CN113876963A - Preparation method of aspirin-silicon dioxide sustained-release body - Google Patents

Preparation method of aspirin-silicon dioxide sustained-release body Download PDF

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CN113876963A
CN113876963A CN202111160143.5A CN202111160143A CN113876963A CN 113876963 A CN113876963 A CN 113876963A CN 202111160143 A CN202111160143 A CN 202111160143A CN 113876963 A CN113876963 A CN 113876963A
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silicon dioxide
aspirin
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inorganic acid
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CN113876963B (en
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胡颖妮
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Guangzhou Lingwe Technology Co ltd
Lengshuijiang Three A New Material Technology Co ltd
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
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Abstract

The invention discloses a preparation method of an aspirin-silicon dioxide slow-release body, which comprises the following steps: the preparation method comprises the steps of preparing silicon dioxide powder by taking water glass and inorganic acid as reaction raw materials without adding a dispersing agent, immersing the silicon dioxide powder into an aspirin solution to prepare silicon dioxide containing aspirin, modifying the silicon dioxide containing aspirin by a dry method by taking hexamethyldisilazane as a modifying agent to prepare an aspirin-silicon dioxide slow-release body, carrying out graft modification on the surface of the silicon dioxide loaded with aspirin, skillfully coating the aspirin with a grafting group to prepare steric hindrance, avoiding the aspirin from flowing out of a mesoporous structure quickly after entering a human body, ensuring stable drug release rate and realizing long-acting release of the drug; partial hydroxyl on the surface of the silicon dioxide is substituted, so that the hygroscopicity of the silicon dioxide is reduced, the agglomeration of the silicon dioxide can be effectively inhibited, and the dispersibility of the silicon dioxide is improved; the mesoporous of the silicon dioxide does not need to use a template agent, and the preparation process is simple and reliable.

Description

Preparation method of aspirin-silicon dioxide sustained-release body
Technical Field
The invention belongs to the technical field of drug carriers, and particularly relates to a preparation method of an aspirin-silicon dioxide slow-release body.
Background
The sustained release technology can realize long-term stable administration, reduce the administration times of patients, reduce toxic and side effects and improve the bioavailability of the medicament, and is a research hotspot in the field of medicine in recent years, wherein a medicament carrier is one of the keys for realizing the sustained release technology. In the last decades, in order to reduce the toxic and side effects and low water solubility of drugs, various drug carriers such as cyclodextrins have been designed to reduce the interference of immune system to drugs, but the cyclodextrin system and drug molecules have weak interaction, and the formed sustained release body has low mechanical strength, weak drug-loading capacity and single response to environmental stimulation, and cannot well cope with complex pathological environments, and has more limitations in clinical treatment.
Silica materials have good biocompatibility, are rich in silicon hydroxyl groups on the surface, can be subjected to diversified chemical modification, and have been widely studied as functional carriers of various drugs in recent years.
CN104188985 discloses a preparation method of targeted controlled release aspirin powder. The preparation process comprises four parts of preparation of a magnetic core-shell nano silicon dioxide drug carrier, partial dissolution of a magnetic core, loading of aspirin on the magnetic drug carrier and secondary coating of aspirin. The acid dissolution and the secondary coating of the polyvinylpyrrolidone polymer sol are adopted to improve the long-acting slow release and controllable release efficiency, the method has better slow release effect, but has longer synthetic route and complex method, and is not beneficial to practical application.
CN104030296 discloses a preparation method of a micro-mesoporous hollow tubular silica material and a micro-mesoporous silica drug sustained-release material obtained by the method. The material has a drug loading of 15% for aspirin, but the release rate is too fast.
Disclosure of Invention
Aiming at the problems in the related art, the invention provides a preparation method of an aspirin-silicon dioxide slow-release body, which aims to overcome the technical problems in the prior related art.
