CN112438966B - Medical quantitative inhalation aerosol - Google Patents
Medical quantitative inhalation aerosol Download PDFInfo
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- CN112438966B CN112438966B CN201910818321.5A CN201910818321A CN112438966B CN 112438966 B CN112438966 B CN 112438966B CN 201910818321 A CN201910818321 A CN 201910818321A CN 112438966 B CN112438966 B CN 112438966B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, ***e
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
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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
- A61M15/00—Inhalators
- A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D83/00—Containers or packages with special means for dispensing contents
- B65D83/14—Containers or packages with special means for dispensing contents for delivery of liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant for a product delivered by a propellant
- B65D83/44—Valves specially adapted therefor; Regulating devices
- B65D83/52—Valves specially adapted therefor; Regulating devices for metering
Abstract
The invention provides a medical metered dose inhalation aerosol with enhanced chemical and physical stability, which comprises an aerosol preparation and a pressurized metered dose inhaler for containing the aerosol preparation, wherein the aerosol preparation contains an active ingredient for treating chronic obstructive pulmonary disease, the pressurized metered dose inhaler comprises a container, a metering valve and an actuator, the container is an aluminum container, and the metering valve is sealed with a chlorinated butyl rubber sealing gasket between a can opening of the container. The invention solves the problem that the ipratropium bromide active ingredients in the medicaments are degraded by reaction with water or ethanol in the storage process and are degraded at an accelerated speed under the influence of improper packing materials, and improves the safety and the effectiveness of the medicaments.
Description
Technical Field
The invention belongs to the technical field of quantitative inhalation aerosols, and particularly relates to a quantitative inhalation aerosol for preventing or treating COPD (chronic obstructive pulmonary disease).
Background
Pressurized Metered Dose Inhalers (MDIs) are effective drug delivery devices for the accurate administration of small doses to the respiratory tract. MDIs generally comprise a pressure-resistant canister containing an aerosol formulation which, in addition to the active ingredient of the drug, contains primarily liquefied propellant and small amounts of other adjuvants, and a metering valve for controlling the amount of drug. If the active ingredient of the drug is dissolved in an aerosol formulation, it is a solution type aerosol (solution MDIs). If the active ingredient of the drug is not dissolved in the aerosol formulation, this is known as suspension aerosols (suspension MDIs). Generally, solution-type aerosols are far less chemically stable than suspension-type aerosols, and often pose technical problems to the formulator (reference 1: C. Vervaet, P. Byron, "Drug-surfactant-promoter interactions in HFA-formulations", International Journal of pharmaceuticals 186(1999) 13-30).
Sold domestically by the German Boringer Vargham pharmaceutical company
(ipratropium bromide solution aerosol) is a solution type aerosol for treating chronic obstructive pulmonary disease. The chemical structure of ipratropium bromide (formula 1) is characterized by the presence of a secondary alcohol phenylacetate linkage, which is prone to two major degradation reactions (ref.2: US 5955058A, Stabilized media enzymatic solution for interactions with associated ipratropium bromide, Sep 21,1999), hydrolysis with water to form tropic acid (formula 2) and transesterification with ethanol to form ethyl tropic acid (formula 3). Existing ipratropium bromide aerosol of Boringer Vargahi pharmaceutical company on the market
The formula of the aerosol comprises water and ethanol, and the formula of the ipratropium bromide solution aerosol is as follows: 0.0374% of ipratropium bromide (monohydrate), 0.0040% of citric acid and 15.0000% of absolute ethyl alcohol% water 0.5000%, and balance HFA134a (ref 3: CN1054282C, stable pharmaceutical aerosol solution formulation, 2000-07-12, page 11, table 3, "Normal concentration"), mainly using citric acid to inhibit both degradation reactions, but did not solve the degradation problem well. Two degradation reactions of ipratropium bromide are as follows:
disclosure of Invention
The invention aims to provide a medical quantitative solution type inhalation aerosol for treating chronic obstructive pulmonary disease, which is used for improving the chemical stability and/or physical stability of active ingredients in the existing solution type aerosol on the market and further improving the drug safety and drug effectiveness of the solution type aerosol.
In terms of chemical stability, the present inventors examined the effect of canister-metering valve combinations of metered dose inhalation aerosols on the degradation reaction of active ingredients in the treatment of chronic obstructive pulmonary disease.
