ISSN:0894-2684    

DOI:10.1089/jam.1995.8.Suppl_1.S-2

年代:1995

数据来源: MAL

摘要:

ABSTRACTChlorofluorocarbons (CFCs) have become widely used in a variety of applications, ranging from aerosols to refrigeration, through their unique combination of the properties of nonflammability and general inertness. However, their chemical stability, which makes CFCs relatively safe and non-toxic, is also responsible for their potential to damage the environment. From 1974 opinion developed that CFCs might indirectly affect the stratospheric 'ozone layer' through their ability to transport halogens, particularly chlorine, to this level. By the mid 1980s a consensus emerged that atmospheric CFCs could contribute significantly to ozone depletion and an annual thinning (a 'hole') in the ozone layer over the Antarctic was reported. Some of the atmospheric chemistry which is believed to occur, and some of the measurements made on the ozone 'layer' are reviewed together with the environmental regulatory actions that have been taken. These are leading to a controlled rapid phase out of a number of industrial chemicals, including CFCs. The pharmaceutical industry uses significant quantities of CFCs as propellants in metered dose inhalers (MDIs). Two suitable alternative molecules, the hydrofluoroalkanes (HFAs) HFA134a and HFA227, which have the required properties but are not ozone depleting, are introduced.

ISSN:0894-2684    

DOI:10.1089/jam.1995.8.Suppl_1.S-3

年代:1995

数据来源: MAL

摘要:

ABSTRACTThe metered dose inhaler (MDI) is currently the most widely used device in the treatment of adult asthma. It is the delivery system of choice in general practice throughout the world where both MDIs and powder inhalers are available. Up to 70% of all UK adult asthma prescriptions are for an MDI and worldwide the figures are likely to be higher. The MDI can be used to dispense a variety of medications and is currently the most economical device available. The cost of converting all MDIs to equivalent powder inhalers would be prohibitive. Patients, who have difficulty coordinating the operation of an MDI, can use it with a spacer device. This obviates the need for hand-lung coordination and the requirement for more than minimal inspiratory effort. In acute attacks, there is currently no alternative to an MDI with a spacer device for effective, easily administered, emergency treatment outside the hospital environment. In an emergency, an MDI with a spacer can act more rapidly than a nebulizer because it is quicker to set up and use. The MDI is inexpensive, requires no power source and is easily portable. It is therefore important that the MDI continues to be available.

ISSN:0894-2684    

DOI:10.1089/jam.1995.8.Suppl_1.S-9

年代:1995

数据来源: MAL

摘要:

ABSTRACTThe Montreal Protocol is an international treaty to phase out chlorofluorocarbons (CFCs) and other substances which destroy stratospheric ozone. The target date for the ban in developed countries, 1 January 2000, was subsequently advanced to 1 January 1996, with CFC production allowed temporarily for uses deemed 'essential' by the Parties. Seventeen governments submitted nominations to the United Nations (UN) Environment Programme requesting essential use exemptions for metered dose inhalers (MDIs). The nominations were reviewed by committees of technical experts and recommendations were considered at the Sixth Meeting of the Parties to the Protocol in October 1994. The Parties granted an exemption for the use of CFCs in MDIs for the treatment of asthma and chronic obstructive pulmonary disease (COPD) during 1996 and 1997. The European Union (EU) accelerated its own CFC phase-out date to 1 January 1995, also building in the possibility of 'essential use' exemptions. In July 1994 the European Commission announced exemption for MDIs from this deadline. Patients and physicians can be confident that MDIs will remain available for the foreseeable future. Furthermore, the small quantity of CFCs which has been exempted for use in MDIs will add very little to the existing environmental burden in the atmosphere.

ISSN:0894-2684    

DOI:10.1089/jam.1995.8.Suppl_1.S-13

年代:1995

数据来源: MAL

摘要:

ABSTRACTAll current metered dose inhalers (MDIs) contain chlorofluorocarbons (CFCs) as the propellant. Two alternative hydrofluoroalkane propellants, HFA134a (tetrafluoroethane) and HFA227 (heptafluoropropane), are being investigated. The replacement of CFCs by HFAs has a major impact on all aspects of the MDI from the basic formulation to the tests required to assess performance. All commonly used surfactants are essentially insoluble in the HFA propellants. The performance of the metering valve is critical to reproducible delivery of drug from an MDI. However, the properties of the two HFA propellants are so different from CFCs that new elastomeric seals have had to be developed. The current CFC11 propellant, which is a liquid at low room temperatures, allows the drug to be introduced into the MDI as a liquid suspension before the metering valve is sealed to the canister. Both HFAs are gases at normal temperature and atmospheric pressure, therefore all handling as a liquefied propellant must be performed under high pressure in totally sealed systems. To ensure adequate performance of non-CFC MDIs new tests and standards have been developed and introduced. The development of non-CFC MDIs represents a challenging task to provide new, safe and efficacious MDI products with the minimum environmental impact.

