Nasal brain-targeted nano odor drug delivery system and application

Abstract

The invention discloses a nasal brain-targeted nano odor drug delivery system and application, and belongs to the technical field of pharmaceutical preparations. According to the brain-targeted nano-odor drug delivery system, chemical groups with low odor threshold values are constructed on the surface of a nano-drug carrier, so that the nano-drug carrier has structural characteristics similar to natural odor molecules, and the nano-drug carrier can be rapidly and tightly combined with an olfactory receptor after nasal drug delivery and is transferred into a central system through an olfactory nerve path, so that the brain-targeted nano-odor drug delivery system is formed. And the targeting drug delivery capability to the central nervous system is improved. The problem that delivery and treatment of central nervous system drugs in vivo are hindered due to the fact that the central nervous system drugs are difficult to penetrate through the blood brain barrier is solved. The nano odor drug delivery system can be used as a central nervous system high-targeting treatment carrier, and a new choice is provided for treatment of central nervous system diseases.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a transnasal brain targeted nano-odor drug delivery system and its application. Background Art

[0002] Central nervous system diseases have become an increasingly serious and costly health challenge worldwide. Effective drug delivery to the brain is one of the major obstacles to treating these diseases. The blood-brain barrier is a substantial barrier to drug delivery to the central nervous system, limiting the penetration of more than 98% of small molecule drugs and almost all macromolecule drugs, posing a huge challenge for drug delivery. In addition, many central nervous system drugs have low solubility, further hindering their delivery and treatment in vivo. Although a variety of innovative technologies and drug delivery methods have been used to try to address these issues, new perspectives and approaches are still needed in terms of material design and expected clinical effects for central nervous system drug delivery.

[0003] After the odor molecules enter the nasal cavity, they bind to the olfactory receptors expressed on the olfactory sensory neurons distributed in the olfactory epithelium and activate the olfactory sensory neurons. The interaction between the odor molecules and the olfactory sensory neurons will be converted into electrical signals and then transmitted to the brain. The body's sensitivity to different odors is different because the receptors of the perception group are different. The concentration of odor molecules and the body's sensitivity to the odor jointly affect the relative intensity of the odor. The olfactory threshold refers to the minimum detection amount or the lowest concentration that can be felt by the human olfactory organ for a certain odor substance. In the composite odor of multiple substances, the lower the threshold, the more obvious the odor of the component. For example, people are sensitive to the odor of methyl mercaptan because they have olfactory receptors that are extremely sensitive to thiols, that is, the olfactory threshold of thiols is extremely low. No relevant research has been reported so far on the development of a nano-odor that can be administered through the olfactory area to simulate the binding and delivery pathway of odor molecules and olfactory receptors and enhance the brain targeting ability of central nervous system drugs. Summary of the invention

[0004] In view of the above technical problems, the purpose of the present invention is to provide a transnasal brain-targeted nano-odor drug delivery system and its application, by constructing chemical groups with low olfactory thresholds on the surface of nano-drug carriers, so that they have structural characteristics similar to natural odor molecules. The brain-targeted nano-odor drug delivery system can quickly and tightly bind to olfactory receptors, and be transported into the central nervous system through the olfactory nerve pathway, thereby improving the targeted drug delivery ability to the central nervous system, thereby efficiently treating central nervous system diseases, and the delivery ability can be adjusted by adjusting the concentration or density of special groups modified by bionics on the surface of the carrier, providing a scientific reference for innovative research for the development of new brain-targeted drug delivery systems for clinical use, which is of great significance for the treatment of central nervous system diseases.

[0005] In order to achieve the above object, the present invention provides the following technical solutions:

[0006] The present invention provides a brain-targeted nano-odor drug delivery system through the nose. The brain-targeted nano-odor drug delivery system consists of a nano-carrier with a group sensitive to olfactory receptors connected to its surface and a loaded drug. The group sensitive to olfactory receptors is biomimetically modified to give it a structure similar to natural odor. After nasal administration, the loaded drug is efficiently delivered to the central nervous system.

