CN109806399B - Sustained release medicine, preparation method and application thereof - Google Patents
Sustained release medicine, preparation method and application thereof Download PDFInfo
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- CN109806399B CN109806399B CN201910157462.7A CN201910157462A CN109806399B CN 109806399 B CN109806399 B CN 109806399B CN 201910157462 A CN201910157462 A CN 201910157462A CN 109806399 B CN109806399 B CN 109806399B
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- Medicinal Preparation (AREA)
Abstract
The invention discloses a slow-release drug, which comprises mesoporous silicon spheres, a drug, guest molecules and host molecules, wherein the mesoporous silicon spheres are provided with mesopores, the drug is loaded in the mesopores, the guest molecules are combined with the outer surfaces of the mesoporous silicon spheres, the host molecules are combined with the guest molecules through host-guest interaction, the host molecules at least partially block the openings of the mesopores, and the host molecules can fall off from the mesoporous silicon spheres under the action of force. The invention also discloses a preparation method of the sustained-release medicine and application of the sustained-release medicine.
Description
Technical Field
The invention relates to the field of biomedicine, in particular to a sustained-release medicine, a preparation method and application thereof.
Background
Osteoarthritis is a degenerative disease, which is caused by degenerative damage of articular cartilage, reactive hyperplasia of articular margin and subchondral bone due to aging, obesity, strain, trauma, joint deformity, etc. Osteoarthritis has a high incidence rate, with 70% of people over 60 years old and 90% of people over 80 years old having osteoarthritis as a radiation lesion. Patients with osteoarthritis feel painful and stiff joints in the early stage, patients with osteoarthritis affect normal activities in the middle stage, and patients with osteoarthritis in the late stage have failed joints and basically lose mobility.
Currently, the clinical treatment for late stage osteoarthritis is mainly artificial joint replacement surgery, but there is no good treatment for early stage osteoarthritis. Oral anti-inflammatory drugs are difficult to reach the diseased site due to lack of blood supply in the joints, resulting in extremely low absorption efficiency, and injection of anti-inflammatory drugs is too short in duration and may cause side effects due to overdose. How to realize intelligent controlled release of the drug at the joint part is a key problem for treating arthritis. The current intelligent drug controlled release carrier induces drug release by means of light, heat, PH, enzyme, redox agent and the like, and is not suitable for being applied in bone joints.
Disclosure of Invention
Based on the above, there is a need for a sustained release drug suitable for bone joint treatment, a preparation method and applications thereof.
A slow release drug comprises mesoporous silicon spheres, a drug, guest molecules and host molecules, wherein the mesoporous silicon spheres are provided with mesopores, the drug is loaded in the mesopores, the guest molecules are combined with the outer surfaces of the mesoporous silicon spheres, the host molecules are combined with the guest molecules through host-guest interaction, the host molecules at least partially plug the openings of the mesopores, and the host molecules can fall off from the mesoporous silicon spheres under the action of force.
In one embodiment, the plugged area is 50% or more of the open area of the mesopores.
In one embodiment, the outer surface of the mesoporous silicon sphere has amino groups, and the guest molecule has acyl groups and/or OTs groups.
In one embodiment, the guest molecule having an acyl group is selected from at least one of betaine, acyl-modified 4, 4-bipyridine, and acyl-modified 2, 2' -bipyridine, and the host molecule is selected from sulfonated calix [4] arene; and/or the guest molecule with the OTs group is selected from cyclodextrin modified by the OTs group, and the host molecule is selected from at least one of azobenzene and adamantane grafted with the molecule.
In one embodiment, the molecules to be grafted of adamantane in the adamantane of the grafting molecules are selected from molecules having a lubricating effect, including one or more of 2-methacryloyloxyethyl phosphorylcholine and 3-sulfopropyl-potassium methacrylate nitrate.
In one embodiment, the mesoporous silicon spheres have a particle size of 50nm to 300nm, and the mesopores have a pore size of 2nm to 6 nm.
In one embodiment, the molecular weight of the host molecule is 740 to 10000.
In one embodiment, the force is applied as a friction force.
