CN115598311A - Inhalation preparation pharmacokinetic evaluation platform and method thereof - Google Patents
Inhalation preparation pharmacokinetic evaluation platform and method thereof Download PDFInfo
- Publication number
- CN115598311A CN115598311A CN202211453021.XA CN202211453021A CN115598311A CN 115598311 A CN115598311 A CN 115598311A CN 202211453021 A CN202211453021 A CN 202211453021A CN 115598311 A CN115598311 A CN 115598311A
- Authority
- CN
- China
- Prior art keywords
- administration
- preparation
- inhalation
- aerosol
- concentration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume, or surface-area of porous materials
- G01N15/02—Investigating particle size or size distribution
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume, or surface-area of porous materials
- G01N15/06—Investigating concentration of particle suspensions
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
Abstract
The invention discloses an inhalation preparation in-vivo and in-vitro pharmacokinetic evaluation platform and a method thereof, wherein an experimental animal model, an atomized preparation administration device, an atomized preparation detection system, a sample collection and analysis system and a pharmacokinetic analysis system are jointly applied, the inhalation preparation is subjected to preclinical pharmacokinetic experimental study by using a technical platform, and main pharmacokinetic parameters are calculated by using a non-compartmental model statistical moment method to evaluate the metabolism and distribution condition of the inhalation preparation in vivo. The invention provides a definite and effective consensus evaluation platform for the research and development of inhalation preparations, and the pharmacokinetic evaluation method disclosed by the invention is professional and reliable, low in cost, strong in specificity and high in accuracy.
Description
Technical Field
The invention belongs to the field of preclinical research of an inhalation preparation, and particularly relates to an inhalation preparation pharmacokinetic evaluation platform and an inhalation preparation pharmacokinetic evaluation method.
Background
With the exacerbation of air pollution and aging of population and the increase of respiratory diseases, more institutions have begun to comprehensively arrange the therapeutic fields of inhalation preparations, nasal sprays and the like. In China, respiratory disease is the third largest chronic disease next to cardiovascular and diabetes, with a large base of patients with asthma and Chronic Obstructive Pulmonary Disease (COPD). Inhalation formulations have the advantage that other modes of administration cannot be substituted in the control of respiratory diseases and are recognized as the primary mode of treatment for asthma and chronic obstructive pulmonary disease. The guidance documents such as GINA global initiative for asthma prevention and treatment, GOLD global initiative for chronic obstructive pulmonary disease, and the like, all list inhalation therapy as the first choice therapy for bronchial asthma and COPD.
The effectiveness of an inhalation formulation depends not only on the amount of drug deposited in the lungs, but also on whether the drug reaches the lungs and the particle size of the drug. The detection of the particle size and the particle size distribution is very important in inhalation toxicity tests, the requirement of inhalation on the particle size of generated aerosol is very strict, the excessive or insufficient particle size does not meet the requirement, and the particle size is usually required to be controlled between 2 and 5 micrometers so as to be well absorbed by the lung. Different types of inhalation formulations have their own advantages and disadvantages, but a consensus has developed in the development of inhalation formulations that the efficacy of pulmonary inhalation depends on the co-action of the drug and the device.
The safety and effectiveness of inhaled formulations are influenced by many factors such as drug aerodynamics, particle size, propellant, device, etc., and imitation of marketed formulations, formulation changes, propellant changes may affect drug absorption and drug deposition in the lung. Currently, many inhalation preparations need to be subjected to non-clinical evaluation, but due to the insufficient corresponding research capability of the industry, a drug research and development organization needs to wait for the stage of research, so that the research and development progress of the drugs is greatly delayed, and the requirement for meeting the accessibility of the drugs is influenced. The preparation of the inhalation preparation is special and has strong medicinal activity, and directly acts on the lung with systemic absorption, so the safety of the lung and the system after exposure needs to be evaluated. Conventional safety assessment techniques do not completely address all safety concerns of inhaled formulations.
Due to the particularity of inhaled medicaments, oral medicaments, intravenous medicaments and the like can be prepared in advance for administration, the concentration, the particle size and the particle size distribution of the aerosol of the inhaled medicaments fluctuate in the aerosol generation process, so that the dose and the particle size need to be fully measured, the aerosol concentration is periodically detected in the administration process of animals to obtain the administration dose, the frequency of periodically detecting the aerosol concentration is very high in one administration period, and a more effective detection and quality control method does not exist at present.
