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William F. S. Sellers - One of the best experts on this subject based on the ideXlab platform.
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Asthma pressurised metered dose inhaler performance: propellant effect studies in delivery systems
Allergy Asthma & Clinical Immunology, 2017Co-Authors: William F. S. SellersAbstract:Background Current pressurised metered dose asthma inhaler (pMDI) propellants are not inert pharmacologically as were previous chlorofluorocarbons, have smooth muscle relaxant‚ partial pressure effects in the lungs and inhaled hydrofluoroalkane 134a (Norflurane) has anaesthetic effects. Volumes of propellant gas per actuation have never been measured. Methods In-vitro studies measured gas volumes produced by pMDIs on air oxygen (O_2) levels in valved holding chambers (VHC) and the falls in O_2% following actuation into lung ventilator delivery devices. Results Volumes of propellant gas hydrofluoroalkane (HFA) 134a and 227ea and redundant chlorofluorocarbons (CFC) varied from 7 ml per actuation from a small salbutamol HFA inhaler to 16 ml from the larger. Similar-sized CFC pMDI volumes were 15.6 and 20.4 ml. Each HFA salbutamol inhaler has 220 full volume discharges; total volume of gas from a small 134a pMDI was 1640 ml, and large 3885 ml. Sensing the presence of liquid propellant by shaking was felt at the 220th discharge in both large and small inhalers. Because of a partial pressure effect, VHC O_2% in air was reduced to 11% in the smallest 127 ml volume VHC following 10 actuations of a large 134a salbutamol inhaler. The four ventilator delivery devices studied lowered 100% oxygen levels to a range of 93 to 81% after five actuations, depending on the device and type of pMDI used. Conclusion Pressurised inhaler propellants require further study to assess smooth muscle relaxing properties.
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Asthma pressurised metered dose inhaler performance: propellant effect studies in delivery systems.
Allergy Asthma & Clinical Immunology, 2017Co-Authors: William F. S. SellersAbstract:Current pressurised metered dose asthma inhaler (pMDI) propellants are not inert pharmacologically as were previous chlorofluorocarbons, have smooth muscle relaxant‚ partial pressure effects in the lungs and inhaled hydrofluoroalkane 134a (Norflurane) has anaesthetic effects. Volumes of propellant gas per actuation have never been measured. In-vitro studies measured gas volumes produced by pMDIs on air oxygen (O2) levels in valved holding chambers (VHC) and the falls in O2% following actuation into lung ventilator delivery devices. Volumes of propellant gas hydrofluoroalkane (HFA) 134a and 227ea and redundant chlorofluorocarbons (CFC) varied from 7 ml per actuation from a small salbutamol HFA inhaler to 16 ml from the larger. Similar-sized CFC pMDI volumes were 15.6 and 20.4 ml. Each HFA salbutamol inhaler has 220 full volume discharges; total volume of gas from a small 134a pMDI was 1640 ml, and large 3885 ml. Sensing the presence of liquid propellant by shaking was felt at the 220th discharge in both large and small inhalers. Because of a partial pressure effect, VHC O2% in air was reduced to 11% in the smallest 127 ml volume VHC following 10 actuations of a large 134a salbutamol inhaler. The four ventilator delivery devices studied lowered 100% oxygen levels to a range of 93 to 81% after five actuations, depending on the device and type of pMDI used. Pressurised inhaler propellants require further study to assess smooth muscle relaxing properties.
Anja H. Pischtiak - One of the best experts on this subject based on the ideXlab platform.