A preparation method of the sustained-release medicine comprises the following steps:
providing the mesoporous silicon spheres;
binding the guest molecules on the outer surface of the mesoporous silicon spheres;
loading the drug in the mesopores; and
the host molecules are combined with the guest molecules through host-guest interaction and the opening of the mesopores is at least partially blocked.
In one embodiment, the step of binding the guest molecule to the outer surface of the mesoporous silica spheres comprises: and carrying out amino modification on the mesoporous silicon spheres.
In one embodiment, the guest molecule has an acyl group, and the step of binding the guest molecule to the outer surface of the mesoporous silica spheres comprises: mixing the amino-modified mesoporous silicon spheres and the guest molecules with acyl groups in a solvent, and carrying out amidation reaction on the amino groups of the mesoporous silicon spheres and the acyl groups of the guest molecules to combine the amino groups and the acyl groups.
In one embodiment, the temperature of the amidation reaction is from 90 ℃ to 110 ℃.
In one embodiment, the method further comprises the following steps: performing acyl chloride modification on the guest molecules with acyl groups before the step of combining the guest molecules on the outer surfaces of the mesoporous silicon spheres.
In one embodiment, the guest molecule has OTs group, and the step of binding the guest molecule to the outer surface of the mesoporous silica spheres comprises: mixing the amino-modified mesoporous silicon spheres and the guest molecules with OTs groups in a solvent, and enabling the amino groups of the mesoporous silicon spheres and the OTs groups of the guest molecules to perform OTs group removing reaction to be combined.
In one embodiment, the method further comprises the following steps: and adding an acid binding agent into the reaction system for removing OTs groups.
In one embodiment, the temperature for the reaction for removing OTs groups is 100 ℃ to 120 ℃.
In one embodiment, the step of loading the drug in the mesopores comprises:
stirring the mesoporous silicon spheres combined with the guest molecules and the medicine in a solvent in a dark place; and
and centrifuging, washing and drying the product after being stirred in dark.
In one embodiment, the step of binding the host molecule to the guest molecule through host-guest interaction and at least partially blocking the opening of the mesopores comprises:
stirring the mesoporous silicon spheres loaded with the drugs and the host molecules in a solvent in a dark place; and
and centrifuging, washing and drying the product after being stirred in dark.
In one embodiment, the host molecule is selected from grafted molecules of adamantane, the grafted molecules of adamantane prepared by a process comprising:
carrying out carbon-carbon double bond modification on adamantane; and
and mixing the adamantane modified by the carbon-carbon double bond, the chain transfer reagent and the molecules to be grafted to perform RAFT reaction to form the adamantane of the grafted molecules.
The application of the slow-release medicine is applied to bone joint treatment medicines.
The mesoporous silicon spheres are used as drug carriers, drugs are loaded in mesopores of the mesoporous silicon spheres, guest molecules and host molecules are self-assembled on the surfaces of the mesoporous silicon spheres through host-guest interaction, and the mesopores are at least partially blocked by the host molecules so as to achieve the purpose of preventing the release of the drugs. The mesoporous part is blocked, so that the slow-release medicine is slowly released under the normal activity state of a human body, the interaction binding force of the host and the guest is weaker than that of a chemical bond, the host molecule falls off under the condition of violent movement, such as high risk of inflammatory factors such as joint friction, the mesoporous part is opened, the medicine is quickly released, and the intelligent release of the medicine is controlled through friction. The slow release medicine is used as a therapeutic medicine for osteoarthritis.
Drawings
FIG. 1 is a transmission electron micrograph of the sustained-release drug according to an embodiment of the present invention, wherein the lower left corner is the particle size distribution and the upper right corner is the zeta potential;
FIG. 2 is a drug release profile of the sustained release drug under different loading conditions according to an embodiment of the present invention, wherein the sustained release drug concentration is 1mg/mL, and the friction frequency is 2 Hz;
fig. 3 is a drug release curve of the sustained-release drug under different frequency conditions according to an embodiment of the present invention, wherein the sustained-release drug concentration is 1mg/mL, and the load is 4N.
