CN117427244A - Drug delivery method and drug delivery structure for respiratory system drug delivery - Google Patents
Drug delivery method and drug delivery structure for respiratory system drug delivery Download PDFInfo
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- CN117427244A CN117427244A CN202311522254.5A CN202311522254A CN117427244A CN 117427244 A CN117427244 A CN 117427244A CN 202311522254 A CN202311522254 A CN 202311522254A CN 117427244 A CN117427244 A CN 117427244A
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- agonist
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- antihistamine
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M19/00—Local anaesthesia; Hypothermia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2210/00—Anatomical parts of the body
- A61M2210/10—Trunk
- A61M2210/1025—Respiratory system
Abstract
The invention discloses a drug administration method and a drug administration structure for respiratory system drug administration, which relate to the technical field of drug administration equipment and comprise the following steps of S1: performing a drug application operation on the drug application structure, preparing a solution of an acetylcholinergic receptor agonist, a GLP-1R agonist, a muscle relaxant antagonist, an antihistamine or a local anesthetic, and adding the solution to the drug application structure; s2: the administration structure prepares an aerosol containing chemical components of the acetylcholinergic receptor agonist, the GLP-1R agonist, the muscle relaxant antagonist, the antihistamine or the local anesthetic from a solution of the acetylcholinergic receptor agonist, the GLP-1R agonist, the muscle relaxant antagonist, the antihistamine or the local anesthetic, and the invention adopts a treatment scheme of aerosol delivery medicines. Compared with the traditional modes of oral administration, injection or nasal spray, the aerosol administration mode formed by atomization is greatly improved in the administration mode, is favorable for the absorption and distribution of medicines in a body, is simple in administration mode and convenient to carry, and improves the medication compliance of patients.
Description
Technical Field
The invention relates to the technical field of medicine application equipment, in particular to a medicine application method and a medicine application structure for respiratory system medicine application.
Background
The existing administration modes of the acetylcholinergic receptor agonist, the GLP-1R agonist, the muscle relaxant antagonist, the antihistamine or the local anesthetic are mostly implemented by nasal spraying, oral administration and injection. In the nasal spray administration process, as the mucous membrane in the nasal cavity is fragile, if the impact force of the spray is too strong, the discomfort of a patient is easily caused, and the liquid injection mode is easy to flow out redundant liquid, so that the liquid medicine is wasted. The oral administration is easy to generate first pass effect of liver, has low bioavailability and can bring inconvenience to dysphagia patients. The injection administration mode is improper in treatment, systemic or local infection is easy to generate adverse reaction if the medicine is excessive or instilled too fast. Accordingly, the present application provides a method and structure for administration of respiratory drug to meet clinical needs.
Disclosure of Invention
The object of the present application is to provide a method and a structure for administration of respiratory drug,
in order to achieve the above purpose, the present application provides the following technical solutions: a method of administering an acetylcholinergic receptor agonist, a GLP-1R agonist, a muscle relaxant antagonist, an antihistamine or a local anesthetic comprising the steps of:
s1: the administration of the pharmaceutical composition is performed by preparing solutions of the acetylcholinergic receptor agonist, GLP-1R agonist, the muscle relaxant antagonist, the antihistamine or the local anesthetic, and adding the solutions to the administration.
S2: the administration structure comprises an acetylcholinergic receptor agonist, a GLP-1R agonist, a muscle relaxant antagonist, an antihistamine or a local anesthetic in solution, and an aerosol containing the acetylcholinergic receptor agonist, the GLP-1R agonist, the muscle relaxant antagonist, the antihistamine or the local anesthetic chemical component, wherein the administration structure adopts an electronic atomization mode.
S3: the delivery structure delivers an aerosol containing an acetylcholinergic receptor agonist, a GLP-1R agonist, a muscle relaxant antagonist, an antihistamine or a local anesthetic chemical component into the respiratory system of a patient.
Further, the acetylcholinergic receptor agonist is valicarb and tartrate thereof, the GLP-1R agonist is Orforglitron (Orgliron), the muscle relaxant antagonist is sugamboge and sodium salt thereof, the antihistamine is clemastine and fumarate thereof, and the local anesthetics include local anesthetics such as lidocaine, tetracaine, actocaine, bupivacaine and the like, and salts thereof.
Further, the acetylcholine receptor agonists are useful for treating xerophthalmia; the GLP-1R agonist is used for treating obesity, the muscle relaxant antagonist is used for antagonizing rocuronium bromide or vecuronium bromide-induced neuromuscular blockade, the antihistamine is used for treating various allergic diseases induced by histamine, and the local anesthetic is used for temporarily blocking the sensory nerve conduction function of a local body part under the state of consciousness of a patient.
Further, the dosage of the acetylcholinergic receptor agonist is 0.03-0.12 mg/d, the dosage of the GLP-1R agonist is 10-100 mg/d, the dosage of the muscle relaxant antagonist is 2-4 mg/kg/d, the dosage of the antihistamine is 1-4 mg/d, and the dosage of the local anesthetic is 20-300 mg/d.
Further, the aerosols containing the chemical component of the acetylcholinergic receptor agonist, GLP-1R agonist, myorelaxant antagonist, antihistamine or local anesthetic each have a fine particle fraction of greater than 50% upon expulsion through the delivery structure.
Further, the aerosols containing the chemical component of the acetylcholinergic receptor agonist, GLP-1R agonist, myorelaxant antagonist, antihistamine or local anesthetic each have a mass median aerodynamic particle size of less than 10 μm upon expulsion through the delivery structure.