The technical scheme of the invention is realized as follows:
a preparation method of aspirin-silicon dioxide sustained release body comprises the following steps:
(1) taking water glass and inorganic acid as reaction raw materials, and preparing silicon dioxide powder without adding a dispersing agent;
(2) immersing the silicon dioxide powder into aspirin solution to prepare aspirin-containing silicon dioxide;
(3) the aspirin-silicon dioxide slow release body is prepared by modifying aspirin-containing silicon dioxide by a dry method by using hexamethyldisilazane as a modifier.
According to the invention, cheap water glass and inorganic acid are reacted to prepare silicon dioxide rich in mesopores, then the silicon dioxide is used for adsorbing aspirin, finally grafting modification is carried out on the surface of the silicon dioxide loaded with the aspirin, the aspirin is coated by utilizing a grafting group ingeniously, steric hindrance is produced, the aspirin is prevented from flowing out of a mesopore structure quickly after entering a human body, and the aspirin-silicon dioxide slow release body prepared by the invention has stable drug release rate and can realize long-acting release.
The invention aims at the modified grafting of silicon dioxide, and has the following specific reaction formula:
Figure BDA0003289841690000021
according to the reaction formula, hexamethyldisilazane is hydrolyzed on the surface of silicon dioxide, hydroxyl of the silicon dioxide is replaced by trimethylsilyl, and the molecular structure of the trimethylsilyl forms an umbrella-like shielding structure on the surface of the silicon dioxide, so that the drug is prevented from flowing out of mesoporous pores of the silicon dioxide too fast, and the long-acting slow-release effect is realized; on the other hand, the surface of the silicon dioxide is rich in hydroxyl, has stronger hydrophilicity, is very easy to absorb moisture, is difficult to disperse and wet in an organic phase, and forms a grafting phenomenon among particles under the action of hydrogen bonds, so that the silicon dioxide is easy to agglomerate, and the dispersibility is very poor.
Secondly, most of the existing silica modification processes are wet modification, namely, silica and modified raw materials are placed in a liquid environment for stirring reaction, but the finished product modified by the wet modification needs separation and purification steps, so that the production steps are many, the cost is high, and the finished product is easy to pollute in the process, so that the dry modification is adopted in the invention; in addition, in view of the present invention, the silica is loaded with aspirin before being subjected to modified grafting, and if wet modification is adopted, part of aspirin is lost in a liquid reaction system, so that conventional wet modification is obviously not suitable for the present invention.
Finally, the existing silica preparation processes all add dispersing agents or other surfactants with the function of dispersing and homogenizing, but the inventor finds that: if the anionic or cationic dispersant is added, the reaction system for synthesizing the silicon dioxide is subjected to precipitation polymerization, so that the preparation of the silicon dioxide is influenced; the inventors have surprisingly found that the addition of no dispersant is an optimal choice, since the neutral dispersant causes the pore size of the silica to be small and the neutral dispersant easily aggregates on the surface of the silica to agglomerate the silica.
Preferably, in the step (1), the water glass is prepared into a water glass aqueous solution by using distilled water as a base solution, the inorganic acid is prepared into an inorganic acid aqueous solution by using distilled water as a base solution, and mixing is performed to synthetically prepare the silica, during which the pH value is maintained at 7 to 8 while stirring and heating are maintained.
Diluting the synthetic raw materials by the base solution, stirring and heating so as to reduce the viscosity of the reaction system; in addition, the larger the oil absorption value of the silicon dioxide is, the better the performance of the silicon dioxide is, and the larger the specific surface area and the pore volume of the silicon dioxide are, so that the applicant finds that compared with other base solutions, the silicon dioxide with the higher oil absorption value can be synthesized by adopting distilled water as the base solution, and the larger specific surface area and the pore volume are beneficial to the subsequent load of aspirin.
Specifically, the modulus of the water glass is 3-4, the silicon dioxide content of the water glass aqueous solution is 10-20 wt%, the inorganic acid is sulfuric acid, the cost is low, and the sulfuric acid content of the sulfuric acid aqueous solution is 20-30 wt%.