Detailed Description
In order to make the objects, technical schemes and advantages of the present invention more clearly understood, the sustained release drug of the present invention, the preparation method and the application thereof are further described in detail by the following embodiments and the accompanying drawings. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The embodiment of the invention provides a slow-release drug, which comprises mesoporous silicon spheres, a drug, guest molecules and host molecules, wherein the mesoporous silicon spheres are provided with mesopores, the drug is loaded in the mesopores, the guest molecules are combined with the outer surfaces of the mesoporous silicon spheres, the host molecules are combined with the guest molecules through host-guest interaction, the host molecules at least partially block the openings of the mesopores, and the host molecules can fall off from the mesoporous silicon spheres under the action of force.
The slow-release drug provided by the embodiment of the invention takes the mesoporous silicon spheres as the drug carrier, the drug is loaded in the mesopores of the mesoporous silicon spheres, the guest molecules and the host molecules are self-assembled on the surfaces of the mesoporous silicon spheres through the host-guest interaction, and the mesopores are at least partially blocked by the host molecules so as to achieve the purpose of preventing the drug from being released. The mesoporous part is blocked, so that the slow-release medicine is slowly released under the normal activity state of a human body, the interaction binding force of the host and the guest is weaker than that of a chemical bond, the host molecule falls off under the condition of violent movement, such as high risk of inflammatory factors such as joint friction, the mesoporous part is opened, the medicine is quickly released, and the intelligent release of the medicine is controlled through friction. The friction controlled drug release mode can be applied to the treatment of osteoarthritis.
In an embodiment, the plugging area of the host molecule at the opening is more than 50% of the opening area of the mesopores, so that the mesopores have a smaller opening degree and release drugs more slowly in a normal activity state of a human body, the host molecule falls off under severe motion to open all the mesopores, the amount of the released drugs is increased obviously compared with the normal activity state, and the drugs are released more intelligently according to the state of the human body.
Molecular self-assembly is the process by which molecules spontaneously form a system with a regular structure under the induction of weak interaction forces (van der waals forces, hydrogen bonding, hydrophobic interactions, classical interactions, charge transfer, etc.). Host-guest interactions are the main driving force for the self-assembly process. The host and guest molecules can be bound by weak interaction forces formed by host-guest interactions. In embodiments of the invention, the combination of the guest molecule and the host molecule may be selected from at least one combination of betaine and sulfonated calix [4] arene, 4, -bipyridine and sulfonated calix [4] arene, 2' -bipyridine and sulfonated calix [4] arene, cyclodextrin and adamantane, and cyclodextrin and azobenzene.
In one embodiment, the mesoporous silicon spheres have amino groups on the outer surface, the guest molecules have acyl groups, and the amino groups of the mesoporous silicon spheres and the acyl groups of the guest molecules can be bonded through an amidation reaction. Preferably, the guest molecule has an acid chloride group, which is more susceptible to amidation reactions with the amino group. In one embodiment, the guest molecule having an acyl group may be selected from at least one of betaine, acyl-modified 4, 4-bipyridine, and acyl-modified 2, 2' -bipyridine, and the host molecule may be selected from sulfonated calix [4] arene.
In another embodiment, the mesoporous silicon spheres have amino groups on the outer surface, and the guest molecules have p-methylsulfonyloxy groups (OTs groups). The amino group of the mesoporous silica sphere and the OTs group of the guest molecule may be bound by an OTs group elimination reaction. The OTs group removing reaction is a reaction that the OTs group of the guest molecule is replaced by the mesoporous silicon sphere with the amino group. In one embodiment, the guest molecule having an OTs group may be selected from cyclodextrins modified with OTs groups, and the host molecule may be selected from at least one of azobenzene and adamantane grafted molecules. The molecules to be grafted of adamantane in the adamantane of the grafting molecules may be molecules having a lubricating effect, such as one or more of 2-Methacryloyloxyethyl Phosphorylcholine (MPC) and 3-sulfopropyl-potassium methacrylate nitrate (SPMK). As the amphiprotic group in the MPC or the sulfonic group in the SPMK can be combined with water molecules to form a hydrogen bond respectively, the adamantane of the grafted molecule has a lubricating effect, so that the lubricity of the sustained-release drug is improved. Meanwhile, the molecular weight of the grafted adamantane is increased, so that the mesopores of the mesoporous silicon spheres can be plugged, and a slow release effect is achieved.