Physical stability, the present inventors examined the effect of canister-metering valve combinations of metered dose inhalation aerosols on their aerodynamic fine particle dose and particle size distribution. Aerodynamic particle size distribution is the most important indicator for in vitro testing of inhaled formulations. In the lung conducting airways, mist particles are deposited by collisions, which are manifested as larger particles settling on the tracheal wall surfaces in the lungs, whereas smaller particles, following the airflow into the next airway branch in the lungs, are subjected to cascade impactor processes which simulate the above process, and inertial collisions are therefore generally considered the "gold standard" for evaluating inhalant aerodynamic size deposition. The invention uses Andersen Cascade Impactor (ACI) to measure the influence of different container tank-metering valve combinations on the aerodynamic particle size of the quantitative inhalation aerosol, and the inspected result has the most objective and accurate reference significance for the drug safety and the drug effectiveness of the quantitative inhalation aerosol.
The inventors first investigated the effect of the combination of three pressure resistant canisters (stainless steel canister, fluorocarbon polymer coated aluminum canister and uncoated aluminum canister) available on the market with two metering valves with different sealing gaskets (epdm and chlorobutyl rubber) on the stability of the metered dose inhalation aerosol of ipratropium bromide. It has been unexpectedly discovered that the canister-metering valve combination has a significant effect on the chemical degradation of ipratropium bromide and the aerodynamic particle size distribution of the aerosol. It has further been surprisingly found that the combination of an aluminum can (including coated aluminum cans, uncoated aluminum cans) and a metering valve with a chlorobutyl rubber sealing gasket has a significant enhancement in the chemical stability of the active ingredient of an ipratropium bromide metered dose inhalation aerosol and the physical stability of the aerosol compared to other can-metering valve combinations.
Based on the above novel findings, the present invention provides a medicinal metered dose inhalation aerosol for the prevention and/or treatment of COPD having a unique canister-metering valve combination, solving the problem that such an aerosol under the influence of an improper canister-metering valve combination: the problem that the active ingredients in the aerosol react with water or ethanol in the storage process due to the special molecular structure to obviously accelerate degradation; and/or the problem of significant abnormal changes in the aerodynamic particle size distribution during storage of the aerosol. Based on the method, the safety and the effectiveness of the medicine are improved.
The invention provides a medical metered dose inhalation aerosol with enhanced chemical and physical stability, which comprises an aerosol preparation and a pressurized metered dose inhaler for containing the aerosol preparation, wherein the aerosol preparation contains an active ingredient for treating chronic obstructive pulmonary disease, the pressurized metered dose inhaler comprises a container, a metering valve and an actuator, the container is an aluminum container, and the metering valve is sealed with a chlorinated butyl rubber sealing gasket at the mouth of the container (the structure of the pressurized metered dose inhaler can be shown by referring to fig. 1).
Further, the active ingredient for treating chronic obstructive pulmonary disease comprises a compound having a secondary alcohol ester structure,
further, the secondary alcohol ester structure is aromatic cyclyl secondary acetic acid ester, the aerosol preparation also comprises water and/or ethanol, and the compound with the secondary alcohol ester structure is subjected to ester hydrolysis and ester exchange reaction with the water and/or the ethanol.
Further, the compound having a secondary alcohol ester structure is an active ingredient for treating chronic obstructive pulmonary disease.
Further, the active ingredient for treating chronic obstructive pulmonary disease is a short-acting anticholinergic drug.
Further, the short-acting anticholinergic may be a short-acting anticholinergic that is not stable well in conventional canister-metering valve combinations, such as ipratropium bromide. In one embodiment of the invention, the short-acting anticholinergic is ipratropium bromide monohydrate.
In the invention, the content of ipratropium bromide monohydrate in the aerosol preparation is more than 0.01wt%, and the specific content is determined according to the actual production condition. For example, it may be 0.01wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05wt%, etc.
In the present invention, the aluminum can is selected from non-coated aluminum cans and also from coated aluminum cans. The aluminum can be made of existing materials or purchased as an existing product, and the coated aluminum can be a variety of coatings which meet medical requirements and do not produce leachates. In one embodiment of the invention, the coated aluminum can is selected from fluorocarbon polymer coated aluminum cans.
In the invention, the aerosol is a solution type aerosol.
