Lipid-containing compositions and uses thereof

Details Lipid-containing compositions and uses thereof Lipid-containing compositions and uses thereof

2000-02-22

2002-08-20

Pryor, Alton (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S558000, C514S560000

Reexamination Certificate

active

06436905

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates primarily to the field of biochemistry and medicine. More particularly, it is concerned with lipid-containing compositions which, in one main aspect of the invention, provide useful surfactants or solubilizing agents for certain substances, particularly drugs or other bioactive materials, and can be especially useful for producing aqueous solutions of substances that are lipid soluble but have poor aqueous solubility. Thus, they can be used as formulating and delivery agents for the formulation and/or delivery, possibly site-specific delivery, of drugs or other bioactive materials in connection with therapeutic (or cosmetic) treatment of mammals. These lipid-containing compositions also provide artificial surfactants having useful therapeutic applications in medicine, e.g. as lung surfactants or as lubricating surfactant materials for inclusion in ocular formulations or other lubricating formulations for medical use. The compositions can, however, have other uses and applications, particularly as solubilizing agents, in different areas of biochemistry or biotechnology and in the food industry for example.
BACKGROUND
There is a continual need for new or improved drug formulation and/or delivery agents, particularly for example in connection with administration of active drugs that have poor aqueous solubility. Improved drug delivery methods are also important in connection with the development of gene therapy where the drug to be administered or delivered is therapeutic genetic DNA or RNA or DNA/RNA fragments which need a carrier vehicle for protection and for facilitating take-up by target cells. Also, there is a need for improved delivery agents for achieving efficient delivery of other sensitive or unstable drugs as well as for achieving efficient delivery of drugs of poor aqueous solubility. There is moreover often a need for efficient and non-toxic solubilizing agents in other fields, for example in the food and cosmetic industries.
Also, a need has been identified for solubilising agents that can be used for solubilising proteins, especially drug receptor proteins for example within phospholipid membranes in such a way as to retain their native conformation and thereby to enable their structure to be determined e.g. by NMR spectroscopy. Elucidation of their structures in this manner may enable more efficient agents to be designed to interact with such receptors and act as potential drugs. Some embodiments of this invention may help to meet these various needs.
With regard to lung surfactants, as is well known, to achieve a proper respiratory function and gaseous exchange, all mammals secrete in their lungs a surfactant for controlling during exhalation and inhalation the surface tension of the fluid film that covers the epithelial respiratory surface lining the alveoli. The alveoli form in effect a series of minute interconnecting fluid-lined sacks, arranged so as to maximize the surface area for gaseous exchange across a fluid/air interface. However, this arrangement presents a potential physico-chemical problem for the body in that the alveoli sacks approximate in form to small bubbles subject to Laplace's law whereby the gaseous pressure within the bubble is inversely proportional to the radius or diameter and is directly proportional to the surface tension of the fluid in the boundary film. Thus, as the diameter of an alveolar sack decreases during exhalation, the pressure therein will tend to increase and this could lead to pressure disparities. Pressure disparities between the alveoli, however, would tend to force air from the smaller alveolar sacks into the larger ones, resulting in a collapse of the former. If this situation occurred in vivo subsequent expansion of the lungs would be far more difficult and the entire lungs may even collapse.
To avoid these problems mammals produce a natural surfactant to lower the surface tension of the fluid film of the alveolar surfaces when the surface area is constricted during exhalation. Conversely, the force needed to inflate the lungs is also equalised. In both cases the lungs are able to deflate and inflate uniformly with a variation in terminal size of different alveoli. Such a degree of functional control is achieved by reducing surface tension in direct proportion to the reduction in surface area and this, in turn, is achieved by an increase in the concentration of surfactant per unit area at the surface. The mechanism is similar to that employed in a Langmuir trough, whereby constriction of an insoluble monolayer squeezes water out of the interface so minimizing the cohesive forces between water molecules acting to ‘pull’ the surface together.
In human neonates, lung surfactant is synthesized around two months prior to term, enabling the lungs to inflate and normal breathing to commence at birth. However, in infants born more than two months premature the quantities of lung surfactant may be greatly reduced or completely absent and this situation prevents the lungs from inflating, resulting in the development of neonatal respiratory distress syndrome (RDS) which remains the most common cause of neonatal mortality.
Endogenous lung surfactant generally consists of 90% (wt./vol.) lipid in combination with 10% protein. The lipoidal fraction is made up of 90% phospholipid of which 80% is phosphatidylcholine (PC), with some 40-45% in the form of the dipalmitoyl ester (DPPC) and the remainder as monoenoic PC. The lipid usually also contains 10-15% phosphatidylglycerol (PG) and 7-8% cholesterol.
In early attempts to develop artificial phospholipid-based surfactants using only phospholipids, or lipoidal mixtures simulating the lipid composition of native lung surfactant, it was found that such artificial surfactants were significantly less effective than the natural product in treating RDS. In particular, it was found that the phospholipids used often failed to completely adsorb and spread at the alveolar air/fluid interface in the absence of certain apoproteins, termed surfactant proteins, which occur in endogeneous surfactant. It is believed that these surfactant proteins act to modify the assembly of phospholipids and transport the latter from T cells lining each alveolus across the aqueous subphase to form a lipid monolayer at the air interface.
This difficulty has been partly overcome by the recent introduction into clinical practice of artificial lung surfactants for treatment of RDS based upon animal derived apoprotein extracts (see Table of Commercial Surfactants below and also Table I at the end of the present description). However, although this development has revolutionized treatment of this disorder, it can result in dramatic cost increases being imposed on health care providers as these known artificial lung surfactants are generally very costly, and also they pose serious questions as to the suitability of using animal proteins in treatment of human neonates.
Table of Existing Commercially Available Artificial Lung Surfactants
Concentration
Conc.
Name
Dose/12 Hrs/Kg
Surfactant
[%]
Ratio
Exosurf*
67.5 mg/5 mls   
13.5 mg/ml
1.35
1
Curosurf
120 mg/1.5 mls
  80 mg/ml
8.0
5.9
ALEC*
100 mg/1.2 mls
83.3 mg/ml
8.33
6.2
Survanta
200 mg/8 mls  
25.0 mg/ml
2.5
1.85
*these specific artificial lung surfactants are not particularly efficient and do not contain proteins.
There is accordingly a need for an effective artificial lung surfactant that can be manufactured cheaply from synthetic materials, and the provision of such an artificial surfactant represents one object of the present invention. It will be appreciated that the implications of this work in developing an effective and cheap artificial lung surfactant may have far reaching consequences in terms of the numbers of individuals that could benefit. A conservative estimate of the mortality rate arising from respiratory distress syndrome (RDS) would suggest, based upon published statistics (“Infant mortality rates” from US Dept. Health and Human Services, 1

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