[0007] Based on the above technical solution, further, the group that the olfactory receptor is sensitive to is a group with a low olfactory threshold, including a thiol group, an aromatic group and an aldehyde group.

[0008] Based on the above technical solution, further, the concentration of the group that is sensitive to the olfactory receptor is not less than the olfactory threshold at the lowest and not more than the concentration when the olfactory receptor is saturated at the highest.

[0009] Based on the above technical solution, further, the carrier includes micelles, skeleton carriers, liposomes, and lipid nanoparticles.

[0010] Based on the above technical solution, further, the transnasal brain targeted nano odor drug delivery system is prepared by a thin film dispersion method.

[0011] Based on the above technical scheme, the specific process of the thin film dispersion method is as follows: dissolving the drug and the carrier in an organic solvent, stirring until the mixture is uniformly mixed, transferring the mixed solution to an eggplant-shaped bottle, and performing reduced pressure rotary evaporation to remove the organic solvent to form a uniform thin film, and adding PBS for hydration to obtain the obtained film.

[0012] Based on the above technical solution, further, the mass ratio of the drug to the carrier is 1:10 to 1:50, and the organic solvent includes methanol, ethanol, and propanol.

[0013] Based on the above technical solution, further, the drug is a water-insoluble drug suitable for treating central nervous system diseases, including agomelatine.

[0014] Based on the above technical solution, further, the material of the carrier is an amphiphilic polymer, including a copolymer of thiolated-N-methacryloyl glycylglycine and hydroxypropyl methacrylate, and thiolated-15-hydroxystearate polyethylene glycol.

[0015] Based on the above technical solution, further, the monomer molar ratio of the copolymer of thiolated-N-methacryloylglycylglycine and hydroxypropyl methacrylate is 5:95-15:85; the thiol grafting ratio in thiolated-15-hydroxystearic acid polyethylene glycol ester is 10-20%.

[0016] Based on the above technical scheme, further, the thiolated-N-methacryloylglycylglycine is prepared by connecting a thiol group to an N-methacryloylglycine fragment by a grafting method; the thiolated-15-hydroxystearate polyethylene glycol ester is prepared by connecting a thiol group to a 15-hydroxystearate polyethylene glycol ester fragment by a grafting method.

[0017] Another aspect of the present invention provides preparations of the above-mentioned transnasal brain targeted nano odor drug delivery system, including suspensions and freeze-dried preparations.

[0018] Based on the above technical solution, further, the lyophilized preparation is obtained by adding a lyophilization protectant to the above brain-targeted nano-odor drug delivery system and then freeze-drying it.

[0019] Based on the above technical scheme, further, the lyoprotectant is one or a combination of two or more of glucose, mannitol, sorbitol, glycine, maltose, trehalose, sucrose, glycerol, polyethylene glycol 2000, polyethylene glycol 4000 or polyethylene glycol 6000, and the added amount of the lyoprotectant is 1% to 5% (w / v).

[0020] Based on the above technical solution, further, the lyophilized preparation is added with a diluent according to the required concentration before use and reconstituted into a solution, and the diluent is one of water for injection, physiological saline or buffer.

[0021] The present invention also provides the use of the above-mentioned transnasal brain targeted nano odor drug delivery system and the preparation of the transnasal brain targeted nano odor drug delivery system in the preparation of drugs for treating central nervous system diseases.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] (1) High degree of biomimetic properties: The nano-odor drug delivery system constructed by the present invention is modified by biomimetic methods, so that the surface of the nano-micelles is enriched with special groups, thereby having the characteristics of odor molecules and being highly compatible with olfactory receptors, thereby simulating the binding and delivery pathway of odor molecules and olfactory receptors.

[0024] (2) Rapid onset of action: The nano-odor drug delivery system constructed by the present invention can quickly and tightly bind to the olfactory receptors, be transported into the central nervous system through the olfactory nerve pathway, and take effect quickly.

[0025] (3) Prolonged onset time: The nano-odor drug delivery system constructed by the present invention has the advantages of nano-micelles, which can improve the solubility of poorly soluble drugs and achieve slow release in the brain after administration, thereby prolonging the administration time.