In the invention, the aerosol preparation also comprises cosolvent anhydrous ethanol, organic acid, water and liquefied propellant. Wherein, the contents of the absolute ethyl alcohol, the organic acid, the water and the liquefied propellant are determined according to the pharmacopoeia standard.
For example, the content of the absolute ethyl alcohol in the aerosol preparation can be 10-20 wt%.
The organic acid is anhydrous citric acid, and the content of the organic acid in the aerosol preparation can be 0.0003-0.006 wt%.
The water may be present in the aerosol formulation in an amount of 0.2 to 1.8 wt%.
In the present invention, the liquefied propellant is a hydrofluoroalkane. In one embodiment of the invention, the hydrofluoroalkane is selected from one or a mixture of HFA134a and HFA 227.
It was found that the above protocol showed little or no hydrolysis and transesterification products and little or no other impurities in the drug in the 6 month accelerated stability test, whether the pressurized metered dose inhaler was "up" or "down".
In the present invention, the active ingredient for treating chronic obstructive pulmonary disease may further include a long-acting anticholinergic drug (LAMA).
LAMA drugs, which are used in respiratory systems, are mainly long-acting anticholinergic antagonists, which have the main effects of dilating bronchial smooth muscle, reducing bronchial mucus secretion and relieving airway hyperreactivity. The action mechanism is as follows: parasympathetic nerves regulate airway smooth muscle tone and airway inflammation in patients with chronic airway disease through peripheral cholinergic receptor signaling pathways.
The effector tissues of LAMA action include the smooth muscle of the airways and the mucous glands. Increased cholinergic activity is an important factor in airway smooth muscle contraction, and increased cholinergic activity and airway smooth muscle hypertrophy are important causes of airway hyperreactivity. In addition, parasympathetic nerves can also regulate inflammatory cells and non-inflammatory cells including fibroblasts through a choline receptor signaling pathway, which together cause airway inflammation and airway remodeling. Tiotropium bromide, glycopyrrolate and aclidinium bromide are all commonly used long-acting anticholinergic drugs that act on the airways primarily by inhalation, usually loaded and administered using a pressurized metered dose inhaler. Tiotropium bromide, glycopyrronium bromide, aclidinium bromide have similar chemical structures to those of the sec-alcohol phenylacetate linkage of ipratropium bromide, and these three compounds also have a linkage of a sec-alcohol arylcyclylacetate (see structural formulas 4, 5, and 6), and thus they have similar chemical properties to ipratropium bromide, and the ester structures thereof also tend to undergo degradation reactions, i.e., hydrolysis reactions and transesterification reactions with ethanol, in the same principle as the two degradation reactions of ipratropium bromide. The solution according to the invention is therefore equally suitable for tiotropium bromide, glycopyrronium bromide and aclidinium bromide.
The invention has the following beneficial effects:
1. the ipratropium bromide quantitative inhalation aerosol provided by the invention has enhanced chemical and physical stability, solves the problem that the active component ipratropium bromide is degraded due to reaction with water or ethanol in the storage process, and improves the safety and effectiveness of medicaments. The metering valve combination of the aluminum can-chlorobutyl rubber sealing gasket has a significant maintenance and enhancement effect on the chemical stability of the aerosol, with no hydrolysis and transesterification products detected, and few other impurities detected, in the 6-month accelerated stability test, whether "upright" or "inverted".
2. The metering valve combination of the aluminum can-butyl chloride rubber sealing ring has remarkable maintaining and enhancing effects on the physical stability of the aerosol, the anderson cascade impactor is used for measuring the aerodynamic particle size distribution of the aerosol, and the result shows that no obvious abnormality of the aerodynamic particle size distribution is seen in 7 days no matter the quantitative inhalation aerosol of the isopropylammonium bromide is in the 'upright' state or in the 'inverted state', in other words, the content of the isopropylammonium bromide with specific particle size given by each layer of the anderson cascade impactor is basically not greatly different in 7 days.
Drawings
FIG. 1 is a schematic view of the structure of a medical metered dose inhalation aerosol according to the present invention;
in fig. 1: 1-canister, 2-metering valve, 3-actuator, 4-sealing gasket, 5-formulation.
FIG. 2 is a schematic diagram of an Anderson cascade impactor.
Detailed Description
The effect of the canister-metering valve combination of isopropyl tropium bromide aerosol on the isopropyl tropium bromide degradation reaction and on the microparticle dose and particle size distribution in the aerodynamics of the isopropyl tropium bromide aerosol is examined below by means of specific embodiments and experiments.