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Characteristics, supply and use of the hydrofluorocarbons HFA 227 and HFA 134a for medical aerosols in the past, present and future. Manufacturers perspectives
Chimica Oggi-chemistry Today, 2020Co-Authors: Anja H. PischtiakAbstract:HFA 227 (heptafluoropropane; Apaflurane) and HFA 134a (tetrafluoroethane; Norflurane), both of which were developed by the chemical industry as CFC substitutes in the eighties, now have been used by the pharmaceutical industry as propellants for medical aerosols, particularly for asthma sprays, for approx. 10 years. Thus, for example, Aventis Pharma Ltd. have in the meantime changed the formulation of their products, Intal® (disodium cromoglycate), and Tilade® (nedocromil) by using HFA 227. Now, innovative approaches of pharmaceutical research are leading to the administration of active substances for the treatment of possibly a large number of known diseases via the lungs or throat. Thus, already in the clinical trial phase are active substances for buccal or respiratory drug delivery for the treatment of diabetes (insulin), pain management (morphine), multiple sclerosis (interferon beta la), osteoporosis (parathyroid hormone), viral diseases and cancers, septic shock and of course, asthma (18). Almost as many companies are developing the technology platforms for administering these active substances to the lungs, nose or throat. For this purpose, among others, the very reasonable and patient-friendly p-MDI technology which has already proved itself over many years in the treatment of asthma, is exploited. The only two propellants affirmed to be suitable for use in metered dose inhalers, HFA 134a and HFA 227ea, are discussed with respect to their physicochemical properties and technical suitability. Comparing HFA 227ea with HFA 134a, smaller amounts of excipients such as ethanol appear to be used for HFA 227ea. Another benefit of HFA 227ea is the higher boiling point, which allows the use of both the cold and pressure filling method, thus minimizing the need for new production equipment. Furthermore, HFA 227ea is preferred for formulations liable to change due to absorption of water during the MDI shelf-life, especially in the case of hygroscopic drugs. HFA 227ea may also be used as a vapour pressure depressant to HFA 134a and for suspension-based p-MDIs in blends with HFA 134a to match the drugs density. In order to ensure that the propellants HFA 227 and HFA 134a used for the p-MDIs are compatible, Solvay Fluor & Derivate GmbH as a manufacturer of HFAs for medical aerosols (Solkane® 227 pharma and Solkane® 134a pharma) have set about investigating important new characteristics. These are, among others, the solubility of oxygen and silicone oil in the HFAs. This paper looks back over the manufacture and use of HFAs in p-MDIs as well as examining the present and future prospects. It summarises existing HFA properties relevant to p-MDI formulations adding new values important for the p-MDI technology recently determined for the first time by Solvay Fluor in HFA 227 and HFA 134a.
Bhargava Ak - One of the best experts on this subject based on the ideXlab platform.
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Anaesthetic in the garb of a propellant
Indian Journal of Anaesthesia, 2015Co-Authors: Shagun Bhatia Shah, Uma Hariharan, Bhargava AkAbstract:Sir, Serendipity is the forerunner of scientific discoveries, and anaesthesia is no exception. Pressurised metered dose inhalers are routinely used for perioperative control of reactive airway disease. They can be mounted on the proximal aspect of the standard endotracheal tube (ETT) connector for direct drug delivery to the tracheobronchial tree by puffs for treatment of bronchospasm. All these inhalers have a propellant, which aids in drug delivery. One such propellant, HFA 134a (hydrofluoroalkane: 1,1,1,2 tetrafluoroethane), is the prime suspect in our current case scenario, discovered while giving general anaesthesia through our Dragus Primus® workstation (Scio four Oxi-plus module). An American Society of Anaesthesiologists (ASA) physical status II, asthmatic patient undergoing an oncosurgical procedure developed bronchospasm immediately after endotracheal intubation following standard general anaesthesia. He was given 10–12 puffs of salbutamol inhaler via the ETT. A bright red rectangle with halothane printed in black popped on the monitor screen. Nothing abnormal, except that halothane, is not available in our operation theatre (OT) for a decade now. We use only isoflurane, sevoflurane and desflurane as inhalational anaesthetics yet the machine was falsely reading halothane. This was an extremely surprising observation, which was further investigated upon. We found that after 4–5 min the red rectangle disappeared, only to reappear