CN114870023A - Slow-release optic nerve protection drug nano synthetic material and preparation method and application thereof - Google Patents
Slow-release optic nerve protection drug nano synthetic material and preparation method and application thereof Download PDFInfo
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- CN114870023A CN114870023A CN202210532523.5A CN202210532523A CN114870023A CN 114870023 A CN114870023 A CN 114870023A CN 202210532523 A CN202210532523 A CN 202210532523A CN 114870023 A CN114870023 A CN 114870023A
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Abstract
The invention discloses a sustained-release optic nerve protection drug nano synthetic material, a preparation method and application thereof, and relates to the technical field of sustained-release drug nano synthetic materials, wherein the synthetic material is prepared by taking 7,8-dihydroxyflavone as a main body and lactic acid-polyglycolic acid copolymer as a sustained-release carrier. The method comprises the following steps: the synthetic material is prepared by the components according to the weight by an ultrasonic emulsification solvent evaporation method. The invention takes 7,8-Dihydroxyflavone (DHF) as a main body, PLGA as a slow release carrier, the drug-loading rate of the synthesized nano synthetic material can reach (10.4 +/-1.8)% (W/W), the encapsulation rate can reach (49.2 +/-2.2)%, and compared with the blank DHF, the nano synthetic material has obvious slow release performance, and the average drug concentration of the intraocular vitreous body is 18.46mg/L and the average drug concentration of the intraocular retina choroid is 0.45mg/L, and the phenomenon of burst release is avoided when the nano synthetic material is measured on the 7 th day after administration.
Description
Technical Field
The invention relates to the technical field of slow-release drug nano synthetic materials, in particular to a slow-release optic nerve protection drug nano synthetic material and a preparation method and application thereof.
Background
Nano-carrier material: the copolymer of polylactic acid (PLA) and polyglycolic acid (PGA), polylactic acid-glycolic acid (PLGA), is a biodegradable material and has wide application in the field of biomedical engineering. Has better biocompatibility and biodegradability, controllable degradation speed and mechanical property, is used for preparing drug sustained-release carriers, artificial catheters, tissue engineering scaffold materials, absorbable sutures and the like at present, and plays an important role in many fields. The research focus is now: PLGA nano-drugs are prepared, and the PLGA nano-drugs are used as carriers of protein and enzyme drugs.
PLGA has been approved by the FDA in the united states for use in humans without toxicity, such as the marketed leuprolide acetate injectable sustained release formulation (lupron depot) for the treatment of advanced prostate cancer, i.e. PLGA is used as a drug carrier. PLGA has biodegradability determined by molecular structure, no immunogenicity and no peptide chain, and the degradation product of PLGA is the natural metabolic product in organism to produce CO finally 2 And H 2 O, does not accumulate in the body and is easily discharged from the body.
7,8-dihydroxyflavone (7, 8-dihydroflavanone, DHF) is an artificially synthesized flavonoid compound. DHF has high affinity and selectivity for TrkB receptors; it has been reported that DHF can mimic the function of BDNF (Brain derived pro-factors), and in mouse Brain tissue, DHF can activate TrkB receptor, reduce glutamate toxicity, generate antioxidant stress effect, and provide neuroprotection.
The 7,8-dihydroxyflavone has protective effect on retinal ganglion cells after injury. It has been reported that 7,8-DHF can activate TrkB receptor, and has protective effect on Retinal Ganglion Cell (RGCs) injury through PI3K/Akt and MAPK/ERK channels. In vitro studies of primary cultured RGCs, it was found that 7,8-DHF can prevent apoptosis and cell death due to cytotoxicity and oxidative stress by activating downstream AKT and MAPK/ERK signaling pathways through TrkB after administration of varying concentrations of 7, 8-DHF. In the glaucoma optic nerve injury model, administration of 7,8-DHF significantly prevented loss of optic ganglion cell fiber layer density and retained retinal inner layer function. 7,8-DHF treatment stimulates activation of TrkB intracellular signaling and ameliorates the increase in soluble A β (1-42) levels in the retinas of hypertensive rats and mice. In a retinal ischemia reperfusion injury model, a BDNF/TrkB signal channel has a neuroprotective effect, and researches show that: DHF partially inhibits the NF-kB mediated inflammatory factor expression from increasing by activating TrkB/Akt/NF-kB signal channels, thereby being capable of reducing apoptosis and inflammation induced by retinal ischemia-reperfusion injury. Not only in molecular, cellular and morphological aspects, the DHF can protect RGCs in a retinal optic nerve injury model, but also in an optic nerve dissociation injury model, a retinal electrogram of a part after DHF treatment can be recovered to be normal, which indicates that the DHF has a certain protective effect on axon injury of optic nerves.
