Lung surfactant compositions with dynamic swelling behavior

Details Lung surfactant compositions with dynamic swelling behavior Lung surfactant compositions with dynamic swelling behavior

2001-08-31

2004-08-03

Krass, Frederick (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S773000, C514S826000, C514S975000, C424S557000, C424S489000, C424S459000, C424S434000

Reexamination Certificate

active

06770619

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to lung surfactant compositions which are capable of forming a dynamic swelling phase when dispersed in a medium containing electrolytes. The dynamic swelling process can be observed by polarising microscopy and results in formation of a birefringent network or tubules at an air/liquid interface. The dynamic swelling process results in a spreading of the lung surfactant over an increased surface area compared to the spreading of the lung surfactant in a non-dynamic swelling phase. The spreading takes place during a specific span of time after dispersion of a lung surfactant in e.g. a physiological electrolyte solution. Hereby, a more active spreading of the lung surfactant into the alveoli can be obtained after administration to the lungs, which in turn opens the possibility to use such a composition as a carrier for therapeutically, prophylactically and/or diagnostically active substances into the lungs or other organs or body areas that are hard to access.
The invention also relates to a pharmaceutical composition and a pharmaceutical kit comprising a lung surfactant composition as well as to a method for the treatment, prevention and/or diagnose of respiratory distress syndrome (IRDS or ARDS) or other pulmonary diseases that are associated with a deficiency of a lung surfactant.
BACKGROUND OF THE INVENTION
Lung surfactants (LS) are complex and highly surface-active materials composed of lipids and proteins that are found in the fluid lining the alveolar surface of the lungs. Their principal property is to reduce the surface tension in the lungs, which is achieved through the presence of the lipids as an organised structure at the air-liquid interface in the alveoli. LS prevents alveolar collapse at low lung volumes and decreases the work of breathing during normal and forced respiration (biophysical functions). In addition, it is involved in the protection of the lungs from injuries and infections caused by inhaled particles and microorganisms (immunological, non-biophysical functions). LS is synthesised and secreted by alveolar type II cells. (For a review, see Robertson and Taeusch, 1995.)
The constitution of a lung surfactant may vary with various factors such as species, age, and general health conditions of the subject. Various natural and synthetic constituents can substitute for each other in a surfactant. Therefore, even a non-rigorous definition of what the lung surfactant is and what should be included in a lung surfactant for therapeutic use is dependent on the situation. Surfactants isolated from lung lavage of healthy mammals contain about 10% protein (half of which is surfactant specific), and about 90% lipids, of which about 80% are phospholipids and about 20% are neutral lipids, including about 10% unesterified cholesterol. The phospholipid fraction contains mostly (about 76%) phosphatidylcholine (PC), about two thirds is dipalmitoyl phosphatidylcholine (DPPC), and the rest is unsaturated. About 11% of the phospholipids are made up of phosphatidylglycerol (PG), about 4% phosphatidylinositol, about 3% phosphatidylethanolamine, about 2% phosphatidylserine, about 1.5% sphingomyelin and about 0.2% lysophosphatidylcholine. Surfactant protein A (SP-A) represents 4% of surfactant and SP-B and SP-C and SP-D each make up less than 1%, according to current estimates.
SP-A and SP-D belong to the collectin subgroup of the G-type lectin superfamily. SP-A binds dipalmitoyl phosphatidylcholine and SP-D binds phosphatidylinositol. SP-A also interacts with alveolar type II cells, implicating SP-A in surfactant phospholipid homeostasis. SP-A is required for the formation of tubular myelin from secreted lamellar body material.
Surfactant deficiency remains the most common and serious pulmonary affliction of premature infants. Surfactant deficiency is the major factor responsible for respiratory distress syndrome of the newborn (IRDS) and for adult respiratory distress syndrome (ARDS). Since the 1960′s, the exogenous administration of lung surfactant for the treatment of these syndromes has been studied.
A pathophysiologic role for surfactant was first appreciated in premature infants with respiratory distress syndrome (IRDS) and hyaline membrane disease Use of exogenous lung surfactant and corticosteroid administration has made a major impact on improving survival and reducing morbidity in this disease with consequent alterations in the clinical and radiographic course.
Initial attempts at improving the treatment of RDS with lung surfactant replacement during the 1960′s (Chu et al., 1967) failed, largely because of a lack of knowledge about lung surfactant compositions and distributions. Liggins and colleagues (Liggins et al., 1972) were the first to utilise corticosteroids for the enhancement of foetal lung maturation, thereby reducing the risks and complications of RDS after birth. It is feasible that combining corticosteroids with thyroid-releasing hormone will enhance prenatal prophylaxis for RDS, and also inositol can be given as a substrate for lung surfactant production to infants in the early course of RDS.
A number of approaches for the design and the use of lung surfactant replacement for RDS have also been tried. The most straightforward approach is to replace with human lung surfactant. Human pulmonary lung surfactant can only be harvested by lavage procedures, though, which may disrupt its preexisting biophysical and biochemical microorganisation. As seen in a study by Hallman and co-workers, (Hallman et al., 1983), such a preparation was successful in clinical trials, but because of the difficulties in obtaining large quantities of human lung surfactant, it is not in commercial production.
These limitations make the production of synthetic lung surfactant desirable A second approach is therefore to learn the functions of the various lung surfactant constituents and then construct lung surfactants that might be more easily obtained or less expensive than the isolation of the natural products.
Exosurf is a commercially available preparation containing DPPC, hexadecanol and tyloxapol. Hexadecanol and tyloxapol mimic, to some degree, the functions of surfactant proteins, PG and other lipids in natural lung surfactant. Several groups have added surfactant proteins to lipids, designing the proteins to mimic structure and function of native surfactant proteins.
Furthermore, there are new strategies that add surfactant proteins to lipid mixtures that include formulating proteins using de novo peptide synthesis or recombinant DNA techniques (Yao et al., 1990)
An ideal therapeutic lung surfactant should share many of the attributes of any ideal therapy. It should be stable, readily available, easy to make, inexpensive and have an easy route of administration, a half-life consonant with the disease process, and fully understood mechanisms of action, metabolism and catabolism. It should have maximum efficacy for the disease without toxicity, intolerance, immunogenicity or side effects. It should mimic the effects of the natural lung surfactant, improve the gas exchange in the lungs, improve lung mechanics, improve functional residual capacity, resist inactivation, display optimal distribution characteristics, and have a known clearance mechanism. Its use should completely reverse the primary disease process and repair or allow the body to repair secondary damage from the primary disease.
Available therapeutic lung surfactants are of two types: those that are prepared from mammalian lungs and those made from synthetic compounds. Bovine and porcine surfactants contain SP-8 and SP-C, associated with phospholipids, but SP-A and SP-D are only present in the whole natural surfactant. Examples of synthetic lung surfactants that are commercially available at present are Exosurf and ALEC.
The commercially available lung surfactants are mostly presented as ready-mixed liquids, but Exosurf and Alveofact are supplied as a lyophilised powder that has to be reconstituted with saline before use.
Surfactant therapy is at pres

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