before extubation seconds after the second dose of salbutamol aerosol puffs. The Drager Primus® workstation flashed a note reading “three mixed agents”(detection of three different inhalational anaesthetic agents simultaneously in the inspiratory gases – nitrous oxide, the inhalational agent being used, which was sevoflurane; and halothane!) after a time lag of approximately 30 s each time after 10–15 puffs of salbutamol aerosol inhaler. It showed inspiratory halothane as 0.5% followed by end-tidal halothane 0.5%, gradually falling to 0 after approximately 5 min depending upon the tidal volume, respiratory rate, fresh gas flow and other ventilatory parameters [Figure 1] irrespective of the inhalational agent being administered. We later found that this time lag was least with desflurane as the inhalational agent and maximum with isoflurane. Occasionally, after three or more doses of 10–12 puffs each, a peach coloured rectangle with “enflurane” printed appeared on the screen when no enflurane was being administered. Figure 1 Drager Primus Anaesthesia workstation showing the halothane red rectangle after asthalin puffs given via the endotracheal tube Both Drager Primus® workstation and Datex Ohmeda S/5® module workstations in our OT produced bizarrre response to salbutamol aerosol inhaler (Asthalin Cipla®). When salbutamol from an ampoule was given as a nebulisation in the anaesthesia circuit, there were no such observations in the agent gas monitor (AGM) of both these workstations. Hence, we concluded that the propellant hydrofluoroalkane (HFA134a), the medium for suspension of salbutamol is responsible for the interaction and not the salbutamol per se. The 134a HFA, propellant in inhalers is chemically 1, 1, 1,2-tetrafluoroethane, also known as Norflurane. In 50 vol% concentration, it can induce anaesthesia, but this moderately potent anaesthetic discovered in 1967 never underwent human trials.[1] AGMs use infrared (IR) analysers. Gases with two or more dissimilar atoms in their molecule (nitrous oxide, carbon dioxide and halogenated anaesthetics) have unique IR light absorption spectra. Absorption spectra of HFA134a match with that of halogenated volatile anaesthetics (8–12 μm range).[1,2] The mechanism of changes produced by HFA 134a-based inhalers in the two anaesthesia workstations mentioned could be as below: In S/5 Datex Ohmeda® anaesthesia workstation, misreading of the propellant as an inhalational anaesthetic so that both the inspiratory as well as expiratory values of the inhalational anaesthetic in use suddenly shoot up without the anesthesiologist changing the dial concentration. In the Drager Primus® workstation, flashing of either halothane or enflurane label (with inspiratory and end tidal concentrations as well) is because of the greater structural similarity between the propellant Norflurane and halothane vis a vis the other anaesthetic agents which the workstation is programmed to read though the monitor never mistakes the propellant for isoflurane, desflurane or sevoflurane. In our institution, we now utilize this peculiar observation as a confirmatory test for two things. Firstly, the correct placement of salbutamol puffs (denoted by inspiratory halothane concentration) and secondly, of salbutamol having reached the trachea in an adequate dose (denoted by end-tidal halothane concentration). Besides salbutamol sulphate, beclomethasone dipropionate and triamcinolone acetonide aerosol inhalers also use HFA-134a as propellant. HFA-134a is also being used as a preanaesthetic vapocoolant spray. In the 1990s, it began replacing dichlorodifluoromethane (Freon) in domestic refrigerators and automobile air conditioners as a high-temperature refrigerant.[3] It replaced chlorofluorocarbons as a propellant in inhalers in December 2008, in compliance with the United Nations Environment Program protocol on ozone depleting substances.[4,5] This is because it has an insignificant ozone depletion potential and a negligible acid rain potential.[3] This propellant has been shown to be safe and nonanaesthetic in standard inhaler doses.[4] HFA134a may result in microsomal enzyme induction.[5] Defluorination of HFA134a has been seen in rat hepatocytes.[6] Due to molecular similarity between halothane (CF3CHClBr) and propellant (CF3CH2F), further research is warranted into halothane-associated hepatitis due to anti-tri-fluoro-acetyl antibodies after repeated administration or long-term use. Because of its high global warming potential (100 years-GWP equals 1430), HFA-123a has been banned from use in Europe since 2011(starting with cars), to be completely phased out by 2017.[3,7,8] Thus, the quest for the ideal propellant for pressurised metered dose inhalers does not end with HFAs.
H Magnussen - One of the best experts on this subject based on the ideXlab platform.