The utility model provides a structure of dosing of respiratory, includes the atomizing storehouse, the inboard medicine storage chamber that is provided with of atomizing storehouse, medicine storage chamber inboard is loaded with can be implemented the atomizing operation the medicine solution and can be to the atomizing core of medicine solution heating atomizing, the surface of atomizing core is provided with the seal receptacle, the seal receptacle butt joint is in medicine storage chamber rear end opening part.
The device comprises an atomization bin, and is characterized by further comprising a shell arranged at the rear of the atomization bin, wherein the rear end face of the shell is provided with an air inlet, the rear end of the shell is provided with a miniature air pump, an air outlet pipe of the miniature air pump is butted with the air inlet, and the air formed after the atomization of the medicinal solution can be driven to be discharged.
The opposite ends of the atomization bin and the shell are connected through the control shell, the front end of the atomization bin is detachably connected with a medicine outlet, the front end of the medicine outlet extends forwards to form a medicine guide pipe which is adapted to the nasal cavity of a patient, and the surface of the medicine guide pipe transversely penetrates through an adjusting pipe communicated with the inner cavity of the medicine guide pipe.
Further, the circuit board is installed to the inboard of control shell, the surface of circuit board is provided with air switch, air switch can be triggered by the inboard air input of air inlet, the circuit board has the heating seat that is located its place ahead through the line connection, steerable the heating seat circular telegram heats, atomizing core installs in the heating seat surface, can realize heat transfer, and atomizing to the heating of medicine solution, further, the battery is installed to the casing inner chamber, the battery is connected through the line with the circuit board, provides the electric energy for the operation of circuit board.
Further, diffusion hole group and focus hole have been seted up relatively to the governing pipe surface, diffusion hole group comprises a plurality of little diffusion holes that are annular structure and distribute, the port aperture of focus hole is less than the port aperture that is located the governing pipe inner wall of governing pipe outer wall, the both ends of governing pipe all are provided with the sealing plug, the governing pipe inboard is provided with the locating lever, the fixed surface of locating lever is connected with the filter screen, the filter screen is just right to the medicine guide tube, works as the governing pipe rotates the switching position, the filter screen is located the diffusion hole of upper and lower distribution, the opposite side of focus hole all the time, the both ends of locating lever are all run through in the sealing plug, and the equal threaded connection in both ends of locating lever has the dog.
Further, the side of medicine storage chamber is provided with detachable catheter, the thread bush with catheter screw thread adaptation has been seted up to the side of atomizing storehouse, the catheter is L column structure, and the top threaded connection of catheter has the lid.
In summary, the invention has the technical effects and advantages that:
the invention carries out heating atomization operation through the solutions of the acetylcholinergic receptor agonist, the GLP-1R agonist, the muscle relaxant antagonist, the antihistamine or the local anesthetic, and adopts the aerosol to transfer the treatment scheme of the medicine, so that the treatment effect of the disease is more ideal. Because aerosol formed by atomization is absorbed by a body along with the spontaneous breathing mode of a patient, compared with the traditional administration modes such as nasal spray, oral administration or injection, the compliance of the patient can be improved. Meanwhile, the medicine can be quickly absorbed by the organism. The bioavailability is far higher than that of common nasal spray administration and oral administration, the blood concentration is close to that of injection administration, but the average residence time in the body is far higher than that of injection administration, which indicates that the medicine can be maintained in the body for a long time and the administration interval can be prolonged. The atomization device is also beneficial to the patient to carry and is convenient for medicine use.
Drawings
In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described below, it being obvious that the drawings in the following description are only some embodiments of the present application, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
Fig. 1 is a schematic perspective view of the present invention.
FIG. 2 is a schematic cross-sectional view of the present invention.
Fig. 3 is a schematic view of the atomizing core according to the present invention.
Fig. 4 is a schematic diagram of the internal structure of the casing of the present invention after being cut away.
Fig. 5 is a schematic view of the structure of the drug guiding tube of the present invention.
Fig. 6 is a schematic diagram of the structure of the drug guide tube and the adjusting tube after being cut away.
In the figure: 1. an atomization bin; 2. a housing; 21. a storage battery; 22. an air inlet; 3. a drug storage cavity; 31. a catheter; 32. a cover body; 4. a drug solution; 5. a micro air pump; 6. a medicine outlet; 7. a drug guide tube; 8. a control housing; 81. a circuit board; 82. a heating seat; 9. a sealing seat; 10. an atomizing core; 11. an adjusting tube; 111. diffusion holes; 112. a focusing hole; 12. a sealing plug; 13. a positioning rod; 14. a filter screen; 15. and a stop block.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
A method of administering respiratory drug delivery comprising the steps of:
s1: the administration of the pharmaceutical composition is performed by preparing solutions of the acetylcholinergic receptor agonist, GLP-1R agonist, the muscle relaxant antagonist, the antihistamine or the local anesthetic, and adding the solutions to the administration.
S2: the administration structure comprises an acetylcholinergic receptor agonist, a GLP-1R agonist, a muscle relaxant antagonist, an antihistamine or a local anesthetic in solution, and an aerosol containing the acetylcholinergic receptor agonist, the GLP-1R agonist, the muscle relaxant antagonist, the antihistamine or the local anesthetic chemical component, wherein the administration structure adopts an electronic atomization mode.
In this step, the manner of electronic nebulization is adapted to the individual age group of patients. The medicine enters the respiratory system of a patient through the aerosol form, and can respectively exert local or systemic effect due to the difference of diffusion speed and deposition concentration generated by the particle size of the aerosol.
S3: the delivery structure delivers an aerosol containing an acetylcholinergic receptor agonist, a GLP-1R agonist, a muscle relaxant antagonist, an antihistamine or a local anesthetic chemical component into the nasal cavity of the patient.
Aerosols containing chemical components of acetylcholinergic receptor agonists, GLP-1R agonists, muscle relaxant antagonists, antihistamines or local anesthetics all have a fine particle fraction of greater than 50% upon expulsion through the delivery structure.