[0026] (4) Large brain-targeted accumulation: The nano-odor drug delivery system constructed by the present invention delivers drugs through the olfactory area and delivers them to the brain by binding to olfactory receptors. Compared with other dosage forms and administration methods, the accumulation in the brain is significantly improved.

[0027] (5) Controllable drug delivery ability: The nano-odor drug delivery system constructed by the present invention can change the amount of drug bound to the olfactory receptors through the ratio of special groups, thereby adjusting the drug delivery ability. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 Schematic diagram of the transnasal brain targeted nano odor drug delivery system of the present invention.

[0029] Figure 2 This is a transmission electron microscopy image of the bionic brain-targeted nano-odor drug delivery system constructed with MGHM / SH-MGHM;

[0030] Figure 3 The results of characterization of particle size distribution of bionic brain-targeted nano-odor drug delivery system constructed with MGHM / SH-MGHM by dynamic light scattering method;

[0031] Figure 4 The in vitro release curve of the bionic brain-targeted nano-odor drug delivery system constructed with MGHM / SH-MGHM in cerebrospinal fluid from 0 to 10 hours;

[0032] Figure 5 To evaluate the targeting effect of the bionic brain-targeted nano-odor drug delivery system constructed with MGHM / SH-MGHM in rat brain tissue by fluorescence imaging quantitative method;

[0033] Figure 6 To evaluate the targeting effect of the bionic brain-targeted nano-odor drug delivery system constructed with MGHM / SH-MGHM in other major tissues of rats by fluorescence imaging quantitative method;

[0034] Figure 7 The pharmacokinetic results of the bionic brain-targeted nano-odor drug delivery system constructed with MGHM / SH-MGHM in cerebrospinal fluid;

[0035] Figure 8 The pharmacokinetic results of the bionic brain-targeted nano-odor drug delivery system constructed with MGHM / SH-MGHM in brain tissue;

[0036] Fig. 9 The pharmacokinetic results of the bionic brain-targeted nano-odor drug delivery system constructed with MGHM / SH-MGHM in plasma;

[0037] Fig.10 The maximum concentration of the bionic brain-targeted nano-odor drug delivery system constructed with MGHM / SH-MGHM in vivo;

[0038] Fig.11 The area under the drug-time curve of the bionic brain-targeted nano-odor drug delivery system constructed with MGHM / SH-MGHM in vivo;

[0039] Fig.12 The pharmacodynamic results of the bionic brain-targeted nano-odor drug delivery system constructed with SH-MGHM85;

[0040] Fig.13 The results of characterization of the particle size distribution of the bionic brain-targeted nano-odor drug delivery system constructed with SH-HS15 by dynamic light scattering method;

[0041] Fig.14 This is the release curve of the bionic brain-targeted nano-odor drug delivery system constructed with SH-HS15;

[0042] Fig.15 These are the pharmacodynamic results of the bionic brain-targeted nano-odor drug delivery system constructed with SH-HS15. DETAILED DESCRIPTION

[0043] Various exemplary embodiments of the present invention are now described in detail, and the detailed description should not be considered as a limitation of the present invention, but should be understood as a more detailed description of certain aspects, characteristics and embodiments of the present invention. The terms "include", "including", "have", "contain" and the like used herein are open terms, which means including but not limited to.

[0044] The present invention is further described below in conjunction with the embodiments. The following description is only a preferred embodiment of the present invention and does not limit the present invention in other forms. Any technician familiar with the profession may use the above disclosed technical content to change it into an equivalent embodiment with equivalent changes. Any simple modification or equivalent change made to the following embodiments based on the technical essence of the present invention without departing from the content of the present invention falls within the protection scope of the present invention. The invention is further described below in conjunction with the drawings and embodiments:

[0045] Example 1

[0046] Preparation of a bionic brain-targeted nano-odor drug delivery system based on MGHM / SH-MGHM.

