CN114470496B

CN114470496B - Nasal and olfactory region circulation drug delivery device

Info

Publication number: CN114470496B
Application number: CN202210063869.5A
Authority: CN
Inventors: 赵应征; 鲁翠涛; 赵子逸
Original assignee: Individual
Current assignee: Individual
Priority date: 2022-01-14
Filing date: 2022-01-14
Publication date: 2024-04-12
Anticipated expiration: 2042-01-14
Also published as: CN114470496A

Abstract

A nasal olfactory circulatory drug delivery device and method of use thereof. The nasal olfactory region circulatory administration device of the present invention comprises: the nasal plug special for the nasal and olfactory region, the catheter system special for the nasal and olfactory region, the one-way switch, the two-way switch, the reversing valve, the expiration response switch and the aerosol container are connected into a whole by applying an integrated wearing type design, and the components are combined in a modularized manner, so that the nasal plug can be detached and replaced. The nasal and olfactory region circulation administration device overcomes the defects and the shortcomings of the existing administration device, is wide in applicable crowd, high in medicine utilization rate and capable of being independently administered by patients, has the dual advantages of quick acting and long acting maintenance, and achieves the purposes of safe, efficient and long-time nasal and olfactory region administration.

Description

Nasal and olfactory region circulation drug delivery device

Technical Field

The invention relates to a nasal administration device, in particular to a nasal and olfactory circulatory administration device.

Background

The blood brain barrier is the most main bottleneck of the drug to play a central disease treatment role, especially for biological macromolecule drugs, the blood brain barrier cannot be effectively crossed, and thus the brain disease treatment role cannot be played.

Due to the presence of the Blood Brain Barrier (BBB), existing routes of administration, such as oral, intravenous, intramuscular, subcutaneous, etc., are not effective in delivering drugs to the Central Nervous System (CNS). In addition, as the amount of drug administered increases, systemic side effects also increase.

The central administration route includes lateral ventricle administration (ICV), direct injection of brain parenchyma, etc., and although targeting is good, the medicine can be directly delivered to the injured brain area to exert curative effect, and complications such as infection may occur after the operation due to traumatism of the cone-cranium operation. In addition, the existing central administration route is high in cost, the economic burden of patients is excessive, and wide application is impractical for thousands of encephalopathy patients. Therefore, finding a central administration route that avoids the blood brain barrier obstruction is the most central problem for drugs to exert the actual therapeutic effect of brain diseases.

Experimental animal researches show that the olfactory nerve pathway in the nasal cavity olfactory region is a noninvasive and convenient central administration way, and the medicine can be directly delivered to the injured brain region by bypassing the blood brain barrier by utilizing the olfactory nerve pathway, so that Alzheimer's disease, parkinson's disease, multiple sclerosis, AIDS and can be treated, and a patient can simply use nasal drops for self-treatment at home. Although the olfactory nerve pathway provides a viable pathway for non-invasive delivery of drugs into the brain, in clinical practice, it has been found that nasal olfactory administration is limited by a number of physiological factors, and conventional drug delivery devices are not effective in delivering drugs to nasal olfactory regions, resulting in the inability to achieve the goal of drug delivery into the brain via the olfactory nerve pathway. Some scholars design an intubation tube to be directly connected to the vicinity of the nasal olfactory region, but because the pore canal structure in the nasal cavity is bent and complex, a plurality of narrow structures exist on the upper nasal canal, and the individual differences are obvious, the intubation method has a plurality of problems, such as the non-uniform dimension specifications of length, angle and the like, and can cause the intense pain of patients, so that the intubation method can not be applied to the nasal olfactory region for administration in practice.

In a word, the prior art cannot utilize the nasal olfactory region to achieve the purpose of drug entering the brain. At present, a drug delivery device for safely, efficiently and long-time delivering drugs to the brain by utilizing a nasal-olfactory region is not yet seen, so that the therapeutic effect of the drugs on central diseases by utilizing a nasal-olfactory region brain access is greatly limited.

Disclosure of Invention

The invention aims to provide a safe, efficient and long-time drug delivery device for delivering drugs to a nasal olfactory region, which has wide application range of drugs, is suitable for various patients, has good compliance and no stimulation and pain sense, and overcomes various defects that the traditional drug delivery device cannot effectively utilize an olfactory nerve channel to deliver drugs into the brain.