Aerosols containing chemical components of acetylcholinergic receptor agonists, GLP-1R agonists, muscle relaxant antagonists, antihistamines or local anesthetics all have mass median aerodynamic particle diameters of less than 10 μm upon expulsion through the delivery structure.
The following examples are embodiments of methods of administration based on an acetylcholinergic receptor agonist, GLP-1R agonist, a muscle relaxant antagonist, an antihistamine or a local anesthetic, wherein the starting materials, the drugs, and the equipment used are all known products and are obtained by purchasing commercially available products.
Terminology:
FPD: the fine particle dose refers to the total mass of active agent emitted from the device upon actuation that is present at an aerodynamic particle size less than a specified limit. If it is not explicitly stated that the other limit is set, the limit is usually set to 5 μm. FPD is measured using an impactor or collider, such as a two-stage collider (TSI), a multi-stage collider (MSI), an Andersen cascade collider, or a Next Generation Impactor (NGI).
FPF: the fine particle fraction is defined as the proportion of the fine particle dose in the released dose, i.e. the proportion of the atomized liquid medicine with a particle size smaller than 5 μm produced by atomization.
MMAD: mass median aerodynamic particle size, meaning that the mass of particles greater than and less than the aerodynamic diameter is half of the total mass, is an effective tool for measuring the "average" particle size.
GSD: geometric standard deviation, a dimensionless parameter, is the aerodynamic diameter (μm) ratio of particles with cumulative distributions below 84.1% and 15.9%.
AUC 0-t : area under the time curve, area surrounded by the blood concentration curve versus the time axis. This parameter is an important index for evaluating the degree of drug absorption, reflecting the in vivo exposure characteristics of the drug.
MRT 0-t : average residence time, drug molecules inThe average in vivo residence time represents the time required to eliminate 63.2% of the drug from the body.
T 1/2 : terminal elimination half-life, the time required for the terminal phase plasma concentration to drop by half. This parameter intuitively reflects the rate of elimination of the drug from the body.
T max : peak time, time required for peak concentration after administration. The parameter reflects the speed of the drug entering the body, and the peak time is short if the absorption speed is high.
C max : peak concentration, the highest blood concentration after administration. This parameter is an important indicator reflecting the rate and extent of absorption of the drug in the body.
F: bioavailability, a measure of the rate and extent to which a drug is absorbed into the blood circulation, is an important indicator for evaluating the extent of drug absorption.
Example 1, valicarb tartrate aerosol inhalation solution composition:
prescription: 0.05mg/mL of valicarb, 14mg/mL of sodium dihydrogen phosphate, 20mg/mL of disodium hydrogen phosphate and 9mg/mL of sodium chloride, and adjusting the pH value to 6.4 by sodium hydroxide and/or hydrochloric acid, and the balance being purified water.
The preparation method comprises the following steps:
(1) Adding buffer salt and osmotic pressure regulator into 80% of solvent in unit dosage volume based on prescription amount to obtain solution A, wherein the unit dosage volume of the embodiment is 3mL; the prescription amount is based on the volume of single dose, and the corresponding addition amount is obtained according to the corresponding concentrations of the valicarb tartrate, the buffer salt and the osmotic pressure regulator;
(2) Adjusting the pH of the solution A to 6.4 by using sodium hydroxide and/or hydrochloric acid to obtain a solution B;
(3) Adding valicarb tartrate into the solution B according to the prescription amount, adding water to the unit dosage volume, and transferring to a medicine storage bin.
Example 2 GLP-1R agonist aerosol inhalation solution composition:
prescription: 1mg/mLGLP-1R agonist, 1.2mg/mL propylene glycol, 0.5mg/mL disodium edentate, 15mg/mL glucose, and pH value adjusted to 5.4 by citric acid, the balance being water for injection.
The preparation method comprises the following steps:
(1) Adding propylene glycol, disodium edentate and an osmotic pressure regulator into 80% of the solvent in unit dose volume according to the prescription amount to obtain a solution A, wherein the unit dose volume of the embodiment is 5mL;
(2) Adjusting the pH of the solution A to 5.4 by using citric acid to obtain a solution B;
(3) Adding GLP-1R agonist into the solution B based on the prescription amount, adding water to the unit dosage volume, and transferring to a medicine storage bin.
Example 3 GLP-1R agonist aerosol inhalation solution composition:
prescription: 10mg/mLGLP-1R agonist, 10mg/mL hydroxypropyl-beta-cyclodextrin, 0.1mg/mL glycerin, 5mg/mL sodium chloride, and the balance water for injection.
The preparation method comprises the following steps:
(1) Adding 80% of solvent in unit dose volume into hydroxypropyl-beta-cyclodextrin, glycerol and osmotic pressure regulator according to the prescription amount to obtain solution A, wherein the unit dose volume of the embodiment is 5mL;
(2) Adjusting the pH of the solution A to 5.4 by using phosphoric acid to obtain a solution B;
(3) Adding GLP-1R agonist into the solution B based on the prescription amount, adding water to the unit dosage volume, and transferring to a medicine storage bin.
Example 4 sodium metasedge aerosol inhalation solution composition:
prescription: 100mg/mL sodium sulfanilate, 0.1mg/mL tris (2-chloroethyl) phosphate, 8mg/mL calcium chloride, and the balance of water for injection, wherein the pH value is adjusted to 7.5 by sodium hydroxide and/or hydrochloric acid.
