CN113577041A - Preparation method of dexmedetomidine hydrochloride silica sol particles - Google Patents
Preparation method of dexmedetomidine hydrochloride silica sol particles Download PDFInfo
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- CN113577041A CN113577041A CN202110872942.9A CN202110872942A CN113577041A CN 113577041 A CN113577041 A CN 113577041A CN 202110872942 A CN202110872942 A CN 202110872942A CN 113577041 A CN113577041 A CN 113577041A
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- dexmedetomidine hydrochloride
- silica sol
- dexmedetomidine
- sol particles
- hydrochloride
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- 229960002746 dexmedetomidine hydrochloride Drugs 0.000 title claims abstract description 53
- VPNGEIHDPSLNMU-MERQFXBCSA-N dexmedetomidine hydrochloride Chemical compound Cl.C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CNC=N1 VPNGEIHDPSLNMU-MERQFXBCSA-N 0.000 title claims abstract description 53
- 239000002245 particle Substances 0.000 title claims abstract description 35
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title abstract description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 18
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000007864 aqueous solution Substances 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 7
- 239000002244 precipitate Substances 0.000 claims abstract description 5
- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims abstract description 3
- 238000003860 storage Methods 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 18
- 229940079593 drug Drugs 0.000 abstract description 15
- 230000000694 effects Effects 0.000 abstract description 8
- 238000001179 sorption measurement Methods 0.000 abstract description 7
- 238000013268 sustained release Methods 0.000 abstract description 7
- 239000012730 sustained-release form Substances 0.000 abstract description 7
- CUHVIMMYOGQXCV-NSHDSACASA-N dexmedetomidine Chemical compound C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CNC=N1 CUHVIMMYOGQXCV-NSHDSACASA-N 0.000 description 14
- 229960004253 dexmedetomidine Drugs 0.000 description 13
- 239000000243 solution Substances 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 4
- 206010039897 Sedation Diseases 0.000 description 3
- 238000002695 general anesthesia Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000001000 micrograph Methods 0.000 description 3
- 239000011859 microparticle Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000036280 sedation Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 208000004880 Polyuria Diseases 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 239000000219 Sympatholytic Substances 0.000 description 1
- 238000011481 absorbance measurement Methods 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 239000000384 adrenergic alpha-2 receptor agonist Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000003962 counterfeit drug Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- HRLIOXLXPOHXTA-UHFFFAOYSA-N medetomidine Chemical compound C=1C=CC(C)=C(C)C=1C(C)C1=CN=C[N]1 HRLIOXLXPOHXTA-UHFFFAOYSA-N 0.000 description 1
- 229960002140 medetomidine Drugs 0.000 description 1
- 229940124636 opioid drug Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229940117828 polylactic acid-polyglycolic acid copolymer Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229940087659 precedex Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 231100000628 reference dose Toxicity 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000000948 sympatholitic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/501—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
Abstract
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.
Description
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.
Claims (6)
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.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101031286A (en) * | 2004-09-09 | 2007-09-05 | 鲁汶天主教大学研究开发部 | Controlled release delivery system for bio-active agents |
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2021
- 2021-07-30 CN CN202110872942.9A patent/CN113577041A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101031286A (en) * | 2004-09-09 | 2007-09-05 | 鲁汶天主教大学研究开发部 | Controlled release delivery system for bio-active agents |
Non-Patent Citations (4)
| Title |
|---|
| PIRJO KORTESUO等: ""Effect of synthesis parameters of the sol–gel-processed spray-dried silica gel microparticles on the release rate of dexmedetomidine"", 《BIOMATERIALS》 * |
| PIRJO KORTESUO等: ""In vitro release of dexmedetomidine from silica xerogel monoliths: effect of sol-gel synthesis parameters"", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
| PIRJO KORTESUO等: "Alkyl-substituted silica gel as a carrier in the controlled release of dexmedetomidine", 《JOURNAL OF CONTROLLED RELEASE》 * |
| PIRJO KORTESUO等: "In vitro evaluation of sol–gel processed spray dried silica gel microspheres as carrier in controlled drug delivery", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
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Application publication date: 20211102 |