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Budesonide Modulite®: Improving the changeover to CFC-free treatments
Respiratory Medicine, 2003Co-Authors: H MagnussenAbstract:Inhaled corticosteroids have been recommended by national and international guidelines as the mainstay for anti-inflammatory treatment in patients with bronchial asthma. Inhaled corticosteroids are delivered by a variety of devices such as pressurized metered dose inhalers (pMDIs), dry powder inhalers (DPIs) and nebulizers. The choice of the devices is dependent on a number of clinical factors such as severity of the disease, ability of the patient to proper usage of the device and the preference of the patient and the doctor. The latter is not always based on strong arguments. Inhalation therapy for treatment of bronchial asthma is performed since more than 200 years using ‘‘asthma cigarettes’’. The first Jet-Nebulizers were brought up in the 1930s, and in 1956, the first CFC-containing pMDI was marketed (Riker Medihaler). These devices were mainly used to deliver inhaled beta-agonists and anticholinergics to the patient, with the benefit of rapid onset of action as compared to the traditional oral route. It took nearly 20 years to develop an inhaled corticosteroid with limited side effects due to a significant first pass metabolism. Dry powder inhalers were developed later. The majority of asthmatic patients is using pMDIs worldwide. The popularity of these devices is based on their design as they are easy to use, small and portable. pMDIs designed by different companies look much more alike than DPIs. The effect of a certain drug delivered by the respiratory route is dependent on a variety of different factors which amongst others are the ability of the patient to inhale correctly and to produce a sufficient inspiratory flow. Drug deposition and the local and systemic metabolism of the compound are important factors determining the effect and the side-effects. Recently, the technology to design and produce devices for respiratory delivery has improved markedly. However in contrast to the progress in inhaler technology, adherence and compliance to the recommended therapy with inhaled corticosteroids remain a serious problem which has to be minimized in order to ensure the clinical benefit of inhaled corticosteroids in patients with bronchial asthma. Chlorofluorocarbons (CFCs) have been used in many products such as refrigeration, plastics, nonmedical aerosol, etc. pMDIs traditionally have been formulated using CFC propellants 11 and 12. The emission of CFCs into the atmosphere is harmful to the ozone layer. This resulted in an Environmental Program under the auspices of the United Nations, and over 40 nations agreed to the Montreal protocol in 1987 for the reduction and later for the cessation of the use of CFCs. The production of CFCs was stopped in 1996 except for ‘‘essential uses’’. Essential uses included the manufacturing of pMDIs containing drugs for patients with airway diseases (asthma and COPD) and on therapy with pMDIs. The European Commission (Strategy for the Phase-Out of CFCs in Metered Dose Inhalers) decided later the criteria according to which CFC containing inhalers should be withdrawn. After years of research in this area, hydrofluoroalkane (HFA) 134a (Norflurane) was selected as a ARTICLE IN PRESS
Shagun Bhatia Shah - One of the best experts on this subject based on the ideXlab platform.
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Anaesthetic in the garb of a propellant
Indian Journal of Anaesthesia, 2015Co-Authors: Shagun Bhatia Shah, Uma Hariharan, Bhargava AkAbstract:Sir, Serendipity is the forerunner of scientific discoveries, and anaesthesia is no exception. Pressurised metered dose inhalers are routinely used for perioperative control of reactive airway disease. They can be mounted on the proximal aspect of the standard endotracheal tube (ETT) connector for direct drug delivery to the tracheobronchial tree by puffs for treatment of bronchospasm. All these inhalers have a propellant, which aids in drug delivery. One such propellant, HFA 134a (hydrofluoroalkane: 1,1,1,2 tetrafluoroethane), is the prime suspect in our current case scenario, discovered while giving general anaesthesia through our Dragus Primus® workstation (Scio four Oxi-plus module). An American Society of Anaesthesiologists (ASA) physical status II, asthmatic patient undergoing an oncosurgical procedure developed bronchospasm immediately after endotracheal intubation following standard general anaesthesia. He was given 10–12 puffs of salbutamol inhaler via the ETT. A bright red rectangle with halothane printed in black popped on the monitor screen. Nothing abnormal, except that halothane, is not available in our operation theatre (OT) for a decade now. We use only isoflurane, sevoflurane and desflurane as inhalational anaesthetics yet the machine was falsely reading