The nasal and olfactory region circulation administration device of the invention has the following advantages which are different from the prior administration device for drugs entering the brain through the nose:

1. high safety and wide applicable crowd: the medicine does not need to be added with adhesives with cilia toxicity (cilia fall-off caused by cilia swing inhibition), mucous membrane absorption promoters with potential safety and other additives, has no influence on physiological microenvironment of nasal cavity and cilia movement, has no side effects such as stimulation and the like, has high safety and is suitable for a wide range of people.

2. Accurate positioning and high medicine utilization rate: as shown in fig. 1, the entrance of the upper nasal passage of the nasal cavity is a region of narrow structure and pain sensitivity, and the existing delivery system cannot safely and painlessly deliver the drug into the upper nasal passage, so that the purpose of nasal olfactory administration cannot be achieved. The nasal and olfactory region circulation administration device of the invention does not need to insert a delivery tube into the nasal and olfactory region (which is unbearable by a user), but uses a special nasal plug for the nasal and olfactory region with unique design to plug the middle nasal tract and the lower nasal tract, thereby ensuring that aerosol can only be delivered into the upper nasal tract. In addition, the nasal and olfactory circulatory administration device of the invention does not need to prepare the medicine into a special dosage form or apply a special carrier; the drug is only prepared into one of liquid, gas or solid (including aqueous solution, oil solution, suspension, emulsion, aerosol, ultra-fine mist, nanoparticle, liposome and micelle) which takes propellant, high-pressure gas or volatile solvent as driving force transmission, so that the positioning and high-efficiency delivery of the nasal meatus and nasal olfactory region on the nasal cavity can be safely and painlessly realized, the drug can not enter the trachea and the lung, and the utilization rate is high.

3. Has the double advantages of quick action and long-acting maintenance: the aerosol particles have small particle size, large contact area with nasal and olfactory regions after entering the nasal passages, uniform distribution, maximum acceleration of drug absorption and high onset of action. Meanwhile, the nasal and olfactory region circulation administration device can carry out continuous long-time administration, so that the nasal and olfactory region circulation administration device has the advantage of long-term maintenance.

4. The drug is administered in the cooperative expiration process, and the expiration resistance of the respiratory tract is utilized to ensure the stay and absorption effect of the drug at the nasal-olfactory region: as shown in figures 2-4, the invention adopts the unique designs of nasal plug special for nasal and olfactory region, special catheter system for nasal and olfactory region, one-way switch, two-way switch, reversing valve, expiration response switch, aerosol container and the like, and ensures synchronous administration of oral expiration and nasal and olfactory region. The expiration response switch is in a closed state in the inspiration process of the user, and no aerosol enters the nasal cavity of the user; when a user slowly exhales, an expiration response switch is started, aerosol in the aerosol container enters a special catheter system for a nasal olfactory region under the driving action of a propellant, high-pressure gas or volatile solvent, and enters an upper nasal passage of a nasal cavity from a special nasal plug for the nasal olfactory region on one side after passing through a reversing valve; when the upper nasal passage on one side is filled with the aerosol, the redundant aerosol bypasses the nasopharynx part and enters the upper nasal passage on the other side, finally overflows from the nasal plug special for the nasal and olfactory region on the other side to the special duct system for the nasal and olfactory region, and enters the nasal plug special for the nasal and olfactory region on one side again through the duct, so that the full utilization of the aerosol is ensured. Therefore, the nasal and olfactory region circulation drug delivery device ensures the stay and absorption effect of the drug at the nasal and olfactory region, and remarkably improves the efficiency of the drug entering the brain through the nasal and olfactory region passage.

5. Patients independently administer the medicine, the compliance is good, and special requirements are not needed: the nasal and olfactory region circulation drug delivery device is simple and convenient to operate, and patients can independently deliver drugs without medical staff to participate in operation, so that the nasal and olfactory region circulation drug delivery device is also applicable to children, old people, mental retardation, coma and other patients.

Drawings

Fig. 1 is a schematic structural design of the nasal olfactory region-specific catheter system of the present invention.

Figure 2 is a schematic structural view of the connection of the nasal olfactory region-specific catheter system and other components of the present invention.

Fig. 3 is a schematic diagram of the application position and structural design of the nasal plug special for the nasal and olfactory region of the present invention.