Example 1
The experiment examines the influence of the accelerated chemical stability of the medical quantitative inhalation aerosol of ipratropium bromide by the combination of different pressure-resistant containers and different sealing washer metering valves.
Canister-metering valve combination type: a non-coating aluminum can-ethylene propylene diene monomer sealing washer metering valve, a fluorocarbon polymer coating aluminum can-ethylene propylene diene monomer sealing washer metering valve, a stainless steel can-ethylene propylene diene monomer sealing washer metering valve; a non-coating aluminum can-chlorinated butyl rubber sealing washer metering valve, a fluorocarbon polymer coating aluminum can-chlorinated butyl rubber sealing washer metering valve, a stainless steel can-chlorinated butyl rubber sealing washer metering valve.
Aerosol formulations: in order to accurately examine the influence of the combination of the canister and the metering valve on the stability, in this embodiment 1, a single variable is controlled, all kinds of the above combinations of the canister and the metering valve are matched with aerosol preparations with the same prescription, and the same preparation process is adopted, and the specific preparation process and the method for obtaining the aerosol by encapsulating the preparation into the pressurized metered dose inhaler are all common technical means in the industry, and are not repeated herein. The aerosol preparation comprises the following components: 0.0374 wt% of ipratropium bromide monohydrate, 0.0040 wt% of citric acid, 15.0000 wt% of absolute ethyl alcohol, 0.5000 wt% of water and the balance of HFA134 a.
Accelerated test conditions: 40 ℃ RH 75%, accelerated for 6 months, each medical metered dose inhaler was kept "upside down" during the test to examine the effect of simultaneous contact of the formulation with the canister and metering valve on its chemical stability.
In the accelerated test process and the end stage, the impurity content of each canister-metering valve combination object is detected, and the results are shown in table 1 below.
TABLE 1 impurity content of various canister-metering valve combination subjects after accelerated testing (40 ℃/RH 75%/6 months accelerated)
Test process data, result data and analysis:
(1) the stainless steel can-butyl chloride seal gasket metering valve combination catalyzed significantly the hydrolysis and transesterification of ipratropium bromide under accelerated test conditions (40 ℃/75% relative humidity, "inverted") for only 6 days, producing 10.4% hydrolysate impurity 2 and 26.9% transesterified product impurity 3, respectively. This finding does not disclose that joining an inverted stainless steel can with a chlorinated butyl rubber gasket by solution of the formulation in an aerosol may produce a catalytic synergy for degradation reactions.
(2) The uncoated aluminum can-epdm rubber seal gasket metering valve combination gave higher amounts of degraded impurities under accelerated test conditions (40 ℃/75% relative humidity/6 month, "inversion"), yielding 3.4% hydrolysate impurity, 2 tropine acid, and 6.7% transesterification product impurity, 3 tropine ethyl ester, respectively.
(3) The combination of the ethylene propylene diene monomer sealing washer metering valve and the uncoated aluminum tank, the fluorocarbon polymer coating aluminum tank and the stainless steel tank respectively not only gives 0.1 to 3.4 percent of hydrolysis impurity 2 tropine acid and 0.18 to 6.7 percent of ester exchange impurity 3 tropine ethyl ester, but also gives 0.38 to 1.5 percent of maximum unknown single impurity.
(4) Either the uncoated aluminum can-chlorobutyl rubber seal gasket metering valve combination or the fluorocarbon polymer coated aluminum can-chlorobutyl rubber seal gasket metering valve combination gave very stable results under accelerated conditions (40 ℃/75% relative humidity/6 month, "inverted") with no detectable impurity of 2 tropine acid, no impurity of 3 tropine acid ethyl ester, and no unknown impurities.
The above results show that different pressure-resistant canister-metering valve combinations have different effects on the chemical stability of the ipratropium bromide solution type aerosol, wherein the metering valve combination of the aluminum canister (containing both the uncoated aluminum canister and the fluorocarbon polymer coated aluminum canister) -the butyl rubber chloride sealing gasket gave very high chemical stability, and neither hydrolysis and transesterification products nor other impurities were detected in the 6-month accelerated stability test, either the "inverted" test or the "upright" test further tested.