[0047] The nanocarrier core used in this embodiment is a micelle;

[0048] The model drug loaded in this example is agomelatine;

[0049] The biomimetic group used in this embodiment is a thiol group;

[0050] The amphiphilic block copolymer monomers used in this example are hydroxypropyl methacrylate and thiolated-N-methacryloylglycylglycine;

[0051] The proportions of the biomimetic group monomer (thiolated N-methylacryloylglycine) used in this embodiment are 5%, 10% and 15% respectively.

[0052] The steps include:

[0053] Step 1: Preparation of amphiphilic block copolymers MGHM / SH-MGHM grafted with thiol groups

[0054] Hydroxypropyl methacrylate and N-methacryloylglycine (molar ratio of monomers is 85:15) were polymerized by free radical solution polymerization to obtain the copolymer derivative MGHM;

[0055] Thiol groups were attached to N-methacryloylglycine fragments by grafting to obtain thiolated-N-methacryloylglycine; hydroxypropyl methacrylate and thiolated N-methacryloylglycine were polymerized by free radical solution polymerization in anhydrous ethanol to obtain copolymer derivatives (copolymerized in a sealed container at 50°C under nitrogen conditions for 24 hours), named SH-MGHM. The ratio of hydroxypropyl methacrylate monomers was 95% / 90% / 85%, and the polymers were named SH-MGHM95, SH-MGHM90 and SH-MGHM85, respectively. SH-MGHM was separated in ether, then dialyzed and freeze-dried.

[0056] Step 2: Construct a bionic brain-targeted nano-odor drug delivery system using MGHM / SH-MGHM;

[0057] The film dispersion method was used to weigh agomelatine and MGHM / SH-MGHM (w:w=1:10-1:50) and dissolve them in anhydrous ethanol. The mixture was slowly stirred at room temperature until uniformly mixed. The mixed solution was transferred to an eggplant-shaped bottle and rotary evaporated under reduced pressure. The anhydrous ethanol was removed in a water bath to form a uniform film. PBS was added for hydration to obtain a bionic brain-targeted nano-odor drug delivery system constructed with MGHM / SH-MGHM.

[0058] Example 2

[0059] The performance of the bionic brain-targeted nano-odor drug delivery system constructed with MGHM / SH-MGHM prepared in Example 1 (the mass ratio of drug to carrier was 1:15) was tested.

[0060] 1. Characterization of the bionic brain-targeted nano-odor drug delivery system constructed with MGHM / SH-MGHM

[0061] Transmission electron microscopy and dynamic light scattering techniques were used to observe the structure, morphology, size and potential of the nano-odor delivery system. Figure 2 and Figure 3 As shown, the particle size of the nano-odor drug delivery system obtained in Example 1 is about 140-165 nm, which is consistent with the nano-micelle size results observed by transmission electron microscopy. The particle size is evenly dispersed and has good monodispersity. The agomelatine-loaded micelles have a relatively stable zeta potential of about -20 mV.

[0062] 2. Encapsulation efficiency of bionic brain-targeted nano-odor drug delivery system constructed with MGHM / SH-MGHM

[0063] The encapsulation efficiency (EE) of the nano-odor drug delivery system was determined by ultracentrifugation. 1 ml of the nano-odor micelle solution was precisely measured and fixed to volume with methanol. The drug-loaded micelles were ultrasonically broken to release all the encapsulated drugs from the micelles. The absorbance value was measured at a wavelength of 303 nm using an ultraviolet spectrophotometer to calculate the total amount of agomelatine. Another 1 ml of the nano-odor micelle solution was placed in an ultrafiltration cup and centrifuged at 3000 × g for 20 min to retain the drug-loaded micelles. The absorbance value of the filtrate was measured using an ultraviolet spectrophotometer to calculate the amount of agomelatine not encapsulated.

[0064] The results showed that the encapsulation efficiencies of MGHM, SH-MGHM95, SH-MGHM90 and SH-MGHM85 micelles were 84.1%, 81.8%, 84.5% and 83.4% (n=3), respectively, indicating that the obtained micelles had a high loading capacity for agomelatine.