Based on the above studies, the present invention intends to achieve the purpose of prolonging the acting time of DHF in the eye and thus achieving a longer and more effective protective effect on retinal ganglion cells in the eye, based on the study that DHF has a protective effect on RGCs in the eye.
Disclosure of Invention
The invention aims to solve the technical problem of providing a slow-release optic nerve protection drug nano synthetic material, a preparation method and application thereof, and solves the problems of short in-vivo drug effect time and the like of the existing drugs.
In order to solve the technical problems, the technical scheme of the invention is as follows:
the invention aims to provide a slow-release optic nerve protection drug nano synthetic material, which is prepared by taking 7,8-dihydroxyflavone as a main body and lactic acid-polyglycolic acid copolymer as a slow-release carrier.
Preferably, the mass ratio of the 7,8-dihydroxyflavone to the lactic acid-polyglycolic acid copolymer is 1: (10-20).
The invention also aims to provide a preparation method of the slow-release optic nerve protection drug nano synthetic material, which comprises the following steps:
the synthetic material is prepared by the components according to the weight by an ultrasonic emulsification solvent evaporation method.
Preferably, the method comprises dissolving the above-mentioned components in an organic solvent to form an oil phase, mixing the oil phase with an aqueous phase to obtain an emulsion, and ultracentrifuging the emulsion to obtain a precipitate, i.e. the synthetic material.
Preferably, the ultrasonic pulverization is performed during the mixing of the oil phase and the aqueous phase.
Preferably, the emulsion is stirred before ultracentrifugation of the emulsion.
The invention also aims to provide application of the slow-release optic nerve protection drug nano synthetic material, and the nano synthetic material is applied to optic nerve protection drugs.
By adopting the technical scheme, the 7,8-Dihydroxyflavone (DHF) is taken as a main body, the PLGA is taken as a slow release carrier, the drug loading rate of the synthesized nano synthetic material can reach (10.4 +/-1.8)% (W/W), the entrapment rate can reach (49.2 +/-2.2)%, and compared with blank DHF, the nano synthetic material has obvious slow release performance, and the average drug concentration of the intraocular vitreous body is 18.46mg/L and the average drug concentration of the intraocular retina choroid is 0.45mg/L, and no sudden release phenomenon is generated when the nano synthetic material is administered on the 7 th day.
Drawings
FIG. 1 is a transmission electron microscope image of a lactic acid-polyglycolic acid copolymer nanoparticle;
FIG. 2 is a transmission electron micrograph of a nanocomposite material of the present invention;
FIG. 3 is a standard curve graph of 7,8-Dihydroxyflavone (DHF) concentration;
FIG. 4 is a graph of the concentration of DHF and the inventive nanocomposite material in a vitreous cavity;
FIG. 5 is a graph of the concentration of DHF and the nanocomposite material of the invention in retinochoroids.
Detailed Description
The following further describes embodiments of the present invention with reference to the drawings. It should be noted that the description of the embodiments is provided to help understanding of the present invention, but the present invention is not limited thereto. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
In the embodiment, the raw materials are all commercially available products, wherein the lactic acid-polyglycolic acid copolymer (PLGA) nanoparticles (the mass ratio of lactic acid to glycolic acid is 50:50, denafil big Dipper biomaterial Co., Ltd.); 7,8-Dihydroxyflavone (DHF) (chemical formula C) 15 H 10 O 4 Molecular weight 254.2375, Sigma company, usa).
Example 1
Precisely weighing 10mg of DHF and 150mg of PLGA, dissolving the two in 3mL of ethyl acetate to form an organic phase (serving as an oil phase), precisely weighing 20.0mL of a polyvinyl alcohol (PVA) aqueous solution containing 2.5mg/mL of the organic phase and the aqueous phase, mixing the oil phase and the aqueous phase, placing the mixture in a probe type ultrasonic pulverizer, and carrying out ultrasonic treatment for 3min under the condition of maintaining the power of 400W to form an emulsion with uniform appearance until DHF multiple emulsion (W/O/W) is formed. Continuously stirring the emulsion in a magnetic stirrer, then ultracentrifuging the obtained nanosuspension for 15min (12000r/min), discarding the supernatant containing free DHF, dispersing the precipitate in distilled water, washing for three times, ultracentrifuging again, collecting the precipitate to obtain the DHF/PLGA nano synthetic material, and freeze-drying for later use.
Example 2
Precisely weighing 10mg DHF and 100mg PLGA, dissolving the two in 3mL ethyl acetate to form an organic phase (serving as an oil phase), precisely weighing 20.0mL polyvinyl alcohol (PVA) aqueous solution containing 2.5mg/mL serving as an aqueous phase, mixing the oil phase and the aqueous phase, placing the mixture in a probe type ultrasonic pulverizer, and performing ultrasonic treatment for 3min under the condition of maintaining the power of 400W to form an emulsion with uniform appearance until DHF multiple emulsion (W/O/W) is formed. Continuously stirring the emulsion in a magnetic stirrer, then ultracentrifuging the obtained nano suspension for 15min (12000r/min), discarding supernatant containing free DHF, dispersing precipitate in distilled water, washing for three times, performing ultracentrifugation again, collecting precipitate to obtain DHF/PLGA nano synthetic material, and freeze-drying for later use.
Example 3
Precisely weighing 10mg of DHF and 200mg of PLGA, dissolving the two in 3mL of ethyl acetate to form an organic phase (serving as an oil phase), precisely weighing 20.0mL of a polyvinyl alcohol (PVA) aqueous solution containing 2.5mg/mL of the organic phase and the aqueous phase, mixing the oil phase and the aqueous phase, placing the mixture in a probe type ultrasonic pulverizer, and carrying out ultrasonic treatment for 3min under the condition of maintaining the power of 400W to form an emulsion with uniform appearance until DHF multiple emulsion (W/O/W) is formed. Continuously stirring the emulsion in a magnetic stirrer, then ultracentrifuging the obtained nanosuspension for 15min (12000r/min), discarding the supernatant containing free DHF, dispersing the precipitate in distilled water, washing for three times, ultracentrifuging again, collecting the precipitate to obtain the DHF/PLGA nano synthetic material, and freeze-drying for later use.
And comparing the blank PLGA nano-particles, and testing the form and the particle size of the DHF/PLGA nano synthetic material.
0.5mL of the prepared PLGA/DHF nanoparticle suspension is diluted moderately and observed by adopting a transmission electron microscope.
As shown in figure 1, the blank PLGA nanoparticles have an average diameter of about 210nm, a round and regular spherical structure in appearance and no adhesion on the surface.
As shown in figure 2, the DHF/PLGA nano synthetic material of the invention is white powder as a whole, is a smooth ceramic white spheroid under an electron microscope, has an average diameter of (210 +/-21.3) nm, and basically has no adhesion among nano particles.
The encapsulation efficiency and the drug loading capacity of the DHF/PLGA nano synthetic material are measured as follows:
the prepared DHF/PLGA nano synthetic material is subjected to ultracentrifugation (2 multiplied by 104r/min) at 4 ℃ for 0.5h, supernatant is collected for three times, after combination, 0.1mol/LpH 7.4.4 Phosphate Buffer Solution (PBS) is used for preparing standard solutions with different concentrations such as 0, 0.2, 0.4, 0.8, 1.6, 2.4mg/L and the like, and an absorption value is measured by an ultraviolet spectrophotometer at the wavelength of 242nm, so that a standard curve of the DHF concentration in the PBS solution is obtained (as shown in figure 3).
The amount of free DHF was calculated as a standard curve with the equation a ═ 0.1497C +0.0161, (r ═ 0.9995 as can be derived from fig. 3), and the encapsulation efficiency and drug loading were calculated as follows:
the encapsulation efficiency is (Wtotal-Wfree)/Wtotal multiplied by 100 percent;
the drug loading rate is (Wtotal-Wfree)/WNP multiplied by 100%
Wherein: wtotal is the total weight of DHF added; wfree is the total weight of DHF in the supernatant; WNP is the total weight of the nano-particles of the DHF/PLGA nano synthetic material.
When 3 batches of DHF-PLGA nano synthetic materials are prepared repeatedly, the average drug loading rate of DHF is (10.4 +/-1.8)% (W/W) and the average encapsulation rate is (49.2 +/-2.2)%.
Detecting the release effect of the DHF-PLGA nano synthetic material in the vitreous body and retina choroid in eyes:
the concentration of intraocular tissue (retina) DHF was measured by High Performance Liquid Chromatography (HPLC) with a column mobile phase of methanol: water: 38% acetic acid (65: 35: 2), flow rate 1mL/s, internal standard liquid DHF standard liquid (DHF 1 mg/L). Since studies have shown significant increases in vitreous and retinal drug concentrations following intravitreal drug injections, we have primarily examined release in vitreous and retinochoroidal tissues.
Respectively adding 0.1mL of internal standard solution and DHF standard solution with different concentrations into the vitreous body and the retina tissue homogenate, wherein the concentrations are respectively 0.5, 1, 2, 4, 6 and 8mg/L, processing according to the sample purification step, then carrying out HPLC analysis, taking the prepared standard sample, dissolving each sample by using 60 mu L of mobile phase, centrifuging for 15min at 12000r/min, taking 25 mu L of supernatant, injecting sample, and determining the peak areas of DHF and the internal standard in the standard sample. And calculating the peak area ratio Y of the DHF to the internal standard DHF, performing linear regression on the concentration X in the tissue to obtain a regression equation, and calculating the concentration of the DHF in the sample according to the equation.
Experimental group
Sprague-Dawley healthy rats, half male and female, with a body weight of 200-; dissolving the DHF/PLGA nano synthetic material in dimethyl sulfoxide, adding PBS for dilution, wherein the concentration is 352mg/mL, and the injection is injected into the vitreous cavity of eyes of each rat, and the dosage is 0.1 mL; after the injection of the medicine, the animals are killed at 2h, 4h, 6h, 8h, 12h, 24h, 48h, 72h, 168h, 336h and 672h respectively, and the retinal tissues of the rats are taken out; the concentration of the rat vitreous body and the retina choroid DHF/PLGA nano synthetic material is measured by adopting a high performance liquid chromatography.
Control group
Sprague-Dawley healthy rats, half male and female, with a body weight of 200-; dissolving common DHF in dimethyl sulfoxide, adding PBS for dilution, wherein the concentration is 25mg/mL, injecting into vitreous cavity of eye of each mouse, and the dosage is 5 μ L; after the injection of the medicine, the animals are killed after 2h, 4h, 6h, 8h, 12h, 24h, 48h, 72h, 168h, 336h and 672h respectively, and the eyeballs of the rats are taken out; the concentration of DHF in the vitreous retina and retina of a rat was determined by high performance liquid chromatography.
The injection of the vitreous body cavity in the eyes of the rat is specifically carried out as follows:
(1) xylazine and ketamine (1: 10) mixed solution, 0.1mL/20g general anesthesia, and corneal surface anesthesia are assisted;
(2) compound tropicamide eye drops are used for binocular dilation, 0.3% tobramycin eye drops are dripped into a conjunctival sac for 3 times to prepare for operation eyes, 0.4% oxybuprocaine hydrochloride eye drops are used for corneal surface anesthesia, and an operation eye operation area is disinfected;
(3) respectively extracting 2 mu L of different liquid medicines of each group by a Hamilton-10 mu L micro-injector according to experimental design;
(4) the eyelid opener is used for opening the eyelid, a 30g B-D needle is used under an operating microscope to pierce the eyeball wall at the position 2-3mm behind the corneal limbus above the temples through the pars plana of the ciliary body;
(5) under an operating microscope, a 30g B-D needle is used for penetrating the eyeball wall at a position 1mm behind the dorsal corneal limbus through a pars plana of a ciliary body and then immediately taking out the needle, a micro syringe enters the eye at an oblique angle of about 45 degrees from a prepared pinhole of the eyeball wall, the needle point always faces backwards to the optic nerve, the needle point is visible through the pupillary region at a position equivalent to the equator part to avoid damaging crystalline lens and retina, liquid medicine or contrast liquid is slowly injected in front of the retina, the needle is slowly drawn out after staying for at least 20 seconds after the injection is finished, the liquid medicine or the vitreous body is prevented from overflowing, and the operating eye is coated with erythromycin eye ointment;
(6) after operation, the eye is applied with 0.3% tobramycin eye solution every day for 3 times every day for 3 days.
As shown in FIGS. 4 and 5, the mean intravitreal drug concentration in the control group (DHF group) was measured to be 19.21mg/L maximum (FIG. 4) and the mean retinal choroidal drug concentration was measured to be 0.41mg/L maximum (FIG. 5) at 2 hours after intravitreal injection. On the 7 th day after the administration, the average drug concentration of the DHF/PLGA nano synthetic material of the invention in the eye is 18.46mg/L (figure 4); on the 7 th day of administration, the average drug concentration of the retina choroid in the eyes was 0.45mg/L (fig. 5), and there was no burst release phenomenon, which indicates that the DHF/PLGA nano synthetic material prepared by the present invention has good slow release performance.
The embodiments of the present invention have been described in detail with reference to the accompanying drawings, but the present invention is not limited to the described embodiments. It will be apparent to those skilled in the art that various changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, and the scope of protection is still within the scope of the invention.
Claims (7)
1. A slow-release optic nerve protection drug nano synthetic material is characterized in that: the synthetic material is prepared by taking 7,8-dihydroxyflavone as a main body and lactic acid-polyglycolic acid copolymer as a slow release carrier.
2. The sustained-release optic nerve protection drug nano-synthetic material of claim 1, which is characterized in that: the mass ratio of the 7,8-dihydroxyflavone to the lactic acid-polyglycolic acid copolymer is 1: (10-20).
3. A method for preparing the sustained-release optic nerve protection drug nano synthetic material according to claim 1 or 2, which is characterized in that: the method comprises the following steps:
the synthetic material is prepared by the components according to the weight by an ultrasonic emulsification solvent evaporation method.
4. The method for preparing the sustained-release optic nerve protection drug nano synthetic material according to claim 3, characterized in that: the method comprises the steps of dissolving the components in the weight ratio in an organic solvent to form an oil phase, mixing the oil phase with a water phase to obtain an emulsion, and ultracentrifuging the emulsion to obtain a precipitate, namely the synthetic material.
5. The method for preparing the sustained-release optic nerve protection drug nano synthetic material according to claim 4, characterized in that: and carrying out ultrasonic crushing in the process of mixing the oil phase and the water phase.
6. The method for preparing the sustained-release optic nerve protection drug nano synthetic material according to claim 4, characterized in that: the emulsion is stirred before ultracentrifugation.
7. Use of the sustained-release optic nerve protection drug nano-synthetic material according to claim 1 or 2, characterized in that: the nano-synthetic material is applied to an optic nerve protection drug.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102233129A (en) * | 2010-04-29 | 2011-11-09 | 上海交通大学 | Long-acting sustained release preparation for preventing or treating retinal damage, and preparation method thereof |
| CN104027793A (en) * | 2014-05-28 | 2014-09-10 | 浙江大学 | Preparation method and application of nerve growth factor controlled-release nano-carrier |
| US20150231266A1 (en) * | 2012-08-23 | 2015-08-20 | Yale University | Neurotherapeutic Nanoparticle Compositions and Devices |
| US20150283095A1 (en) * | 2012-11-16 | 2015-10-08 | Universidad De Santiago De Chile | Nanoparticles with biodegradable and biocompatible polymer plga, loaded with the drug for human use pentoxifylline |
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- 2022-05-12 CN CN202210532523.5A patent/CN114870023A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102233129A (en) * | 2010-04-29 | 2011-11-09 | 上海交通大学 | Long-acting sustained release preparation for preventing or treating retinal damage, and preparation method thereof |
| US20150231266A1 (en) * | 2012-08-23 | 2015-08-20 | Yale University | Neurotherapeutic Nanoparticle Compositions and Devices |
| US20150283095A1 (en) * | 2012-11-16 | 2015-10-08 | Universidad De Santiago De Chile | Nanoparticles with biodegradable and biocompatible polymer plga, loaded with the drug for human use pentoxifylline |
| CN104027793A (en) * | 2014-05-28 | 2014-09-10 | 浙江大学 | Preparation method and application of nerve growth factor controlled-release nano-carrier |
Non-Patent Citations (1)
| Title |
|---|
| FLAVIA MESSINA ET AL.: "Evaluation of the neuroprotectivemechanisms of 7，8-Dihydroxyflavone andgeneration of corresponding sustainedrelease nano/microparticles for improvedocular drug delivery" * |
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