Example 2
This experiment compared the chemical and physical stability of the ipratropium bromide solution type aerosol of the metering valve combination of the uncoated aluminum can-chlorobutyl rubber gasket with the ipratropium bromide solution type aerosol of the commercial blinge negerjon pharmaceutical company in an acceleration test.
According to reference 4 (Boringer Vargohy, "isopropyl ammonium Bromide aerosol)
Instructions for that matter "),
a stainless steel canister-metering valve combination with a gasket of unknown material was used.
Comparison group: aerosol formulations of ipratropium bromide solution commercially available from Boringer-Vargahil pharmaceutical
The device adopts a metering valve combination of a stainless steel tank and an unknown gasket, and is respectively provided with a positive comparison group and an inverted comparison group.
Experimental groups: the invention relates to an ipratropium bromide solution type aerosol, which adopts a non-coating aluminum can-butyl chloride rubber sealing washer metering valve combination and is respectively provided with a positive experiment group and an inverted experiment group. Aerosol formulation formula of ipratropium bromide solution type aerosol of experimental group and ipratropium bromide aerosol of comparative group
Are the same as above.
Accelerated test conditions: accelerated at 40 deg.C and RH 75% for 6 months.
In the process of accelerating the test and at the end stage, the change conditions of the impurity content of the investigation objects of the comparison group and the experiment group and the change conditions of the dose of the fine particles for describing the in vitro lung administration efficiency are detected, and the detection results are shown in the following tables 2 and 3.
TABLE 2 impurity content and fine particle dose (40 deg.C/75% relative humidity) for each acceleration phase of the experimental group
TABLE 3 impurity content and fine particle dose (40 deg.C/75% relative humidity) for each acceleration phase of the control group
| Acceleration stage (placing mode) | 0 month | Accelerate 6 months (inversion) | Accelerate 6 months (upright) |
| Impurity 2 (%) | ND | 0.06 | 0.06 |
| Impurity 3 (%) | ND | ND | ND |
| Maximum unknown simple impurity (%) | 0.15 | 1.1 | 1.1 |
| Total impurities (%) | 0.53 | 3.2 | 3.0 |
| Fine particle dose (%) | 33 | 28 | 23 |
Test process data, result data and analysis:
1. in the 6 month accelerated stability test, referring to table 2, the experimental group of the ipratropium bromide solution-type aerosol of the present invention (i.e., the non-coated aluminum can-metering valve combination containing a chlorinated butyl rubber sealing gasket), whether "upside down" or "upright", showed that the expected degradation products, i.e., the hydrolysate (impurity 2) and the transesterification product (impurity 3), were barely detectable, indicating that the non-coated aluminum can-metering valve combination containing a chlorinated butyl rubber sealing gasket completely blocked the degradation reaction of ipratropium bromide in the solution-type aerosol. See Table 3 for a corresponding comparison group of inlet solution type ipratropium bromide aerosol-
0.06% hydrolysate (impurity 2) was detected in the accelerated stability test for 6 months, and no transesterified product (impurity 3) was detected.
2. In the 6-month accelerated stability test, referring to table 2, the experimental group of the aerosol formulation of the present invention in solution with ipratropium bromide did not detect any of the largest unknown single impurities. See Table 3 for a corresponding control group of ipratropium bromide aerosol-
But 1.1% of the maximum unknown simple impurity was detected.
3. In the 6-month accelerated stability test, referring to table 2, the test group of the aerosol formulation of ipratropium bromide solution of the present invention detected a total impurity of 0.02% at 6 months of acceleration. See Table 3 for a corresponding comparative set of aerosol solutions of ipratropium bromide-
The total impurities were detected at 3.2% (inverted) and 3.0% (upright) respectively, at an acceleration of 6 months.
It can be seen that the metering valve combination of the uncoated aluminum can-chlorobutyl rubber sealing gasket has a significant maintenance and enhancement effect on the chemical stability of the aerosol, with no hydrolysis and transesterification products detected, and almost no other impurities detected, in either the "upright" or "inverted" accelerated stability tests, for 6 months.