The detection of the particle size and the particle size distribution of the inhalation preparation is very important in inhalation administration tests, the requirement of inhalation administration on the particle size of generated aerosol is very strict, the particle size which is too large or too small does not meet the requirement, the particle size is usually controlled between 1 to 4 micrometers to be well absorbed by the lung, and the reasonable inhalation preparation administration device and the administration mode have very important influence on the pharmacokinetics metabolism. At present, different animal models and effective pharmacokinetic evaluation platforms and methods are not established yet.
Disclosure of Invention
Aiming at the problems in the prior art, the invention jointly applies an experimental animal model, an atomized preparation administration device, an atomized preparation detection system, a sample collection and detection system and a pharmacokinetic analysis system, establishes an inhaled preparation pharmacokinetic evaluation platform, can solve the problems of consistency and effectiveness of inhaled preparation clinical prodrug metabolism research, and provides an evaluation platform which is clear and effective in consensus for the research and development of inhaled preparations.
The invention also aims to provide an evaluation method of the inhalation preparation pharmacokinetic evaluation platform, which is professional and reliable and has high accuracy.
In order to achieve the purpose, the invention adopts the following technical scheme:
an inhalation preparation pharmacokinetics evaluation platform comprises an experimental animal model, an atomized preparation dosing device, an atomized preparation detection system, a sample collection and detection system and a pharmacokinetics analysis system;
the experimental animal model is an experimental animal model which is established based on a physiological similarity or approximation principle and is based on a rat, a dog or a monkey;
the aerosol preparation administration device is an oral-nasal exposure inhalation administration device;
the atomized preparation detection system comprises an aerosol concentration detection system, a particle size and distribution detection analysis system and an ambient air monitoring system;
the sample collection and detection system can perform quantitative blood drawing on the experimental animal according to preset collection time, and perform blood concentration detection by an LC-MS/MS analysis method;
the pharmacokinetic analysis system performs pharmacokinetic parameter analysis by a non-compartmental model statistical moment method.
An evaluation method of the evaluation platform comprises the following steps:
s1, preparation of a dosing preparation: weighing an inhalation preparation to be analyzed, adding physiological saline to prepare an administration preparation group with the concentration of 0.1-3mg/mL, and taking the physiological saline with the same volume as a blank group;
s2, construction of an experimental animal model: constructing a small animal experiment model by using a rat, constructing a large animal experiment model by using a dog or a monkey, wherein the experimental animals are male and female, provide 12 hours of sunlight irradiation every day, and monitor and control the environmental temperature range to be 18-26 ℃ and the relative humidity range to be 40-70%;
s3, inhalation preparation administration: the medicine is inhaled by an atomized preparation administration device according to a set speed, the administration time of large animals is 100min, the administration time of small animals is 4-40min, the administration concentration of each group is 0.8-1.2mg/ml, and the administration dosage is 100ug/kg according to the weight of experimental animals;
s4, detection of an inhalation preparation: monitoring the concentration of the aerosol, sampling the aerosol after the concentration is stabilized in real time, and detecting the particle size and distribution of the aerosol;
s5, sample collection and detection: quantitatively drawing blood from the experimental animal according to preset collection time, preparing a plasma sample to be detected, and detecting the blood concentration by an LC-MS/MS analysis method;
s6, pharmacokinetic analysis: after the plasma concentration data is processed, pharmacokinetic parameter analysis is carried out by a non-atrioventricular model statistical moment method.
Further, the dosing rate of step S3 is set to: generating aerosol of the small animals for 15L/min, diluting for 0L/min, exhausting for 16L/min, and automatically adjusting the flow of the exhausted air by the administration device; the aerosol of the large animals generates 40L/min, the dilution is 0L/min, the air exhaust is 42L/min, and the air exhaust flow is automatically adjusted by the drug administration device.
Further, the aerosol sampling method in step S4 includes: sampling is carried out twice, each sampling time is 10min, the interval between the two sampling times is more than 10min, and the sampling flow is 2L/min.
