阅读说明：本技术 一种盐酸右美托咪定硅溶胶微粒的制备方法 (Preparation method of dexmedetomidine hydrochloride silica sol particles ) 是由 何�雄 刘选 贺莲 张静 杨世平 刘达 刘娟 梁致红 于 2021-07-30 设计创作，主要内容包括：本发明属于药物缓释技术领域,具体是涉及到一种盐酸右美托咪定硅溶胶微粒的制备方法,包括如下步骤,控制盐酸右美托咪定的水溶液的pH值为2.5-3,所述盐酸右美托咪定的浓度为4-6g/L,加入四乙氧基硅烷,反应,控制反应体系中二氧化硅的粒径为15-30nm,静置保存,将沉淀物干燥,得到盐酸右美托咪定硅溶胶微粒；所述盐酸右美托咪定的水溶液和四乙氧基硅烷硅溶胶的体积比为(1.5-2.5)：1,本发明具有较大的吸附率和载药量,较好的缓释效果。(The invention belongs to the technical field of drug sustained release, and particularly relates to a preparation method of dexmedetomidine hydrochloride silica sol particles, which comprises the following steps of controlling the pH value of aqueous solution of dexmedetomidine hydrochloride to be 2.5-3, controlling the concentration of dexmedetomidine hydrochloride to be 4-6g/L, adding tetraethoxysilane for reaction, controlling the particle size of silicon dioxide in a reaction system to be 15-30nm, standing for storage, and drying precipitates to obtain the dexmedetomidine hydrochloride silica sol particles; the volume ratio of the dexmedetomidine hydrochloride aqueous solution to the tetraethoxysilane silica sol is (1.5-2.5): 1, the invention has larger adsorption rate and drug-loading rate and better sustained-release effect.)

1. A method for preparing dexmedetomidine hydrochloride silica sol particles is characterized by comprising the following steps,

controlling the pH value of an aqueous solution of dexmedetomidine hydrochloride to be 2.5-3, controlling the concentration of the dexmedetomidine hydrochloride to be 4-6g/L, adding tetraethoxysilane for reaction, controlling the particle size of silicon dioxide in a reaction system to be 15-30nm, standing for storage, and drying precipitates to obtain dexmedetomidine hydrochloride silica sol particles; the volume ratio of the dexmedetomidine hydrochloride aqueous solution to the tetraethoxysilane is (1.5-2.5): 1.

2. the method for preparing dexmedetomidine hydrochloride silica sol particles as set forth in claim 1, wherein the substance for controlling the pH of the aqueous solution of dexmedetomidine hydrochloride is hydrochloric acid.

3. The method for preparing dexmedetomidine hydrochloride silica sol particles as set forth in claim 1, wherein tetraethoxysilane is added with continuous stirring.

4. The method for preparing dexmedetomidine hydrochloride silica sol particles as set forth in claim 1, wherein the dexmedetomidine hydrochloride concentration is 5 g/L.

5. The process for producing dexmedetomidine hydrochloride silica sol particles according to claim 1, wherein the particle size of silica in the reaction system is 20 nm.

6. The method according to claim 1, wherein the volume ratio of the dexmedetomidine hydrochloride aqueous solution to tetraethoxysilane is 2: 1.

Technical Field

The invention belongs to the technical field of drug sustained release, and particularly relates to a preparation method of dexmedetomidine hydrochloride silica sol particles.

Background

Medetomidine is a highly selective alpha 2 adrenergic receptor agonist, has central sympatholytic and anxiolytic effects, and can produce a sedative effect approximating natural sleep; meanwhile, the traditional Chinese medicine composition has certain analgesic and diuretic effects, has no obvious inhibition on respiration, and possibly has certain protective properties on the functions of organs such as heart, kidney, brain and the like. Can be used for sedation of patients treated by endotracheal intubation breathing machine, anesthesia in perioperative period and sedation in invasive examination or treatment.

Dexmedetomidine hydrochloride injection, developed by Orion corporation and yapei, was first approved in the united states in 1999 under the trade name Precedex, and currently 11 counterfeit drugs were approved for sale. Hengrui in Jiangsu in 2009 was first imitated and approved for marketing at home, Hengrui in 9 months in 2017 was approved by FDA at 200 μ g/2 mL.