The preparation method comprises the following steps:
(1) Adding tris (2-chloroethyl) phosphate and an osmotic pressure regulator into 80% of the volume of a unit dose of a solvent based on the prescribed amount to obtain a solution A, wherein the volume of the unit dose of the embodiment is 5mL;
(2) Adjusting the pH of the solution A to 7.5 by using sodium hydroxide and/or hydrochloric acid to obtain a solution B;
(3) Adding sodium sulfanilamide into the solution B based on the prescription amount, adding water to the unit dosage volume, and transferring to a medicine storage bin.
Example 5 clemastine fumarate aerosol inhalation solution composition:
prescription: 10mg/mL of chloromatastine fumarate, 20mg/mL of propylene glycol, 5mg/mL of carbitol and 18mg/mL of sorbitol, and the pH value is adjusted to 5.0 by citric acid and/or sodium citrate, and the balance is water for injection.
The preparation method comprises the following steps:
(1) Adding propylene glycol, sorbitol and carbitol into 80% of the volume of the unit dose based on the prescription amount to obtain a solution A, wherein the volume of the unit dose of the embodiment is 2mL;
(2) Adjusting the pH value of the solution A to 5.0 by using citric acid and/or sodium citrate to obtain a solution B;
(3) And (3) adding the clemastine fumarate into the solution B according to the prescription amount, adding water to the unit dosage volume, and transferring to a medicine storage bin.
Example 6, lidocaine hydrochloride nebulized inhalation solution composition:
prescription: 20mg/mL lidocaine hydrochloride, 0.5mg/mL sodium metabisulfite, 9mg/mL sodium chloride, 1mg/mL methyl parahydroxybenzoate, and the balance of water for injection, wherein the pH value is adjusted to 6.5 by sodium hydroxide and/or hydrochloric acid.
The preparation method comprises the following steps:
(1) Adding sodium metabisulfite, an osmotic pressure regulator and a bacteriostatic agent into a solvent with the volume of 80% of the unit dose according to the prescription amount to obtain a solution A, wherein the volume of the unit dose of the embodiment is 10mL;
(2) Adjusting the pH of the solution A to 6.5 by using sodium hydroxide and/or hydrochloric acid to obtain a solution B;
(3) Adding lidocaine hydrochloride into the solution B according to the prescription amount, adding water to the unit dosage volume, and transferring to a medicine storage bin.
Example 7 lidocaine hydrochloride aerosol inhalation solution composition:
prescription: 100mg/mL lidocaine hydrochloride, 0.5mg/mL sodium bisulphite, 0.2mg/mL citric acid, 10mg/mL sodium chloride, and the balance of water for injection, wherein the pH value is adjusted to 6.5 by sodium hydroxide and/or hydrochloric acid.
The preparation method comprises the following steps:
(1) Adding sodium bisulphite, citric acid and an osmotic pressure regulator into a solvent with the volume of 80% of the unit dose according to the prescription amount to obtain a solution A, wherein the volume of the unit dose of the embodiment is 5mL;
(2) Adjusting the pH of the solution A to 6.5 by using sodium hydroxide and/or hydrochloric acid to obtain a solution B;
(3) Adding lidocaine hydrochloride into the solution B according to the prescription amount, adding water to the unit dosage volume, and transferring to a medicine storage bin.
Example 8, tetracaine hcl aerosol inhalation solution composition:
prescription: 30mg/mL lidocaine hydrochloride, 0.5mg/mL hydroxyethyl cellulose, 0.1mg/mL benzyl alcohol, 10mg/mL sodium chloride, and the balance of water for injection, wherein the pH value is adjusted to 6.0 by citric acid and/or sodium citrate.
The preparation method comprises the following steps:
(1) Adding hydroxyethyl cellulose, an osmotic pressure regulator and a bacteriostatic agent into a solvent with the volume of 80% of the unit dose by taking the prescription amount as a basis to obtain a solution A, wherein the volume of the unit dose of the embodiment is 2mL;
(2) Adjusting the pH value of the solution A to 6.0 by using citric acid and/or sodium citrate to obtain a solution B;
(3) And adding the tetracaine hydrochloride into the solution B according to the prescription amount, adding water to the unit dosage volume, and transferring to a medicine storage bin.
Example 9, articaine hydrochloride nebulized inhalation solution composition:
prescription: 40mg/mL of atecan hydrochloride, 0.5mg/mL of sodium metabisulfite and 1mg/mL of sodium chloride, and the pH value is regulated to 6.0 by hydrochloric acid, and the balance is water for injection.
The preparation method comprises the following steps:
(1) Adding sodium metabisulfite and an osmotic pressure regulator into 80% of the volume of a unit dose according to the prescription amount to obtain a solution A, wherein the volume of the unit dose of the embodiment is 2mL;
(2) Adjusting the pH of the solution A to 6.0 by using hydrochloric acid to obtain a solution B;
(3) Adding the atecan hydrochloride into the solution B according to the prescription amount, adding water to the unit dosage volume, and transferring to a medicine storage bin.
Example 10 bupivacaine hydrochloride aerosol inhalation solution composition:
prescription: 5mg/mL of bupivacaine hydrochloride, 0.5mg/mL of sodium metabisulfite, 0.001mg/mL of monothioglycerol, 2mg/mL of ascorbic acid and 1mg/mL of methylparaben, and adjusting the pH value to 5.0 by sodium hydroxide and/or hydrochloric acid, and the balance being water for injection.
The preparation method comprises the following steps:
(1) Adding sodium metabisulfite, monothioglycerol, ascorbic acid and a bacteriostatic agent into 80% of the solvent in unit dose volume according to the prescription amount to obtain a solution A, wherein the unit dose volume of the embodiment is 10mL;
(2) Adjusting the pH value of the solution A to 5.0 by using sodium hydroxide and/or hydrochloric acid to obtain a solution B;
(3) And adding bupivacaine hydrochloride into the solution B according to the prescription amount, adding water to the unit dosage volume, and transferring to a medicine storage bin.