[0065] 3. In vitro release behavior of the bionic brain-targeted nano-odor drug delivery system constructed with MGHM / SH-MGHM

[0066] The in vitro release of the nano-odor drug delivery system was investigated by dynamic dialysis. 2 ml of the nano-odor drug delivery system solution was accurately measured and placed in a 3.5 kDa dialysis bag. The two ends of the dialysis bag were tied tightly and placed in artificial cerebrospinal fluid (aCSF, sodium chloride 0.72% (w / v), potassium chloride 0.02% (w / v), magnesium sulfate 0.05% (w / v), sodium bicarbonate 0.22% (w / v), calcium chloride 0.02% (w / v), D-glucose 0.40% (w / v), pH 7.4, sterile). The mixture was shaken at 37°C and 200 rpm / min in a shaker for 10 h. 2 ml of the release medium was drawn at 0, 2, 4, 6, 8, and 10 h, and the same amount of the same release medium was added in time. The content of agomelatine in the release medium at different time points was determined by UV-visible spectrophotometry, and the cumulative release rate was calculated.

[0067] The drug release curve is Figure 4As shown, the agomelatine solution can reach the maximum cumulative release at 2 hours, and the bionic brain-targeted nano-odor drug delivery system constructed with MGHM / SH-MGHM has a cumulative release rate of (99.42±2.32)% in the cerebrospinal fluid at 6 hours.

[0068] The results showed that the nano-odor drug delivery system prepared in Example 1 had an obvious sustained-release effect in the cerebrospinal fluid without a burst-release effect, and the addition of thiol groups had no effect on the release of the drug.

[0069] 4. Brain targeting capability of the bionic brain-targeted nano-odor drug delivery system constructed with MGHM / SH-MGHM

[0070] In order to preliminarily explore the brain targeting ability of the brain-targeted agomelatine nasal spray delivery system constructed in the present invention, MGHM, SH-MGHM95, SH-MGHM90 and SH-MGHM85 micelles were used to encapsulate the hydrophobic fluorescent dye Cy7 with the same physicochemical properties as agomelatine, and the distribution of micelles in rats was observed by small animal in vivo imaging.

[0071] The Cy7-loaded micelle solution was prepared by a thin film dispersion method. Cy7 and MGHM, SH-MGHM95, SH-MGHM90 and SH-MGHM85 were weighed and dissolved in anhydrous ethanol. The mixture was slowly stirred at room temperature until uniformly mixed. The mixed solution was transferred to an eggplant-shaped bottle and rotary evaporated under reduced pressure to form a uniform thin film. 600 μl of 0.1 M PBS was added and hydrated for 5 minutes to obtain a Cy7-loaded micelle solution.

[0072] Fifteen rats were randomly divided into five groups (n=3), namely, Cy7 suspension, MGHM micelle, SH-MGHM95 micelle, SH-MGHM90 micelle and SH-MGHM85 micelle groups. Each rat was nasally administered with 100 μl of Cy7 solution and Cy7 micelle solution with the same fluorescence intensity. The rats were killed 4 hours after administration, and the heart, liver, spleen, lung, kidney and brain tissues were taken out and placed under a small animal imaging instrument to observe the fluorescence intensity of the isolated organs and perform quantitative analysis of the fluorescence intensity.

[0073] The results are as follows Figure 5 and Figure 6 The results showed that the in vitro brain fluorescence intensity of the MGHM micelle, SH-MGHM95 micelle, SH-MGHM90 micelle and SH-MGHM85 micelle groups were 1.60, 1.80, 2.02 and 2.66 times that of the free Cy7 group, respectively. In addition, the toxicity to the heart, liver, spleen, lung and kidney was low when administered in the form of nano-odor micelles, among which the toxicity to the liver and lung was significantly reduced. It was proved that the constructed micelles had a brain tissue-specific targeted drug delivery effect in vivo after nasal spray administration, and the delivery ability of the nano-odor micelles was related to the concentration or density of the special groups modified by biomimetic modification.