Further, the aerosol particle size and distribution detection method in step S4 is: during the aerosol generation period, the particle size and the particle size distribution were measured 1 time.
Further, step S4 includes ambient air monitoring and control: the oxygen concentration range is monitored and controlled in real time to be 19-22%, the temperature range is 18-26 ℃, the carbon dioxide concentration is less than 1%, and the relative humidity range is 30-70%.
Further, the collection time of the large animal sample in step S5 is 12 collection time points: before administration, 30min, 60min, 100min, 130min, 3h, 4h, 6h, 8h, 10h, 12h and 24h after inhalation administration; the small animal sample collection time was 12 collection time points: pre-dose, 0.033h, 0.083h, 0.167h, 0.333h, 0.667h, 1h, 2h, 4h, 8h, 10h and 24h after the start of inhaled administration.
Further, the blood concentration data processing method in step S6 is: for feedingPre-drug plasma concentration data was calculated as "0", post-drug T max Previous concentration data below the quantitative Down line (BLQ) was calculated as "0", T max The subsequent BLQ concentration data did not participate in the calculation.
Further, step S6 was conducted to calculate pharmacokinetic parameters by using the non-compartmental statistical moment method of Phoenix WinNonLin 7.0 software.
Further, the pharmacokinetic parameters of step S6 include C max 、T max 、AUC (0-t) 、AUC (0-∞) 、T 1/2 、Cl、Vd、MRT (0-t) And MRT (0-∞) 。
Compared with the prior art, the invention has the following beneficial effects:
the evaluation platform and the method for pharmacokinetics of the inhalation preparation provided by the invention are professional and reliable, have low analysis cost, strong specificity and high accuracy, and are suitable for in vivo and in vitro evaluation of innovative drugs of the inhalation preparation class;
the platform and the method for evaluating the pharmacokinetics of the inhalation preparation can effectively detect and control the concentration and the particle size of aerosol in the administration period of the inhalation preparation aiming at the particularity of the inhalation preparation, thereby obtaining accurate administration dosage of the inhalation preparation and controllable particle size of the aerosol of the inhalation preparation.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention and not to limit the invention.
FIG. 1 is a schematic representation of a pharmacokinetic evaluation platform of an inhaled formulation according to the invention;
FIG. 2 is a flow chart of the method for evaluating the pharmacokinetics of the inhalation formulation of the present invention;
FIG. 3 is a graph of mean plasma concentration versus time for SD rats at various time points;
fig. 4 is a graph of mean plasma concentration versus time for beagle dogs at various time points.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below with reference to the specific embodiments of the present invention.
The reagents or instruments used in the examples of the present invention are not indicated by manufacturers, and are all conventional reagent products commercially available from commercial sources.
Example (b):
referring to fig. 1, the pharmacokinetic evaluation platform for an inhaled formulation of the present invention includes an experimental animal model, an atomized formulation administration device, an atomized formulation detection system, a sample collection and detection system, and a pharmacokinetic analysis system;
the experimental animal model is an experimental animal model which is established based on a physiological similarity or approximation principle and is based on rats, dogs or monkeys;
the atomized preparation administration device is an oral-nasal exposure inhalation administration device;
the atomized preparation detection system comprises an aerosol concentration detection system, a particle size and distribution detection analysis system and an ambient air monitoring system;
the sample collection and detection system can perform quantitative blood drawing on the experimental animal according to preset collection time and perform blood concentration detection by an LC-MS/MS analysis method;
the pharmacokinetic analysis system performs pharmacokinetic parameter analysis by a non-compartmental model statistical moment method.
1. The method, as shown in FIG. 2.
1.1 formulation of the administration preparation
The administration preparation is used as the preparation at present, and the preparation method comprises the following steps:
group 1: accurately weighing 110mg of inhalation preparation, placing the inhalation preparation in a proper container, adding normal saline, fixing the volume to 110mL, and performing vortex oscillation and uniform mixing to obtain a 1mg/mL administration preparation group;
group 2: and (5) diluting normal saline to 110mL, and performing vortex shaking and uniform mixing to obtain the blank group.