Experimental example 11, aerodynamic Particle Size Distribution (APSD):
aerodynamic particle size distribution, also known as mist distribution. The detection can reflect the particle size distribution of the formed medicine aerosol in human body, and is beneficial to evaluating the safety and effectiveness of inhaled medicines in clinical application. Theoretically, the distribution proportion of the drug aerosol particles in the nasal cavity, the oral cavity, the pharyngeal portion and the lung can be determined by using the parameter, and the possible deposition position of the drug aerosol can be predicted. And is also an important parameter for controlling and evaluating the quality of the product.
The method is based on the following steps: the aerodynamic characteristics of the fine particles of the inhalation preparation are determined by reference to the general rule 0951 of the fourth edition of Chinese pharmacopoeia 2020.
The NGI is placed in an incubator with the temperature of 5+/-3 ℃ for at least 90 minutes; preheating compression atomizing suction machine. The NGI was assembled and connected to a leak detector, the pressure of the leak detector was set to 4KPa, and a leak rate test was initiated, with a pressure plateau of 60 seconds indicating good leak tightness of the device. The atomizing device, the NGI, the high-capacity vacuum pump and the critical flow control are connected in sequence from left to right; and then the air flowmeter is connected to detect the constant flow rate, and the high-capacity vacuum pump and the critical flow control are started and the knob is adjusted to stabilize the flow rate. The critical flow control time parameter is set to 305 seconds. 2.5mL of sample is added into the liquid storage bin, and the compression aerosol inhalation machine and the critical flow control 'RUN' key are simultaneously started. The compressed aerosol inhaler was turned off for 300 seconds, and after 5 seconds the high capacity vacuum pump and critical flow control were turned off. After the test process is finished, cleaning and transferring the artificial throat+adapter and 1-7 grade collecting tray (including the filter tray) parts respectively:
precisely weighing 20ml of water, respectively adding into a Stage1-Stage6 collecting tray, uniformly mixing, respectively precisely weighing 1ml of water, placing into a 10ml measuring flask, adding water, quantitatively diluting to scale, and shaking uniformly to obtain Stage1-Stage6 sample solution; precisely weighing 50ml of water, adding into a Stage7 collecting tray, and uniformly mixing to obtain a Stage7 sample solution; taking MOC-level filter paper, placing the filter paper into a beaker, precisely measuring 50ml of water, placing the filter paper into the beaker, extruding the filter paper by using a glass rod, uniformly stirring, filtering, and taking the subsequent filtrate as MOC sample solution; taking a orolaryngeal device, sealing one end, precisely measuring 50ml of water, placing in the orolaryngeal, and shaking uniformly to obtain a test sample solution of the orolaryngeal; and (3) cleaning an atomization cup with a proper amount of water, transferring to a 100ml measuring flask, adding water for quantitative dilution to a scale, shaking uniformly, precisely transferring to a 1 ml-10 ml measuring flask, adding water for quantitative dilution to the scale, and shaking uniformly to obtain a cup residual solution. And precisely measuring 10 mu L of each sample solution to be measured, respectively injecting into a liquid chromatograph, and recording a chromatogram. And (3) importing the measurement results of all stages of samples of the particle size distribution into CITDAs software one by one to obtain corresponding results of all indexes.
The aerodynamic particle size distribution of each example was tested using an NGI device and the results were as follows:
table 1: aerodynamic particle size distribution
| Sample of | FPD | FPF(％) | MMAD(μm) | GSD |
| Example 1 | 5.36μg | 68.547 | 7.562 | 1.699 |
| Example 2 | 88.05μg | 67.321 | 3.841 | 1.704 |
| Example 3 | 1.01mg | 59.683 | 4.128 | 1.923 |
| Example 4 | 10.53mg | 63.011 | 4.127 | 1.745 |
| Example 5 | 0.95mg | 60.28 | 4.231 | 1.968 |
| Example 6 | 1.98mg | 60.259 | 4.250 | 1.832 |
| Example 7 | 10.24mg | 66.317 | 6.681 | 1.865 |
| Example 8 | 2.89mg | 59.830 | 3.917 | 1.944 |
| Example 9 | 4.35mg | 57.632 | 4.518 | 1.861 |
| Example 10 | 0.52mg | 60.286 | 3.803 | 1.908 |
After the aerosol particles of the drug are inhaled, the deposition, dissolution, diffusion and other behaviors at various positions are different due to different properties (size and density). Large drug aerosol particles with the particle size of 5-10 mu m are mostly deposited on the mucous membrane of the upper respiratory tract, and aerosol particles with the particle size of less than 5 mu m can reach the lung, so that the effect is rapid, and the adverse reaction of the whole body is less. Examples 1-10 all showed a fine ion fraction (FPF) of greater than 50% after aerosol inhalation administration, indicating that the device of the present invention produced a drug dose that meets the clinical requirements. Aerodynamic particle size MMAD of examples 1 and 7 is 5-10 μm and drug is deposited mainly in the oropharynx, and can be targeted to focus for therapeutic purposes. While other embodiments have aerodynamic particle sizes MMAD of less than 5 μm, facilitating drug deposition into the lungs, and more facilitating rapid absorption for systemic effects.
Example 12, delivery rate and total delivered amount evaluation:
the total amount delivered refers to the mass or volume of drug released by a prescribed volume of drug solution through an aerosolization system, which is converted to a percentage of the total amount of aerosolized drug solution, which provides guidance for the patient's intended dosage. The delivery rate refers to the mass or volume of drug released by the nebulization system per unit time of a prescribed volume of drug solution, which is converted to a percentage of the total amount of nebulized drug solution, which can determine the desired treatment time of the patient. The rate of delivery and the total amount of delivery may reflect the rate of drug onset and the total amount of drug that a patient may inhale, as well as important parameters for controlling and assessing product quality. The detection method and device are to consider the atomizer and the atomized liquid as a whole, and only examine the drug delivery rate and the total delivery amount inhaled by the breathing mode of an adult, except for other regulations, but when the drug is used for a neonate, an infant or a child, the corresponding breathing mode must be selected for detection.