Fig. 4 is a schematic diagram of the application of the nasal olfactory circulatory delivery device of the present invention.

Fig. 5 is an aerosol delivery profile of the nasal and olfactory region-specific catheter system of the present invention upon exhalation.

Detailed Description

Hereinafter, specific embodiments of the present invention will be described in detail. It should be noted that the technical features or combinations of technical features described in the following embodiments should not be regarded as being isolated, and they may be combined with each other to achieve a better technical effect.

As shown in fig. 1 to 5, the nasal and olfactory region circulatory administration device of the present invention comprises: a nasal plug 10 dedicated to the nasal and olfactory region, a catheter system 20 dedicated to the nasal and olfactory region, a one-way switch 30, a two-way switch 40, a reversing valve 50, an exhalation response switch 60, and an aerosol container 70; the nasal and olfactory region circulation drug delivery device provided by the invention is characterized in that the components are connected into a whole by an integrated wearable design, and the components are combined in a modularized manner and can be detached and replaced.

The nasal plug 10 special for the nasal and olfactory region is prepared from a soft material with good biocompatibility and good elasticity and air tightness, has a cylindrical, gourd-shaped, conical or external structure adapting to nasal anatomy structure, the nasal plug 10 special for the nasal and olfactory region is divided into a head part, a waist part and a bottom part, the nasal plug 10 special for the nasal and olfactory region comprises a hollow channel 11, and two ends of the hollow channel 11 are respectively opened at the head part and the bottom part of the nasal plug 10 special for the nasal and olfactory region.

The surface of the nasal plug 10 special for the nasal and olfactory region is provided with annular bulges, and the bulges are any one of round, semicircular, elliptic, prismatic, triangular, trapezoidal or wavy and are used for fixing the position of the nasal plug 10 special for the nasal and olfactory region in the nasal cavity and simultaneously plugging the inlets of the outer nostril, the middle nasal passage and the lower nasal passage.

The special catheter system 20 for the nasal and olfactory region consists of a communicating pipe 21 and a duct 22, wherein the communicating pipe 21 is provided with a Y-shaped structure, the duct 22 is provided with a U-shaped structure and is arranged in the communicating pipe, the inlet of the duct 22 is wide, the outlet of the duct is narrow, and aerosol for conveying backflow enters the nasal cavity again.

A unidirectional switch 30 is located at the outlet of the duct 22 of the nasal-olfactory-region dedicated catheter system 20 for opening and closing the outlet of the duct 22. The two-way switch is positioned at the bottom of the U-shaped structure of the special catheter system 20 in the nasal and olfactory region and is used for regulating and controlling the asynchronous opening and closing of the inlets of the communicating pipe 21 and the duct 22 behind the reversing valve 50.

The reversing valve 50 is located at the crossing of the Y-shaped structure of the nasal and olfactory area special catheter system 20, and is used for ensuring that the reversing valve 50 changes the direction of the passage once every breath.

An expiration response switch 60 is positioned at the lower portion of the reversing valve 50 for ensuring that the expiration response switch 60 is opened during expiration, and the expiration response switch 60 is electronically controlled or autonomously controlled by the user.

An aerosol container 70 is located at the bottom of the Y-shaped structure of the nasal-olfactory-region dedicated conduit system 20 for storing aerosol. Aerosol refers to a liquid, gas or solid with propellant, high pressure gas or volatile solvent as the driving force for transmission, including: one or more of aqueous solution, oil solution, suspension, emulsion, aerosol, ultra-fine mist, nanoparticle, liposome and micelle

A method of using a nasal olfactory circulatory delivery device comprising the steps of:

(1) The special nasal plug 10 for the nasal and olfactory region is plugged into nasal cavities at two sides of a user, and the position is adjusted until the hollow channel 11 of the special nasal plug 10 for the nasal and olfactory region is closed, and then the nasal cavity is completely plugged;

(2) The user keeps a static state and inhales normally, and the exhalation response switch 60 is in a closed state during inhalation, so that no aerosol enters the nasal cavity of the user;

(4) The user exhales slowly, and when exhaling, the exhales the response switch 60 is started, the aerosol in the aerosol container 70 enters the special nasal-olfactory region duct system 20 under the driving action of the propellant, the high-pressure gas or the volatile solvent, and enters the nasal upper nasal passage from the special nasal plug 20 of one nasal-olfactory region through the reversing valve 50; when the upper nasal passage on one side is filled with the aerosol, the redundant aerosol bypasses the nasopharynx part and enters the upper nasal passage on the other side, finally flows back to the special nasal plug 10 on one side from the hollow passage 11 of the special nasal plug 10 on the other side to the special nasal plug 20 on the nasal and olfactory region, and enters the special nasal plug 10 on the nasal and olfactory region again through the duct 22, so that the full utilization of the aerosol is ensured.