1.2 Establishment of experimental animal model
(1) Experimental model of small animal: SD rats with week age of 6-10 weeks, body weight range of 160-300g, 4-12 male and female, wherein 1-3 male and 1-3 female are used for experiment; breeding 1 mouse in a big mouse breeding cage and a small mouse breeding cage; providing approximately 12 hours of solar radiation per day; dark time may be intermittently interrupted due to the need to study related activities; monitoring the ambient temperature and relative humidity of the animal house at 20-26 deg.C and 40-70% every day;
(2) Large animal experiment model: beagle dogs, age 6-12 months, weight 5-12kg, 4-8 male and female, wherein 1-3 male and 1-3 female experiments are reserved; breeding in stainless steel moving cages, wherein each cage is provided with 1 cage; providing light for about 12 hours per day; dark time may be intermittently interrupted due to the need to study related activities; the temperature and relative humidity of the animal room environment were monitored daily and controlled at 18-26 deg.C and 40-70%.
It should be noted that, in step 1.2 (2), the large animal experimental model may also be: the cynomolgus monkey is 36-54 months old, the weight range is 2.5-5kg, the male and female are 2-8 respectively, wherein 1 male and 1 female are reserved for experiments; breeding in stainless steel moving cages, wherein each cage is provided with 1 cage; providing light for about 12 hours per day; dark time may be intermittently interrupted due to the need to study related activities; the temperature and relative humidity of the animal room environment were monitored daily and controlled at 18-26 deg.C and 40-70%.
1.3 Administration of inhalation formulations
The administration route is inhalation administration, and the animal is fixed on an inhalation tower by using an animal mouth and nose fixer, and the administration preparation is subjected to aerosol generation inhalation administration by using a liquid generation device. Wherein SD rat selects small animal oral and nasal inhalation exposure system, beagle dog or cynomolgus monkey selects large animal oral and nasal exposure system;
(1) Oronasal exposure inhalation administration device: the air compressor compresses air or oxygen, and the gas phase passes through the fine nozzle from the air outlet in a high-speed airflow; according to the Venturi effect, negative pressure is generated around the nozzle, the liquid medicine in the liquid storage tank is carried to be entrained into high-speed airflow and is crushed into fog drops with different sizes, wherein more than 99% of the fog drops are formed by large-particle fog drops, the fog drops fall back into the liquid storage tank through the interception and collision of the nozzle to re-atomize the remaining fine fog particles, aerosol-state liquid medicine particles are formed in the air and are ejected at high speed, the particle spectrum diameter is about 5 mu m, and the particle size is stable;
(2) Inhalation dosing rate settings: the aerosol of the large animals generates 40L/min, the dilution is 0L/min, the air exhaust is 42L/min, and the air exhaust flow is automatically adjusted by the drug delivery device; generating aerosol of the small animals for 15L/min, diluting for 0L/min, exhausting for 16L/min, and automatically adjusting the flow of the exhausted air by the administration device;
(3) Administration concentration and time: the oral and nasal exposure is carried out by inhalation, the administration time of large animals is 100min, the administration time of small animals is 4-40min, the administration concentration of each group is 1mg/ml, the dose is 100ug/kg, and the actual administration dose is calculated according to the weight of animals.
1.4 Inhalation formulation testing
(1) Aerosol sampling: sampling by using a porous glass plate, injecting 10mL of physiological saline into the porous glass plate, sampling twice after the concentration of a real-time mass concentration monitor is displayed stably, wherein each sampling time is 10min, the sampling time interval is more than 10min, and the sampling flow is 2L/min; sampling and analyzing, wherein the concentration after analysis is within +/-20% of the average value;
(2) And (3) particle size detection: particle size detection is carried out for 1 time during aerosol generation, and a new generation of medicinal impactor CopleymodeL170, new Partack HELOS and a particle size monitoring and analyzing system are adopted to respectively detect the particle size and the particle size distribution;
(3) Monitoring and controlling ambient air; the oxygen concentration is controlled between 19 percent and 22 percent; the concentration of carbon dioxide is less than 1%; controlling the temperature to be 18-26 ℃; the relative humidity is 30-70%;
the experimental conditions and particle size results of the oral-nasal exposure of SD rats and beagle dogs are shown in the following tables 1 and 2 respectively.