Table 2: different breathing characteristics of breathing simulator
Adult, pediatric, infant breathing patterns were selected to examine drug delivery rate versus total delivered. A breathing simulator and a filter paper device with filter paper are installed. The samples of examples 1-10 were added to the reservoir and the drug outlet of the device of the invention was connected to the adapter and filter paper device and the breathing simulator was set to the breathing rate of each mode. Starting the breathing simulator, setting the time of the first stage to be 1min, setting different times according to the volume of the sample in other stages, starting the device according to the invention at the beginning of the breathing cycle, and simultaneously closing the device according to the invention at the end of the breathing cycle. The filter paper, the filter paper device and the medicine contained in the adapter are cleaned and recycled to be used as the sample solution of each stage. The amount of active material collected by the first stage filter paper is the delivery rate compared to the collection time, and the sum of the amounts of active material collected by all filter papers and filter paper devices is the total amount delivered. The drug delivery rate and total amount delivered for adult, pediatric, and infant respiratory modes results are as follows:
table 3: drug delivery effect-adult mode
Table 4: drug delivery effect-childhood pattern
Table 5: drug delivery effect-infant mode
Example 13 pharmacokinetic comparison study of different modes of administration:
the present invention delivers drugs in aerosolized form to the respiratory tract and/or lungs via specific devices to exert local or systemic effects. Compared with the common nasal spray, most of aerosol generated by atomization has the particle size MMAD smaller than 10 mu m, which is more beneficial to the in-vivo diffusion, deposition and absorption of the aerosol; compared with the common oral preparation, the medicine of the inhalation preparation can directly reach the absorption or action part, has quick absorption or action, can avoid the first pass effect of the liver and reduce the dosage; compared with injection preparations, the compliance of patients can be improved, and meanwhile, adverse reactions of partial medicaments can be reduced or avoided. The commercially available formulations of example 1, example 2, example 4, example 6 and the respective different modes of administration were selected to examine the differences between the different modes of administration.
The specific experimental process comprises the following steps:
(1) Animal administration: several male SD rats for experiments, ranging from 180 to 200g in weight, were randomly grouped by weight, and 12 rats per group. Administration was as required in table 6.
Table 6: rat administration procedure
(2) Sampling operation: blood was drawn from the jugular vein of the rats by catheterization 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 480, 720min after administration, respectively. The blood samples were placed in heparinized centrifuge tubes and immediately centrifuged at 3000rpm for 15min at 4℃to obtain 50. Mu.L of plasma samples, which were stored at-20 ℃. To 50. Mu.L of the plasma sample, 10. Mu.L of an internal standard working solution (1000 ng/mL) was added, the sample was vortexed and mixed for 30s, extracted with 1.5mL of ethyl acetate vortexed for 5min, centrifuged at 12000rpm for 10min, the upper organic phase was transferred to another tube, dried under a gentle stream of nitrogen, the residue was redissolved with 200. Mu.L of methanol, vortexed and mixed for 3min, centrifuged at 12000rpm for 10min, and the supernatant was taken for LC-MS/MS measurement. The results are shown in Table 7.
Table 7: pharmacokinetic parameters of different modes of administration in rats
As can be seen from Table 7, the plasma concentrations of the drugs in example 1 and example 2 are significantly higher than those in the same commercial products, and the Tmax is within 20 minutes, so that the onset time of atomization administration is significantly faster than that of ordinary nasal spray administration and oral administration; area under the curve at time of Administration (AUC) 0-t ) The aerosol is also obviously higher than the common nasal spray administration and oral administration, which shows that the aerosol of the device can be rapidly absorbed by the organism. Example 4 and example 6 compared with the corresponding commercially available injections, the blood concentration was close to that of the administration by injection, but the mean residence time in the body (MR T0-t ) But far higher than injection administration, which indicates that the drug can be maintained in the body for a longer time and the administration interval can be prolonged. The bioavailability in each group of examples is far higher than that of common nasal spray administration and oral administration, and is equivalent to injection administration.
Example 14: referring to the structure for applying an acetylcholinergic receptor agonist, a GLP-1R agonist, a muscle relaxant antagonist, an antihistamine or a local anesthetic shown in fig. 1, 2 and 3, the structure comprises an atomization bin 1, a medicine storage cavity 3 is arranged on the inner side of the atomization bin 1, a medicine solution 4 capable of being subjected to atomization operation and an atomization core 10 capable of heating and atomizing the medicine solution 4 are arranged on the inner side of the medicine storage cavity 3, a sealing seat 9 is arranged on the surface of the atomization core 10, and the sealing seat 9 is in butt joint with an opening at the rear end of the medicine storage cavity 3. The heating and atomizing operation is carried out by the drug solution 4, and a therapeutic scheme of aerosol delivery of the drug is adopted.
The device also comprises a shell 2 arranged at the rear of the atomization bin 1, an air inlet 22 is formed in the rear end face of the shell 2, a miniature air pump 5 is arranged at the rear end of the shell 2, an air outlet pipe of the miniature air pump 5 is in butt joint with the air inlet 22, and air formed after the medicine solution 4 is atomized can be discharged. In the process, the patient does not need to repeatedly suck the air flow into the nasal cavity, the automatic nasal cavity suction device has the advantages of being automatic, reducing the discomfort of the nasal cavity of the patient in the long-term suction process, and the air flow containing chemical components can be quickly and accurately input into the nasal cavity of the patient, so that the application efficiency is improved.