[0074] 5. Pharmacokinetic study of the bionic brain-targeted nano-odor drug delivery system constructed with SH-MGHM85

[0075] 75 rats were randomly divided into 5 groups, namely Cy7 suspension, MGHM micelles, SH-MGHM95 micelles, SH-MGHM90 micelles and SH-MGHM85 micelles. Cerebrospinal fluid, blood and brain tissue were collected from each group at 0.25h, 0.5h, 1h, 3h and 6h after administration. 0.25mL blood sample was taken from the orbit, transferred to a 1.5ml centrifuge tube pre-washed with heparin sodium solution, and then centrifuged at 1500×g for 15min at 4℃ to collect the supernatant. Cerebrospinal fluid samples were extracted from the foramen magnum, centrifuged at 3000rpm for 15min at 4℃, and the supernatant was collected. Brain samples were collected, and physiological saline was added to the tissue at a ratio of 1:2 (v / v, tissue: physiological saline). Agomelatine was extracted after the tissue was ground into a slurry using a tissue grinder. The concentration of agomelatine in the samples was quantified using HPLC-MS / MS. Pharmacokinetic data were derived from the area under the curve (AUC). Pharmacokinetic parameters were derived from drug concentration-time data using DAS2.0 software.

[0076] The results are as follows Figure 7 , Figure 8 and Fig. 9 As shown in Figure 2, the concentrations in rat cerebrospinal fluid, brain tissue, and plasma reached their peak 15 minutes after administration. Fig.10 As shown in Figure 2, different proportions of thiols in micellar preparations significantly affect their pharmacokinetic behavior. The higher the thiol content, the higher the peak concentration in brain tissue, cerebrospinal fluid and plasma samples, and the AUC also has the same trend. Fig.11 As shown, the AUC of SH-MGHM95 micelle, SH-MGHM90 micelle and SH-MGHM85 micelle formulations were higher than that of MGHM micelle control group. 0-∞ The increases were 116.67%, 117.08% and 124.02%, respectively, indicating enhanced drug delivery and retention capabilities. Similar trends were observed in brain tissue. The higher the density of thiol groups on the surface of nanoodor micelles, the higher the accumulation of brain-targeted drugs.

[0077] 6. Pharmacodynamics of the bionic brain-targeted nano-odor drug delivery system constructed with SH-MGHM85

[0078] According to the above results, we selected the SH-MGHM85 micelle group with the highest brain accumulation for pharmacodynamic evaluation. The antidepressant effect of the nano-odor micelles was evaluated using a modified forced swimming test. A 15-min pre-swim was performed 24 hours before the test. Subsequently, the rats were taken out of the water, dried with a towel, and then returned to the cage to more clearly detect the antidepressant activity. The rats received the drug three times 1, 5, and 23.5 h before the swimming test. During the test, the rats showed behaviors that could not be completely still. The score was based on two types of active behaviors: swimming and climbing, and the time sampling technique was used to record the main behavior every 5 seconds: swimming was defined as vigorous movements beyond just keeping the head above the water, and climbing involved vigorous forepaw movements against the wall of the water tank. 30 rats were randomly divided into 5 groups (n=6), and the dosage and method of administration were shown in Table 1.

[0079] Table 1. Administration method and dosage

[0080]

[0081] The results are as follows Fig.12 As shown, first, the immobility time of the treated animal group was significantly reduced compared with that of the untreated animals. Second, compared with oral agomelatine, intranasal administration significantly reduced the inactivity behavior of rats, and the dosage was only 1 / 3 of that of the oral group, showing sufficient efficacy. The reduction in immobility time confirmed that agomelatine encapsulated in the nano-odor micelles effectively reached the site of action and exhibited antidepressant activity.

[0082] To further verify the delivery effect of the nano-odor drug delivery system, a bionic brain-targeted nano-odor drug delivery system with SH-HS15 as the carrier was constructed.

[0083] Example 3 Preparation of a bionic brain-targeted nano-odor drug delivery system using SH-HS15 as a carrier,

[0084] The nanocarrier core used in this embodiment is a micelle;

[0085] The model drug loaded in this example is agomelatine;

[0086] The biomimetic group used in this embodiment is a thiol group;

[0087] The amphiphilic compound used in this example is 15-hydroxystearate polyethylene glycol;

[0088] The proportion of the biomimetic groups used in this embodiment is 15%.

[0089] The steps include:

[0090] Step 1: Preparation of amphiphilic compound SH-HS15 grafted with thiol groups

[0091] Thiol-15-hydroxystearate polyethylene glycol ester obtained by grafting thiol groups onto 15-hydroxystearate polyethylene glycol ester segments is named SH-HS15, wherein the grafting ratio of thiol groups is 15%.

[0092] Step 2: Construct a bionic brain-targeted nano-smell with SH-HS15 as the carrier

[0093] The film dispersion method was used to weigh agomelatine and SH-HS15 (w:w=1:10-1:50) and dissolve them in anhydrous ethanol. The mixture was slowly stirred at room temperature until uniformly mixed. The mixed solution was transferred to an eggplant-shaped bottle and rotary evaporated under reduced pressure. The anhydrous ethanol was removed in a water bath to form a uniform film. PBS was added for hydration to obtain a bionic brain-targeted nano-odor drug delivery system constructed with SH-HS15.

[0094] Example 4

[0095] The bionic brain-targeted nano-odor drug delivery system prepared in Example 3 with SH-SH15 as the carrier (the mass ratio of drug to carrier is 1:15) was tested for efficacy, and the results are as follows.

[0096] 1. Characterization of the bionic brain-targeted nano-odor drug delivery system constructed with SH-SH15

[0097] Dynamic light scattering technology was used to detect the size and potential of the nano-odor drug delivery system prepared in Example 3. Fig.13 The results show that the nanometer odor drug delivery system prepared in Example 3 is about 10 to 25 nm, with uniform particle size and good monodispersity; the nanometer odor drug delivery system has a relatively stable zeta potential of about -3 to -5 mV.

[0098] 2. Encapsulation efficiency of the bionic brain-targeted nano-odor drug delivery system constructed with SH-SH15

[0099] The encapsulation efficiency (EE) of the nano-odor delivery system was determined by ultracentrifugation, and the determination method was the same as in Example 2. The results showed that the encapsulation efficiency of the nano-odor prepared in Example 3 was 91% to 95%, indicating that the obtained micelles had a high loading capacity for agomelatine.

[0100] 3. In vitro release behavior of the bionic brain-targeted nano-odor drug delivery system constructed with SH-SH15

[0101] The in vitro release of the nano-odor drug delivery system was investigated by dynamic dialysis, and the determination method was the same as in Example 2. The results showed that the nano-odor drug delivery system prepared in Example 3 had an obvious sustained release effect in the cerebrospinal fluid, without a burst release effect, and the addition of thiol groups had no effect on the release of the drug. The release curve of the bionic brain-targeted nano-odor constructed by HS15-SH is shown in Fig.14 shown.

[0102] 4. Pharmacokinetic study of the bionic brain-targeted nano-odor drug delivery system constructed with SH-SH15

[0103] The Cy7-loaded micelle solution was prepared by a thin film dispersion method, and the specific process was the same as in Example 2.

[0104] 30 rats were randomly divided into 2 groups, namely Cy7 suspension group and SH-HS15 micelle group, and the determination method was the same as Example 2. Pharmacokinetic data were obtained from the area under the curve (AUC). Pharmacokinetic parameters were obtained from the drug concentration-time data using DAS2.0 software.

[0105] The results showed that the concentrations in rat cerebrospinal fluid, brain tissue and plasma reached peak values ​​15 minutes after administration. In addition, in cerebrospinal fluid, the AUC of SH-HS15 micelle preparation was 0-∞ The drug delivery and retention capacity of the oral suspension control group were 137.57%, indicating that the drug delivery and retention capacity were enhanced. A similar trend was also observed in brain tissue.

[0106] 5. Pharmacodynamics of the bionic brain-targeted nano-odor drug delivery system constructed with SH-SH15

[0107] The antidepressant effect of the nano-odor drug delivery system was evaluated using a modified forced swimming test. The assay method was the same as in Example 2. 30 rats were randomly divided into 5 groups (n=6). The dosage and method of administration were shown in Table 2.

[0108] Table 2. Administration method and dosage

[0109]

[0110] The results are as follows Fig.15 As shown in the results, compared with oral agomelatine, intranasal administration significantly reduced the inactivity of rats, and the dosage was only 1 / 10 of that of the oral group, exerting a significant therapeutic effect. The shortening of the immobility time once again verified that agomelatine wrapped in nano-odorant effectively reached the site of action and exhibited antidepressant activity.

[0111] The above description is merely an example and explanation of the concept of the present invention. The technicians in this technical field may make various modifications or additions to the specific embodiments described or replace them in a similar manner. As long as they do not deviate from the concept of the invention or exceed the scope defined by the claims, they are all within the protection scope of the present invention.

Claims

1. A transnasal brain targeted nano-odor drug delivery system, characterized in that: The brain-targeted nano-odor drug delivery system consists of a nano-carrier with a group sensitive to olfactory receptors connected to the surface and loaded drugs.

2. The transnasal brain targeted nano-odor drug delivery system according to claim 1, characterized in that: The sensitive groups of the olfactory receptors are groups with low olfactory thresholds, including thiol groups, aromatic groups and aldehyde groups; the carriers include micelles, skeleton carriers, liposomes and lipid nanoparticles.

3. The transnasal brain targeted nano-odor drug delivery system according to claim 1, characterized in that: The transnasal brain targeted nano-odor drug delivery system is prepared by a thin film dispersion method, and the specific process is: dissolving the drug and the carrier in an organic solvent, stirring until the mixture is uniform, transferring the mixed solution to an eggplant-shaped bottle, and performing reduced pressure rotary evaporation to remove the organic solvent to form a uniform thin film, and adding a buffer solution for hydration to obtain the obtained solution.

4. The transnasal brain targeted nano-odor drug delivery system according to claim 3, characterized in that: The mass ratio of the drug to the carrier is 1:10 to 1:50, and the organic solvent includes methanol, ethanol, and propanol; the drug is a water-insoluble drug suitable for treating central nervous system diseases, including agomelatine.

5. The transnasal brain targeted nano-odor drug delivery system according to claim 3, characterized in that: The material of the carrier is an amphiphilic polymer, including a copolymer of thiolated-N-methacryloyl glycylglycine and hydroxypropyl methacrylate, and thiolated-15-hydroxystearic acid polyethylene glycol ester.

6. The transnasal brain targeted nano-odor drug delivery system according to claim 5, characterized in that: The monomer molar ratio of thiolated-N-methacryloyl glycylglycine and hydroxypropyl methacrylate is 5:95-15:85; and the thiol grafting ratio in thiolated-15-hydroxystearic acid polyethylene glycol ester is 10-20%.

7. The transnasal brain targeted nano-odor drug delivery system according to claim 5, characterized in that: The thiolated-N-methacryloyl glycylglycine is prepared by connecting a thiol group to an N-methacryloyl glycine fragment by a grafting method; the thiolated-15-hydroxystearic acid polyethylene glycol ester is prepared by connecting a thiol group to a 15-hydroxystearic acid polyethylene glycol ester fragment by a grafting method.

8. The preparation of the transnasal brain targeted nano-odor drug delivery system according to any one of claims 1 to 7, characterized in that: Including suspension and freeze-dried preparations.

9. The preparation of the transnasal brain targeted nano-odor drug delivery system according to claim 8, characterized in that: The lyophilized preparation is obtained by adding a lyophilization protectant to the brain-targeted nano-odor delivery system and then freeze-drying the mixture; The lyophilization protective agent is one or a combination of two or more of glucose, mannitol, sorbitol, glycine, maltose, trehalose, sucrose, glycerol, polyethylene glycol 2000, polyethylene glycol 4000 or polyethylene glycol 6000, and the added amount of the lyophilization protective agent is 1% to 5%.

10. Use of the transnasal-brain targeted nano-odor drug delivery system according to any one of claims 1 to 7, or the preparation of the transnasal-brain targeted nano-odor drug delivery system according to claim 8 or 9 in the preparation of drugs for treating central nervous system diseases.

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