(5) The user circulates the steps (3) and (4) to finish the delivery of the aerosol to the nasal olfactory region.

Example 1 test packets for nasal olfactory devices

The nasal olfactory region circulatory drug delivery device of the present invention comprises: the drug delivery device is applied to the following test by integrally connecting all components by using an integrated wearing type design.

Experimental animals: the saanen goats (saanen goats) have the nasal structures closest to the human beings, so that the saanen goats are taken as experimental animal subjects, the male and female are not limited, and 3 saanen goats are taken as the following groups: 1 in 3-4 years old, 1 in 7-8 years old, and 1 in 11-13 years old, representing young, adult, and aged sabot goats, respectively.

Experimental drugs: oil-soluble quantum dots and water-soluble quantum dots with the same molar concentration and fluorescence intensity are used as drug objects, water-soluble CdSe/ZnS quantum dots are used for preparing quantum dot aqueous solution and quantum dot-starch ultrafine powder mist (starch adsorption quantum dots, particle size of 400-600 nm), and oil-soluble quantum dots are used for preparing quantum dot oil solution (petroleum ether), quantum dot O/W emulsion, quantum dot-gelatin nanoparticles (particle size of 100-200 nm) and quantum dot liposome.

The nasal passages and volumes on the nasal cavities of animals were detected by imaging according to the design of table 1, and nasal plugs with appropriate sizes for nasal and olfactory regions were selected and plugged into the nostrils of animals. The body of the animal is in a negative 30-degree body position (the head is slightly lower) after anesthesia, an oxygen pipe is inserted into the mouth, and the animal is dosed by referring to an application method of a nasal-olfactory region circulation dosing device, and after the dosing is finished, the animal is kept in the body position for 10 minutes and then wakes up. Experimental groups were dosed using the nasal olfactory circulatory dosing device of the present invention according to the table 1 design (the exhalation response switch was electronically controlled) and control groups were dosed according to the table 1 design with simultaneous reference to the experimental groups.

Table 1 test packets for nasal olfactory circulatory drug delivery devices

Note that: and/represents that the feature or structure is not present; * Indicating that the settings or parameters varied significantly from the experimental set.

Example 2 test results for each set

After administration according to the design of table 1, nasal cavities of experimental animals were dissected, the degree of retention of each group of drugs in the nasal-olfactory region was evaluated, brain tissues were isolated, and the concentration of quantum dots in the brain was detected, etc.

Degree of retention of drug in nasal olfactory region: the relative extent of retention of the drug in the nasal-olfactory region was assessed by the fluorescence intensity of the nasal-olfactory region.

Detection of quantum dot concentration in brain tissue: and (3) detecting the concentration of the quantum dots in each group of brain tissues by using a fluorescence detection method, and comparing the brain entering effects of the quantum dots at 12h, 24h and 48h after administration.

The test results of each group are shown in Table 2, the effect of each index in the table is represented by "+" or "-" (+whether the evaluation index is good or high or whether the evaluation index is poor or low), the overall evaluation of safety and effectiveness is given by integrating the indexes, and the overall evaluation is a percentage, the higher the score, the better the representative effect.

Table 2 test results of nasal olfactory cycle drug delivery device

The results in table 2 show that the overall evaluation of the safety and effectiveness of the olfactory region circulating drug administration device of the experimental group is obviously higher than that of the control group, and the experimental group has the advantages of high retention degree of the drug in the olfactory region, high brain entering effect of 12h, 24h and 48h quantum dots, good safety and the like, wherein the experimental groups 4 to 6 are best evaluated.