The opposite ends of the atomization bin 1 and the shell 2 are connected through a control shell 8, the front end of the atomization bin 1 is detachably connected with a medicine outlet 6, the front end of the medicine outlet 6 extends forwards to form a medicine guide tube 7 which is adapted to the nasal cavity of a patient, and in the use process, the medicine guide tube 7 is close to the lower part of the nasal cavity of the patient, and the surface of the medicine guide tube 7 transversely penetrates through an adjusting tube 11 which is communicated with the inner cavity of the medicine guide tube.
As shown in fig. 2, a circuit board 81 is mounted on the inner side of the control housing 8, and an air switch is provided on the surface of the circuit board 81, and the air switch can be triggered by the air flow inputted from the inner side of the air inlet 22. The air switch is turned on. The circuit board 81 operates, in the process, the patient does not need to repeatedly suck to form the airflow triggering the air switch, the discomfort of the nasal cavity in the long-term sucking process of the patient is reduced, the stability of airflow output in the continuous operation process of the whole medicine application equipment is ensured, and the medicine application device has the advantages of high efficiency and portability.
As shown in fig. 4, the circuit board 81 is connected with a heating seat 82 positioned in front of the circuit board through a circuit, the heating seat 82 can be controlled to be electrified for heating, the atomizing core 10 is arranged on the surface of the heating seat 82, heat transfer can be realized, after the atomizing core 10 is rapidly heated, the medicine solution 4 can be evaporated, gas containing an acetylcholinergic receptor agonist, a GLP-1R agonist, a muscle relaxant antagonist, an antihistamine or a local anesthetic chemical component is generated, and the gas is discharged through the medicine guide tube 7.
As shown in fig. 4, a storage battery 21 is installed in the inner cavity of the casing 2, and the storage battery 21 is connected with the circuit board 81 through a circuit to supply electric energy for the operation of the circuit board 81. The battery 21 can be externally connected with a power supply to perform charging operation, and after the circuit board 81 is electrified, the heating seat 82 can be controlled to be electrified and heated, and heat is transferred to the heating core.
As shown in fig. 5 and 6, the outer surface of the adjusting tube 11 is relatively provided with a diffusion hole group 111 and a focusing hole 112, the diffusion hole group 111 is formed by a plurality of small diffusion holes distributed in an annular structure, the aperture of a port of the focusing hole 112 on the outer wall of the adjusting tube 11 is smaller than that of a port of the adjusting tube 11 on the inner wall of the adjusting tube 11, when the adjusting tube 11 rotates to switch positions, if the diffusion hole group 111 is opposite to the air flow outlet of the medicine guide tube 7, when the air flow overflows through the medicine guide tube 7, the diffusion hole group 111 can drive the air flow to overflow uniformly and dispersedly.
When the focusing hole 112 is opposite to the air flow outlet of the medicine guide tube 7, the air flow can be discharged in a centralized manner in the process of overflowing through the focusing hole 112, and the air flow can be suitable for nasal cavity forms of different patients by switching different air flow discharging modes, so that the air flow can be conveniently regulated according to the use habit of the patients, is suitable for different patient groups, and the two ends of the regulating tube 11 are respectively provided with the sealing plugs 12, so that the air flow can be prevented from overflowing, and the air flow can be ensured to be rapidly and comprehensively discharged through the medicine guide tube 7.
As shown in fig. 5 and 6, a positioning rod 13 is arranged at the inner side of the adjusting tube 11, a filter screen 14 is fixedly connected to the surface of the positioning rod 13, the filter screen 14 is opposite to the medicine guide tube 7, when the adjusting tube 11 rotates to switch positions, the filter screen 14 is always positioned at the opposite sides of the diffusion holes 111 and the focusing holes 112 which are distributed up and down, the filter screen 14 can prevent impurities in the nasal cavity of a patient from falling into the medicine outlet 6, and the cleanliness in the medicine outlet 6 is ensured. Both ends of the positioning rod 13 penetrate through the sealing plug 12, and both ends of the positioning rod 13 are connected with the stop blocks 15 in a threaded manner, when the adjusting tube 11 is detached from the medicine guide tube 7, the sealing plug 12 and the stop blocks 15 can be detached, and cleaning operation is carried out on the filter screen 14 and the adjusting tube 11, so that the portable operation is advantageous.
As shown in fig. 2, a detachable liquid guide tube 31 is arranged on the side surface of the medicine storage cavity 3, a thread sleeve matched with the thread of the liquid guide tube 31 is arranged on the side surface of the atomization bin 1, the liquid guide tube 31 is of an L-shaped structure, the top end of the liquid guide tube 31 is in threaded connection with a cover body 32, the cover body 32 is opened, medicine solution 4 is injected into the medicine storage cavity 3 through the liquid guide tube 31, and the adding operation of medicine liquid is completed, so that the medicine application structure can be used for a long time.
Finally, it should be noted that: the foregoing description of the preferred embodiments of the present invention is not intended to be limiting, but rather, although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments described, or equivalents may be substituted for elements thereof, and any modifications, equivalents, improvements or changes may be made without departing from the spirit and principles of the present invention.
Claims (10)
1. A method of administering respiratory drug delivery, comprising: the method comprises the following steps:
s1: performing a drug application operation on the drug application structure, preparing a solution of an acetylcholinergic receptor agonist, a GLP-1R agonist, a muscle relaxant antagonist, an antihistamine or a local anesthetic, and adding the solution to the drug application structure;
s2: the administration structure is characterized in that an acetylcholinergic receptor agonist, a GLP-1R agonist, a muscle relaxant antagonist, an antihistamine or a local anesthetic solution is prepared into aerosol containing chemical components of the acetylcholinergic receptor agonist, the GLP-1R agonist, the muscle relaxant antagonist, the antihistamine or the local anesthetic, wherein the administration structure adopts an electronic atomization mode;
s3: the delivery structure delivers an aerosol containing an acetylcholinergic receptor agonist, a GLP-1R agonist, a muscle relaxant antagonist, an antihistamine or a local anesthetic chemical component into the respiratory system of a patient.
2. A method of administering respiratory drug according to claim 1, wherein: the acetylcholinergic receptor agonist refers to valicarb and tartrate thereof, the GLP-1R agonist refers to Orforglipirn, the muscle relaxant antagonist is sugamboge and sodium salt thereof, the antihistamine is chloromatastin and fumarate thereof, and the local anesthetics comprise local anesthetics such as lidocaine, tetracaine, ateocaine, bupivacaine and the like and respective salts thereof.
3. A method of administering respiratory drug according to any one of claims 1 to 2, wherein: the acetylcholinergic receptor agonist is used for treating xerophthalmia, the GLP-1R agonist is used for treating obesity or diabetes or Alzheimer's disease or nonalcoholic steatohepatitis, the muscle relaxant antagonist is used for antagonizing rocuronium bromide or vecuronium bromide-induced neuromuscular blocking, the antihistamine is used for treating various allergic diseases induced by histamine, and the local anesthetic is used for temporarily blocking the sensory nerve conduction function of a local body part under the condition that a patient is conscious.
4. A method of administering respiratory drug according to any one of claims 1 to 2, wherein: the dosage of the acetylcholinergic receptor agonist is 0.03-0.12 mg/d, the dosage of the GLP-1R agonist is 10-100 mg/d, the dosage of the muscle relaxant antagonist is 2-4 mg/kg/d, the dosage of the antihistamine is 1-4 mg/d, and the dosage of the local anesthetic is 20-300 mg/d.
5. A method of administering respiratory drug according to claim 1, wherein: the aerosol containing the chemical component of the acetylcholinergic receptor agonist, GLP-1R agonist, myorelaxant antagonist, antihistamine or local anesthetic all have a fine particle fraction of greater than 50% upon expulsion through the delivery structure.
6. A method of administering respiratory drug according to claim 1, wherein: the aerosols containing the chemical component of the acetylcholinergic receptor agonist, GLP-1R agonist, myorelaxant antagonist, antihistamine or local anesthetic each have a mass median aerodynamic particle size of less than 10 μm upon expulsion through the delivery structure.
7. The utility model provides a structure of dosing of respiratory system, including atomizing storehouse (1), its characterized in that: the medicine storage device is characterized in that a medicine storage cavity (3) is arranged on the inner side of the atomization bin (1), medicine solution (4) capable of being subjected to atomization operation and an atomization core (10) capable of heating and atomizing the medicine solution (4) are loaded on the inner side of the medicine storage cavity (3), a sealing seat (9) is arranged on the surface of the atomization core (10), and the sealing seat (9) is in butt joint with an opening at the rear end of the Chu Yaoqiang (3);
the device also comprises a shell (2) arranged at the rear of the atomization bin (1), wherein an air inlet (22) is formed in the rear end face of the shell (2), a micro air pump (5) is arranged at the rear end of the shell (2), an air outlet pipe of the micro air pump (5) is in butt joint with the air inlet (22), and air formed after the atomization of the medicine solution (4) can be driven to be discharged;
the opposite ends of the atomization bin (1) and the shell (2) are connected through the control shell (8), the front end of the atomization bin (1) is detachably connected with the medicine outlet (6), the front end of the medicine outlet (6) extends forwards to form a medicine guide tube (7) which is adapted to the nasal cavity of a patient, and the surface of the medicine guide tube (7) transversely penetrates through an adjusting tube (11) which is communicated with the inner cavity of the medicine guide tube.
8. A respiratory delivery structure according to claim 7, wherein: the circuit board (81) is installed to the inboard of control shell (8), the surface of circuit board (81) is provided with air switch, air switch can be triggered by the inboard air input of air inlet (22), circuit board (81) are connected with through the circuit and are located heating seat (82) in its place ahead, steerable heating seat (82) circular telegram heats, atomizing core (10) are installed in heating seat (82) surface, can realize heat transfer, and to medicine solution (4) heating atomizing, battery (21) are installed to casing (2) inner chamber, battery (21) are connected through the circuit with circuit board (81), provide the electric energy for the operation of circuit board (81).
9. A respiratory delivery structure according to claim 7, wherein: the utility model discloses a medicine guide tube, including regulation pipe (11), diffusion hole group (111) and focus hole (112) have been seted up relatively to regulation pipe (11) surface, diffusion hole group (111) comprise a plurality of little diffusion holes that are annular structure and distribute, focus hole (112) are located the port aperture of regulation pipe (11) outer wall and are less than the port aperture that is located regulation pipe (11) inner wall, both ends of regulation pipe (11) all are provided with sealing plug (12), regulation pipe (11) inboard is provided with locating lever (13), the fixed surface of locating lever (13) is connected with filter screen (14), filter screen (14) are just to medicine guide tube (7), works as when regulation pipe (11) rotate the switching position, filter screen (14) are located diffusion hole (111) of upper and lower distribution all the time, the opposite side of focus hole (112), both ends of locating lever (13) all run through in sealing plug (12), and the both ends of locating lever (13) all threaded connection has dog (15).
10. A respiratory delivery structure according to claim 7, wherein: the side of medicine storage chamber (3) is provided with detachable catheter (31), the thread bush with catheter (31) screw thread adaptation has been seted up to the side of atomizing storehouse (1), catheter (31) are L column structure, and the top threaded connection of catheter (31) has lid (32).
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