Dexmedetomidine was marketed with a positive therapeutic effect. The clinical application guidance for dexmedetomidine (2013) states that dexmedetomidine may be used alone or in combination in the induction phase of general anesthesia, in combination in the maintenance phase of general anesthesia, or in combination in the recovery phase of general anesthesia. ' expert consensus on analgesia after adult day surgery (2017) indicates that ' intravenous drip small dose dexmedetomidine (the load amount is 0.5-1 mu g/kg for 15min, and the maintenance amount is 0.2-0.7 mu g/kg-1. h-1) can enhance the analgesia effect and reduce the dosage of opioid drugs, but needs to prevent excessive sedation and adverse cardiovascular reactions '.

The medicine has obvious first-pass effect after oral administration and low bioavailability, and patients anesthetized by operation are not suitable for oral administration, so the medicine is generally prepared into injection for administration; but the distribution of the rapid distribution phase of the dexmedetomidine hydrochloride injection is halfStage of decline (t)_1/2) About only 6 minutes; terminal clearing half-life (t)_1/2) About only 2 hours, and thus has the disadvantages of short half-life and short action time.

Chinese patent CN 109381444 a discloses a dexmedetomidine nano-preparation, which comprises: the dexmedetomidine is wrapped by the polylactic acid-polyglycolic acid copolymer, and the polyvinyl alcohol is used as an emulsifier to obtain the dexmedetomidine nano preparation which has a spherical structure, the particle size of 250-350 nm, high dispersibility and slow release functions, the anesthesia time of the dexmedetomidine can be effectively prolonged, the tolerance dose is improved, and the application range of the dexmedetomidine is expanded. The invention also discloses a preparation method of the dexmedetomidine nano preparation, which is simple and easy to popularize. It measured encapsulation and drug loading rates, with maximum of 92% and 16.7%, respectively.

Disclosure of Invention

The invention aims to solve the technical problem of providing a method for preparing dexmedetomidine hydrochloride silica sol particles, which has high adsorption rate and drug loading capacity and good slow release effect.

The invention relates to a method for preparing dexmedetomidine hydrochloride silica sol particles, which comprises the following steps,

controlling the pH value of an aqueous solution of dexmedetomidine hydrochloride to be 2.5-3, controlling the concentration of the dexmedetomidine hydrochloride to be 4-6g/L, adding tetraethoxysilane for reaction, controlling the particle size of silicon dioxide in a reaction system to be 15-30nm, standing for storage, and drying precipitates to obtain dexmedetomidine hydrochloride silica sol particles; the volume ratio of the dexmedetomidine hydrochloride aqueous solution to the tetraethoxysilane is (1.5-2.5): 1.

preferably, the substance controlling the pH of the aqueous solution of dexmedetomidine hydrochloride is hydrochloric acid.

Preferably, tetraethoxysilane is added with constant stirring.

Preferably, the concentration of dexmedetomidine hydrochloride is 5 g/L.

Preferably, the particle size of silica in the reaction system is controlled to 20 nm.

Preferably, the volume ratio of the dexmedetomidine hydrochloride aqueous solution to the tetraethoxysilane is 2: 1.

the invention has the beneficial effects that the invention uses silicon dioxide (SiO) with good monodispersity and particle size of about 20nm₂) The sol is used as a drug carrier to prepare the drug-loaded nano-silica gel loaded with dexmedetomidine hydrochloride. The adsorption and release performance of the system on dexmedetomidine hydrochloride is investigated through infrared spectrum and ultraviolet visible absorption spectrum. The results show that the silica sol has a large adsorption rate (86.6%) and drug loading (59.9%) of dexmedetomidine hydrochloride, and a slow release performance (79.6% release within 48 h) (see fig. 6).

Drawings

FIG. 1 is a scanning electron microscope image of dexmedetomidine hydrochloride silica sol particles of the present invention when the silica gel particle size is 10 nm.

FIG. 2 is a scanning electron microscope image of dexmedetomidine hydrochloride silica sol particles of the present invention when the silica gel particle size is 30 nm.

FIG. 3 is a scanning electron microscope image of dexmedetomidine hydrochloride silica sol particles of the present invention when the silica gel particle size is 20 nm.

FIG. 4 is a graph showing the effect of pH on the release of dexmedetomidine hydrochloride silica sol particles.

FIG. 5 shows the mean concentration of dexmedetomidine in serum after administration of reference drug a (0.1mg dexmedetomidine hydrochloride) and microparticle formulation b (4.6mg dexmedetomidine hydrochloride).

FIG. 6 is a graph showing the sustained release of dexmedetomidine hydrochloride silica sol particles of the present invention.

Detailed Description

Example 1

Preparing dexmedetomidine hydrochloride solution by using distilled water, adjusting the pH value to 2.5 by using 0.0025mol/L hydrochloric acid, controlling the concentration of dexmedetomidine hydrochloride to be 5g/L, putting 10ml into a 100ml beaker, adding 5ml of tetraethoxysilane under the condition of continuous stirring, immediately turning the solution turbid, keeping the solution for one day in a closed state at room temperature, and separating a lower-layer precipitate from a supernatant. The precipitate was dried at low temperature and ground for sustained release test. And (5) the supernatant is reserved for absorbance measurement, and the adsorption rate and the drug loading rate are calculated.

Through calculation, the adsorption rate and the drug loading rate are respectively 86.8% and 62.3%, the system has a trend of increasing the release amount and the release rate of dexmedetomidine hydrochloride along with the prolonging of time, the release rate is 76.8% within 48h, the release rate is slower, and the dexmedetomidine hydrochloride can be used as a drug carrier, and particularly shown in figure 6.

The specific analysis method comprises the following steps:

the sample was scanned on a UV-Vis absorption spectrometer and the maximum absorption wavelength of dexmedetomidine hydrochloride was found to be at 220 nm. 5 dexmedetomidine hydrochloride solutions with different concentrations were prepared, and the linear relationship between absorbance and concentration was found, i.e., the following formula C.

C-13.982 a-0.1342, wherein: c is the drug concentration; a is absorbance, and the linear correlation coefficient of the relational expression is 0.9895.

Adsorption rate ═ C₀-C)/C₀86.8%, wherein: c₀Is the initial concentration; c is the supernatant concentration. The linear correlation coefficient of the relation is 0.9895.

(C) drug loading rate₀-C) × V/m (drug loaded silica sol) ═ 86.8%, where: v is the total volume of liquid; c is the concentration of the supernatant; and m is the total mass of the medicine-carrying silica sol.

Example 2

The effect of different pH values on the release rate of the product was measured by varying the pH of the dexmedetomidine hydrochloride solution under the conditions of example 1, see in particular figure 4.

Example 3

The particle size of the silica sol was varied under the conditions of example 1 and the effect of different particle size values on the particle size and morphology of the product was measured, see in particular figures 1-3. It can be seen that when the particle size is 20nm, the morphology of the product is better, the particle dispersion degree is better,

example 4

The comparison of the sustained release effect of the conventional drug a (0.1mg dexmedetomidine hydrochloride dissolved in 5ml 0.9% sodium chloride solution) on the market and the microparticle formulation b of the present application is shown in detail in fig. 5. Three dogs weighing 8.6-10.1kg (12-26 months old), two males and one female, 60mg of silica gel microparticles containing 4.6mg of dexmedetomidine suspended in 5ml of 0.9% sodium chloride solution were injected subcutaneously onto the dorsal surface of the neck; dexmedetomidine hydrochloride 0.1mg was dissolved in 5ml of 0.9% sodium chloride solution and 4 beagle dogs weighing 8.3-10.5kg (13-34 months old) were injected subcutaneously as a reference. The dexmedetomidine concentration in serum was measured by taking blood samples before and after administration at 0.5, 1, 2, 4, 6, 8, 24, 48h, respectively. The last sampling point for the reference dose was 8 hours.

As can be seen from fig. 5, the conventional drug a reaches the maximum release amount about one hour after administration and completely decomposes about 7 hours after administration, the dexmedetomidine hydrochloride silica sol particle b reaches the maximum release amount about 5 hours, and the dexmedetomidine hydrochloride still remains in the serum as long as about 50 hours after administration, which indicates that the sustained-release effect of the dexmedetomidine hydrochloride is obviously better than that of the conventional drug a.

Those of ordinary skill in the art will understand that: the discussion of any embodiment above is meant to be exemplary only, and is not intended to intimate that the scope of the disclosure, including the claims, is limited to these examples; within the spirit of the present disclosure, features from the above embodiments or from different embodiments may also be combined, steps may be implemented in any order, and there are many other variations of different aspects of one or more embodiments in this application as described above, which are not provided in detail for the sake of brevity.

It is intended that the one or more embodiments of the present application embrace all such alternatives, modifications and variations as fall within the broad scope of the appended claims. Therefore, any omissions, modifications, substitutions, improvements, and the like that may be made without departing from the spirit and principles of one or more embodiments of the present disclosure are intended to be included within the scope of the present disclosure.