Preferably, in the step (1), the water glass aqueous solution and the inorganic acid aqueous solution are added to the reaction vessel in a concurrent flow manner for mixing and reacting. In actual batch production, if one-way feeding is adopted to precipitate silicon dioxide, due to the large feeding amount, even if a high-speed stirrer is adopted, the viscosity of the feed liquid is difficult to avoid to rise gradually, so that the fluidity of the feed liquid is reduced rapidly, and the serious agglomeration phenomenon occurs.
The applicant also finds that the long parallel flow time also has an influence on the specific surface area of the silicon dioxide, and through experiments, the long parallel flow time is 30-120min, so that the silicon dioxide with a larger specific surface area can be prepared, and the loading of the drug is facilitated.
Specifically, before the water glass aqueous solution and the inorganic acid aqueous solution are injected into the reaction container, part of the base solution is injected and heated to 40-60 ℃, the feed liquid after the silicon dioxide is synthesized is heated to 70-90 ℃, and then the aging and precipitation are carried out for 1-3 hours.
Preferably, in the step (1), ultrasonic agitation is used. The reason why ultrasonic agitation is particularly preferable in the present application is that: the synthesized silicon dioxide needs to be loaded with a drug subsequently, and ultrasonic stirring can cause the formation, growth and collapse of bubbles in a reaction system continuously, the collapse of the bubbles can cause impact on the interior of the silicon dioxide with low condensation polymerization degree, part of chemical bonds are broken, the internal space of the silicon dioxide finished product is larger, and the drug loading capacity is improved.
Preferably, in the step (1), a feed liquid obtained by mixing and reacting the water glass aqueous solution and the inorganic acid aqueous solution is acidified and filtered to obtain a silica filter cake, and the silica filter cake is washed to prepare a dry powder.
The PH also affects the oil absorption of the silica, and more preferably, the acidified PH is 2 to 4, which allows for the production of silica having a greater oil absorption and improved silica performance.
More preferably, the silicon dioxide filter cake is washed by using sulfuric acid with the concentration of 1 wt% and distilled water as washing liquids in sequence, so that the content of sodium ions and sulfate radicals of silicon dioxide in the filter cake is reduced, and then the filter cake is dried to prepare powder.
Specifically, the feed liquid obtained after the mixing reaction of the water glass aqueous solution and the inorganic acid aqueous solution is acidified and aged for at least 0.5h by adjusting the pH value to 2-4, and is cooled to 60-70 ℃, and then is filtered, wherein the operation of preparing the silicon dioxide filter cake into powder is as follows: and (3) uniformly dispersing the filter cake in a small amount of water again to prepare slurry, and drying in a spray drying mode to obtain powder.
Specifically, the operation of step (2) is: immersing the powder prepared in the step (1) into aspirin solution until the adsorption is balanced, and filtering and drying to prepare the aspirin-containing silicon dioxide.
Preferably, the specific operation of step (3) is: placing the silicon dioxide containing aspirin in a vacuum drying oven to spread, increasing the contact area with hexamethyldisilazane, wherein the hexamethyldisilazane accounts for 1-10% of the mass of the silicon dioxide containing aspirin, the hexamethyldisilazane contacts the surface of the silicon dioxide containing aspirin in a gas form to perform graft modification, setting the temperature of the vacuum drying oven to be 30-40 ℃, and starting a vacuum pump to pump vacuum after reacting for a certain period of time.
And (3) reacting in a vacuum drying oven, so that the hexamethyldisilazane is prevented from contacting air and being rapidly hydrolyzed into trimethylsilanol and hexamethyldisiloxane by being hydrolyzed into water. The application adopts the low temperature of 30-40 ℃ to dry the adsorbed water on the surface of the silicon dioxide, which is because the drying temperature is too high, the silicon dioxide is subjected to the phenomenon of pore combination, the pore volume is reduced, aspirin is extruded, and the drug-loading rate is reduced.
Preferably, the duration of the graft modification is 1-6h, when the duration is less than 1h, the methyldisilazane does not fully react with silicon dioxide, when the duration exceeds 6h, most of exposed hydroxyl groups are substituted by trimethylsilyl groups, and the remaining small part of hydroxyl groups are increased in steric hindrance due to the increase of trimethylsilyl groups with an umbrella-shaped structure, so that the contact with hexamethyldisilazane is not facilitated, the duration is increased, and the grafting rate is not obviously improved.
The invention has the beneficial effects that:
(1) according to the invention, cheap water glass and inorganic acid are reacted to prepare silicon dioxide rich in mesopores, then the silicon dioxide is used for adsorbing aspirin, finally grafting modification is carried out on the surface of the silicon dioxide loaded with the aspirin, the aspirin is coated by using a grafting group ingeniously, the steric hindrance is manufactured, the aspirin is prevented from flowing out of a mesopore structure quickly after entering a human body, the drug release rate is stable, and the long-acting release of the drug can be realized;
(2) according to the invention, the silicon dioxide is subjected to graft modification, and partial hydroxyl on the surface of the silicon dioxide is replaced, so that the hygroscopicity of the silicon dioxide is greatly reduced, the silicon dioxide is easy to store, and meanwhile, the reduction of the hydroxyl can effectively inhibit the recrystallization or reaggregation of the silicon dioxide, the dispersibility of the silicon dioxide is improved, and the further processing at a later stage is convenient;
(3) the mesoporous silica does not need to use a template agent, has simple and reliable preparation process, can be changed into other medicines according to the needs, and has wider application range.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
(1) Preparing water glass aqueous solution and dilute sulfuric acid aqueous solution;
the water glass with the modulus of 3.35 is used as a raw material to prepare the water glass aqueous solution with the silicon dioxide content of 20 wt%, and the concentration of the dilute sulfuric acid aqueous solution is 30 wt%.
(2) Under the condition of 40 ℃, 50L of bottom water is injected into the stirring reaction kettle, 75 liters of the water glass aqueous solution and the dilute sulfuric acid aqueous solution are parallelly flowed through a constant flow pump, the pH value of the system is kept neutral, the parallel flow time is 30 minutes, the temperature is adjusted to 90 ℃ after the parallel flow is finished, and the aging precipitation is carried out for 1 hour.
(3) Adding dilute sulfuric acid into the feed liquid prepared in the step (2), adjusting the pH value to 3, aging for 0.5 hour, cooling to 60 ℃, and filtering;
washing the filter cake with 1 wt% sulfuric acid, mixing with tap water and pure water, filtering to obtain silica filter cake, dispersing the filter cake in small amount of water to obtain slurry, and spray drying to obtain the powder.
The BET specific surface area of the silica powder obtained after drying was 346m2G, pore volume of 1.97cm3(ii)/g, the average pore diameter is 22nm, and the pores are mesoporous.
(4) 3.000g of aspirin bulk drug was weighed and dissolved in 150.0ml of absolute ethanol to obtain an aspirin ethanol solution. Adding 1.5000g of the silicon dioxide powder into the aspirin ethanol solution, adopting a dynamic adsorption form, adsorbing for 24 hours until the adsorption is balanced, and drying in vacuum to obtain the silicon dioxide containing aspirin.
(5) Hydrophobic treatment of aspirin-containing silica with hexamethyldisilazane in the gas phase: weighing 100.000g of aspirin-containing silicon dioxide after vacuum drying, placing the silicon dioxide in a vacuum drying oven to spread as much as possible, weighing 6.000g of hexamethyldisilazane, placing the hexamethyldisilazane in a watch glass, placing the watch glass in the vacuum drying oven, setting the temperature of the vacuum drying oven at 35 ℃, setting the treatment time at 6h, and starting a vacuum pump to evacuate after the treatment is finished.
Comparative example
The aspirin-containing silica obtained in step (4) in example 1 was used as a control example (i.e., no vapor phase hydrophobic treatment was performed).
Example 2
(1) Preparing water glass aqueous solution and dilute sulfuric acid aqueous solution;
the water glass with the modulus of 3.35 is used as a raw material to prepare the water glass aqueous solution with the silicon dioxide content of 10 wt%, and the concentration of the dilute sulfuric acid aqueous solution is 20 wt%.
(2) Under the condition of 60 ℃, 50L of bottom water is injected into the stirring reaction kettle, the water glass aqueous solution and the dilute sulfuric acid aqueous solution are subjected to cocurrent flow of 75 liters by a constant flow pump, the pH value of the system is kept neutral, the cocurrent flow time is 30 minutes, the temperature is adjusted to 70 ℃ after the cocurrent flow is finished, and the aging precipitation is carried out for 1 hour.
(3) Adding dilute sulfuric acid into the feed liquid prepared in the step (2), adjusting the pH value to 3, aging for 0.5 hour, then cooling to 70 ℃, and filtering;
washing the filter cake with 1 wt% sulfuric acid, mixing with tap water and pure water, filtering to obtain silica filter cake, dispersing the filter cake in small amount of water to obtain slurry, and spray drying to obtain the powder.
The BET specific surface area of the silica powder obtained after drying was 431m2Per g, pore volume of 1.61cm3(ii)/g, the average pore diameter is 17nm, and the pores are mesoporous.
(4) 3.000g of aspirin bulk drug was weighed and dissolved in 150.0ml of absolute ethanol to obtain an aspirin ethanol solution. Adding 1.5000g of the silicon dioxide powder into the aspirin ethanol solution, adopting a dynamic adsorption form, adsorbing for 24 hours until the adsorption is balanced, and drying in vacuum to obtain the silicon dioxide containing aspirin.
(5) Hydrophobic treatment of aspirin-containing silica with hexamethyldisilazane in the gas phase: weighing 100.000g of aspirin-containing silicon dioxide after vacuum drying, placing the silicon dioxide in a vacuum drying oven to spread as much as possible, weighing 10.000g of hexamethyldisilazane, placing the hexamethyldisilazane in a watch glass, placing the watch glass in the vacuum drying oven, setting the temperature of the vacuum drying oven at 40 ℃, setting the treatment time at 3h, and starting a vacuum pump to evacuate after the treatment is finished.
Example 3
(1) Preparing water glass aqueous solution and dilute sulfuric acid aqueous solution;
the water glass with the modulus of 3.35 is used as a raw material to prepare the water glass aqueous solution with the silicon dioxide content of 15 wt%, and the concentration of the dilute sulfuric acid aqueous solution is 25 wt%.
(2) Under the condition of 50 ℃, 50L of bottom water is injected into the stirring reaction kettle, 75 liters of the water glass aqueous solution and the dilute sulfuric acid aqueous solution are parallelly flowed through a constant flow pump, the pH value of the system is kept neutral, the parallel flow time is 90 minutes, the temperature is adjusted to 80 ℃ after the parallel flow is completed, and the aging precipitation is carried out for 1 hour.
(3) Adding dilute sulfuric acid into the feed liquid prepared in the step (2), adjusting the pH value to 3, aging for 0.5 hour, then cooling to 70 ℃, and filtering;
washing the filter cake with 1 wt% sulfuric acid, mixing with tap water and pure water, filtering to obtain silica filter cake, dispersing the filter cake in small amount of water to obtain slurry, and spray drying to obtain the powder.
The BET specific surface area of the silica powder obtained after drying was 381m2G, pore volume of 1.75cm3(ii)/g, the average pore diameter is 19nm, and the pores are mesoporous.
(4) 3.000g of aspirin bulk drug was weighed and dissolved in 150.0ml of absolute ethanol to obtain an aspirin ethanol solution. Adding 1.5000g of the silicon dioxide powder into the aspirin ethanol solution, adopting a dynamic adsorption form, adsorbing for 24 hours until the adsorption is balanced, and drying in vacuum to obtain the silicon dioxide containing aspirin.
(5) Hydrophobic treatment of aspirin-containing silica with hexamethyldisilazane in the gas phase: weighing 100.000g of aspirin-containing silicon dioxide after vacuum drying, placing the silicon dioxide in a vacuum drying oven to spread as much as possible, weighing 10.000g of hexamethyldisilazane, placing the hexamethyldisilazane in a watch glass, placing the watch glass in the vacuum drying oven, setting the temperature of the vacuum drying oven at 30 ℃, setting the treatment time at 1h, and starting a vacuum pump to evacuate after the treatment is finished.
1. Measuring ultraviolet absorbance by using an ethanol solution of aspirin with a known concentration, drawing a standard curve of the relationship between the absorbance and the concentration of the aspirin in the ethanol solution, and calculating the adsorption quantity of aspirin adsorbed on each gram of silicon dioxide powder in examples 1-3, wherein the adsorption quantity of aspirin adsorbed on each gram of silicon dioxide powder in example 1 and the adsorption quantity of aspirin adsorbed on each gram of silicon dioxide powder in a comparison example are 1.13g/g of SiO2Example 2 is 0.79g/g of SiO2And example 3 is 0.91g/g of SiO2。
2. The drug release test was performed for examples 1-3 and the control:
(1) the preparation method of the physiological liquid for simulating the human body environment comprises the following steps: 0.24g KH was weighed out2PO4，3.63g Na2HPO4·12H2Dissolving 8g of NaCl and 0.2g of KCl in 900mL of deionized water, adjusting the pH value to 7.4, and adding deionized water to the volume of 1000 mL;
(2) weighing 0.1000g of vacuum-dried aspirin-silicon dioxide slow-release body, placing in a conical flask, adding 100mL of physiological solution simulating human body environment, placing in a constant temperature shaking table at 37 ℃, and setting the rotating speed at 150 rpm/min;
(3) transferring 2 × 1.8mL of solution by using a liquid transfer gun at 6h, 12h, 18h, 24h, 36h and 48h, and centrifuging in a refrigerated centrifuge at the rotating speed of 11000rpm and the temperature of 37 ℃.
(4) Taking supernatant, measuring ultraviolet absorbance by using aspirin simulation physiological liquid with known concentration, drawing a standard curve of the relationship between the absorbance and the concentration of the aspirin in the simulation physiological liquid, and calculating the drug release amount of the comparative example and the examples 1-3, wherein the results are as follows:
Figure BDA0003289841690000071
as can be seen from the above table, the drug loading amount of examples 1 to 3 was sufficient, and the effect of long-acting sustained release was achieved; the drug release behaviors of the comparative example and the example 1 can be obtained, and the modified grafted silicon dioxide realizes the encapsulation of aspirin and achieves excellent long-acting slow release effect.
3. The preparation process of the silicon dioxide prepared in the example 1 is repeated, and a comparative experiment is carried out under four conditions of adding PEG-6000, chitosan and PVP as dispersing agents and not adding the dispersing agents respectively, according to the chemical industry standard HG/T3072-2008: measurement of dibutyl phthalate (DBP) absorption value to determine oil absorption value.
The experimental results are as follows: the oil absorption value of the silica added with PEG-6000 is 3.12, the oil absorption value of the silica added with chitosan is 3.24, the oil absorption value of the silica added with PVP is 3.19, and the oil absorption value of the silica added with no dispersant is 3.52.
4. The preparation process of the silicon dioxide prepared in example 1 is repeated, the distilled water, the 50% ethanol aqueous solution and the absolute ethanol are respectively used as base solutions to prepare the water glass aqueous solution and the sulfuric acid aqueous solution, and the comparison experiment is carried out on the distilled water, the 50% ethanol aqueous solution and the absolute ethanol, and the reaction conditions are determined according to the chemical industry standard HG/T3072-2008: measurement of dibutyl phthalate (DBP) absorption value to determine oil absorption value.
The experimental results are as follows: the oil absorption value of the silicon dioxide prepared by using distilled water as a base solution is 3.61, the oil absorption value of the silicon dioxide prepared by using a 50% ethanol aqueous solution as the base solution is 3.52, and the oil absorption value of the silicon dioxide prepared by using an anhydrous ethanol aqueous solution as the base solution is 3.49.
5. Testing whether the dispersion performance of the modified silica is improved:
dimethyl sulfoxide (DMSO) is a common organic solvent for pharmaceutical preparations, and therefore DMSO and water were chosen as test solvents for this test.
Respectively taking 0.2g of example 1 and the comparative example, respectively adding 20mL of water, ultrasonically stirring for 40 minutes, standing and cooling, and observing the state of the mixed solution; then, 0.2g of example 1 and the comparative example were taken, 20mL of silicone oil was added, and the mixture was stirred with ultrasound for 40 minutes, and then left to stand and cool, and the state of the mixture was observed.
The results are as follows:
Figure BDA0003289841690000081
the hydrophobicity is better improved, the agglomeration phenomenon is obviously improved, the dispersibility is improved, and the particle distribution is more uniform, which shows that part of hydroxyl on the surface of the modified silicon dioxide is replaced by organic branched chains, and the hydroxyl on the surface of the silicon dioxide is reduced, so that the hydrogen bond action between the silicon dioxide is weakened.
Variations and modifications to the above-described embodiments may occur to those skilled in the art, which fall within the scope and spirit of the above description. Therefore, the present invention is not limited to the specific embodiments disclosed and described above, and some modifications and variations of the present invention should fall within the scope of the claims of the present invention. Furthermore, although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims (10)

1. A preparation method of aspirin-silicon dioxide sustained release body is characterized by comprising the following steps:
(1) under the premise of not adding a dispersing agent, water glass and inorganic acid are used as reaction raw materials to synthesize and prepare silicon dioxide powder;
(2) immersing the silicon dioxide powder into aspirin solution to prepare aspirin-containing silicon dioxide;
(3) the aspirin-silicon dioxide slow release body is prepared by modifying aspirin-containing silicon dioxide by a dry method by using hexamethyldisilazane as a modifier.
2. The production method according to claim 1, wherein in the step (1), the water glass is prepared as an aqueous water glass solution using distilled water as a base, and the inorganic acid is prepared as an aqueous inorganic acid solution using distilled water as a base, and the aqueous inorganic acid solution and the distilled water are mixed to synthesize the silica.
3. The method according to claim 2, wherein in the step (1), the aqueous water glass solution and the aqueous inorganic acid solution are fed into a reaction vessel in a concurrent flow manner to be mixed and reacted.
4. The production method according to claim 3, wherein in the step (1), the cocurrent time period is 30 to 120 min.
5. The production method according to any of claims 1 to 4, wherein in the step (1), ultrasonic agitation is used.
6. The method according to any one of claims 2 to 4, wherein in the step (1), a feed solution obtained by mixing and reacting the water glass aqueous solution and the inorganic acid aqueous solution is acidified and filtered to obtain a silica cake, and the silica cake is washed to prepare a dried powder.
7. The method of claim 6, wherein the acidified pH is 2-4.
8. The preparation method according to claim 6, wherein the silica filter cake is washed with 1 wt% sulfuric acid and distilled water as washing solutions, and then dried to form powder.
9. The preparation method according to claim 1, wherein the specific operation of the step (3) is: spreading the aspirin-containing silicon dioxide in a vacuum drying oven, and enabling the hexamethyldisilazane to contact the surface of the aspirin-containing silicon dioxide in a gas form to perform graft modification, wherein the temperature of the vacuum drying oven is set to be 30-40 ℃.
10. The method of claim 9, wherein the graft modification is carried out for a period of 1 to 6 hours.
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US20050074386A1 (en) * 2001-12-26 2005-04-07 Rhodia Chimie Low water uptake silicas
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