Compared with the experimental group, the control group has poorer overall evaluation of safety and effectiveness, and the control group 2 adopts a hard plastic nasal plug and causes damage to nasal mucosa; the retention degree of the medicaments in the nasal and olfactory regions of the control groups 4-8 is low, so that the cerebral efficiency of the quantum dots is low; the drugs in the control groups 9 to 14 cannot effectively enter the nasal-olfactory region, so that the effect of entering the brain is not achieved.

The results in table 2 prove that any component and parameter in the technical protection scheme of the nasal and olfactory region circulatory drug delivery device are mutually synergistic and indispensable, and the lack of any component and parameter in the technical protection scheme of the invention can have great influence on the brain entering effect of the drug. The nasal and olfactory region circulating drug delivery device has the characteristics of safety, high efficiency and convenience in application, and has good application prospect.

The foregoing detailed description is directed to embodiments of the invention which are not intended to limit the scope of the invention, but rather to cover all modifications and variations within the scope of the invention. Further, various modifications, additions and substitutions in other forms and details may be made by those skilled in the art within the scope and spirit of the invention as disclosed in the accompanying claims. Of course, such modifications, additions and substitutions are intended to be included within the scope of the invention as set forth in the accompanying claims.

Claims

1. The nasal and olfactory region circulation administration device is characterized in that the administration device comprises: the nasal obstruction special for the nasal and olfactory region, the catheter system special for the nasal and olfactory region, a one-way switch, a two-way switch, a reversing valve, an expiration response switch and an aerosol container; the special nasal plug for the nasal and olfactory region is prepared from soft materials with good biocompatibility and good elasticity and air tightness, the special nasal plug for the nasal and olfactory region is divided into a head part, a waist part and a bottom part, the special nasal plug for the nasal and olfactory region comprises a hollow channel, and two ends of the hollow channel are respectively opened at the head part and the bottom part of the special nasal plug for the nasal and olfactory region; the special catheter system for the nasal and olfactory region consists of a communicating pipe and a duct, wherein the communicating pipe is of a Y-shaped structure, the duct is of a U-shaped structure and is arranged in the communicating pipe, the inlet of the duct is wide and the outlet of the duct is narrow, and aerosol for conveying reflux enters the nasal cavity again; the special nasal and olfactory region catheter system connects the special nasal plug, the one-way switch, the two-way switch, the reversing valve, the expiration response switch and the aerosol container into a whole; the one-way switch is positioned at the duct outlet of the special duct system for the nasal and olfactory region and is used for opening and closing the duct outlet; the bidirectional switch is positioned at the bottom of the U-shaped structure of the special catheter system in the nasal and olfactory region and is used for regulating and controlling the asynchronous opening and closing of the rear communication pipe and the culvert inlet of the reversing valve; the reversing valve is positioned at the crossing part of the Y-shaped structure of the special catheter system in the nasal and olfactory region and is used for ensuring that the reversing valve changes the direction of a passage once every breath; the expiration response switch is positioned at the lower part of the reversing valve and used for ensuring that the expiration response switch is opened during expiration; the aerosol container is positioned at the bottom of the Y-shaped structure of the special catheter system for the nasal and olfactory region and is used for storing aerosol; the drug delivery device is characterized in that the drug delivery device is integrally connected with all components by an integrated wearable design, and all components are combined in a modularized mode and can be detached and replaced.

2. The device for cyclic delivery of a nasal and olfactory region of claim 1 wherein the nasal plug has a configuration that conforms to the anatomy of the nasal cavity.

3. The device for cyclically administering the medicine to the nasal and olfactory region according to claim 1, wherein the surface of the nasal plug special for the nasal and olfactory region is provided with annular protrusions, and the protrusions are any one of round, semicircular, elliptic, prismatic, triangular, trapezoidal or wavy shapes, and are used for fixing the position of the nasal plug special for the nasal and olfactory region in the nasal cavity and simultaneously blocking the entrance of the outer nostril, the middle nasal meatus and the lower nasal meatus.

4. The nasal olfactory region circulatory delivery device of claim 1 wherein the exhalation responsive switch is electronically controlled or user-controlled.

5. The nasal and olfactory patch circulatory delivery device of claim 1 wherein the aerosol is a liquid, gas or solid with propellant, high pressure gas or volatile solvent as the delivery driving force, comprising: one or more of aqueous solution, oil solution, suspension, emulsion, aerosol, ultra-fine mist, nanoparticle, liposome and micelle.