Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2001-09-17
2004-11-30
Page, Thurman K. (Department: 1616)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S046000, C424S043000, C424S489000, C424S450000, C514S826000, C514S851000
Reexamination Certificate
active
06824761
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to pharmaceutical products for use in the treatment of asthma and to deliver devices including the products.
This invention relates to pharmaceutical products for use in the treatment of asthma and to delivery devices including the products.
It has been estimated that asthma affects between 4 and 10 percent of the population, causing distress and alarm to both sufferers and bystanders. Asthma attacks appear to be precipitated in many cases by a number of factors such as exercise or pollutants in the inspired air. Other agents such as pollen and airborne particles may predispose an asthma sufferer to an attack by sensitising the airways. This has led to the belief that effective treatment should include administration of drugs which reduce the sensitivity of asthma sufferers to allergens or which neutralise the allergic reaction.
The lungs and airways of non-asthmatics may contain a natural protective barrier which prevents pollutants and other potential irritants from reaching receptors which would otherwise produce an acute attack. Studies have suggested that it is possible to simulate in the lungs of asthma sufferers the situation in normal lungs by causing surface-active phospholipids (SAPL) to bind to the tissue surface of the lungs, thereby reducing the number of receptors exposed to noxious stimuli and reducing the broncho-constrictor reflex.
SAPLs are used clinically for the treatment of respiratory distress syndrome (RDS) in neonates. In this role, it has been assumed that the SAPL functions by reducing the high surface tension forces at the air-water interface within the alveoli, thereby reducing the pressure needed to expand the lungs, see Bangham et al., Colloids & Surfaces, 10 (1984), 337 to 341. Thus, commercially available formulations of SAPL have been designed co spread rapidly over an air-aqueous interface, thereby reducing what is otherwise a very high surface tension of water.
Limited clinical studies have been carried out to determine the effect of commercial SAPLs marketed for treatment of RDS in neonates on asthmatic subjects,—see Kurashima et al Jap. J. Allergol 1991; 40, 160. This paper reported some amelioration of bronchoconstriction in asthmatic adults using an SAPL obtained by extraction from bovine lungs. In another study on children, also using an SAPL obtained from bovine lungs, no significant changes in lung function or histamine response were found,—see Oetomo et al—American Journal of Respiratory and Critical Care Medicine 153; 1996, page 1148.
EP 0 528 034A describes the use of pulmonary surface active material as an ingredient of an antiasthmatic, which is in the form of a liquid or suspension for injection or spraying into the patient's air way.
The invention provides a therapeutic combination product for use in the prevention and/or treatment of asthma comprising
(a) a medicament comprising a surface active phospholipid (SAPL) composition in finely divided form, the SAPL including a component which enhances spreading of the medicament over a surface at about normal mammalian body temperature; and
b) an antiasthma drug;
wherein ingredients (a) and (b) are provided in a form for administration together or separately.
It is believed that the finely divided powder of ingredient (a), which preferably comprises at least first and second components, has two important effects:
First, the medicament (a) has surfactant properties, which enable it to spread rapidly over the surfaces of the lungs and air passages. It is an important feature of the present invention that the medicament (a) is in the form of a powder, that is, it is in solid form. The “dry” surfactant has a high surface activity. It is believed that, on contact of a first component of the medicament (a) with the mucous within the lungs, the presence of a second component results in a lowering of the melting point of the first component, promoting rapid spreading of the first component over the liquid-air interface as a thin film at body temperature. For example, the normal melting temperature of dipalmitoyl phosphatidyl choline, which is a preferred first component is about 40° C., that is, above the normal body temperature. When used in combination with a suitable second component, such as a phosphatidyl glycerol, however, the melting point of the dipalmitoyl phosphatidyl choline can in effect be reduced to below the normal body temperature.
Second, once the surface active medicament is in situ over the surfaces of the lungs and air passages, a component of the composition is thought to migrate across the mucous layer enabling a thin hydrophobic lining or coating co be adsorbed onto the tissue surface. Thus, over and above the surface tension reducing properties mentioned above the medicament of the invention is believed to provide a protective effect by virtue of the adsorbed layer in binding to the epithelium, the phospholipid may mask the irritant receptors which elicit the bronchorestrictor reflex, that is, which cause narrowing of the bronchi.
The medicament (a) is in finely divided solid form. It is believed that, as a consequence of the high surface activity of medicament (a) in that form there results a significant drop in surface tension on contact with the aqueous mucous layer of the lung, giving enhanced effectiveness of ingredient (a) and permitting improved access to the lung surfaces for the antiasthma drug(s) to be administered. Thus, the use of the medicament (a) in combination with an antiasthma drug is believed to enhance the effectiveness of the antiasthma drug.
Moreover, as mentioned above, the binding of the phospholipid component to the lung surface is believed to reduce bronchorestrictor as a consequence of a reduction, in receptor-mediated activity attributable to the masking of irritant receptors. That reduced bronchorestriction acts cumulatively with the anti-bronchorestrictive activity of the antiasthma drug. Thus, in some circumstances it may be possible for dosages of an antiasthma drug to be administered to a given patient to be reduced, as a consequence of the synergistic effect of medicament (a) in enhancing the effectiveness of the antiasthma drug as well as the additional anti-bronchorestrictive activity of medicament (a) itself.
“Finely divided” as used herein means that the material has a particle size distribution which is such that at least a major proportion by weight of the particles are small enough to enter into a patient's airways and, preferably, deep into the lungs when inhaled. In practice, the first and second components preferably each have a particle size distribution which is such that not less than 90%, by weight, of the particles of those components in combination, and more preferably of each of the first and second components, have a particle size of not greater than 10 &mgr;m, and especially of not greater than 5 &mgr;m. Advantageously, the median particle size of the combined first and second components, and more preferably of each of the first and second components is not more than 10 &mgr;m, and preferably not more than 5 &mgr;m. The median particle size may be less than 3 &mgr;m, for example, about 1.2 &mgr;m. It may be desirable in some circumstances for the particles to have a median particle size of at least 0.5 &mgr;m. The size of the particles may be calculated by laser diffraction, or by any other method by which the aerodynamic diameter of particles can be determined. “Median particle size” as used herein means mass median aerodynamic diameter (“MMAD”). The MMAD may be determined using any suitable method, for example, using a Multi-Stage Liquid Impinger in accordance with the method described in European Pharmacopoeia (supplement 1999) 2.9.18 (Aerodynamic assessment of fine particles). Alternatively, the size distribution of the particles may be characterised by their volume mean diameter (VMD). Advantageously, the VMD is not more than 10 &mgr;m, for example not more than 5 &mgr;m, and preferably less than 3 &mgr;m. Finely divided dry powders of this kind (which ma
Hills Brian Andrew
Staniforth John Nicholas
Woodcock Derek Alan
Britannia Pharmaceuticals Limited
Haghighatian Mina
Page Thurman K.
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