Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Lipoproteins – e.g. – egg yolk proteins – cylomicrons – etc.
Patent
1995-05-22
1998-01-13
Tsang, Cecilia J.
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Lipoproteins, e.g., egg yolk proteins, cylomicrons, etc.
530422, 530426, 530427, 424520, 424557, 514975, C07K 1400, A61K 3542
Patent
active
057081441
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to a process for the purification of animal pulmonary surfactant by means of extraction and separation of undesired components consisting of lipidic substances of a low polar power.
DESCRIPTION OF THE BACKGROUND
Pulmonary surfactant (PS) is a vital material, coating the surface of pulmonary alveoli, which acts reducing the surface tension at the air-liquid interface, thus stabilizing alveoli and preventing them from collapsing during respiration.
Lack of PS causes a severe respiratory disease named respiratory distress, which is the cause of high morbidity and mortality, particularly in pre-term infants and in adults affected by various pathologies involving a severe pulmonary insufficiency.
The effectiveness of a substitutive therapy based on the instillation of exogenous pulmonary surfactant material in lungs has already been widely proved.
Natural surfactants and pharmaceutical compositions for the use thereof in respiratory distress have been disclosed in a number of patents: GB 2,050,832, U.S. Pat. No. 4,397,839 and EP 0,119,056 (Tokyo Tanabe); EP 0,145,005 (Veb Arzneimittel Dresden); EP 0,286,011 (Chiesi).
All of the processes for the preparation of surfactant material starting from animal lungs disclosed in said patents are substantially based on an extraction step, characterized by a number of washing, centrifugation and extraction operations, with suitable organic solvents, and a subsequent purification step in order to separate the active fraction and remove impurities as well as undesired inactive components.
The purification step is of paramount importance in obtaining an active material having a well-defined, reproducible composition.
Natural PS is a complex lipoprotein mainly consisting of phospholipids and specific proteins.
Phospholipids, particularly phosphatidylcholine (PC), its disaturated form dipalmitoyl phosphatidylcholine (DPPC) and phosphatidylglycerol play an essential role in the physiological function of natural surfactant in reducing the surface tension in alveoli.
Specific apoproteins of surfactant, identified as SP-B and SP-C, are also vital for the biological action of natural surfactant, since they promote surfactant adsorption and distribution on the lung surface.
Surfactant disclosed in GB 2,050,832 and in U.S. Pat. No. 4,397,839 is subjected to a series of dialysis, centrifugation, washing, filtration, drying (or freeze-drying) procedures in order to remove impurities and the neutral lipids and cholesterol excesses.
Nevertheless, the resulting active material has a widely variable composition, in fact the inventors: themselves, in the subsequent EP Patent 0,119,056, make use of a semi-synthetic preparation consisting of a natural lipoprotein, extracted from mammal lung, mixed with phospholipids and synthetic fatty acids, in order to obtain a better composition.
Surfactant disclosed in EP 0,145,005 is purified by extraction with a water-insoluble alcohol and subsequent separation from the fraction which is insoluble in said alcohol. However, an active material is obtained having a very low content in phospholipids, which are present in a ratio of 40-70% by weight.
On the contrary, surfactant disclosed in EP 0,286,011, which is of a completely natural origin, has a satisfactory composition characterized by a high polar lipid content and substantially free from such inactive components as carbohydrates, neutral lipids and cholesterol. In this case, the purification of the crude surfactant material is carried out by elution through a column of Lipidex.RTM., a particularly hydrophobic resin which is specifically suitable for the separation of polar lipids. However this purification method, although proving to be highly effective, suffers from a series of drawbacks industrial scale, above all the use of large amounts of chlorinated solvents.
The extraction with supercritical fluid provides an effective alternative method for the purification of natural substances.
Supercritical fluids are substances which in ambient
REFERENCES:
patent: 4749522 (1988-06-01), Kamarei
patent: 4776173 (1988-10-01), Kamarei et al.
patent: 5024995 (1991-06-01), Robertson et al.
Chiesi Paolo
Pighi Roberto
Recchia Walter
Servadio Vittorino
Ventura Paolo
Chiesi Farmaceutici S.p.A.
Mohamed Abdel A.
Tsang Cecilia J.
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