TABLE 1 SD rat oronasal Exposure Experimental conditions and corresponding particle size parameters
TABLE 2 beagle oral nasal exposure conditions and corresponding particle size parameters
1.5 Sample collection and detection
(1) The large animal sample collection time was 12 collection time points: before administration, 30min, 60min, 100min (end of administration), 110min, 130min, 3h, 4h, 6h, 8h, 10h and 24h after the start of inhalation administration; the small animal sample collection time was 12 collection time points: before administration, 0.033h, 0.083h, 0.167h, 0.333h, 0.667h, 1h, 2h, 4h, 8h, 10h and 24h after the start of inhalation administration;
(2) Sample collection mode and treatment: all experimental animals were bled by jugular vein or other suitable venipuncture, about 1mL each time, placed in K2EDTA anticoagulation tube, added with 50uL of 500mM citric acid aqueous solution, whole blood: the volume ratio of 500mM citric acid aqueous solution is 20. Placing the collected whole blood sample into a marked centrifugal tube, placing the centrifugal tube on ice, transferring the sample to a sample centrifugal chamber, and centrifugally separating plasma within 1 hour, wherein the centrifugal condition is 2200g,10 minutes and 2-8 ℃, and the plasma sample is temporarily stored in an ultra-low temperature refrigerator before analysis;
(3) LC-MS/MS analysis, determining the concentration of the inhalation preparation in each group of samples, and the experimental conditions are as follows:
(1) a chromatographic column: octadecylsilane chemically bonded silica gel column with specification of 25cm × 4.6mm,5 μm;
(2) mobile phase: ph2.5, volume ratio of 0.2% triethylamine and acetonitrile 80, flow rate: 0.8mL/min, detection wavelength: 237nm;
(3) diluting the solvent: the volume ratio of the 0.05% phosphoric acid solution to the acetonitrile is 90;
(4) preparation of control solutions: weighing 5-20.00mg of Tiger ammonium bromide, dissolving with a diluent solvent, metering to 100mL, and shaking up;
(5) standard curve series solutions: precisely measuring a proper amount of a reference solution, diluting the reference solution with a diluting solvent to prepare a series of solutions containing 250ng, 100ng, 50ng, 25ng, 10ng and 5ng per 1mL, precisely measuring 20 mu L of each linear solution, respectively injecting the linear solutions into a liquid chromatograph, recording a chromatogram, and performing linear regression by taking the concentration as an abscissa (X) and the peak area as an ordinate (Y);
(6) and (3) sample determination: and (3) immediately adding 200 mu L of internal standard working solution into 50 mu L of sample, supplementing acetonitrile with the same volume into blank, carrying out vortex mixing, centrifuging for 7 minutes at 18000g, taking 180 mu L of supernatant into a corresponding 96-hole sample inlet plate, adding 40 mu L of ultrapure water, mixing uniformly, and carrying out LC-MS/MS sample injection analysis.
And (3) analyzing the sample and simultaneously evaluating the day accuracy of the analysis batch by using the quality control sample. Quality control standard: the accuracy of the quality control samples should be between 85.00-115.00% for each quality control concentration level to 50% quality control samples and at least 2/3 of the total quality control concentration level.
1.6 Pharmacokinetic analysis
(1) When the plasma concentration data is processed to calculate the drug-induced parameters, the plasma concentration data before administration is calculated according to '0', and T is calculated after administration max Previous concentration data below the quantitative Down line (BLQ) was calculated as "0", T max The subsequent BLQ concentration data do not participate in calculation uniformly;
(2) The following main pharmacokinetic parameters were calculated by using a non-room model statistical moment method of Phoenix WinNonlin 7.0 software: c max 、T max 、AUC (0-t) 、AUC (0-∞) 、T 1/2 、Cl、Vd、MRT (0-t) And mrT (0-∞) 。
2. Results
The established LC-MS/MS analysis method is used to determine the blood concentration of SD rats at each time point under the administration dosage of 11.39mg/kg, 11.19mg/kg and 11.01mg/kg respectively, and the average blood concentration-time curve is shown in figure 3.