ISSN:0894-2684    

DOI:10.1089/jam.1995.8.Suppl_1.S-19

年代:1995

数据来源: MAL

摘要:

ABSTRACTChlorofluorocarbon (CFC) propellants used in metered dose inhalers (MDI) must be replaced under the terms of the Montreal Protocol. Following a review of the available data, HFA134a (1,1,1,2 tetrafluoroethane) was selected as a potential alternative propellant. However, because this data was insufficient to satisfy the stringent requirements for pharmaceuticals, additional toxicological assessments were performed. These included genotoxicology, animal inhalation studies, reproductive toxicology, local tolerability and safety pharmacology studies. A special grade of HFA134a, containing relatively high concentrations of all likely impurities, was used for all pivotal studies. HFA134a was devoid of genotoxicity and had exceptional low acute toxicity. No toxicity was seen in rats or dogs exposed to concentrations of up to 5% or 12% respectively for up to one year. No fetotoxicity, effects on reproductive performance, peri- or postnatal development was demonstrated. HFA134a was devoid of oncogenic potential in rats and mice. There was no evidence of sensitisation or local irritation to the skin or eyes. All species demonstrated high systemic HFA134a concentrations. An extensive toxicological evaluation, at very high multiples of the likely patient exposure, has indicated that HFA134a is a suitable alternative to CFC propellants for MDIs.

ISSN:0894-2684    

DOI:10.1089/jam.1995.8.Suppl_1.S-29

年代:1995

数据来源: MAL

摘要:

ABSTRACTThe safety, tolerability and pharmacokinetics of the chlorine-free propellant HFA134a were assessed in healthy subjects after single and repeat doses. Absorption and disposition were investigated in healthy subjects and severe chronic obstructive pulmonary disease (COPD) patients using labelled HFA134a. There were no clinically significant changes in vital signs, ECG, pulmonary function tests and laboratory parameters measured. No serious adverse events were reported. In both subjects and patients HFA134a was mainly eliminated by exhalation within the first few minutes after administration and was distributed throughout the body with no obvious accumulation in any specific region. HFA134a was rapidly absorbed after inhalation with doserelated blood concentrations which declined rapidly after dosing (t½=31 min). Metabolism was not a significant route of elimination of HFA134a. Studies were also performed with salmeterol and salbutamol MDIs reformulated with HFA134a. The results showed that these MDIs were safe and well tolerated in healthy subjects and gave a similar pharmacodynamic response to the current MDIs

ISSN:0894-2684    

DOI:10.1089/jam.1995.8.Suppl_1.S-35

年代:1995

数据来源: MAL

摘要:

ABSTRACTCurrent metered dose inhalers (MDIs) contain chlorofluorocarbon (CFC) propellants. A new propellant HFA134a, with no effect on ozone, may be a suitable alternative. Four asthma medications, salbutamol, salmeterol, fluticasone propionate (FP) and beclomethasone dipropionate (BDP), currently containing standard CFC propellants, were formulated with HFA134a for investigation. Single doses of salbutamol (200 μg) and salmeterol (50 μg, 100 μg) provided equivalent protection against bronchial provocation, after histamine and methacholine respectively, compared with the current preparation. A double-blind 4 week study comparing the two formulations of salbutamol, used as required in mild to moderate asthma, showed similar effects on morning peak expiratory flow rates (PEFR) and inhaler use. Salmeterol (50 μg) twice daily was compared with the current formulation in a 4 week trial. Improvement in morning PEFR was similar for both formulations. A double-blind study compared the two formulations of FP (250 μg) twice daily in moderate asthmatics previously taking 400-1,000 μg of inhaled corticosteroid daily. Morning PEFR improved in both groups. Safety and tolerability of the HFA134a product were similar to current formulations. The HFA134a formulations of salbutamol, salmeterol and FP provide equivalent efficacy with a similar safety profile to the existing formulations at equivalent

ISSN:0894-2684    

DOI:10.1089/jam.1995.8.Suppl_1.S-41

年代:1995

数据来源: MAL

摘要:

ABSTRACTFocus groups were conducted with physicians, pharmacists and patients prior to semistructured interviews with physicians and patients. The survey was conducted in Spain, Germany and the UK. There were high levels of awareness of environmental issues, with ozone layer damage and global warming being of particular concern. Most respondents were aware of chlorofluorocarbon (CFC) use in aerosols and in refrigerators. However, their presence in asthma metered dose inhalers (MDIs) was much less widely known. German physicians had the highest awareness (78%) while only 1 in 10 of UK patients was aware. Patients expressed concern on learning that they inhale CFCs. Reaction to the concept of a non-CFC propellant was universally favourable, though sometimes qualified with the need for adequate safety and efficacy data. Patients expected to be informed of the change by doctors, pharmacists or patient information leaflets. Physicians expected to receive information as soon as possible but did not want patients informed until launch. Manufacturers and representatives would be the primary information sources for physicians. Pack changes should be minimised. Communicating the change to nonCFC propellants to physicians, pharmacists and patients is all important.

ISSN:0894-2684    

DOI:10.1089/jam.1995.8.Suppl_1.S-49

年代:1995

数据来源: MAL

ISSN:0894-2684    

DOI:10.1089/jam.1995.8.Suppl_1.S-53

年代:1995

数据来源: MAL