It is understood that the outer surface of the mesoporous silicon spheres and the guest molecule may also be bonded by a reaction between other groups, such that the guest molecule is bonded to the outer surface of the mesoporous silicon spheres by a chemical bond, preferably a covalent bond.
In one embodiment, the mesoporous silicon spheres may have a particle size of 50nm to 300nm, and the pore diameter of the mesopores may be 2nm to 6 nm. The particle size of the mesoporous silicon spheres and the pore diameter of the mesopores in the range are more suitable for lubrication and drug release of bone joint positions. The particle size of the mesoporous silicon spheres and the pore size of the mesopores can be adaptively adjusted according to the action part of the sustained-release drug and the type of the drug.
The molecular weight and diameter of the host molecule are such that the host molecule has a suitable size to be able to plug the mesoporous portion. In one embodiment, the host molecule may have a molecular weight of 740 to 10000. Within the molecular weight range, the host molecule can have a large shape and structure by folding, rolling and the like, so that the mesopores can be at least partially blocked, and a slow release effect is achieved. The species, molecular weight and diameter of the host molecule can be adaptively adjusted according to the pore diameter of the mesopores of the mesoporous silicon spheres.
In one embodiment, the force is applied as a friction force. Under the condition that bone joints are subjected to severe friction, such as inflammatory reaction, the severe friction causes the local temperature of the joints to rise, the interaction force of a host and an object is weakened, the host molecules and the object molecules are separated, the host molecules fall off from the mesoporous silicon spheres, the openings of the mesopores are opened, and the medicine can be rapidly released from the mesopores to play an anti-inflammatory role.
The embodiment of the invention also provides a preparation method of the sustained-release medicine, which comprises the following steps:
s10, providing the mesoporous silicon spheres;
s20, binding the guest molecules on the outer surface of the mesoporous silicon spheres;
s30, loading the drug in the mesopores; and
s40, combining the host molecule with the guest molecule through host-guest interaction and at least partially blocking the opening of the mesopore.
In step S10, the mesoporous silicon spheres may be prepared by a template extraction method. In one embodiment, before step S20, the method includes: and modifying the mesoporous silicon spheres with amino. The step of amino modification can be performed during the preparation process of the mesoporous silicon spheres.
In one embodiment, the preparation of the mesoporous silicon spheres may include:
s12, mixing a silicon source, a template agent and a form control catalyst in a solvent, centrifuging, cleaning and drying to form silicon spheres;
s14, mixing, refluxing, centrifuging, washing and drying the amino source reagent and the silicon spheres in a solvent to form amino modified silicon spheres; and
and S16, mixing the amino-modified silicon spheres and a template agent in a solvent, refluxing, centrifuging, cleaning and drying to form the amino-modified mesoporous silicon spheres.
In step S12, the silicon source may be selected from tetraethyl orthosilicate (TEOS), the templating agent may be selected from cetyltrimethylammonium bromide (CTAB), the morphology control catalyst may be selected from sodium hydroxide, and the solvent may be water. The preparation temperature of the silicon spheres can be 75-85 ℃. The types and proportions of the silicon source, the template agent and the morphology control catalyst can be adjusted according to actual conditions, and are not described in detail herein.
In step S14, the amino source reagent is used to provide the modified amino group and may be selected from 3-Aminopropyltriethoxysilane (APTES) and the solvent may be anhydrous toluene. The temperature of the refluxing step may be 105 ℃ to 115 ℃. And after the silicon spheres are formed, the amino groups are modified before the mesoporous silicon spheres are formed, so that the blocking of the amino groups by shape change in the forming process of the silicon spheres is avoided, and the binding property of the amino groups on the silicon spheres is improved.
In step S16, the template agent is used to remove the template agent from the silicon spheres to form mesopores. The stripper plate agent may be selected from concentrated hydrochloric acid and the solvent may be methanol. The temperature of the refluxing step may be 55-65 ℃.
In step S20, the mesoporous silicon spheres and the guest molecules may be bonded by a chemical reaction to form a covalent bond.