halothane. This was an extremely surprising observation, which was further investigated upon. We found that after 4–5 min the red rectangle disappeared, only to reappear before extubation seconds after the second dose of salbutamol aerosol puffs. The Drager Primus® workstation flashed a note reading “three mixed agents”(detection of three different inhalational anaesthetic agents simultaneously in the inspiratory gases – nitrous oxide, the inhalational agent being used, which was sevoflurane; and halothane!) after a time lag of approximately 30 s each time after 10–15 puffs of salbutamol aerosol inhaler. It showed inspiratory halothane as 0.5% followed by end-tidal halothane 0.5%, gradually falling to 0 after approximately 5 min depending upon the tidal volume, respiratory rate, fresh gas flow and other ventilatory parameters [Figure 1] irrespective of the inhalational agent being administered. We later found that this time lag was least with desflurane as the inhalational agent and maximum with isoflurane. Occasionally, after three or more doses of 10–12 puffs each, a peach coloured rectangle with “enflurane” printed appeared on the screen when no enflurane was being administered. Figure 1 Drager Primus Anaesthesia workstation showing the halothane red rectangle after asthalin puffs given via the endotracheal tube Both Drager Primus® workstation and Datex Ohmeda S/5® module workstations in our OT produced bizarrre response to salbutamol aerosol inhaler (Asthalin Cipla®). When salbutamol from an ampoule was given as a nebulisation in the anaesthesia circuit, there were no such observations in the agent gas monitor (AGM) of both these workstations. Hence, we concluded that the propellant hydrofluoroalkane (HFA134a), the medium for suspension of salbutamol is responsible for the interaction and not the salbutamol per se. The 134a HFA, propellant in inhalers is chemically 1, 1, 1,2-tetrafluoroethane, also known as Norflurane. In 50 vol% concentration, it can induce anaesthesia, but this moderately potent anaesthetic discovered in 1967 never underwent human trials.[1] AGMs use infrared (IR) analysers. Gases with two or more dissimilar atoms in their molecule (nitrous oxide, carbon dioxide and halogenated anaesthetics) have unique IR light absorption spectra. Absorption spectra of HFA134a match with that of halogenated volatile anaesthetics (8–12 μm range).[1,2] The mechanism of changes produced by HFA 134a-based inhalers in the two anaesthesia workstations mentioned could be as below: In S/5 Datex Ohmeda® anaesthesia workstation, misreading of the propellant as an inhalational anaesthetic so that both the inspiratory as well as expiratory values of the inhalational anaesthetic in use suddenly shoot up without the anesthesiologist changing the dial concentration. In the Drager Primus® workstation, flashing of either halothane or enflurane label (with inspiratory and end tidal concentrations as well) is because of the greater structural similarity between the propellant Norflurane and halothane vis a vis the other anaesthetic agents which the workstation is programmed to read though the monitor never mistakes the propellant for isoflurane, desflurane or sevoflurane. In our institution, we now utilize this peculiar observation as a confirmatory test for two things. Firstly, the correct placement of salbutamol puffs (denoted by inspiratory halothane concentration) and secondly, of salbutamol having reached the trachea in an adequate dose (denoted by end-tidal halothane concentration). Besides salbutamol sulphate, beclomethasone dipropionate and triamcinolone acetonide aerosol inhalers also use HFA-134a as propellant. HFA-134a is also being used as a preanaesthetic vapocoolant spray. In the 1990s, it began replacing dichlorodifluoromethane (Freon) in domestic refrigerators and automobile air conditioners as a high-temperature refrigerant.[3] It replaced chlorofluorocarbons as a propellant in inhalers in December 2008, in compliance with the United Nations Environment Program protocol on ozone depleting substances.[4,5] This is because it has an insignificant ozone depletion potential and a negligible acid rain potential.[3] This propellant has been shown to be safe and nonanaesthetic in standard inhaler doses.[4] HFA134a may result in microsomal enzyme induction.[5] Defluorination of HFA134a has been seen in rat hepatocytes.[6] Due to molecular similarity between halothane (CF3CHClBr) and propellant (CF3CH2F), further research is warranted into halothane-associated hepatitis due to anti-tri-fluoro-acetyl antibodies after repeated administration or long-term use. Because of its high global warming potential (100 years-GWP equals 1430), HFA-123a has been banned from use in Europe since 2011(starting with cars), to be completely phased out by 2017.[3,7,8] Thus, the quest for the ideal propellant for pressurised metered dose inhalers does not end with HFAs.