4. Tables 2 and 3 also compare the experimental groups of the present invention with the comparative groups
I.e. the change in the fine particle dose in the 6 month accelerated stability test. According to the description of reference 5 (chinese pharmacopoeia 2015 edition "guidelines for stability testing of raw drugs and formulations", page 354), the fine particle dose is one of the key stability items that need to be investigated in aerosol development, because it is one of the parameters for evaluating the in vitro efficacy of pulmonary drug delivery of aerosols. Experimental group the ipratropium bromide solution type aerosol of the present invention gives a stable fine particle dose in a non-coated aluminum can-chlorobutyl rubber gasket metering valve combination, the fine particle dose percentage of the sample at 40 ℃/75% relative humidity/6 months is the same as "0 months" under "upside down" and is 32%, and 34% under "upright" and is slightly higher than "0 months"; and the corresponding inlet solution type aerosol of the comparison group
The fine particle dose of the sample at 40 ℃/75% relative humidity/6 month was 28% ("inverted") and 23% ("upright"), respectively, which were not much reduced from "0 month" (32%). In further evaluation, the dose change rates of the experimental group were 0% when inverted and only 6% when upright, while the dose change rates of the comparative group reached 12.5% when inverted and more 28.12% when upright, which are actually different, and these effect changes were surprising and unexpected.
The data in tables 2 and 3 above show thatThe chemical stability and the physical stability of the ipratropium bromide solution type aerosol of the invention are higher than those of the comparative group
The physical stability is enhanced by selecting a reasonable canister-metering valve combination in the compatibility test of the packaging material and the preparation.
Example 3
The effect of the different canister-metering valve combinations on the physical stability of the aerosol formulations of the ipratropium bromide solution type is also shown in the measurement of the Aerodynamic Particle Size Distribution (APSD).
Aerodynamic particle size distribution is a "key mass attribute" (CQA) in the development of metered inhalation aerosol products using the concept of "mass origin design (QbD)" in accordance with the guidelines of reference 6 (guidelines for Quality control opinions for metered dose inhaler and dry powder inhaler products issued by the FDA in us 4.2018). The aerodynamic particle size distribution was determined using an anderson cascade impactor (ACI, the structure of which is shown in fig. 2, comprising 8 stages — 0-7 stages and the last filter paper "F layer") (reference 7: chinese pharmacopoeia 2015 edition, "measurement of fine particle aerodynamic properties of inhalation formulations", page 126).
This example 3 examined the stability effect of two different canister-metering valve combinations on the aerodynamic particle size distribution of an aerosol solution of ipratropium bromide (formulated as the "normal concentration" in table 3 of CN 1054282C) at room temperature for 7 days, either "inverted" or "upright".
Combination 1: the ipratropium bromide solution type aerosol adopts a non-coating aluminum can-butyl chloride rubber sealing washer metering valve combination.
And (3) combination 2: isopropyltolonium bromide solution type aerosol of Boringer Yiger John
It adopts a stainless steel tank-notMetering valve combinations for sealing gaskets are known.
Combination 1 of the aerosol of the solution of ipratropium bromide of the present invention and combination 2 of the aerosol of the solution of ipratropium bromide
The aerosol preparation has the same prescription, and the prescription components are as follows: 0.0374 wt% of ipratropium bromide monohydrate, 0.0040 wt% of citric acid, 15.0000 wt% of absolute ethyl alcohol, 0.5000 wt% of water and the balance of HFA134 a.
Example 3 the aerodynamic particle size distribution of combination 1 and combination 2 was measured using an anderson cascade impactor and the data results are shown in tables 4 and 5, respectively.
TABLE 4 aerodynamic particle size distribution of combination 1 stability test results at room temperature (microgram/Press)
TABLE 5 aerodynamic particle size distribution of combination 2 stability test results at room temperature (microgram/Press)
Test process data, result data and analysis:
the aerodynamic particle size distributions of tables 4 and 5 are not the same at room temperature over a period of one week. Combination 1 non-coated aluminum can-chlorobutyl rubber sealing gasket metering valve combination of table 4 shows no significant abnormality in aerodynamic particle size distribution within 7 days, whether the inhaler is "upright" or "inverted", in other words, each layer of the anderson cascade impactor gives essentially no large difference in the content of ipratropium bromide of a specific particle size over 7 days. In contrast, the combination 2 stainless steel can-unknown sealing gasket metering valve combination of table 5 shows that some levels of the sample under "inversion" within 7 days at room temperature give an aerodynamic particle size distribution anomaly; for example, the fine particle dose given in layer 3 increased from 0.168 micrograms/knock on day 1 to 0.487 micrograms/knock on day 6, and similarly, the varying degrees of fine particle dose were given in layers 4, 6 and 7. In contrast, the sample of combination 2 "upright" under the same conditions gave no major variation in aerodynamic particle size distribution. The results demonstrate that the combination of combination 2 stainless steel can-unknown sealing gasket metering valve causes the ipratropium bromide solution type aerosol sample to have reduced physical stability under "inverted" conditions; the combination 1 of non-coating aluminum can and chlorinated butyl rubber sealing ring metering valve has no effect, so that the reasonable combination selection of the can and the metering valve can enhance the physical stability of the aerosol.
The drug used in the experiments in examples 1-3 above was ipratropium bromide belonging to the short-acting anticholinergic (SAMA) class for the treatment of COPD. While other agents for treating COPD that belong to the long-acting anticholinergic (LAMA) group, such as tiotropium bromide (formula 4), glycopyrronium bromide (formula 5) and aclidinium bromide (formula 6), have chemical structural formulas similar to that of ipratropium bromide, i.e., both have aromatic cyclic secondary alcohol acetate linkages, and thus are also prone to two similar degradation reactions, hydrolysis reactions and transesterification reactions with ethanol. The chemical stability of these active ingredients can also be enhanced by the addition of citric acid to aerosols of tiotropium, glycopyrronium or aclidinium bromide. Based on the same chemical structure characteristics and the same drug action mechanism, the technical scheme of the aluminum can-butyl chloride rubber sealing washer metering valve combination provided by the invention can further enhance the physical and chemical stability of the tiotropium bromide, glycopyrronium bromide or aclidinium bromide solution type aerosol.
Claims (12)
1. A metered dose inhalation aerosol for medical use, characterized in that it has enhanced chemical and physical stability, the aerosol comprising an aerosol formulation comprising an active ingredient for the treatment of chronic obstructive pulmonary disease and a pressurized metered dose inhaler for containing the aerosol formulation, the pressurized metered dose inhaler comprising a canister (1), a metering valve (2) and an actuator (3), the canister (1) being an aluminium canister, the metering valve (2) being sealed to the mouth of the canister (1) with a chlorinated butyl rubber sealing gasket (4);
the active ingredient for treating the chronic obstructive pulmonary disease is a compound with a secondary alcohol ester structure; the secondary alcohol ester structure is aromatic cyclic secondary acetate;
the aerosol formulation further comprises water or ethanol.
2. Aerosol according to claim 1, characterized in that the active ingredient for the treatment of chronic obstructive pulmonary disease is selected from short-acting anticholinergic drugs.
3. Aerosol according to claim 2, characterized in that the active ingredient for the treatment of chronic obstructive pulmonary disease is selected from ipratropium bromide.
4. Aerosol according to claim 3, characterized in that the active principle for the treatment of chronic obstructive pulmonary disease is selected from ipratropium bromide monohydrate.
5. Aerosol formulation according to claim 4, wherein ipratropium bromide monohydrate is present in the aerosol formulation in an amount of greater than 0.01% by weight.
6. Aerosol according to claim 5, wherein ipratropium bromide monohydrate is present in the aerosol formulation in an amount selected from 0.01 to 0.05% by weight.
7. Aerosol of any one of claims 1 to 6, wherein the aluminium can is a non-coated aluminium can or a coated aluminium can; the coated aluminum can is selected from fluorocarbon polymer coated aluminum cans.
8. The aerosol formulation of any one of claims 1 to 6, wherein the aerosol formulation is a solution aerosol formulation.
9. Aerosol according to any one of claims 1 to 6, wherein the aerosol formulation further comprises a co-solvent anhydrous ethanol, an organic acid, water and a liquefied propellant.
10. The aerosol preparation of claim 9, wherein the absolute ethyl alcohol is contained in the aerosol preparation in an amount of 10-20 wt%; the organic acid is anhydrous citric acid, and the content of the organic acid in the aerosol preparation is 0.0003-0.006 wt%; the content of the water in the aerosol preparation is 0.2-1.8 wt%.
11. Aerosol according to claim 9, wherein the liquefied propellant is a hydrofluoroalkane selected from one or both of HFA134a and HFA 227.
12. Aerosol according to claim 1, characterized in that the active ingredient for the treatment of chronic obstructive pulmonary disease is a long-acting anticholinergic; the long-acting anticholinergic drug is at least one of tiotropium bromide, glycopyrrolate or aclidinium bromide.
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