute ammonia water, etc. the

The beneficial effects of the present invention are that the preparation method only has two steps of polymer modification and polymer encapsulation of mesoporous SiO ₂ , and all experimental instruments and equipment are commonly used instruments and equipment in laboratories, and the operations adopted are also common in the chemical field. operation, so the preparation method is easy to operate; in addition, this preparation method only needs to change the addition amount of polymer and mesoporous SiO ₂ , and the invention result can be well controlled; at the same time, the present invention does not have the step of synthesizing mesoporous silicon spheres, and has and Only polymer and mesoporous SiO ₂ these two influencing factors are affecting the result of the present invention, it is easy to control the grafting amount of polymer on the surface of mesoporous SiO ₂ ; in addition, the organic matter used in the present invention contains carboxyl, can realize The control of drugs under different acidic or alkaline conditions, that is, the control of drugs at different pH values.

Description of drawings

Fig. 1 is a flowchart of the present invention;

Fig. 2 is the controlled release curve in the phosphate buffer solution with pH value of 2.0 and 7.4 after sample B in Example 1 is loaded with ibuprofen. the

Detailed ways

The present invention will be described in further detail below in conjunction with the accompanying drawings. the

Example 1

A kind of preparation method of the material of controlled release drug, as shown in Figure 1, comprises the following steps:

1) Modification of organic compounds containing double bonds and carboxyl groups

Dissolve the silane coupling agent and organic matter containing double bonds and carboxyl groups in absolute ethanol according to the volume ratio of 0-100%, add the initiator after passing nitrogen for two hours, continue to react at 70°C for 4-48 hours, and then pass through n-hexane extraction, obtained polymer, marked as P;

2) The above polymer P was grafted onto mesoporous SiO ₂

Add polymer P and mesoporous _SiO2 into absolute ethanol at a mass ratio of 1-80%, reflux at 70°C for 8-24 hours, finally filter and wash, and dry at 60-80°C for 5-10 hours , to obtain a solid powder of mesoporous _SiO2 coated with polymer P, marked as B.

The drug loaded in sample B can be water-soluble drug gentamycin, etc., slightly soluble drug aspirin, etc., or insoluble drug ibuprofen, etc. Further, after sample B is loaded with drug, the release system at different pH values can be citric acid buffer system, phosphate buffer system, simulated gastric juice, simulated body fluid, dilute hydrochloric acid, dilute ammonia water, etc. the

Example 2

Dissolve 8mL of vinyl-triethoxysilane and 80mL of methacrylic acid in absolute ethanol, add a certain amount of initiator azobisisobutyronitrile (AIBN) quickly after passing through _N2 for two hours, and continue the reaction at 70°C After 24 hours, the solid material was obtained by n-hexane extraction, and the polymer was obtained by multiple ethanol dissolution/n-hexane extraction processes, labeled as P.

Add 0.25 g of P and 0.5 g of _SiO2 with double mesoporous (large and small pore diameters are 21.0 nm and 2.7 nm, respectively) into absolute ethanol, reflux at 70 °C for 12 h, finally wash by filtration, and dry at 70 °C A solid powder was obtained, labeled B.

The above-mentioned sample B is used to load ibuprofen with a drug loading rate of 25.1%. The drug-loading system performs sensitive release of ibuprofen in phosphate buffer solutions with pH values of 2.0 and 7.4 respectively. The controlled release effect is shown in Figure 2 shown. the

Example 3

Dissolve 8mL of vinyl-triethoxysilane and 80mL of methacrylic acid in absolute ethanol, add a certain amount of initiator azobisisobutyronitrile (AIBN) quickly after passing through _N2 for two hours, and continue the reaction at 70°C After 24 hours, the solid material was obtained by n-hexane extraction, and the polymer was obtained by multiple ethanol dissolution/n-hexane extraction processes, labeled as P.

Add 0.05 g of P and 0.5 g of _SiO2 with double mesoporous (large and small pore diameters are 21.0 nm and 2.7 nm, respectively) into absolute ethanol, reflux at 70 °C for 12 h, finally wash by filtration, and dry at 70 °C A solid powder was obtained, labeled B.

The above-mentioned sample B is used for loading ibuprofen with a drug loading rate of 26.7%, and its drug-loading system performs sensitive release of ibuprofen in phosphate buffer solutions with pH values of 2.0 and 7.4, respectively. the

Example 4

Dissolve 8mL of vinyl-triethoxysilane and 80mL of methacrylic acid in absolute ethanol, and quickly add a certain amount of initiator azobisisobutyronitrile (AIBN) after passing through N2 for two hours, and continue the reaction at 70°C for 24 After 4 hours, the solid material was obtained by n-hexane extraction, and the polymer was obtained by multiple ethanol dissolution/n-hexane extraction processes, labeled as P. the

Add 0.1 g of P and 0.5 g of _SiO2 with double mesoporous (large and small pore diameters are 21.0 nm and 2.7 nm, respectively) into absolute ethanol, reflux at 70 °C for 12 h, finally wash by filtration, and dry at 70 °C A solid powder was obtained, labeled B.

The above-mentioned sample B is used to load ibuprofen with a drug loading rate of 35.9%, and its drug-loading system performs sensitive release of ibuprofen in phosphate buffer solutions with pH values of 2.0 and 7.4, respectively. the

Since this preparation method only has two steps of polymer modification and polymer encapsulation of mesoporous SiO ₂ , and all experimental instruments and equipment are commonly used in laboratories, the operations used are also common operations in the chemical field, so the preparation method is simple to operate. .

Example 5

Dissolve 8mL of vinyl-triethoxysilane and 80mL of methacrylic acid in absolute ethanol, add a certain amount of initiator azobisisobutyronitrile (AIBN) quickly after passing through _N2 for two hours, and continue the reaction at 70°C After 24 hours, the solid material was obtained by n-hexane extraction, and the polymer was obtained by multiple ethanol dissolution/n-hexane extraction processes, labeled as P.

Add 0.4 g of P and 0.5 g of _SiO2 with dual mesoporous (large and small pore diameters are 21.0 nm and 2.7 nm, respectively) into absolute ethanol, reflux at 70 °C for 12 h, finally wash by filtration, and dry at 70 °C A solid powder was obtained, labeled B.

The above-mentioned sample B is used to load ibuprofen with a drug loading rate of 24.6%, and its drug-loading system performs sensitive release of ibuprofen in phosphate buffer solutions with pH values of 2.0 and 7.4, respectively. the

Example 6

Dissolve 10mL of vinyl-trimethoxysilane and 80mL of methacrylic acid in absolute ethanol, add a certain amount of initiator azobisisobutyronitrile (AIBN) quickly after _two hours of nitrogen flow, and continue the reaction at 70°C for 10 After 4 hours, the solid material was obtained by n-hexane extraction, and the polymer was obtained by multiple ethanol dissolution/n-hexane extraction processes, labeled as P.

Add 2.0 g of P and 0.5 g of _SiO2 with double mesoporous (large and small pore diameters are 15 nm and 2 nm, respectively) into absolute ethanol, reflux at 70 °C for 24 h, finally wash by filtration, and dry at 80 °C to obtain a solid Powder, labeled B.

The above-mentioned sample B is used for loading ibuprofen, and its drug-carrying system performs sensitive release of ibuprofen in phosphate buffer solution with pH values of 2.0 and 7.4 respectively. The organic matter used in the present invention contains carboxyl groups, which can realize the control of drugs under different acidic or alkaline conditions, that is, the control of drugs at different pH values. the

Example 7

Dissolve 40mL of vinyl-triethoxysilane and 40mL of methyl methacrylate in absolute ethanol, and quickly add a certain amount of initiator dibenzoyl peroxide after passing through _N2 for two hours, and continue the reaction at 70°C for 48 After 4 hours, the solid material was obtained by n-hexane extraction, and the polymer was obtained by multiple ethanol dissolution/n-hexane extraction processes, labeled as P.

Add 2.0 g of P and 0.5 g of _SiO2 with double mesoporous (large and small pore diameters are 30 nm and 3 nm, respectively) into absolute ethanol, reflux at 70 °C for 24 h, finally wash by filtration, and dry at 80 °C to obtain a solid Powder, labeled B.

The above-mentioned sample B is used for loading ibuprofen, and its drug-carrying system performs sensitive release of ibuprofen in phosphate buffer solution with pH values of 2.0 and 7.4 respectively. the

Example 8

Dissolve 80mL of methacrylic acid in absolute ethanol, add a certain amount of initiator sodium persulfate quickly after passing through _N2 for two hours, continue to react at 70°C for 4 hours, obtain solid matter by n-hexane extraction, and pass through several times The ethanol dissolution/n-hexane extraction process yielded a polymer, marked as P.

Add 0.005 g of P and 0.5 g of SiO2 with double mesoporous (large and small pore diameters are 18 nm and 2 nm _, respectively) into absolute ethanol, reflux at 70 °C for 8 hours, finally wash by filtration, and dry at 60 °C to obtain a solid Powder, labeled B.

The above-mentioned sample B is used for loading ibuprofen, and its drug-carrying system performs sensitive release of ibuprofen in phosphate buffer solution with pH values of 2.0 and 7.4 respectively. the

Example 9

Dissolve 20mL of 3-(methacryloyloxy)propyltrimethoxysilane and 80mL of methacrylic acid in absolute ethanol, and quickly add a certain amount of initiator azobisisobutyronitrile (AIBN) after passing through _N2 for two hours , after continuous reaction at 70°C for 12 hours, the solid material was obtained by n-hexane extraction, and the polymer was obtained through multiple ethanol dissolution/n-hexane extraction processes, marked as P.

Add 1.5 g of P and 0.5 g of _SiO2 with dual mesoporous (large and small pore diameters are 25 nm and 3 nm, respectively) into absolute ethanol, reflux at 70 °C for 24 h, finally wash by filtration, and dry at 80 °C to obtain a solid Powder, labeled B.

The above-mentioned sample B is used for loading ibuprofen, and its drug-carrying system performs sensitive release of ibuprofen in phosphate buffer solution with pH values of 2.0 and 7.4 respectively. the

The present invention does not have the step of synthesizing mesoporous silicon spheres, and only the addition of polymer and mesoporous _SiO2 influences the results of the present invention. It is easy to control the grafting amount of polymer on the surface of mesoporous _SiO2 .

Example 10

Dissolve 50mL of _3- (methacryloyloxy)propyltriethoxysilane and 80mL of methacrylic acid in absolute ethanol, and add a certain amount of initiator azobisisobutyronitrile (AIBN ), after continuous reaction at 70°C for 24 hours, the solid material was obtained by n-hexane extraction, and the polymer was obtained through multiple ethanol dissolution/n-hexane extraction processes, marked as P.

Add 0.8 g of P and 0.5 g of _SiO2 with double mesoporous (large and small pore diameters are 30 nm and 2 nm, respectively) into absolute ethanol, reflux at 70 °C for 10 h, finally wash by filtration, and dry at 70 °C to obtain a solid Powder, labeled B.

The above-mentioned sample B is used for loading ibuprofen, and its drug-carrying system performs sensitive release of ibuprofen in phosphate buffer solution with pH values of 2.0 and 7.4 respectively. the

This preparation method only needs to change the addition amount of polymer and mesoporous _SiO2 , and the invention result can be well controlled.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection of the present invention. within range. the

Claims (7)

1. A preparation method of a material for controlled release of medicine, characterized in that, comprising the following steps: 1) Modification of organic compounds containing double bonds and carboxyl groups Dissolve the silane coupling agent and organic matter containing double bonds and carboxyl groups in absolute ethanol according to the volume ratio of 0-100%, add the initiator after passing nitrogen for two hours, continue to react at 70°C for 4-48 hours, and then pass through Extracted with n-hexane to obtain a polymer, marked as P; The silane coupling agent is vinyltriethoxysilane, vinyltrimethoxysilane, 3-(methacryloyloxy)propyltrimethoxysilane or 3-(methacryloyloxy)propyltrimethoxysilane Ethoxysilane; The organic compound containing double bonds and carboxyl groups is acrylic acid, methacrylic acid or methyl methacrylate; 2) The above polymer P was grafted onto mesoporous SiO ₂ Add polymer P and mesoporous _SiO2 into absolute ethanol at a mass ratio of 1-80%, reflux at 70°C for 8-24 hours, and finally filter and wash, and dry at 60-80°C for 5-10 hours , to obtain a solid powder of mesoporous _SiO2 coated with polymer P, marked as B. 2. The preparation method according to claim 1, characterized in that: the initiator is an organic peroxide, azo and inorganic peroxy initiator. 3. The preparation method according to claim 2, characterized in that: the organic peroxide initiator is dibenzoyl peroxide. 4. The preparation method according to claim 2, characterized in that: the azo initiator is azobisisobutyronitrile. 5. The preparation method according to claim 2, characterized in that: the inorganic peroxygen initiator is a persulfate. 6. The preparation method according to claim 1, characterized in that: the mesoporous SiO2 has a double mesoporous structure, and the particle diameter is 20-1000nm. 7. The preparation method according to claim 6, characterized in that: the diameter of the large pores of the double mesoporous structure is 15-30 nm, and the diameter of the small pores is 2-3 nm.