The established LC-MS/MS analysis method is used for measuring the blood concentration of the beagle dog under different test article dosing at each time point, and the average blood concentration-time curve is shown in figure 4.
A non-room model statistical moment method of Phoenix WinNonlin 7.0 software is adopted to calculate pharmacokinetic parameters, and the relevant pharmacokinetic parameters are shown in tables 3 and 4.
TABLE 3 summary of major pharmacokinetic parameters in SD rats
TABLE 4 summary of major pharmacokinetic parameters of beagle dogs
Claims (10)
1. An inhalation preparation pharmacokinetics evaluation platform is characterized by comprising an experimental animal model, an atomized preparation dosing device, an atomized preparation detection system, a sample collection and detection system and a pharmacokinetics analysis system;
the experimental animal model is an experimental animal model which is established based on a physiological similarity or approximation principle and is based on rats, dogs or monkeys;
the aerosol preparation administration device is an oral-nasal exposure inhalation administration device;
the atomized preparation detection system comprises an aerosol concentration detection system, a particle size and distribution detection analysis system and an ambient air monitoring system;
the sample collection and detection system can perform quantitative blood drawing on the experimental animal according to preset collection time and perform blood concentration detection by an LC-MS/MS analysis method;
the pharmacokinetic analysis system performs pharmacokinetic parameter analysis by a non-compartmental model statistical moment method.
2. An evaluation method based on the evaluation platform of claim 1, comprising the steps of:
s1, preparation of a drug administration preparation: weighing an inhalation preparation to be analyzed, adding physiological saline to prepare an administration preparation group with the concentration of 0.1-3mg/mL, and taking the physiological saline with the same volume as a blank group;
s2, construction of an experimental animal model: constructing a small animal experiment model by using a rat, constructing a large animal experiment model by using a dog or a monkey, wherein the experimental animals are half male and half female, provide 12 hours of sunlight irradiation every day, monitor and control the environmental temperature range to be 18-26 ℃ and the relative humidity range to be 40-70%;
s3, inhalation preparation administration: the medicine is inhaled by an atomized preparation administration device according to a set speed, the administration time of large animals is 100min, the administration time of small animals is 4-40min, the administration concentration of each group is 0.8-1.2mg/ml, and the administration dosage is 100ug/kg according to the weight of experimental animals;
s4, detection of an inhalation preparation: monitoring the concentration of the aerosol, sampling the aerosol after the concentration is stabilized in real time, and detecting the particle size and distribution of the aerosol;
s5, sample collection and detection: quantitatively drawing blood from the experimental animal according to preset collection time, preparing a plasma sample to be detected, and detecting the blood concentration by an LC-MS/MS analysis method;
s6, pharmacokinetic analysis: after the blood concentration data is processed, pharmacokinetic parameters are analyzed by a non-atrioventricular model statistical moment method.
3. The method of claim 2, wherein the administration rate of step S3 is set to:
generating aerosol of the small animals at 15L/min, diluting at 0L/min, exhausting at 16L/min, and automatically adjusting the flow of the exhausted air by the administration device;
the aerosol of the large animals generates 40L/min, the dilution is 0L/min, the air exhaust is 42L/min, and the air exhaust flow is automatically adjusted by the drug administration device.
4. The evaluation method according to claim 2, wherein the aerosol sampling method of step S4 is: sampling is carried out twice, each sampling time is 10min, the interval between the two sampling times is more than 10min, and the sampling flow is 2L/min.
5. The evaluation method according to claim 2, wherein the aerosol particle size and distribution detection method of step S4 is: during the aerosol generation period, the particle size and the particle size distribution were measured 1 time.
6. The evaluation method according to claim 2, wherein step S4 comprises ambient air monitoring and control: the oxygen concentration range is monitored and controlled in real time to be 19-22%, the temperature range is 18-26 ℃, the carbon dioxide concentration is less than 1%, and the relative humidity range is 30-70%.
7. The method of claim 2, wherein the large animal sample collection time of step S5 is 12 collection time points: before administration, 30min, 60min, 100min, 130min, 3h, 4h, 6h, 8h, 10h, 12h and 24h after inhalation administration;
the small animal sample collection time was 12 collection time points: before administration, 0.033h, 0.083h, 0.167h, 0.333h, 0.667h, 1h, 2h, 4h, 8h, 10h and 24h after the start of inhalation administration.