In one embodiment, the guest molecule has an acyl group, such as betaine, and the step of binding the guest molecule to the outer surface of the mesoporous silicon sphere may include: mixing the amino-modified mesoporous silicon spheres and the guest molecules with acyl groups in a solvent, and carrying out amidation reaction on the amino groups of the mesoporous silicon spheres and the acyl groups of the guest molecules to combine the amino groups and the acyl groups.
In one embodiment, the method further comprises: performing acyl chloride modification on the guest molecules with acyl groups before the step of combining the guest molecules on the outer surfaces of the mesoporous silicon spheres. The acyl chloride group formed by acyl chlorination is easier to perform amidation reaction with the amino group of the mesoporous silicon sphere. The step of acyl chloride modification can be mixing the guest molecule with acyl with a reagent containing active chlorine. The reagent containing active chlorine may be at least one selected from thionyl chloride and oxalyl chloride. Acyl chloride refers to a process in which an acyl group-containing substance is reacted with a reagent containing active chlorine to produce an acid chloride substance. And the acyl chlorination reaction of the betaine is to react the carboxyl of the betaine and the active chlorine reagent to form acyl chloride groups.
In one embodiment, the temperature of the amidation reaction may be from 90 ℃ to 110 ℃.
In one embodiment, the guest molecule has an OTs group, for example a cyclodextrin modified with an OTs group. The step of binding the guest molecule to the outer surface of the mesoporous silica spheres may include: mixing the amino-modified mesoporous silicon spheres and the guest molecules with OTs groups in a solvent, and enabling the amino groups of the mesoporous silicon spheres and the OTs groups of the guest molecules to perform OTs group removing reaction to be combined.
In one embodiment, the preparation process of the OTs group modified cyclodextrin comprises: under alkaline conditions, the hydroxyl groups of the cyclodextrin and the reagent containing p-methylsulfonyl are mixed and subjected to a substitution reaction to form p-methylsulfonyloxy groups. The reagent containing a p-methylsulfonyl group may be selected from methylsulfonyl chloride.
Preferably, the preparation process of the OTs group modified cyclodextrin further comprises: and (3) carrying out suction filtration on the product after the substitution reaction to remove precipitates, adjusting the PH value of the supernatant to 7-8, carrying out suction filtration to collect the precipitates and recrystallizing. Through further treatment after the substitution reaction, the obtained OTs group-modified cyclodextrin has higher purity, and is more favorable for further combination with mesoporous silicon spheres and main molecules.
In one embodiment, the temperature for the reaction to remove the OTs groups is from 100 ℃ to 120 ℃.
Preferably, the method further comprises the following steps: and adding an acid binding agent into the reaction system for removing OTs groups. The acid-binding agent is used as a catalyst and is used for absorbing acid generated in the OTs group removing reaction, the acid-binding agent can be alkalescent substance, and the alkalescent substance and the acid form a salt, so that the influence of the acid on the reaction or the reaction balance is avoided, and the reaction speed is accelerated. The acid scavenger may be ethylenediamine.
In step S30, the step of loading the drug in the mesopores may include:
stirring the mesoporous silicon spheres combined with the guest molecules and the medicine in a solvent in a dark place; and
and centrifuging, washing and drying the product after being stirred in dark.
In step S40, the step of binding the host molecule to the guest molecule through host-guest interaction and at least partially blocking the opening of the mesopores comprises:
stirring the mesoporous silicon spheres loaded with the drugs and the host molecules in a solvent in a dark place; and
and centrifuging, washing and drying the product after being stirred in dark.
The loading step of the drug is carried out after the step of combining the guest molecules with the mesoporous silicon spheres, so that the situation that the guest molecules cannot be combined on the surfaces of the mesoporous silicon spheres due to the fact that the drug shields the surfaces of the mesoporous silicon spheres can be avoided.
In step S30 and step S40, oxidation of the drug is avoided by a light-shielding self-assembly process.
In one embodiment, the host molecule is selected from adamantane grafted molecules, and the host-guest interaction of adamantane and cyclodextrin is strong and is a good host-guest reagent. However, the molecular weight of adamantane is small, and the mesopores of mesoporous silicon cannot be blocked, the molecular weight of adamantane is improved by grafting molecules on adamantane, the adamantane grafted with the molecules can be used as a main molecule to block the mesopores so as to prevent the release of the drug, and the adamantane grafted with the molecules falls off under the action of friction so as to realize the rapid release of the drug and realize the slow release of the drug controlled by friction. Meanwhile, the molecules to be grafted can be a reagent with a lubricating effect, so that the slow release of the medicament is realized, and the lubricating property of the slow release medicament is further improved. The molecule to be grafted is preferably a molecule or polymer having a relatively large molecular weight, and may be, for example, 5000 to 20000.
In one embodiment, the method for preparing adamantane for grafting molecules may comprise:
carrying out carbon-carbon double bond modification on adamantane; and
the method comprises the following steps of mixing adamantane modified by carbon-carbon double bonds, a Chain Transfer reagent and molecules to be grafted containing the double bonds to perform Reversible Addition-Fragmentation Chain Transfer Polymerization (RAFT) reaction to form the adamantane of the grafted molecules.
The short term RAFT reversible addition-fragmentation chain transfer polymerization is one of the living/controlled free radical polymerization. The RAFT reaction is used for connecting 1 or more carbon-carbon double bond modified adamantane and a molecule to be grafted containing a double bond in the molecular structure of a chain transfer reagent through an addition reaction to form a high polymer of the adamantane and the molecule to be grafted, so that the molecular weight of the adamantane is improved.
In one embodiment, the step of modifying the adamantane by a carbon-carbon double bond comprises: mixing adamantane and a reagent containing a carbon-carbon double bond in a solvent; filtering to remove the precipitate; and (4) carrying out rotary evaporation on the filtered supernatant to obtain a solid phase and purifying the solid phase. The reagent containing a carbon-carbon double bond may be acryloyl chloride. The solvent may be DMF. The purification step may be column chromatography. Preferably, the system for modifying the carbon-carbon double bond of adamantane further comprises an acid-binding agent, wherein the acid-binding agent is used for absorbing acid formed by the carbon-carbon double bond modification reaction and improving the reaction rate. The acid-binding agent can be triethylamine. Preferably, the method further comprises the following steps: a step of mixing the adamantane and the acid scavenger and performing an ice bath to avoid too violent reaction of the adamantane before mixing the adamantane and the reagent containing the carbon-carbon double bond.
Preferably, the system for RAFT reaction includes an initiator for initiating the RAFT reaction. In one embodiment, the chain transfer agent may be selected from 2- [ [ (butylthio) thiooxymethyl ] thio ] propanoic acid. The initiator may be selected from azobisisobutyronitrile. The temperature of the RAFT reaction may be in the range 65 ℃ to 75 ℃. Preferably, the RAFT reaction is carried out under nitrogen. Preferably, the RAFT reaction is carried out under exclusion of light.
Preferably, the method further comprises the steps of performing rotary evaporation and dialysis purification on the product of the RAFT reaction.
The embodiment of the invention also provides application of the slow release medicine, and the slow release medicine can be applied to bone joint treatment medicines.
Example 1
(1) 1g of cetyltrimethylammonium bromide (CTAB) and 3.5mL of sodium hydroxide solution (2mol/L) were added to 480mL of deionized water to obtain a mixed solution, and the mixture was stirred at 80 ℃ for 30 min. 5mL of tetraethyl orthosilicate (TEOS) was added dropwise to the mixture and stirring was continued for 2h at 80 ℃. Centrifuging, cleaning and vacuum drying to obtain the silicon spheres.
(2) 1g of the product of step (1) was dispersed in 100mL of anhydrous toluene, and 5mL of 3-Aminopropyltriethoxysilane (APTES) was added and refluxed at 110 ℃ for 24 hours. And centrifuging, washing and vacuum drying to obtain the amino modified silicon spheres.
(3) Dispersing 1g of the product obtained in the step (2) in 100mL of methanol, adding 1mL of concentrated hydrochloric acid, refluxing at 60 ℃ for 24h, centrifuging, cleaning and drying in vacuum to obtain amino-modified mesoporous silicon spheres (MSN-NH)2)。
(4) 1.2mL of thionyl chloride is added dropwise to 0.9g of betaine hydrochloride, the reaction is carried out at room temperature until no gas is generated, and rotary evaporation and drying are carried out to obtain the acyl-chlorinated betaine.
(5) 100mg of MSN-NH2Dispersed in 20mL of N, N-Dimethylformamide (DMF), and 50mg of the product of step (4) was added and stirred at 100 ℃ for 12 hours. And centrifuging, cleaning and drying in vacuum to obtain the betaine modified mesoporous silicon spheres (bMSN).
(6) 0.5g of calix [4] arene (C4A) is dispersed in 5mL of concentrated sulfuric acid and stirred at room temperature for 1 h. The reaction exothermed vigorously and, after cooling to room temperature, 10mL of saturated brine was added dropwise to the calix [4] arene solution. Filtering, recrystallizing to obtain sulfonated calix [4] arene (SC [4] A).
(7) 20mg bMSN was dispersed in 10mL of 0.5mmol/L rhodamine B (RhB, model drug molecule, used only for characterizing the preparation steps and the slow release results, not representing the drug type) solution, and stirred at room temperature in the dark for 24 h. And 20mg of SC 4 was added to the solution]A, continuously stirring for 24 hours at room temperature in a dark place, centrifuging, cleaning and drying in vacuum to obtain the sulfonated glass [4]]Aromatic hydrocarbon coated betaine mesoporous silicon sphere sustained-release medicine
Please refer to fig. 1, for the prepared
Transmission electron microscope characterization and zeta potential characterization are carried out, and the result shows that the mesoporous silicon sphere slow-release medicine prepared by the method has a regular spherical shapeShape and stable structure.
Referring to FIGS. 2 and 3, the prepared
The drug release experiments were performed under different frequency conditions under different frictional loading conditions. The results show that the main molecules can not fall off under the low load condition (1N), and the drug release is limited; the high load and high frequency can activate main molecules to fall off, so that a large amount of drugs can be released; the more severe the rubbing conditions, the higher the load, the faster the drug release, and the more cumulative drug release.
Example 2
(1) - (3) preparing amino modified mesoporous silicon spheres in the same way as the example.
(4) 27g of cyclodextrin was dissolved in 150mL of deionized water, 9mL of NaOH solution (5.8mol/L) was added dropwise to the cyclodextrin solution, and the mixture was stirred at room temperature for 30min, whereby the solution became pale green. To the pale green solution was added dropwise 13mL of a solution of p-toluenesulfonyl chloride in acetonitrile (1.58mol/L), and the mixture was stirred at room temperature for 3 hours. The precipitate was removed by suction filtration, and hydrochloric acid (2mol/L) was added dropwise to the supernatant until the pH was 7.5, followed by standing in a refrigerator overnight. And (4) carrying out suction filtration, collecting the precipitate, and recrystallizing with deionized water for 3 times to obtain the OTs group modified cyclodextrin (OTs-CD).
(5) 100mg of MSN-NH2Dispersed in 20mL of N, N-Dimethylformamide (DMF), 50mg of OTs-CD and 2mL of ethylenediamine (acid-binding agent) were added, and the mixture was stirred at 110 ℃ for 24 hours. Centrifuging, cleaning and vacuum drying to obtain the cyclodextrin mesoporous silicon spheres (MSN-CD).
(6) 3.1g of adamantane was dissolved in 300mL of DMF solution, 3.1mL of triethylamine was added, and the mixture was ice-cooled for 10 min. 4.0mL of acryloyl chloride was added dropwise to the solution, stirred for 2h in an ice bath and then stirred at room temperature overnight. Filtering to remove precipitate, performing rotary evaporation on the supernatant to obtain a solid product, and purifying by column chromatography to obtain the adamantane modified by the carbon-carbon double bond.
(7) 291mg of the product of (6), 112.7mg of 2- [ [ (butylthio) thiooxymethyl ] thio ] propionic acid and 7.77mg of azobisisobutyronitrile were dissolved in 100mL of toluene, stirred at 70 ℃ under nitrogen for 6 hours, 1.2g of 2-Methacryloyloxyethyl Phosphorylcholine (MPC) was added to the solution, and stirred at 70 ℃ under nitrogen for another 6 hours. Rotary evaporation to obtain crude product, dialysis purification to obtain grafted molecule adamantane P (Ad-MPC).
(8) 20mg of MSN-CD is dispersed in 10mL of 0.5mmol/L rhodamine B (RhB, model drug molecule, used only for characterizing preparation steps and slow release results and not representing drug types) solution, and stirred at room temperature in a dark place for 24 h. Adding 30mg of adamantane P (Ad-MPC) grafted with molecules into the solution, continuously stirring for 24 hours at room temperature in a dark place, centrifuging, cleaning and drying in vacuum to obtain the mesoporous silicon sphere sustained-release medicine of the cyclodextrin coated by the adamantane
(Ad-MPC)。
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (9)
1. A slow-release medicine is characterized by comprising mesoporous silicon spheres, a medicine, guest molecules and host molecules, the mesoporous silicon spheres have mesopores, the drug is loaded in the mesopores, the guest molecules are combined with the outer surfaces of the mesoporous silicon spheres, the host molecule is combined with the guest molecule through host-guest interaction, the host molecule at least partially plugs the opening of the mesopore, the main molecules can fall off from the mesoporous silicon spheres under the action of friction force, the outer surfaces of the mesoporous silicon spheres are provided with amino groups, the guest molecule has OTs group, the guest molecule with OTs group is selected from cyclodextrin modified by OTs group, the main molecule is selected from adamantane of grafting molecule, the molecule to be grafted of adamantane in the adamantane of grafting molecule is selected from the molecule with lubricating effect, the molecule with lubricating effect is selected from 2-methacryloyloxyethyl phosphorylcholine.
2. The sustained-release drug according to claim 1, wherein the plugging area is 50% or more of the opening area of the mesopores.
3. The sustained-release drug according to claim 1, wherein the mesoporous silica spheres have a particle size of 50nm to 300nm, and the pores have a pore size of 2nm to 6 nm.
4. A process for the preparation of a sustained release medicament as claimed in any one of claims 1 to 3, comprising:
providing the mesoporous silicon spheres;
binding the guest molecules on the outer surface of the mesoporous silicon spheres;
loading the drug in the mesopores; and
the host molecules are combined with the guest molecules through host-guest interaction and the opening of the mesopores is at least partially blocked.
5. The method for preparing a sustained-release drug according to claim 4, wherein the step of binding the guest molecule to the outer surface of the mesoporous silica spheres is preceded by: and carrying out amino modification on the outer surface of the mesoporous silicon spheres.
6. The method for preparing a sustained-release drug according to claim 5, wherein the guest molecule has OTs groups, and the step of binding the guest molecule to the outer surface of the mesoporous silica spheres comprises: mixing the amino-modified mesoporous silicon spheres and the guest molecules with OTs groups in a solvent, and enabling the amino groups of the mesoporous silicon spheres and the OTs groups of the guest molecules to perform OTs group removing reaction to be combined.
7. The process for preparing a sustained-release drug according to claim 4,
the step of loading the drug in the mesopores comprises: stirring the mesoporous silicon spheres combined with the guest molecules and the medicine in a solvent in a dark place; centrifuging, cleaning and drying the product after being stirred in a dark place; and/or the presence of a gas in the gas,
the step of binding the host molecule to the guest molecule through host-guest interaction and at least partially blocking the opening of the mesopores comprises: stirring the mesoporous silicon spheres loaded with the drugs and the host molecules in a solvent in a dark place; and centrifuging, washing and drying the product after being stirred in the dark.
8. The method for preparing an extended release drug of claim 4, wherein the method for preparing the grafted molecule of adamantane comprises:
carrying out carbon-carbon double bond modification on adamantane; and
and mixing the adamantane modified by the carbon-carbon double bond, the chain transfer reagent and the molecules to be grafted to perform RAFT reaction to form the adamantane of the grafted molecules.
9. Use of a sustained release medicament as claimed in any one of claims 1 to 3 in the manufacture of a medicament for the treatment of bone joints.
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