8. The evaluation method according to claim 2, wherein the blood concentration data processing method of step S6 is: the pre-dose plasma concentration data is calculated as "0", post-dose T max Previous concentration data below the quantitative Down line (BLQ) was calculated as "0", T max The subsequent BLQ concentration data did not participate in the calculation.
9. The evaluation method according to claim 2, wherein step S6 is performed by calculating pharmacokinetic parameters using a non-cellular statistical moment method using Phoenix WinNonLin 7.0 software.
10. The method of claim 2, wherein the pharmacokinetic parameters of step S6 include C max 、T max 、AUC (0-t) 、AUC (0-∞) 、T 1/2 、Cl、Vd、MRT (0-t) And MRT (0-∞) 。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211453021.XA CN115598311A (en) | 2022-11-21 | 2022-11-21 | Inhalation preparation pharmacokinetic evaluation platform and method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211453021.XA CN115598311A (en) | 2022-11-21 | 2022-11-21 | Inhalation preparation pharmacokinetic evaluation platform and method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115598311A true CN115598311A (en) | 2023-01-13 |
Family
ID=84853454
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211453021.XA Pending CN115598311A (en) | 2022-11-21 | 2022-11-21 | Inhalation preparation pharmacokinetic evaluation platform and method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115598311A (en) |
-
2022
- 2022-11-21 CN CN202211453021.XA patent/CN115598311A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7453556B2 (en) | Process for determining the particle size distribution of an aerosol and apparatus for carrying out such a process | |
| US5156776A (en) | Aerosol generating system | |
| US7414720B2 (en) | Measuring particle size distribution in pharmaceutical aerosols | |
| Gerde et al. | Dissolv It: an in vitro method for simulating the dissolution and absorption of inhaled dry powder drugs in the lungs | |
| Nadarassan et al. | Aerodynamic characteristics of a dry powder inhaler at low inhalation flows using a mixing inlet with an Andersen Cascade Impactor | |
| US11054414B2 (en) | Exposure system | |
| CN115068450B (en) | Fudosteine aerosol inhalation solution composition, medicine assembly and application thereof | |
| WO2023125472A1 (en) | Spraying assembly | |
| CN111896698B (en) | In-vitro evaluation platform and method for inhalation preparation | |
| EP0539674A1 (en) | Aerosol generating system | |
| Barry et al. | An in vitro analysis of the output of salbutamol from different nebulizers | |
| Silkstone et al. | An investigation of in vitro/in vivo correlations for salbutamol nebulized by eight systems | |
| CN115598311A (en) | Inhalation preparation pharmacokinetic evaluation platform and method thereof | |
| Magramane et al. | Formulation and characterization of pulmonary drug delivery systems | |
| Saeed et al. | Aerosol delivery via noninvasive ventilation: role of models and bioanalysis | |
| CN110179772A (en) | A kind of ambroxol hydrochloride preparation and preparation method thereof for Neulized inhalation | |
| CN111610261B (en) | Method for screening an aerosolization device suitable for use with beta 2 receptor agonists | |
| Buzgeia et al. | In-Vitro In-Vivo Correlation (IVIVC) of Inhaled Products Using Twin Stage Impinger | |
| Babenko et al. | 1H NMR quantification of spray dried and spray freeze-dried saccharide carriers in dry powder inhaler formulations | |
| Maloney et al. | Performance testing for dry powder inhaler products: towards clinical relevance | |
| Alaboud | In-vitro inhalation performance for formoterol dry powder and metred dose inhalers. In-vitro characteristics of the emitted dose from the formoterol dry powder and metred dose inhalers to identify the influence of inhalation flow, inhalation volume and the number of inhalation per dose. | |
| Sood et al. | Jet nebulization of prostaglandin E1 during neonatal mechanical ventilation: stability, emitted dose and aerosol particle size | |
| Sosnowski | Critical assessment of the quantitative criteria used in the comparison of nebulizers | |
| Mehri | Aerosol deposition measurements with ODAPT mask adapter | |
| CN116908345A (en) | Method for detecting content of formoterol fumarate inhalation solution |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |