WO2005027933A1

WO2005027933A1 - Unsaturated phosphatidylcholines and uses thereof

Info

Publication number: WO2005027933A1
Application number: PCT/AU2004/001290
Authority: WO
Inventors: Yi Chen; Brian Andrew Hills
Original assignee: The Corporation Of The Trustees Of The Order Of The Sisters Of Mercy In Queensland
Priority date: 2003-09-23
Filing date: 2004-09-21
Publication date: 2005-03-31

Abstract

The present invention relates generally to a method for providing formation, ultrafiltration and/or lubrication between two or more opposing or in contact surfaces. More particularly, the present invention effects one or more of surface tension reduction anti-stick, barrier formation, ultrafiltration, lubrication and/or effector of cellular therapeutic, and regeneration between two or more surfaces by the application or absorption of an unsaturated phosphatidylcholine alone or in combination with a saturated phosphatidylcholine. The present invention further provides compositions comprising unsaturated phosphatidylcholine species alone or in combination with a saturated phosphatidylcholine and their use in the treatment and/or prophylaxis of particular medical conditions such as osteoarthritis, surgical adhesion, burns injuries, ocular disorders, ultra-filtration failure in peritoneal dialysis, barrier disorders of the skin and mucosa, middle ear disorders, as a facilitation of cellular therapeutics and regenerative medicine and for lubricating interactive surfaces in artificial joints.

Description

UNSATURATED PHOSPHATIDYLCHOLINES AND USES THEREOF

BACKGROUND OF THE INVENTION

FIELD OF THE INVENTION

The present invention relates generally to a method for providing formation, ultrafiltration and/or lubrication between two or more opposing or in contact surfaces. More particularly, the present invention effects one or more of surface tension reduction anti-stick, barrier formation, ultrafiltration, lubrication and/or effector of cellular therapeutic, and regeneration between two or more surfaces by the application or absorption of an unsaturated phosphatidylcholine alone or in combination with a saturated phosphatidylcholine. The present invention further provides compositions comprising unsaturated phosphatidylcholine species alone or in combination with a saturated phosphatidylcholine and their use in the treatment and/or prophylaxis of particular medical conditions such as osteoarthritis, surgical adhesion, burns injuries, ocular disorders, ultrafiltration failure in peritoneal dialysis, barrier disorders of the skin and mucosa, middle ear disorders, as a facilitation of cellular therapeutics and regenerative medicine and for lubricating interactive surfaces in artificial joints.

DESCRIPTION OF THE PRIOR ART

Bibliographic details of the publications referred to in this specification are also collected at the end of the description.

Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country. Phosphatidylcholine is a phospholipid which is a major constituent of cell membranes. Phosphatidylcholine is also known as PtdCho and lecithin.

Phosphatidylcholines are produced by vegetable, animal and microbial sources although the fatty acid make-up of phosphatidylcholines from plant and animal sources differ. Saturated fatty acids, such as palmitic and stearic, make up 19-24% of soy lecithin; the monounsaturated oleic acid contributes 9-11%; linoleic acid provides 56-60%; and α- linolenic acid makes up 6-9%. In egg yolk lecithin, the saturated fatty acids, palmitic and stearic, make up 41-46% of egg lecithin, oleic acid 35-38%, linoleic acid 15-18% and α- linoleic 0-1%. Soy lecithin is clearly richer in polyunsaturated fatty acids than egg lecithin. Unsaturated fatty acids are mainly bound to the second or middle carbon of glycerol. Choline comprises about 15% of the weight of phosphatidylcholine.

Surface active phospholipids (SAPL) such as phosphatidylcholines have been shown to have important roles in physiological systems although they are no part of the bi-layer of the cell membrane. They are, rather, a lamellate lining on the surface of the cell membrane. One of the most important physiological activities of SAPL is as a boundary lubricant on physiological surfaces which need to slide over one another. SAPL provides activity as both a release agent, to allow the initiation of movement between the surfaces and as a boundary lubricant to facilitate the relative movement of the surfaces. Surfaces such as the peritoneum and pleural mesothelium have almost frictionless movement at physiological speeds due to the boundary lubricant activity of SAPL adsorbed to these surfaces. The boundary lubricant activity of these molecules occurs when they are adsorbed to a surface by their polar ends, which leaves the non-polar ends comprising the fatty acid chains oriented outwards. These fatty acid chains align with neighbouring fatty acid chains to present a hydrocarbon outermost surface. This arrangement is depicted in

Figure 1 (Hills, Peritoneal Dialysis International 20: 503-515, 2000).

Previously, the majority of work in the field of research on human phosphatidylcholines has focussed on dipalmitoylphosphatidylcholine (DPPC), a phosphatidylcholine species with two saturated fatty acid chains, as the source of SAPL for two reasons. First, DPPC is the dominant phosphatidylcholine species found in the lung where the study on SAPL or surfactant started initially and where the relevant lung diseases caused by the deficiency of SAPL or surfactant have been targeted by using exogenous SAPL which contains mainly DPPC. Second, DPPC is the only one commercially available for medical treatment.

However, there have been published reports that the SAPL profiles on the surfaces of non- lung tissues are very different from that in the lung.

There is a need, therefore, to investigate the SAPL profiles on the surfaces of all the tissues where SAPL may have therapeutic or industrial value.

SUMMARY OF THE INVENTION

Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.

The present invention is predicated in part on the identification of the surface tension reduction, anti-stick, barrier formation, ultrafiltration, lubrication and cellular therapeutic and regeneration properties of unsaturated phosphatidylcholines. Lubrication in this context includes providing boundary lubrication between two or more sliding, in contact or otherwise opposing surfaces. These properties of phosphatidylcholine molecules are exploited to provide methods for the treatment and/or prophylaxis of particular medical conditions such as osteoarthritis, adhesion, burns injuries, ocular disorders, ultra-filtration failure in peritoneal dialysis, and barrier disorders of the skin and mucosa as well as providing lubrication between physiological or physical surfaces including lubrication of surgical instruments, artificial joints and catheters.

As used herein, the term "unsaturated phosphatidylcholine" refers to a compound of the general Formula (I), shown below:

wherein R and R' may be the same or different, and one or both is an unsaturated fatty acid chain. The present invention preferably relates to methods and uses of the unsaturated phosphatidylcholines selected from the list of palmitoyl-oleoyl-phosphatidylcholine (POPC), palmitoyl-linoleoyl-phosphatidylcholine (PLPC), dilinoleoyl-phosphatidylcholine (DLPC), dioleoyl-phosphotidylchloine (DOPC), stearoyl-linoleoyl-phosphatidylcholine (SLPC), stearoyl-arachidonoyl-phosphatidylcholine (SAPC) or functional homologs, analogs or derivatives thereof. The present invention, however, extends to the use of a combination of unsaturated phosphatidylcholines and a saturated phosphatidylcholine. The preferred saturated phosphatidylcholine is dipalmitoylphosphatidylcholine (DPPC). In a particularly preferred embodiment, when a combination is used, the DPPC is present in an amount of up to 20% of the total phosphatidylcholine content by weight in the composition.

In one aspect, the present invention contemplates the use of unsaturated phosphatidylcholines of the general Formula (I) alone or in combination with a saturated phosphatidylcholine as anti-stick and/or release and/or boundary lubricant agents between physiological and non-physiological surfaces.

In a preferred embodiment, the present invention contemplates a method of treating a subject suffering from undesirable adhesion of one tissue with adjacent or surrounding tissues, by administering to the subject an effective amount of one or more unsaturated phosphatidylcholine species of the general Formula (I) alone or in combination with a saturated phosphatidylcholine. Examples of such conditions characterized by undesirable adhesion include surgical adhesions and adhesion related disorders, temporary adhesion of arthritic joints and congestive disorders of the middle ear, such as serous otitis media and ocular disorders. In relation to the latter embodiment, the preferred species is an unsaturated phosphatidylcholine which is proposed to be useful for wetting the eyes and offering the required lubrication. Other ocular products contemplated herein are compositions to coat a contact lens or eye bandage or to prevent colonisation of eye surfaces with microorganisms. In this regard, the incorporation the phosphatidylcholine in eye drops is particularly preferred. The present invention also contemplates industrial uses of the unsaturated phosphatidylcholine species alone or in combination with a saturated phosphatidylcholine which exploit, inter alia, the anti-stick and/or release and/or lubrication properties thereof. In one embodiment, the anti-stick and/or release and/or lubricant properties of the unsaturated phosphatidylcholines contemplated by the present invention may be used as release agents for plastic/rubber moulding.

Another aspect of the invention, relates to the use of unsaturated phosphatidylcholines of the general Formula (I) alone or in combination with a saturated phosphatidylcholine and methods of using unsaturated phosphatidylcholines of the general Formula (I) alone or in combination with a saturated phosphatidylcholine which exploit, inter alia, their semi- permeability properties.

In a preferred embodiment, the present invention contemplates the use of unsaturated phosphatidylcholines of the general Formula (I) alone or in combination with a saturated phosphatidylcholine for the modulation of the ultrafiltration ability of a membrane. The membrane may be a physiological membrane in an animal, such as the peritoneal membrane. In a related embodiment, the present invention provides a method for the treatment of ultrafiltration failure in a subject undergoing peritoneal dialysis, said method comprising administering to the subject an unsaturated phosphatidylcholine of the general Formula (I) alone or in combination with a saturated phosphatidylcholine.

Another aspect of the present invention relates to the use of unsaturated phosphatidylcholines alone or in combination with a saturated phosphatidylcholine as therapeutic agents for thermal injuries, such as but not limited to, burns and scalds.

The unsaturated phosphatidylcholines described herein may also be used to treat conditions in a subject which are caused or exacerbated by an insufficient or damaged lipid barrier in the skin or mucosa of the subject. The methods described herein exploit, røter alia, the barrier formation properties of the phosphatidylcholines of the general Formula (I) to restore the integrity of the lipid barrier on the skin or gastric mucosa of the subject. The methods described are particularly useful for the treatment of conditions such as atopic dermatitis, psoriasis, skin aging, cornification disorders, ocular disorders, stomach ulcers, peptic ulcers, duodenal ulcers, inflammatory conditions of the airway, reactive airway disease, asthma and the like.

The present invention also demonstrates that the unsaturated phosphatidylcholines contemplated herein are more effective in reducing the coefficient of kinetic friction between two surfaces than the saturated phosphatidylcholine, DPPC. Therefore, the present invention provides unsaturated phosphatidylcholines which are superior boundary lubricants when compared to the surface active phospholipids in the prior art.

Accordingly, the present invention contemplates a method for providing boundary lubrication between two surfaces wherein at least one of the surfaces is a physiological surface in an animal, said method comprising adsorbing to one or more of said surfaces, an effective amount of one or more unsaturated phosphatidylcholine species of Formula (I) alone or in combination with a saturated phosphatidylcholine. Similarly, the present invention also contemplates a method of treating a subject requiring reduced friction between tissue surfaces, which includes rheumatic disease. This aspect of the present invention also includes the treatment and/or prevention of surgical adhesions.

Another aspect of the present invention contemplates a method to improve or restore the resilience of cartilage in a subject, said method comprising administering to subject a therapeutically effective amount of one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine. This aspect of the present invention also provides a method for the treatment of osteoarthritis, wherein an unsaturated phosphatidylcholine is administered to a joint thereby providing both boundary lubrication to the joint and/or increasing the resilience and/or cushioning of the cartilage in the joint.

The present invention also contemplates the use of the unsaturated phosphatidylcholines defined by the general Formula (I) alone or in combination with a saturated phosphatidylcholine for the lubrication of non-physiological surfaces such as medical prostheses to reduce wear, increase functional life and/or ease or facilitate installation

The present invention also contemplates the use of unsaturated phosphatidylcholines alone or in combination with a saturated phosphatidylcholine to provide lubrication between a prosthesis, medical device or instrument and a physiological surface or tissue. Examples of when this type of lubrication would be useful includes providing lubrication to prostheses and other medical devices such as catheters, electrodes, electrical leads and inserted or implanted drugs during installation in a subject.

Furthermore, the present invention contemplates the use of unsaturated phosphatidylcholines alone or in combination with a saturated phosphatidylcholine as anti- wear and anti-friction agents for the working surfaces of surgical instruments.

In a preferred embodiment of the present invention, the surgical instrument is a surgical saw, reamer or drill.

Specifically, the present invention contemplates a method of reducing the temperature of the operating surface of a surgical saw, reamer or drill temperature during operation, said method comprising adsorbing one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine onto the working surface of said surgical saw or drill.

The present invention further provides a method for the treatment of disorders of the middle ear in a patient, said method comprising administering to the patient a therapeutically effective amount of one or more unsaturated phosphatidylcholines of Formula (I) alone or in combination with a saturated phosphatidylcholine.

In a preferred embodiment, the disorder is glue ear.

The present invention further contemplates the use of compounds of Formula (I) alone or in combination with a saturated phosphatidylcholine to facilitate cellular therapeutics and regenerative medicine. In particular, the present invention contemplates a method for facilitating cellular regenerative therapy in a subject, said method comprising administering to a site in need of regeneration, a compound of general Formula (I) alone or in combination with a saturated phosphatidylcholine.

The present invention also provides lubricant compositions for medicinal or industrial use comprising one or more unsaturated phosphatidylcholine species or derivatives thereof.

The present invention further provides pharmaceutical or industrial compositions comprising one or more unsaturated phosphatidylcholines of general Formula (I) alone or in combination with a saturated phosphatidylcholine together with one or more pharmaceutically or industrially acceptable carriers and/or diluents.

The preferred saturated phosphatidylcholine, when used, is DPPC.

The composition of the present invention also has applications in wetting eyes, coating contact lenses and eye bandages and for preventing colonisation of eye surfaces with microorganisms.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 is diagrammatic representation of the mechanism by which a surfactant can impart boundary lubrication. Note that the surfactant must be first adsorbed to the surface before it can lubricate.

Figure 2 is a graphical representation showing a comparison of the osmotic pressures produced by POPC, PLPC and DPPC for the same glucose driving force.

Figure 3 is a graphical representation showing the coefficient of static friction for several unsaturated phosphatidylcholine species in comparison to DPPC, in both wet and dry conditions.

Figure 4 is a graphical representation showing the coefficient of kinetic friction for several unsaturated phosphatidylcholine species in comparison to DPPC, in both wet and dry conditions.

A summary of the abbreviations used herein is shown below in Table 1 :

TABLE 1 Abbreviations

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention relates generally to methods for facilitating surface tension reduction, anti-stick, barrier formation, ultrafiltration, lubrication and/or as an effector of cellular therapeutics and regeneration between two or more surfaces by the application of unsaturated phosphatidylcholines alone or in combination with a saturated phosphatidylcholine. Examples of uses for unsaturated phosphatidylcholines that utilise the activities identified by the present invention include: methods for providing release between two surfaces, particularly including physiological surfaces such as joints, airways and eustachian tubes; methods for improving or restoring the ultrafiltration capacity of physiological membranes, such as the peritoneal membrane; and methods for barrier formation on a surface. Based on the properties of phosphatidylcholine molecules identified in accordance with the present invention, methods are also provided for the treatment and/or prophylaxis of particular medical conditions such as osteoarthritis, adhesion, burns injuries, middle ear disorders (such as glue ear), to facilitate cellular therapeutics and regeneration ultra-filtration failure in peritoneal dialysis and barrier disorders of the skin and mucosa.

The present invention is also predicated, in part, on a method for providing boundary lubrication between two or more sliding surfaces by the by the adsorption of one of more unsaturated phosphatidylcholine species alone or in combination with a saturated phosphatidylcholine onto one or more of the sliding surfaces. Medical applications, or in- vivo use, of the unsaturated phosphatidylcholine lubricants of the present invention are particularly preferred. Lubrication of the interface of two physiological surfaces is contemplated, and therefore, the present invention contemplates treatments wherein restoration or maintenance of lubrication between the surfaces is required. The present invention also contemplates lubrication of the interaction of non-physiological surfaces with a physiological surface, such as the lubrication of surgical instruments or implants for installation into the body or contacts lenses or eye bandages. The lubrication of two non- physiological surfaces in-vivo, such as lubrication of interactive surfaces of artificial joints is also contemplated. It is to be understood that unless otherwise indicated, the subject invention is not limited to specific formulations of components, manufacturing methods, dosage regimens or the like, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

The singular forms "a", "an" and "the" include plural aspects unless the context clearly dictates otherwise. Thus, for example, reference to an unsaturated phosphatidylcholine includes a single unsaturated phosphatidylcholine, as well as two or more unsaturated phosphatidylcholines .

In describing and claiming the present invention, the following terminology is used in accordance with the definitions set forth below.

The terms "compound", "active agent", "chemical agent", "pharmacologically active agent", "medicament", "active" and "drug" are used interchangeably herein to refer to a chemical compound that induces a desired pharmacological and/or physiological effect. The terms also encompass pharmaceutically acceptable, pharmacologically active ingredients and/or industrially useful reagents comprising the active agents specifically mentioned herein including but not limited to salts, esters, amides, prodrugs, active metabolites, analogs and the like. When the terms "compound", "active agent", "chemical agent" "pharmacologically active agent", "medicament", "active" and "drug" are used, then it is to be understood that this includes the active agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, prodrugs, metabolites, analogs, etc.

Reference to a "compound", "active agent", "chemical agent" "pharmacologically active agent", "medicament", "active" and "drug" includes combinations of two or more actives such as two or more phosphatidylcholines. A "combination" also includes multi-part such as a two-part composition where the agents are provided separately and given or dispensed separately or admixed together prior to dispensation. For example, a multi-part pharmaceutical pack may have two or more unsaturated phosphatidylcholines maintained separately. A saturated phosphatidylcholine such as DPPC may also be included in the pharmaceutical pack, but only in combination with unsaturated phosphatidylcholines.

The terms "effective amount" and "therapeutically effective amount" of an agent as used herein mean a sufficient amount of the agent (e.g. unsaturated phosphatidylcholine) to provide the desired therapeutic or physiological effect or outcome. Undesirable effects, e.g. side effects, are sometimes manifested along with the desired therapeutic effect; hence, a practitioner balances the potential benefits against the potential risks in determining what is an appropriate "effective amount". The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, mode of administration and the like. Thus, it may not be possible to specify an exact "effective amount". However, an appropriate "effective amount" in any individual case may be determined by one of ordinary skill in the art using only routine experimentation.

By "pharmaceutically acceptable" carrier, excipient or diluent is meant a pharmaceutical vehicle comprised of a material that is not biologically or otherwise undesirable, i.e. the material may be administered to a subject along with the selected active agent without causing any or a substantial adverse reaction. Carriers may include excipients and other additives such as diluents, detergents, coloring agents, wetting or emulsifying agents, pH buffering agents, preservatives, and the like.

Similarly, a "pharmacologically acceptable" salt, ester, emide, prodrug or derivative of a compound as provided herein is a salt, ester, amide, prodrug or derivative that this not biologically or otherwise undesirable.

The terms "treating" and "treatment" as used herein refer to reduction in severity and/or frequency of symptoms of the condition being treated, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms of the condition and/or their underlying cause and improvement or remediation or amelioration of damage following a condition.

"Treating" a subject may involve prevention of a condition or other adverse physiological event in a susceptible individual as well as treatment of a clinically symptomatic individual by ameliorating the symptoms of the condition.

A "subject" as used herein refers to an animal, preferably a mammal and more preferably human who can benefit from the pharmaceutical formulations and methods of the present invention. There is no limitation on the type of animal that could benefit from the presently described pharmaceutical formulations and methods. A subject regardless of whether a human or non-human animal may be referred to as an individual, patient, animal, host or recipient. The compounds and methods of the present invention have applications in human medicine, veterinary medicine as well as in general, domestic or wild animal husbandry. The compositions also have industrial applications.

As indicated above, the preferred animals are humans or other primates such as orangoutangs, gorillas, marmosets, livestock animals, laboratory test animals, companion animals or captive wild animals, as well as avian species.

Examples of laboratory test animals include mice, rats, rabbits, guinea pigs and hamsters. Rabbits and rodent animals, such as rats and mice, provide a convenient test system or animal model. Livestock animals include sheep, cows, pigs, goats, horses, donkeys and camels.

Reference herein to "phosphatidylcholine" should be understood to refer to a compound of the structure shown in Formula (I) below:

wherein R and R¹ may be the same or different and each is a fatty acid chain.

Unsaturated phosphatidylcholines are to be understood as phosphatidylcholine molecules wherein at least one of the fatty acid chains (R and/or R¹) is unsaturated. This includes the situation where both fatty acid chains (R and/or R¹) are unsaturated. By "unsaturated" in the context means that the fatty acid chain contains at least one double and/or triple carbon-carbon bond.

Accordingly, as used herein, the term "unsaturated phosphatidylcholine" refers to a compound of the general Formula (I):

wherein R and R' may be the same or different, and one or both is an unsaturated fatty acid chain.

A compound of the general Formula (I) is referred to herein as such, or referred to as an "unsaturated phosphatidylcholine". In preferred embodiments of the present invention, the compound of the general Formula (I) is: (i) palmitoyl-oleoyl-phosphatidylcholine (POPC);

(ii) palmitoyl-linoleoyl-phosphatidylcholine (PLPC);

(iii) dilinoleoyl-phosphatidylcholine (DLPC);

(iv) dioleoyl-phosphotidylchloine (DOPC); (v) stearoyl-linoleoyl-phosphatidylcholine (SLPC); or

(vi) stearoyl-arachidonoyl phosphatidyl-choline (SAPC).

or a functional homolog, analog or derivative thereof.

Traditionally, phospholipids such as phosphatidylcholines have previously been known as a major constituent of cell membranes. However, the current invention is predicated, in part, on the discovery that phosphatidylcholines are also a major constituent of the outer phospholipid coating on both lung and non-lung tissues, and this layer has several physiological functions. It is proposed, therefore, that the unsaturated phosphatidylcholines of the present invention will be useful as effector molecules to facilitate cellular therapeutic, and regenerative medicine.

In particular, in cellular therapeutics, Mesenchymal Stem Cells (MSCs) are used to repair articular cartilage damage. Hyaluronic acid (HA) solution is used for carrying MSCs to the site of treatment. It is proposed herein to add an SAPL product to the media or vehicles previously provided by HA only. SAPL will 1) supply the nutrient for cell growth in cellular therapeutics; 2) provide better lubricant for existing and newly-grown cartilage tissue and 3) resolve and prevent effusion in the joint, which could be the case before and during the repairing the damaged cartilage tissue. Therefore, once the additional SAPL is introduced inside the joint, it helps with the initial surviving and later maintenance of the normal function for the newly grown cartilage. The similar situations apply to the area of regenerative medicine for making artificial blood vessels, cartilage, skin, bone, wounds, internal or external regions or organs.

Accordingly, the present invention contemplates a method for facilitating cellular regenerative therapy in a subject, said method comprising administering to a site in need of regeneration, a compound of general Formula (I) alone or in combination with a saturated phosphatidylcholine.

The cellular regeneration may involve stem cells or adult cells.

In accordance with the present invention, phosphatidylcholine profiles were obtained by determining the concentrations of different phosphatidylcholines on the surfaces of bovine articular cartilage, human peritoneum, porcine eye, porcine eustachian tube, porcine stomach, porcine brachial and equine tendon. SAPL profiles were also obtained from natural products such as egg yolk, banana fruit, banana skin and lecithin capsule containing soybean oil. The dominant phosphatidylcholine species found in non-lung tissues were determined to be POPC, PLPC, DLPC, DOPC, SLPC and SAPC which are generally referred to as unsaturated phosphatidylcholines, as they comprise at least one unsaturated fatty acid chain. This is in contrast to the lung where the saturated PC, DPPC is the dominant PC species. It was also found that the majority of phosphatidylcholine species isolated from the natural products were also unsaturated phosphatidylcholine species. The present invention contemplates the use of unsaturated phosphatidylcholines alone or in combination with a saturated phosphatidylcholine such as DPPC. When DPPC is present in an amount of up to 20% by weight of the total phosphatidylcholine content. By "up to 20%" includes <1% or 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%. By "<1%" includes 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%.

The present invention is predicated, in part, on the identification of five useful properties of unsaturated phosphatidylcholine molecules, namely: (i) anti-stick and release activity;

(ii) semi-permeability;

(iii) barrier formation; and

(iv) lubrication. (v) facilitation

The present invention also contemplates uses of, and methods incorporating the use of, unsaturated phosphatidylcholine molecules which exploit one or more of the above- mentioned properties. Described herein are several exemplary methods contemplated by the present invention, which exploit one or more of the above-mentioned properties. However, these methods and uses are provided by way of example only, and are not intended to be limiting. The present invention contemplates other uses or applications of unsaturated phosphatidylcholine molecules which exploit one or more of the above- mentioned properties.

In one aspect, the present invention contemplates the use of unsaturated phosphatidylcholines of the general Formula (I) alone or in combination with a saturated phosphatidylcholine as anti-stick, lubrication and/or release agents.

The term "anti-stick" as used herein should be understood to refer to a reduction in the ability of one surface to adhere to another, or a reduction in the tackiness of a surface. Therefore, an "anti-stick agent" should be understood as an agent that is applied to a surface to prevent adherence of the surface comprising the anti-stick agent to another surface. The term, "Release agent" as used herein, should be understood as an agent which facilitates separation of two contact surfaces, by reducing the force required to separate the surfaces when the release agent is present when compared to the force required in the absence of the release agent.

"Adherence" as contemplated herein is any form of force holding the subject surfaces together. The nature of this force in no way limits the invention, and includes adherence by chemical bond formation, dispersion forces, physical bonding and the like. Accordingly, the concept of release contemplated by the present invention, is the reduction in any of the above forces holding the surfaces together.

Accordingly, the present invention provides a method for preventing adherence or sticking between two surfaces, said method comprising administering to one or more of said surfaces an unsaturated phosphatidylcholine of the general Formula (I) alone or in combination with a saturated phosphatidylcholine.

A related aspect of the present invention provides a method for facilitating or assisting release between two or more adhered surfaces, said method comprising administering to one or more of said surfaces an unsaturated phosphatidylcholine of the general Formula (I) alone or in combination with a saturated phosphatidylcholine, wherein administration of the unsaturated phosphatidylcholine of the general Formula (I) alone or in combination with a saturated phosphatidylcholine occurs before, during or after adherence of the surfaces.

In a preferred embodiment of this aspect of the present invention, at least one of the surfaces where an anti-stick or release agent would be of -benefit is a "physiological surface". As used herein, the term "physiological surface" is to be understood to include any surface on or within the body of an animal. The present invention is particularly useful wherein the physiological surface requires low friction interaction with another physiological or non-physiological surface. Examples of such surfaces include the peritoneum, the pleural membrane, the gastrointestinal tract, the interactive surfaces of skeletal joints, eye lenses and cornea, epithelial layers such as the oesophagus and trachea, cartilage and physiological surfaces in contact with medical implants and prostheses. Further surfaces that require low-friction interaction with other surfaces would be readily identified by a person skilled in the art, and the provided examples are in no way intended to be limiting.

The present invention also provides a method of treating a subject suffering from undesirable adhesion of one tissue with adjacent or surrounding tissues, said method comprising administering to the subject an effective amount of one or more unsaturated phosphatidylcholine species of the general Formula (I) alone or in combination with a saturated phosphatidylcholine.

In a preferred embodiment, the undesirable adhesion of one tissue with adjacent or surrounding tissues occurs as a result of surgery in the subject. Such an adhesion is also referred to herein as a "surgical adhesion".

Adhesions and adhesion related disorders (ARD) are one of the most common complications of surgery. Hospital admissions for ARD rival those for heart bypass, appendectomy and other well known operations. Complications of adhesions may affect a subject even 50 years after an operation.

Adhesions are internal scars, strand like fibrous tissue which form an abnormal bond between two parts of the body after trauma, through complex processes involving injured tissues and the peritoneum. For most subjects, adhesion formation has little effect. However, for some subjects, adhesions can cause severe clinical consequences.

Adhesions usually occur in response to trauma, injury of various kinds and are an almost inevitable outcome of surgery, although this is not always the case. Any peritoneal injury can result in fibrous adhesion formation. Adhesions have been found in subjects undergoing first time surgery. For example, infection, endometriosis, chemotherapy, radiation and cancer may damage tissue and initiate adhesions. Adhesions can also form in the peritoneal cavity in response to long-term treatment on peritoneal dialysis (Rubin et al, Am. J Kidney Dis. 18: 97-102, 1991) The most common cause of adhesion formation is after surgery. Adhesions normally occur at the site of the surgical procedure. It has been shown that adhesions that form after surgery are a result of the body's normal healing process. Adhesions frequently develop during the first three to five days after surgery.

Surgical procedures most commonly associated with adhesion formation are ovarian cystectomy, myomectomy, total abdominal hysterectomy, salpingostomy/fimbrioplasty, excision of endometriosis, excision of ectopic pregnancy, cesarean section and adhesiolysis.

Following reproductive pelvic surgery performed by laparotomy, 55-100% of patients are shown to have adhesions at subsequent surgeries. The number of hospital readmissions for adhesion related complications rival the number of operations for heart bypass, hip replacements and appendix operations.

It is not unusual for several organs to be adhered to each other causing traction (pulling) of nerves. Nerve endings may also become entrapped within a developing adhesion causing severe pain.

Intestinal obstruction is one of the most severe consequences of adhesions, 30-41% of subjects who require abdominal re-operation have adhesion-related intestinal obstruction. Adhesions involving the bowel can cause a bowel obstruction or blockage. Adhesions can form elsewhere such as around the heart, spine and in the hand where they may lead to other problems (e.g. ARD).

For small-bowel obstruction, the proportion rises to 65-75%. The clinical consequences of adhesions are not confined to the gut; adhesions are a leading cause of secondary infertility in women and can cause substantial abdominal and pelvic pain.

Adhesions are almost an inevitable outcome of surgery and the problems that they cause are widespread and sometimes severe. Without limiting the present invention to any one mode of action, it is proposed herein that adhesions which result from trauma or surgery are generally preceded by physical contact of the surfaces that would normally move independently of each other. For example, as mentioned herein, adhesions often occur between bodily tissues and the peritoneum in patients after surgery. However, the anti-stick properties of the unsaturated phosphatidylcholines of the present invention are proposed to prevent sticking between the tissue surfaces which would allow the free movement of one surface relative to the other and therefore prevent the formation of adhesions.

Accordingly another aspect of the invention relates to a method of treating surgical adhesions in a subject or preventing surgical adhesions in a subject, said method comprising administering an effective amount of unsaturated phosphatidylcholine of the general Formula (I) alone or in combination with a saturated phosphatidylcholine to the subject before, during and/or after the surgical procedure.

In another embodiment, the present invention contemplates a use of unsaturated phosphatidylcholines alone or in combination with a saturated phosphatidylcholine, which exploits, ter alia, the anti-stick properties of the unsaturated phosphatidylcholine, for the treatment of arthritic joints and/or other physiological surfaces that suffer from temporary adhesion including rheumatic disease and for maintaining contact lenses in eyes.

As used herein, the term "temporary adhesion" refers to a non-permanent adhesion of two physiological surfaces. Adhesion may be considered temporary if it is not mediated by the formation of fibrous tissue which bind the two adhered surfaces together. One example of a temporary adhesion of a physiological surface is temporary adhesion of a joint which occurs as a result of insufficient lubrication. Insufficient lubrication of a joint may be caused by inflammatory or rheumatic disease and/or "squeezing out" of the synovial fluid from a joint after long periods of inactivity or pressure.

Due to the widespread and debilitating effects of osteoarthritis and other rheumatic diseases, considerable attention has been paid to developing an agent effective for irrigating arthritic joints. Such an agent would help to keep the joint mobile and reduce mechanical stress causing pain during movement. Additionally, the agent would desirably: -

(i) Reduce wear of the articular surfaces;

(ii) Facilitate release of surfaces in initiating motion; (iii) Render the surfaces hydrophobic and, hence, less permeable to fluid whose expression from the joint can contribute to the hydration of cartilage which is a common finding in arthritis; and

(iv) Facilitate cellular therapeutics and regenerative medicine.

It is to be noted that an agent of the aforementioned type would also be effective in other tissues where surfaces are in sliding contact such as the heart, lungs and in muscle fibres.

It has been recognized that one of the major components of synovial fluid is hyaluronic acid, which has a co-efficient of kinetic friction below 0.02. However, its lubricating ability fails when it is loaded above about 0.5-1 kg cm^"2. It would, therefore, fall well below the normal load of about 3 kg cm^"2 borne by the knee joints of humans.

The finding of the failure of hyaluronic acid to effectively lubricate under such loads has raised the question as to the nature of the surface active ingredient which would normally be present in a joint rendering the articular surfaces of the joint hydrophobic.

The increase in phospholipid concentration at a particular site, resulting from the introduction of an unsaturated phosphatidylcholine at the site, can serve as a release agent, that is, prevent the sticking of a joint after standing when fluids can be "squeezed out".

Thus, the surface active phospholipid can be used as a release agent when used in conjunction with the synovial fluid of a joint, or of those sites of the body where surfaces are in contact. Such a use would result in increased mobility and decreased pain, if present, at the particular site.

Accordingly, the present invention contemplates the use of one or more unsaturated phosphatidylcholine species of the general Formula (I) alone or in combination with a saturated phosphatidylcholine as release agents when said unsaturated phosphatidylcholine is used in conjunction with the synovial fluid of a particular joint or at a particular site in a body where surfaces are in contact.

In another aspect, the present invention contemplates a method for treating disorders of the middle ear using an unsaturated phosphatidylcholine of the general Formula (I) alone or in combination with a saturated phosphatidylcholine.

In a preferred embodiment, the disorder of the middle ear comprises a blockage of the eustachian tube.

Blockage of the eustachian tubes often occurs in persons experiencing discomfort arising from changes in ambient pressure, such as aviators and divers, and this can lead to pain and damage to the hearing. Partial or total blockage of the eustachian tube can potentiate the onset of serous otitis media (more commonly known as glue ear) which is a very common disorder in children in the age range of about 7 to 12. This can cause partial deafness leading to lack of attention in school and developmental problems.

Currently, the only available procedure for dealing with the problem of glue ear is to fit grommets or ventilation tubes, although antibiotics can offer short-term relief. Grommets are small plastic tubular inserts which require to be inserted by a surgical procedure involving an incision in the tympanic membrane. The procedure has disadvantages, quite apart from the need for a surgical procedure, including the risk of infection in the middle ear arising from direct contact with a contaminated environment and the requirement that the patient must avoid getting water in the treated ear, thus excluding the child from all aquatic activities. A further problem is that grommets tend to fall out.

It is also believed that the exudation of serous fluid can cause plug formation to occur in the eustachian tube in adults which can cause obstruction to air flow and thus prevent ventilation of the middle ear. This problem has major implications in underwater diving activities, aviation and emergency escape from submarines. This is also an area which is addressed by the present invention.

This aspect of the present invention is predicated, in part, upon the proposition that in the healthy natural ear, the surfaces of the eustachian tubes contain a natural lining or coating which provides easy release thus preventing or deterring the surfaces of the tubes from sticking together. This aspect of the present invention, therefore, seeks to overcome the above problems by administering an agent capable of providing the same kind of action as the natural release agent in circumstances where the natural release agent has failed or is deficient.

Therefore, according to another aspect of the present invention, there is provided a method for the treatment of disorders of the middle ear in a patient, said method comprising administering to the patient a therapeutically effective amount of one or more unsaturated phosphatidylcholines of Formula (I) alone or in combination with a saturated phosphatidylcholine .

Preferably, the unsaturated phosphatidylcholine of the general Formula (I) should be capable of persisting on the surface of the eustachian tube for at least about three months, preferably at least about six months (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months) so that the tube will retain a surface active layer over such an extended period and will be less likely to block. Preferably, the unsaturated phosphatidylcholine of the general Formula (I) is prepared as a solid which is capable of forming an adherent layer on the surface of the tube. A physical or chemical binding of the unsaturated phosphatidylcholine of the general Formula (I) to the surface of the eustachian tube is highly desirable. In a particularly preferred embodiment of the present invention, the disorder of the middle ear is serous otitis media ("glue ear").

Although the preceding examples, which exploit, wter alia, the anti-stick and release properties of unsaturated phosphatidylcholines of the general Formula (I), relate to medical uses of the unsaturated phosphatidylcholine species, the present invention also contemplates industrial application of the unsaturated phosphatidylcholine species.

Accordingly, in another aspect, the present invention contemplates the use of unsaturated phosphatidylcholines alone or in combination with a saturated phosphatidylcholine as anti- stick or release agents in an industrial process.

As used herein the term "industrial process" refers to any process wherein two non- physiological surfaces may be in contact and prevention of adhesion or sticking between the surfaces is desirable or release between two adhered surfaces is desirable. Examples of non-physiological surfaces that may be treated include:

(i) working surfaces of tools such as blades, drill bits and the like; (ii) moving mechanical parts such as gears, cogs, pistons and the like;

(iii) casts and moulds;

(iv) artificial j oints .

Other non-physiological or industrial surfaces which would benefit from the methods and uses comprising unsaturated phosphatidylcholines of the general Formula (I) would be readily apparent to one of skill in the art. Accordingly, the present invention is in no way limited to the specific examples described herein.

In a related aspect, the present invention contemplates a method for preventing adherence of a first non-physiological surface with a second non-physiological surface, said method comprising administering to the first non-physiological surface, or the interface of the first and second surfaces, an effective amount of an unsaturated phosphatidylcholine of the general Formula (I) alone or in combination with a saturated phosphatidylcholine.

As used with reference to the above aspect of the invention, the term "effective amount" refers to the amount of unsaturated phosphatidylcholine of the general Formula (I) needed to prevent adherence of the first non-physiological surface with the second surface.

In a related aspect, the present invention contemplates a method for promoting release between a first non-physiological surface with a second non-physiological or physiological surface which are adhered together, said method comprising administering to the first non- physiological surface, or the interface of the first and second surfaces, an effective amount of an unsaturated phosphatidylcholine of the general Formula (I) alone or in combination with a saturated phosphatidylcholine.

In a preferred embodiment, the anti-stick and/or release properties of the unsaturated phosphatidylcholines contemplated by the present invention may be used as release agents for plastic/rubber moulding.

Plastic or rubber products are commonly produced by pouring molten plastic into a metal mould and then removing the moulded product from the mould itself. However, rubber moulding will adhere to some extent to the metal mould by dispersion forces, even when there are no specific chemical interactions. Therefore, some degree of adherence will occur. Typically, the problems associated with this adherence are overcome by the use of release agents, which are referred to herein as "mould release agents".

Accordingly, in another aspect, the present invention contemplates the use of an unsaturated phosphatidylcholine of the general Formula (I) alone or in combination with a saturated phosphatidylcholine as mould release agents. In a related aspect, the present invention contemplates a method for providing release between and mould and a moulded object, said method comprising administering to the mould or to the interface of the mould and the moulded object, either before during or after pouring the material to be moulded into the mould, an unsaturated phosphatidylcholine of the general Formula (I) alone or in combination with a saturated phosphatidylcholine.

Another aspect of the invention, relates to uses of unsaturated phosphatidylcholines of the general Formula (I) and methods of using unsaturated phosphatidylcholines of the general Formula (I) which exploit, inter alia, the semi-permeability property of unsaturated phosphatidylcholines of the general Formula (I).

In a preferred embodiment, the present invention contemplates the use of unsaturated phosphatidylcholines of the general Formula (I) for the modulation of the ultrafiltration ability of a membrane. In a preferred embodiment, the membrane is a physiological membrane in an animal, and in an even more preferred embodiment, the membrane is the peritoneal membrane in an animal. In a yet more preferred embodiment, the membrane is the peritoneal membrane in a human, who is undergoing peritoneal dialysis.

Accordingly, another aspect of the present invention provides a method of treating a subject suffering from peritoneal ultra-filtration failure, wherein the subject is undergoing peritoneal dialysis, said method comprising administering to the patient a therapeutically effective amount of unsaturated phosphatidylcholine of Formula (I) alone or in combination with a saturated phosphatidylcholine.

"Peritoneal dialysis" is a technique whereby infusion of dialysis solution into the peritoneal cavity is followed by a variable dwell time and subsequent drainage. Continuous ambulatory peritoneal dialysis (CAPD) is a continuous treatment consisting of four to five 2-L dialysis exchanges per day. Diurnal exchanges last 4 to 6 hours, and the nocturnal exchange remains in the peritoneal cavity for 6 to 8 hours. Continuous cyclic peritoneal dialysis, in reality, is a continuous treatment carried out with an automated cycler machine. Multiple short-dwell exchanges are performed at night with the aid of an automated cycler machine. Other peritoneal dialysis treatments consist of intermittent regimens.

During peritoneal dialysis, solutes and fluids are exchanged between the capillary blood and the intraperitoneal fluid through a biologic membrane, the peritoneum. The three- layered peritoneal membrane consists of 1) the mesothelium, a continuous monolayer of flat cells, and their basement membranes; 2) a very compliant interstitium; and 3) the capillary wall, consisting of a continuous layer of mainly nonfenestrated endothelial cells, supported by a basement membrane. The mesothelial layer is considered to be less of a transport barrier to fluid and solutes, including macromolecules, than is the endothelial layer. The capillary endothelial cell membrane is permeable to water through aquaporins (radius of approximately 0.2 to 0.4 nm). In addition, small solutes and water are transported through ubiquitous small pores (radius of approximately 0.4 to 0.55 nm). Sparsely populated large pores (radius of approximately 0.25 nm, perhaps mainly venular) transport macromolecules passively. Diffusion and convection move small molecules through the interstitium with its gel and sol phases, which are restrictive owing to the phenomenon of exclusion. The splanchnic blood flow in the normal adult ranges from 1.0 to 2.4 L/min, arising from celiac and mesenteric arteries. The lymphatic vessels located primarily in the subdiaphragmatic region drain fluid and solutes from the peritoneal cavity through bulk transport.

Dialysis solution contains electrolytes in physiologic concentrations to facilitate correction of acid-base and electrolyte abnormalities. High concentrations of glucose in the dialysis solution generate ultrafiltration in proportion to the overall osmotic gradient, the reflection coefficients of small solutes relative to the peritoneum, and the peritoneal membrane hydraulic permeability. Removal of solutes such as urea, creatinine, phosphate, and other metabolic end products from the body depends on the development of concentration gradients between blood and intraperitoneal fluid, and the transport is driven by the process of diffusion. The amount of solute removal is a function of the degree of its concentration gradient, the molecular size, membrane permeability and surface area, duration of dialysis, and charge. Ultrafiltration adds a convective component proportionately more important as the molecular size of the solute increases.

Creatinine and urea clearance rates are the most commonly used indices of dialysis adequacy in clinical settings. Contributions of residual renal clearances are significant in determining the adequacy of dialysis. The mass-transfer area coefficient (MTAC) represents the clearance rate by diffusion in the absence of ultrafiltration and when the rate of solute accumulation in the dialysis solution is zero. Peritoneal clearance is influenced by both blood and dialysate flow rates and by the MTAC. Therefore, the maximum clearance rate can never be higher than any of these parameters. At infinite blood and dialysate flow rates, the clearance rate is equal to the MTAC and is mass-transfer-limited. Large molecular weight solutes are mass-transfer-limited; therefore, their clearance rates do not increase significantly with high dialysate flow rates. In CAPD, blood flow and MTAC rates are higher than is the maximum achievable urea clearance rate. However, the urea clearance rate approximately matches the dialysate flow rate, suggesting that the dialysate flow rate limits CAPD clearances.

"Peritoneal ultrafiltration failure", also referred to herein as "ultrafiltration failure" or "UFF", refers to any process whereby the ultra-filtration ability of the peritoneal membrane is reduced or impaired and there is a decrease in the clearance of compounds such as urea, creatine, uric acid or reverse dextrose from the blood of the subject undergoing peritoneal dialysis. Ultrafiltration failure can be broadly characterized into three subtypes, Type I, Type II and Type III membrane failure.

Type I membrane failure is responsible for 70-80%) of all instances of UFF. It is characterized by an increase in solute transport. This causes an increase in glucose absorption, which leads to blunting of the osmotic gradient. The etiology of type I failure is unknown. Some studies suggest severe and multiple episodes of peritonitis and time on dialysis, while others point to the use of unphysiologic dialysis solutions. Conventional dialysis solutions are considered unphysiologic because of the low pH, hyperosmolarity (glucose based solutions), presence of lactate and most importantly, glucose degradation products (GDPs) resulting from heat sterilization.

Treatment of type I membrane failure includes resting the peritoneum for at least 4 weeks and up to 16 weeks. This temporary modality change to hemodialysis has been associated with remesofhelialization of the peritoneal membrane and an increase in ultrafiltration. The continuation of more hypertonic dialysate solutions should be discouraged, as it exposes the peritoneal membrane to further damage. The dialysis prescription may need to be changed to cycling or IPD in order to improve ultrafiltration and reduce absorption. Even with these changes, ultrafiltration may still be a problem. For some patients, a permanent modality change to hemodialysis may be the only option.

Type II membrane failure, or sclerosing peritonitis, is characterized by low solute and water transport. It is relatively rare, occurring in less than 1% of peritoneal dialysis patients. The term peritoneal sclerosis encompasses a wide array of peritoneal alterations. Sclerosis refers to a thickening of the membrane. Some amount of sclerosis occurs in most peritoneal dialysis patients over time. Simple sclerosis has a low clinical impact, and rarely extends to the whole peritoneum. Sclerosing peritonitis is an entirely different story. It is characterized by a dramatic formation of thick fibrous sheaths that cover, bind and constrict the viscera, thereby, compromising the motility of the bowel. It can extend into the abdominal organs, and has a high mortality rate. Possible etiologic factors include the dialysate solutions, the presence of a peritoneal catheter (foreign body) in the peritoneum, peritonitis and the presence of autoimmune disease. Sclerosing peritonitis can occur in non-dialysis patients as well.

Treatment of type II membrane failure usually involves stopping PD and removing the catheter. Surgery may be needed if intestinal obstruction or bowel necrosis is present. Immunosuppression is used to combat the uncontrolled inflammatory process. Total parental nutrition may be necessary to rest the bowel. Due to the high mortality rate associated with type II failure, prevention measures should be undertaken. The use of more biocompatible solutions is recommended. Close adherence to diet and fluid restrictions will decrease the amount of hypertonic dialysate needed. Meticulous attention in following correct connectology procedures can help reduce the incidence of peritonitis. When signs and symptoms of peritonitis are noted, fast and complete treatment is necessary to ensure eradication of the infection.

Type III membrane failure is due to an increase in lymphatic absorption. This leads to lower net ultrafiltration. The membrane transport rates are unchanged in type III failure. It is estimated that type III membrane failure may be a contributing factor in approximately 60% of UFF. The etiology is unclear, but may be related to an increase in intraperitoneal pressure. There is a strong negative correlation between intraperitoneal pressure and net ultrafiltration. Each increase of intraperitoneal pressure of 1cm H₂O is associated with decrease ultrafiltration of 74 ml after a two-hour exchange. Diagnosis is often made by exclusion of other causes of UFF .

Existing treatments include decreasing intraperitoneal pressure by changing to CCPD or decreasing volumes. Utilizing shorter dwells and draining the patient at peak UF before extensive reabsorbtion occurs can maximize net UF.

The present invention has application for the restoration of ultra-filtration (UF) activity of the peritoneal membrane for patients undergoing all methods of peritoneal dialysis. In a preferred embodiment, the present invention, the methods of peritoneal dialysis contemplated by the invention include Continuous Ambulatory Peritoneal Dialysis (CAPD) and Automated Peritoneal Dialysis (APD).

Accordingly, yet another aspect of the invention contemplates a method for treating peritoneal ultrafiltration failure in a patient undergoing peritoneal dialysis, said method comprising administering to the patient, or the peritoneum thereof, an effective amount of one or more unsaturated phosphatidylcholines of the general Formula (I) alone or in combination with a saturated phosphatidylcholine. In a preferred embodiment, the ultrafiltration failure is Type I ultrafiltration failure, as described herein. In another preferred embodiment, the ultrafiltration failure is Type II ultrafiltration failure, as described herein. In yet another preferred embodiment, the ultrafiltration failure is Type III ultrafiltration failure, as described herein.

Another aspect of the present invention relates to the application of unsaturated phosphatidylcholines as therapeutic agents for thermal injuries such as but not limited to burns and scalds.

In the past, early post-bum treatment of bums injuries has mainly centred on the selection and amount of fluid administered to the patient. Many solutions have been evaluated for treatment efficacy including blood, plasma, isotonic crystalloid solutions and more recently some high molecular weight polymers have been evaluated (Horton et al, Ann. Surg. 211: 301, 1990).

Tissue damage from thermal injuries such as scalds and bu s is manifest by a number of microscopic and macroscopic features. Macroscopically, symptoms of thermal injury include but are not limited to swelling, haemorrhage and eschar formation. Microscopically, thermal injuries have symptoms including but not limited to oedema, vascular necrosis, vascular thrombosis, fibrin deposition, increased microvascular permeability and perivascular fibrosis.

Thermal injury also leads to damage of red blood cells. In subjects with full thickness bums, increased whole blood viscosity and sludging of red blood cells occur in small vessels and capillaries of the bum area. Thermally injured red blood cells have damaged cell membranes which have increased sensitivity to mechanical and osmotic stresses.

Animal models have indicated that intravenous surface active phospholipids administered in the immediate post-bum period can reduce the damage associated with full thickness bums, decrease wound contraction, reduce bum area temperature, increase red blood cell tolerance for thermal damage and ultimately reduce wound healing time (Paustian et al, Burns 19(3): 187-191, 1993).

In accordance with the present invention, a method for the treatment of thermal injuries using unsaturated phosphatidylcholines is provided. Without limiting the present invention to any one mode of action, it is proposed that intravenously administered unsaturated phosphatidylcholines of the general Formula (I) provide protection to the bum injury itself and also slow or halt the progressive destruction of surrounding tissues. It is considered that the therapeutic effect of the unsaturated phosphatidylcholine is predominantly by maintaining the vascular integrity and reducing the vascular permeability that is a result of the thermal injury.

Therefore, another aspect of the present invention contemplates a method for the treatment of tissue damage as a result of thermal injury, said method administering to a subject a therapeutically effective amount of one or more unsaturated phosphatidylcholines of the general Formula (I) alone or in combination with a saturated phosphatidylcholine.

In further preferred embodiment, the unsaturated phosphatidylcholine is administered to the subject as soon as possible after the bum injury and more preferably in the 12 hours post-bum period and most preferably in the 1 hour post-burn period.

Another aspect of the present invention relates to the barrier-formation properties of unsaturated phosphatidylcholines of the general Formula (I).

Phosphatidylcholines play a predominant role in the formation of a barrier on the skin and mucosa in animals. In the skin, phosphatidylcholines provide the fatty acids which are essential for the barrier layers in form of palmitic and stearic acid (saturated PC) as well as linoleic acid (unsaturated PC) for the formation of ceramide I in the epidermis.

In the epidermis, a "brick-wall" type stmcture is formed, wherein the dead comeocytes are analogous with the bricks with the intracellular lipids as the mortar. With their characteristic bi-layered stmcture, the lipids build up barrier layers which run through the epidermis like stripes. The barrier layers influence the transepidermal water loss (TEWL) which is the amount of water evaporating per hour and square centimetre of skin. On the other hand, the TEWL gives valuable information on the condition of the barrier layers. An increased TEWL means that there is a lack of barrier substances and that the skin is drying out. Where the lipid barrier of the skin is insufficient or damaged, microorganisms as well as other substances such as allergens, irritants and toxins may easily penetrate into the skin and the risk of irritations, allergies and inflammations caused by external influences increases.

Accordingly, in one aspect, the present invention provides a method for treating disorders of the skin in a subject, wherein the disorder is caused or exacerbated by an insufficient or damaged lipid barrier in the skin, said method comprising administering to said subject, or the affected skin of the subject, an effective amount of unsaturated phosphatidylcholines of the general Formula (I) alone or in combination with a saturated phosphatidylcholine.

In a preferred embodiment of the present invention, the disorder, which is caused or exacerbated by an insufficient or damaged lipid barrier in the skin, is selected from the group consisting of atopic dermatitis, psoriasis, skin aging and cornifϊcation disorders.

As used herein, the term "insufficient or damaged lipid barrier", with regard to the skin or mucosa in a subject, refers to a state of the lipid barrier in the skin or mucosa of a subject wherein the lipid barrier no longer provides optimal or suitable protection of the skin or mucosa from a microorganism, allergen, irritant, toxin or the like. An insufficient or damaged lipid barrier may be assessed by any means which would be readily ascertained by one of skill in the art. However, one diagnostic indicator of an insufficient or damaged lipid barrier is an increase in transepidermal water loss in the subject when compared to other members of the species of the subject or when compared to the subject before the event that caused the mucosa to become insufficient or damaged. Alternatively, an insufficient or damaged lipid barrier may be inferred by the subject showing symptoms of a condition which is caused or exacerbated by an insufficient or damaged lipid barrier in the skin and or mucosa of the subject. Such conditions would be readily ascertained by one of skill in the art, although exemplary conditions include: atopic dermatitis, psoriasis, skin aging, cornifϊcation disorders, stomach ulcers, peptic ulcers, duodenal ulcers, inflammatory conditions of the airway, reactive airway disease, asthma and the like.

In another aspect, the present invention relates to methods of treating disorders of the mucosa in an animal subject, wherein said disorder is caused or exacerbated by an insufficient or damaged lipid barrier in the mucosa, said method comprising administering to said subject, or the affected mucosa of the subject, an effective amount of unsaturated phosphatidylcholines of the general Formula (I) alone or in combination with a saturated phosphatidylcholine.

As used herein, the term "mucosa" relates to all mucous membranes of an animal subject. Exemplary mucosal membranes include the gastric mucosa (including the oesophagus, stomach, small intestine and large intestine), the respiratory mucosa (including the trachea, lungs and nasal mucosa), the oral mucosa, and the like.

In one embodiment, the disorder of the mucosa wherein said disorder is caused or exacerbated by insufficient lipid barrier formation in the mucosa, is a disorder of the gastric mucosa. In an even more preferred embodiment, the disorder of the gastric mucosa is a stomach ulcer, peptic or duodenal ulcer.

The direct cause of peptic ulcers is the destruction of the gastric or intestinal mucosal lining of the stomach by hydrochloric acid, an acid normally present in the digestive juices of the stomach. Infection with the bacterium Helicobacter pylori is thought to play an important role in causing both gastric and duodenal ulcers. Helicobacter pylori may be transmitted from person to person through contaminated food and water. Antibiotics are the most effective treatment for H. pylori peptic ulcers.

Injury of the gastric mucosal lining, and weakening of the mucous defences are also involved in the formation of gastric ulcers. Excess secretion of hydrochloric acid, genetic predisposition, and psychological stress are important contributing factors in the formation and worsening of duodenal ulcers.

Another major cause of ulcers is the chronic use of anti-inflammatory medications, such as aspirin. Cigarette smoking is also an important cause of ulcer foπnation and ulcer treatment failure.

Without limiting the present invention to any one theory or mode of action, it is thought that administration of exogenous unsaturated phosphatidylcholine of the general Formula (I) to the subject or the affected mucosa, completely or partially restores the barrier properties of the gastric mucosa. Complete or partial restoration of the gastric mucosa is thought to provide increased protection to the gastric mucosa from infectious agents such as H. pylori and physical or chemical insult such as hydrochloric acid

Accordingly, the present invention provides a method for treating or preventing stomach, peptic or duodenal ulcers in a subject, said method comprising administering to the subject an effective amount of unsaturated phosphatidylcholines of the general Formula (I) alone or in combination with a saturated phosphatidylcholine.

In another embodiment, the disorder of the mucosa wherein said disorder is caused or exacerbated by insufficient lipid barrier formation in the mucosa, is a disorder of the respiratory mucosa. In an even more preferred embodiment, the disorder of the respiratory mucosa is an inflammatory disorder.

In a preferred embodiment, the subject is a human.

The present invention also relates to a method of providing boundary lubrication between two surfaces, said method comprising adsorbing onto the surface to be lubricated one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine. The present invention contemplates, therefor, the use of unsaturated phosphatidylcholines as boundary lubricants. The applications of boundary lubricants are diverse, and a situation wherein a boundary lubricant would be effective would be readily ascertained by a person skilled in the relevant art.

The applications described below are exemplary applications of a boundary lubricant, with a particular focus on medical and/or therapeutic applications. However, these aspects are not intended to be limiting, and the present invention contemplates any use of an unsaturated phosphatidylcholine molecule defined by the general Formula (I) as a boundary lubricant.

Lubrication of visceral movement or the general sliding of one tissue against its neighbours is often dismissed as attributable to minimal quantities of fluid present. In engineering applications, this mode of lubrication is termed hydrodynamic lubrication, by which motion generates a wedge of fluid separating the sliding surface from its counterface, but this wedge can only be maintained at velocities well above physiological sliding speeds. The other mode of lubrication is termed boundary lubrication and depends upon the deposition from the fluid of a "boundary lubricant" that adsorbs (reversibly binds) to the surface to impart lubricity.

On physiological surfaces, it has been found that surface active phospholipid adsorbed to the surface appear lamellated (Hills, J Appl Physiol. 73: 1034-1039, 1992; Hills, J Rheumatol 17: 349-356, 1990). This mechanism exploits weak interplanar bonds of these "sheetlike" structures, and is conducive to shearing between the planes. By this mechanism, surface active phospholipids in vivo greatly reduce the coefficient of kinetic friction between sliding physiological surfaces.

Furthermore, the results of lubrication assays, as shown in Figures 3 and 4, demonstrate that the unsaturated phosphatidylcholines of the present invention, particularly POPC, are more effective in reducing the coefficient of kinetic friction between two surfaces than the saturated phosphatidylcholine (DPPC) used in the prior art. Therefore, the present invention provides unsaturated phosphatidylcholines which are superior boundary lubricants when compared to the saturated phosphatidylcholine species such as DPPC contemplated by the prior art.

Accordingly, the present invention contemplates a method for providing boundary lubrication between two surfaces wherein at least one of the surfaces is a physiological surface in an animal, said method comprising adsorbing to one or more of said surfaces, an effective amount of one or more unsaturated phosphatidylcholine species of Formula (I) alone or in combination with a saturated phosphatidylcholine.

In a related aspect, the present invention contemplates a method of treating a subject requiring reduced friction between tissue surfaces, said method comprising administering to the subject an effective amount of one or more unsaturated phosphatidylcholine species of Formula (I) alone or in combination with a saturated phosphatidylcholine.

As used herein, the term "physiological surface" is to be understood to include any surface on or within the body of an animal wherein the surface requires low friction interaction with another surface. Examples of such surfaces include the peritoneum, the pleural membrane, the gastrointestinal tract, the interactive surfaces of skeletal joints, epithelial layers such as the oesophagus and trachea and cartilage. Further surfaces that require low- friction interaction with other surfaces would be readily identified by a person skilled in the art, and the provided examples are in no way intended to be limiting.

The present invention also specifically contemplates adhesions involving adhesion of the flexor tendon to surrounding tissue.

The flexor tendons are found on the palm side of the hand. They are connected to the forearm muscles that move the fingers. The tendons emanate from the ends of these muscles and travel through a canal at the wrist called the carpal tunnel, traverse the palm, and then travel on the palm side of the fingers to attach to the bone at the end of the fingers. When the muscle contracts, this entire unit shortens and the finger therefore flexes, or bends, down to the palm. Each finger has two flexor tendons; one travels to the bone at the end of the finger (the distal phalanx), and the other travels to the middle joint of the finger (the middle phalanx) and attaches to this bone. There is a separate muscle-and- tendon unit for the thumb, which has but a single flexor tendon.

Deep lacerations of the wrist, palm, or fingers can partially or completely divide the flexor tendons. Should both tendons be completely divided, the finger is unable to bend at any of the joints. Flexor tendons have an elastic property, especially the end attached to the muscle in the forearm. When they are divided, they tend therefore to retract and separate further. A divided tendon in the finger, palm, wrist, or forearm is commonly repaired in order to restore the ability of the finger to flex (bend toward the palm).

A common result of injury to the flexor tendons and of surgery to repair flexor tendon injury is the formation of adhesions, which may subsequently limit the range of flexion and extension in the fingers of the patient. Adhesions are particularly problematic when trauma has occurred adjacent to phalangeal fractures, which may cause adhesions between the tendons and their fϊbro-osseous tunnel.

Accordingly, in another aspect, the present invention contemplates a method of treating or preventing undesirable adhesion of damaged tissue with adjacent or surrounding tissue(s), wherein said adhesion involves an adhesion of the flexor tendon in a subject, said method comprising administering to the subject a therapeutically effective amount of one or more compounds of the general Formula (I) alone or in combination with a saturated phosphatidylcholine.

An additional use is the reduction of membrane permeability such as the chorioamnionic sac. Such membrane surfaces are also rendered hydrophobic. This property is also potentially useful in the treatment of arthritic joints since an impermeable hydrophobic articular surface is desirable even if joint lubrication is hydrodynamic.

Surprisingly, the present inventors have identified that unsaturated phosphatidylcholines have superior lubricant quality when compared to both hyaluronic acid and saturated phosphatidylcholines such as DPPC.

Accordingly, the present invention provides a method of treating rheumatic disease in a subject, said method comprising administering to the affected joint(s) of the subject a therapeutically effective amount of one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine.

Osteoarthritis is a progressive disease that, inter alia, causes breakdown of the cartilage cushioning the bone ends within joints, resulting in pain and stiffness. It is one of the oldest and most common human diseases and is three times more common in women than in men. There is no cure, but proper treatment can help relieve the symptoms and prevent or correct serious joint problems.

Osteoarthritis is caused mainly by wear and tear. Other factors that contribute to its development include a family history of arthritis, overweight and overuse or injury to certain joints.

Most people do not develop signs of osteoarthritis until after age 40. It probably affects almost every person over age 60 to some extent, although not everyone has symptoms. It can affect any joint, but generally occurs in the back, neck, hips, knees, feet and hands.

Symptoms usually begin slowly and may be mild at first. Patients often report that the pain is usually worse after a lot of activity, during movement after long periods of inactivity, or before or during a change in the weather. Swelling and loss of flexibility in the joint may also occur. Over time, the cartilage that serves as a cushion between the bones may completely wear away, causing the bones to rub against each other. This can cause the bone ends to thicken and form bony growths or spurs. In the fingers these bony lumps are called Bouchard's or Heberden's nodes. In accordance with the present invention, it has been identified that decreased cushioning or resilience of the cartilage, is associated with the depletion of surface active phospholipids from the cartilage. Hence, treatment of such SAPL-depleted cartilage with one or more unsaturated phosphatidylcholines should restore the mechanical properties of the cartilage, in addition to providing boundary lubrication, as described supra.

Accordingly, another aspect of the present invention contemplates a method to improve or restore the resilience of cartilage in a subject, said method comprising administering to subject a therapeutically effective amount of one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine.

In light of the foregoing, a further aspect of the present invention contemplates a method for treating osteoarthritis, said method comprising administering to a subject, or osteoarthritic joint of a subject a therapeutically effective amount of one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine, wherein said administration provides boundary lubrication to said joint and/or increases the resilience and/or cushioning of the cartilage in said joint.

Mammals are the preferred subjects for this treatment, with humans, horses and companion animals such as cats and dogs being particularly preferred subjects.

The present invention also contemplates the use of the unsaturated phosphatidylcholines defined by the general Formula (I) for the lubrication of non-physiological surfaces such as medical prostheses.

Many prostheses, particularly artificial hip joints, undergo a gradual wear process and have a limited lifespan. The hip joint, in particular transfers very large loads wherein it carries the weight of the upper body, and the legs transfer the forces of locomotion to the torso. In spite of these conditions, an artificial hip joint can perform well for 15 years or more, depending on type and level of activity. However, the younger the patient at the time of replacement, the greater the likelihood a repeat operation may have to be considered in a normal lifespan. Moreover, as the polyethylene cup of the prosthetic joint wears and third body debris is produced, the metal surface of an artificial femoral head may become rougher. This roughness in rum may promote further abrasive wear of the polyethylene cup. This wear produces debris and although the debris particles are very small (usually less than a micron across) they are not tolerated by the human body. The body's normal cell growth and regeneration decrease in their vicinity.

The present invention provides unsaturated phosphatidylcholine molecules which have superior boundary lubricant properties when compared to previously used saturated phosphatidylcholines. The molecules of the present invention therefore, have application for the lubrication of prostheses. This lubrication would reduce friction on the interactive surfaces of the prosthesis and therefore reduce wear between said surfaces. Consequently, the methods of the present invention would also reduce the generation of sub-micron debris by a prosthesis and thereby increase the effective life of the prosthesis.

Accordingly, the present invention contemplates a method for reducing wear on, and/or increasing the functional life of, and/or easing or facilitating installation of a prosthesis, said method comprising adsorbing one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine, onto at least part of the surface of said prosthesis prior to implantation.

In a related aspect, the present invention also contemplates a prosthesis or prosthetic implant wherein the prosthesis comprises one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine, adsorbed onto at least part of the surface of said prosthesis.

In preferred embodiments of the present invention, the prosthesis is selected from the list consisting of: artificial joints, including hip and knee joints, surgical screws and plates, catheters, cochlear implants, heart valves, artificial hearts, artificial blood vessels, slow release pharmaceutical compositions, contact lenses, prosthetic tendons (including flexor tendons), pacemakers, electrical leads, electrodes, and cosmetic implants. The present invention also contemplates the use of an unsaturated phosphatidylcholine to provide lubrication between a prosthesis, medical device or instrument and a physiological surface or tissue. Examples of when this type of lubrication would be useful includes providing lubrication during the installation of prostheses and other medical devices such as catheters, electrodes, electrical leads and inserted or implanted drugs in a subject.

Accordingly, in a related aspect, the present invention contemplates the use of one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine as a general surgical lubricant.

Another aspect of the present invention relates to the use of unsaturated phosphatidylcholines alone or in combination with a saturated phosphatidylcholine as anti- wear and anti-friction agents for mechanical surfaces such as surgical instruments.

When metal mechanical parts or assemblies fail, it is usually the result of fracture, corrosion, or wear. Wear certainly seems to be the least understood of these three factors; however, its importance in medical applications should not be overlooked. It is often assumed that wear and friction are very much the same thing, but lowering friction does not necessarily lower wear. Limited experience has caused some to maintain that a direct relationship exists between higher hardness and lower wear. The fact is that large-scale testing on a variety of materials shows that these are two distinct properties. Wear and friction are quite different.

Wear can be defined as both material loss and deformation at contact surfaces. Wear results in particle generation and surface degradation. Therefore, reducing the wear of surgical instruments lowers the production of wear particles and thus the possibility of introducing foreign matter into the body. Extended instrument life and consistent performance are other reasons for instrument designers to consider means of minimizing wear. Many types of wear have been observed and classified, as discussed below (ASM Metals Handbook, 7^th Ed., Vol. 6, 1982; Schumacher, Chemical Engineering, 155-160, 1977).

Adhesive Wear: Adhesive wear is a common form of metal loss. In surgical instrument applications, adhesive wear and galling are the most frequently occurring forms of wear. Adhesive wear takes place when no outside abrasives are present between two wear surfaces. At low loads, an oxide film usually forms on the contact surfaces. This prevents metallic bonding between the mating materials but results in a low rate of wear referred to as oxidative or mild wear.

As loads are increased, a transition is reached: the oxide film breaks down and metallic bonding (cold welding) takes place between the two surfaces. This is referred to as severe metallic wear and causes rapid material loss and high wear-particle generation.

Galling is a special case of severe adhesive wear. The wear particles can no longer be accommodated by the surface roughness and contact clearances. At this point, the contact surfaces become cold welded. Further movement causes the surface metal to de-form and tear. In extreme cases, metal seizure occurs. When contact pressures are high, galling and seizure can transpire with minimal amounts of sliding (less than one revolution or fractions of a millimetre).

Abrasive Wear: Abrasive wear occurs when a hard material scratches or gouges the surface of a softer material. The abrasive material can be either of the sliding surfaces or particles between the two surfaces. When the contact stress is too low to crush the abrasive particles, the cutting action is defined as low-stress scratching abrasion. This usually results in surface scratches with little sub-surface deformation. In high-stress grinding abrasion, however, the loads are great enough to crash the abrasive material. This action usually causes permanent plastic deformation of the base metal, along with material removal. Gouging abrasion occurs when high stresses create significantly large grooves on the contact surfaces.

Erosion: Erosion is material loss from the abrasive action of moving fluids on a component. Erosion can be intentional as when high-pressure liquid streams are used to^* perform rapid machining operations.

Components that experience large pressure changes and turbulent flow can wear due to cavitation erosion. Cavitation is the formation and collapse of numerous small bubbles during turbulent flow. The ultrasonic shock of the collapsing bubbles scrubs the metal surface, which can cause long-term surface loss. Fluid valves and pumps are examples of applications in which cavitation may occur. Surface destruction is accelerated by the presence of solid particles within a fluid stream.

Wear caused by suspended solid particles is referred to as impingement erosion. A material's resistance to impingement erosion varies with the angle of particle impingement and material hardness.

Fretting: Fretting wear is material loss that takes place between tight-fitting surfaces that are subject to vibrational movements (such as riveted or otherwise-fastened joints and electrical connections). Material loss is from a combination of oxidative and abrasive wear. The oscillation of the two surfaces causes the formation of oxide films that are then abraded away by oxidized wear debris. The affected surfaces sometimes look as if they were mechanically deformed, so this wear is sometimes called false brinelling. It is also referred to as fretting corrosion, friction oxidation, chafing, fatigue or wear oxidation.

Several tests have been used by industry for measuring the wear and galling resistance of materials. Three popular ones - for which much data exist -are ASTM G 83 "Standard Test Method for Wear Testing with a Crossed-Cylinder Apparatus", ASTM G 99 "Standard Test Method for Galling Resistance of Materials" and ASTM G 99 "Standard Test Method for Pin-on-Disk Wear Testing".

For the crossed-cylinder test (ASTM G 83), two cylindrical specimens are positioned perpendicular to each other in the test machine. (Some commercially available machines have an optional force-measuring system for determining coefficients of friction.) The test equipment allows one specimen to rotate at speeds of up to 400 rpm. The second, nonrotating specimen is pressed against the moving specimen at a specified load by means of an arm and attached weights. The test duration and rotational speed are varied depending on which of three test procedures is specified. The amount of wear is determined by weighing the specimens before and after the test. Results have been reported as weight loss, but are typically converted to volume loss.

Wear is generally affected by several factors, among them materials selection, friction, surface load, sliding distance, surface hardness, surface finish and lubrication. Controlling these factors can contribute to a successful application by helping to prevent wear and premature product failure.

Friction is the resistance to movement encountered when one surface slides or attempts to slide over another. Friction is generally described as either static or dynamic. The resistance to the initiation of sliding is called static friction and is generally greater than the dynamic friction that continues once sliding has begun. Friction is expressed in terms of static and dynamic (or kinetic) coefficients.

The coefficient of friction, f, is considered to be one of the general physical properties of a material and is defined as the ratio of the sliding force to the total force pressing the two surfaces together.

A variety of testing instruments have been developed to measure the force required to initiate or sustain sliding. Both sliding and rotational set ups are commonly used. For example, a gauge may be employed to measure the force required to initiate and sustain the sliding of a block on a horizontal surface. These force measurements are then divided by the block weight to determine the static and dynamic coefficients of friction. Such a set up is referred to as a flat-on-flat (FOF) arrangement.

Torsional load cells have also been used to measure the resistance to rotation caused by pressing blocks of one material against round samples of another. In these cases, the measured resistance is divided by the normal contact load to calculate the frictional coefficients. Organic solvents are routinely used for final cleaning in unlubricated friction tests, so as to remove surface films. Oils on the contact surfaces generally alter test results by giving unusually low friction values.

Both wear and friction are important considerations in the design of medical devices, equipment and the tooling used for instrument manufacture. Many medical applications require special attention to reduce or eliminate unintentional material implantation caused by the generation of metallic debris. Patient exposure to any contamination originating from the tooling and manufacturing must also be minimized.

End-users are demanding devices that are well designed, functional and consistent in performance and appearance. Devices need to perform reliably each time they are used: it is unacceptable, for example, for instruments to bind, seize or stick. In order to meet the high expectations placed on medical devices, designers, manufacturers and engineers must consider the wear, galling, and friction characteristics of their materials and should be familiar with the available means of enhancing these critical properties.

In accordance with the present invention, it has been identified that the boundary lubricant properties of unsaturated phosphatidylcholines make them effective as both anti-wear and anti-friction agents for surgical instruments, and superior for this application over saturated phosphatidylcholines, such as DPPC.

Accordingly, another aspect of the present invention relates to a method for reducing wear on a surgical instrument, said method comprising adsorbing one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine, onto the surface of said instrument.

The present invention also provides a method of reducing friction on a surgical instrument, said method comprising adsorbing one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine, onto the surface of said instrument.

Furthermore the present invention also contemplates a surgical instrument, which comprises one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine adsorbed onto at least part of the surface of said instrument.

The use of powered surgical instruments has been shown to damage surrounding tissues by thermal necrosis. The presence of aseptic thermal necrosis has been attributed to the heat generated by excessive speeds of drilling.

One of the first reports to demonstrate the development of aseptic thermal necrosis was by Thomson (J Oral Surg. 16: 22-33, 1958). Using extraskeletal pins drilled into the mandibles of dogs, a temperature rise to 39 degrees Celsius for a 125 rpm speed to 65 degrees Celsius for the 1,000 and 2,000 rpm speeds occurred 2.5 mm from the site when no coolant was applied. The bone specimens showed acute histological reactions, mainly degeneration of osteocytes, changes in bone stainability, and tears and fragmentation of the bone around the hole edges. These reactions increased in severity with increased drill speed and increased the postoperative interval. The recommendation for minimizing the histological and thermal effects was a drilling speed of 500 rpm. A continuation of Thomson's work was done by Pallen (J. Oral Surg. 18: 400-408. 1960) and Rafel (J. Oral Surg. 20: 21-23, 1962) to include cooling, intermittent pressure, and speeds up to 350,000 rpm. Their conclusions indicate the use of a continuous water spray, intermittent cutting pressure, and short periods of cutting to reduce the temperature. For the use of speeds over 1,000 rpm, Pallen noted a delayed healing and the beginning of thermal necrosis, which resulted in nonviable bone about the pins. Rafel, on the other hand, found that high speed bur cutting, 350,000 rpm, with water spray was well tolerated by the patient and reduced postoperative complications. In accordance with the present invention, it has been observed that adsorption of an unsaturated phosphatidylcholine onto the working surface of a powered surgical instrument, reduces the temperature of said working surface during operation. This, therefore, also reduces aseptic thermal necrosis of the surrounding tissue when compared with the use of the same surgical instrument at the same speed without adsorbed unsaturated phosphatidylcholine. Furthermore, the methods of present invention allow the use of higher speed cutting for an equivalent heat output when compared to the use of 'untreated' instruments. Cutting speed should be understood to refer to the number of reciprocations or revolutions of the working surface of the saw, reamer or drill in a given time period. Accordingly, "higher speed cutting" refers to the use of the saw reamer or drill with at an increased number of reciprocations or revolutions per minute.

The term "working surface" as used herein with reference to a surgical saw, reamer or drill is the surface which is in contact with the bone, and which effects cutting, drilling or reaming of the bone. For example, in the case of a surgical saw, the "working surface" would be the blade or wire, whereas in the case of a surgical drill or reamer, the "working surface" would be the bit or reamer head, respectively.

Accordingly, the present invention contemplates a method of reducing the temperature of the working surface of a surgical saw, reamer or drill temperature during operation, wherein the method comprises adsorbing one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine onto the working surface of said surgical saw or drill.

In a further related aspect, the present invention contemplates a method of sawing, reaming or drilling bone in a subject, said method comprising the use of a surgical saw, reamer or drill which comprises one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine adsorbed onto at least part of the working surface of said surgical saw or drill, wherein the method results in reduced thermal injury and/or aseptic thermal necrosis of said bone. Administration of the unsaturated phosphatidylcholine alone or in combination with a saturated phosphatidylcholine in the form of a pharmaceutical composition is contemplated to involve any convenient method that is appropriate for the condition which it is treating. The phosphatidylcholine of the pharmaceutical composition is contemplated to exhibit therapeutic activity when administered in an amount which depends on the particular case. The variation depends, for example, on the human or animal and the phosphatidylcholine chosen. A broad range of doses may be applicable. Considering a subject, for example, from about 0.1 mg to about 10 ng of phosphatidylcholine (e.g. 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg or 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 mg or 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 mg or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 g) may be administered in this amount or per kilogram of body weight per day. When DPPC is present, it is present in an amount of up to 20% of total phosphatidylcholine weight. Dosage regimes may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered hourly, daily, weekly, monthly or other suitable time intervals or the dose may be proportionally reduced as indicated by the exigencies of the situation. The unsaturated phosphatidylcholine may be administered in a convenient manner such as by the oral, intravenous (where water soluble), intraperitoneal, intramuscular, subcutaneous, intradermal or suppository routes, implanting (e.g. using slow release molecules), directly injected into a joint, or administered directly onto a physiological surface (eg. the eustachian tube). The unsaturated phosphatidylcholine may be administered in the form of pharmaceutically acceptable nontoxic salts, such as acid addition salts or metal complexes, e.g. with zinc, iron or the like (which are considered as salts for purposes of this application). Illustrative of such acid addition salts are hydrochloride, hydrobromide, sulphate, phosphate, maleate, acetate, citrate, benzoate, succinate, malate, ascorbate, tartrate and the like. If the active ingredient is to be administered in tablet form, the tablet may contain a binder such as tragacanth, com starch or gelatin; a disintegrating agent, such as alginic acid; and a lubricant, such as magnesium stearate. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions (where water soluble). The form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of superfactants. The preventions of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thirmerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the unsaturated phosphatidylcholine in the required amount in the appropriate solvent optionally with various of the other ingredients enumerated above. Some form of sterilization is then generally carried out. Generally, dispersions are prepared by incorporating the various sterilized phosphatidylcholine into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.

In the case of sterile powders, the preferred methods of preparation are vacuum drying and the fireeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.

Pharmaceutically acceptable carriers and/or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

Therefore, in another aspect of the present invention, pharmaceutical compositions are provided, wherein said composition comprises one or more unsaturated phosphatidylcholines of the general Formula (I) alone or in combination with a saturated phosphatidylcholine together with a pharmaceutically acceptable carrier or diluent.

In further preferred embodiments of the present invention, the pharmaceutical compositions contemplated by the present invention comprise one or more of the compounds selected from the group consisting of POPC, PLPC, DLPC, DOPC, SLPC and SAPC.

Pharmaceutical compositions of saturated phosphatidylcholines, specifically DPPC, have been found to form crystals when diluted in propylene glycol, this problem was found to be further exacerbated when the compositions were kept at refrigerated temperatures, ie. less than 4°C. When used clinically, these compositions containing the crystals were found to cause fluid accumulation at the site of administration in an equine model.

However, the unsaturated phosphatidylcholines of the present invention form no such crystals in propylene glycol when prepared at a similar concentration. Therefore, the unsaturated phosphatidylcholines of the present invention have greater clinical convenience when compared to saturated phosphatidylcholines such as DPPC. This is manifest as the ability to avoid the formation of side-effect causing crystals, at higher concentrations and/or lower temperatures than compositions comprising DPPC in propylene glycol.

Specifically, in accordance with the present invention, it has been identified that solutions of unsaturated phosphatidylcholine species such as POPC, PLPC, DLPC, DOPC, SLPC and SAPC do not form crystals in the diluent at any temperature above 0°C, when prepared at a concentration of 200mg/ml or less.

Accordingly, in one preferred embodiment, the pharmaceutical composition comprises unsaturated phosphatidylcholines of the general Formula (I) alone or in combination with a saturated phosphatidylcholine together with propylene glycol as a carrier or diluent. In particularly preferred pharmaceutical composition comprises one or more of POPC, PLPC, DLPC, DOPC, SLPC and/or SAPC at a total concentration of 200mg/ml in propylene glycol.

In another preferred embodiment, the pharmaceutical composition comprises the unsaturated phosphatidylcholines of the general Formula (I) alone or in combination with a saturated phosphatidylcholine in a sterile powder form or in the form of eye drops. In relation to the latter oculus products are also be used to coat the surface of contact lens either during the manufacturing of these lens or just before they are put on by the users in order to minimise the friction damage between the contact lens and the eye surface (Lubrication) and at the same time to prevent the possible colonisation of harmful microorganisms on the surface of contact lens, therefore the infections (Barrier formation).

Also contemplated by the present invention are pharmaceutical compositions comprising one or more unsaturated phosphatidylcholine species or derivatives thereof, and optionally one or more other saturated or unsaturated phosphatidylcholine species. It is contemplated that compositions comprising one or more unsaturated phosphatidylcholine species will have distinct pharmaceutical properties when compared to compositions comprising only saturated phosphatidylcholines.

In accordance with these methods, the unsaturated phosphatidylcholine defined in accordance with the present invention may be co-administered with one or more other compounds or molecules. By "co-administered" is meant simultaneous administration in the same formulation or in two different formulations via the same or different routes or sequential administration by the same or different routes. By "sequential" administration is meant a time difference of from seconds, minutes, hours or days between the administration of the two types of molecules. These molecules may be administered in any order.

In a preferred embodiment of the present invention, the unsaturated phosphatidylcholine may be co-administered with agents that promote the adsorption of the unsaturated phosphatidylcholine onto any tissue surface. Particularly preferred agents include phosphatidylglycerol and the surfactant proteins, SP-A, SP-B, SP-C and SP-D (Chailley- Heu et al, Biochem. J. 328: 251-256, 1997).

In another aspect, the present invention provides industrial compositions, said composition comprising unsaturated phosphatidylcholines of the general Formula (I) alone or in combination with a saturated phosphatidylcholine together with an industrially acceptable carrier or diluent.

The present invention is further described by the following non-limiting Examples:

EXAMPLE 1 Phosphatidylcholine content of animal and plant tissues Phosphatidylcholine content was determined using standard assays and the results are shown in Table 2. Figure 1 also shows the mechanism of boundary lubrication.

TABLE 2 The relative percentages of Phosphatidylcholine species. D- Di, L- Linoleoyl, P- Palmitoyl, O- Oleoyl, S- Stearoyl, A- Arachidonoyl, PC - Phosphatidylcholine

EXAMPLE 2 Comparison of osmotic pressures produced by POPC, PLPC and DPPC for the same glucose driving force

Comparisons of osmotic pressures produced by POPC, PLPC and DPPC were measures using standard assays and the results are shown in Figure 2. EXAMPLE 3 Coefficients of static friction

Coefficients of static friction were measured using standard assays and the results are shown in Figure 3.

EXAMPLE 4 Coefficients of kinetic friction

Coefficients of kinetic friction were measured using standard assays and the results are shown in Figure 4.

EXAMPLE 5 Lubrication and cooling of bone saws using unsaturated phosphatidylcholines

Bone saws were lubricated with an unsaturated phosphatidylcholine species prior to and during a bone-sawing procedure in an arthroplasty (hip replacement).

Measurements of the bone saw blade temperature during the bone-sawing procedure were made using an infra-red thermometer focussed upon the saw blade as it cut through the human hip.

It was found that lubrication of the bone saw with an unsaturated phosphatidylcholine reduced the rise in temperature of the blade during operation by 40-60% when compared to an 'untreated' blade (ie. one not lubricated with an unsaturated phosphatidylcholine). This level of heat reduction is sufficient to see an associated reduction in thermal injury to the bone tissue. EXAMPLE 6 Crystallization of phosphatidylcholines in propylene glycol

During clinical trials on horses using DPPC in some cases there had been what can best be described as a "gouty reaction". Gout is caused by crystals of various minerals forming in synovial fluid. In these trials, the injectate was 400mg DPPC in 2mL of propylene glycol (PG).

Subsequent investigation identified that microcrystals of DPPC were forming in some vials of injectate, especially when these vials were stored in the refrigerator, where pharmaceuticals tend to be kept. Although this could be eliminated by heat treatment prior to injection, crystal formation in the formulation was still considered a problem.

The solubility of the unsaturated phosphatidylcholines POPC and PLPC were then examined in PG as a solvent. It was found that solutions of 200mg/mL produced no crystals. Hence, a useful clinical formulation of unsaturated phosphatidylcholine would be 400mg POPC in 2ml PG. This retains PG as the ideal FDA-approved vehicle for lipidic substances. Mixtures of unsaturated PLs would further reduce the tendency to precipitate the solute as crystals.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features. BIBLIOGRAPHY

ASM Metals Handbook, 7^th Ed., Vol. 6, 1982

Chailley-Heu et al, Biochem. J. 328: 251-256, 1997

Hills, J. Rheumatol. 77:349-356, 1990

Hills, J. Appl. Physiol. 75:1034-1039, 1992

Hills, Peritoneal Dialysis International 20: 503-515, 2000

Horton et al, Ann. Surg. 277:301, 1990

Pallen, J. Oral Surg. 75:400-408, 1960

Paustian et al, Burns 79f5 .T 87-191, 1993

Rafel, J. Oral Surg. 20:21-23, 1962

Rubin et al, Am. J Kidney Dis. 18: 97-102, 1991

Schumacher, Chemical Engineering:155-\60, 1977

Thomson, J. Oral Surg. 16:22-33, 1958

Claims

1. A method for providing one or more of anti-stick, barrier formation, ultrafiltration or boundary lubrication and/or a cellular or regenerative therapeutic said method comprising adsorbing onto the surface to be lubricated one or more compound(s) of the general Formula (I) below:

wherein:

R and R¹ may be the same or different and each is a fatty acid chain and wherein at least one of R and/or R¹ is unsaturated alone or in combination with a saturated phosphatidylcholine .

2. The method of Claim 1, wherein said surface is a physiological surface in an animal.

3. The method of Claim 1 wherein the method is employed to treat an undesirable adhesion.

4. The method of Claim 3 wherein the adhesion is a surgical adhesion or an adhesion related to temporary adhesion of arthritic joints and congestive disorders of the middle ear.

5. A method of treating rheumatic disease in a subject, said method comprising administering to the affected joint(s) of the subject a therapeutically effective amount of one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine.

6. The method of Claim 5, wherein said subject is a mammal.

7. The method of Claim 6 wherein said mammal is a human.

8. The method of Claim 6 wherein said mammal is a horse.

9. The method of any one of Claims 4 to 8, wherein said rheumatic disease is osteoarthritis.

10. A method for reducing wear on, and/or increasing the functional life of, and/or easing or facilitating installation of a prosthesis, said method comprising adsorbing one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine, onto at least part of the surface of said prosthesis prior to implantation.

11. A prosthesis or prosthetic implant wherein said prosthesis has one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine, adsorbed to at least part of the surface of said prosthesis.

12. The method of Claim 10, or prosthesis of Claim 11, wherein said prosthesis is selected from the list consisting of artificial joints, including hip and knee joints, surgical screws and plates, catheters, cochlear implants, heart valves, artificial hearts, artificial blood vessels, slow release pharmaceutical compositions, contact lenses, prosthetic tendons (including flexor tendons), pacemakers, electrical leads, electrodes, and cosmetic implants.

13. A method for reducing wear on a surgical instrument, said method comprising adsorbing one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine, onto the surface of said surgical instrument.

14. A method of reducing friction on said surgical instrument, said method comprising adsorbing one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine, onto the surface of said surgical instrument.

15. A surgical instrument, which comprises one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine, adsorbed onto at least part of the surface of said instrument.

16. The use of said surgical instrument of Claim 15.

17. The method of Claim 13 or 14, said surgical instrument of Claim 13 or use of Claim 14, wherein said surgical instrument is a surgical saw, reamer or drill.

18. A method of reducing temperature of a working surface of a surgical saw, reamer or drill temperature during operation, wherein said method comprises adsorbing one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine, onto said working surface of said surgical saw or drill.

19. A method of sawing, reaming or drilling bone in a subject, said method comprising using a surgical saw, reamer or drill which comprises one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine, adsorbed onto at least part of said working surface of said surgical saw or drill, wherein said method results in reduced thermal injury and/or aseptic thermal necrosis of said bone.

20. The use of one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine, as a surgical lubricant.

21. A method to improve or restore the resilience of cartilage in a subject, said method comprising administering to subject a therapeutically effective amount of one or more compound(s) of the general Formula (I) alone or in combination with a saturated phosphatidylcholine .

22. A method of treating or preventing undesirable adhesion of damaged tissue with adjacent or surrounding tissue(s) said method comprising administering to the subject a therapeutically effective amount of one or more compounds of the general Formula (I) alone or in combination with a saturated phosphatidylcholine.

23. The method of Claim 22, wherein said adhesion is a result of surgery.

24. The method of Claim 22, wherein said adhesion is a result of inflammation.

25. The method of Claim 22, wherein said adhesion is a result of infection.

26. The method of Claim 23 wherein said adhesion is an adhesion of the flexor tendon to surrounding tissue.

27. The method, prosthesis, surgical instrument and/or the use of any one of the preceeding claims wherein the recited compound of the general Formula (I) is palmitoyl- oleoyl-phosphatidylcholine (POPC).

28. The method, prosthesis, surgical instrument and/or use of any one of the preceeding claims wherein the recited compound of the general Formula (I) is palmitoyl-linoleoyl- phosphatidylcholine (PLPC).

29. The method, prosthesis, surgical instrument and/or use of any one of the preceeding claims wherein the recited compound of the general Formula (I) is dilinoleoyl- phosphatidylcholine (DLPC).

30. The method, prosthesis, surgical instrument and/or use of any one of the preceeding claims wherein the recited compound of the general Formula (I) is dioleoyl- phosphotidylchloine (DOPC).

31. The method, prosthesis, surgical instrument and/or use of any one of the preceeding claims wherein the recited compound of the general Formula (I) is stearoyl-linoleoyl- phosphatidylcholine (SLPC).

32. The method, prosthesis, surgical instrument and/or use of any one of the preceeding claims wherein the recited compound of the general Formula (I) is stearoyl-arachidonoyl phosphatidyl-choline (SAPC).

33. A method for treating peritoneal ultrafiltration failure in a patient undergoing peritoneal dialysis, said method comprising administering to the patient, or the peritoneium thereof, an effective amount of one or more unsaturated phosphatidylcholines of the general Formula (I) alone or in combination with a saturated phosphatidylcholine.

34. The method of Claim 33, wherein the ultrafiltration failure is Type I ultrafiltration failure.

35. The method of Claim 33, wherein the ultrafiltration failure is Type II ultrafiltration failure.

36. The method of Claim 33, wherein the ultrafiltration failure is Type III ultrafiltration failure.

37. A method for the treatment of tissue damage as a result of thermal injury, said method administering to a subject a therapeutically effective amount of one or more unsaturated phosphatidylcholines of the general Formula (I) alone or in combination with a saturated phosphatidylcholine.

38. The method of Claim 37, wherein the unsaturated phosphatidylcholine is administered to the bum injury within 12 hours of the post bum injury.

39. A method for treating disorders of the skin in a subject, wherein the disorder is caused or exacerbated by an insufficient or damaged lipid barrier in the skin, said method comprising administering to said subject, or the affected skin of the subject, an effective amount of unsaturated phosphatidylcholines of the general Formula (I) alone or in combination with a saturated phosphatidylcholine.

40. The method of Claim 39, wherein the disorder is selected from the group consisting of atopic dematitis, psorasis, skin aging and comification disorders.

41. A method for the treatment of disorders of the middle ear in a patient, said method comprising administering to the patient a therapeutically effective amount of one or more unsaturated phosphatidylcholines of Formula (I) alone or in combination with a saturated phosphatidylcholine.

42. The method of Claim 41 wherein the disorder is glue ear.

43. A method for facilitating cellular regenerative therapy in a subject, said method comprising administering to a site in need of regeneration, a compound of general Formula (I) alone or in combination with a saturated phosphatidylcholine.

44. The method of Claim 43 wherein the cellular regenerative therapy comprises stem cell proliferation.

45. The method of Claim 43 wherein the cellular regenerative therapy comprises regeneration of adult cells.

46. The method of Claim 43 or 44 or 45 wherein the site is cartilage, muscle, bone, an organ, skin, a wound or internal or external tissue region.

47. A pharmaceutical composition comprising one or more compounds of the general Formula (I) alone or in combination with a saturated phosphatidylcholine together with one or more pharmaceutically acceptable carriers or diluents.

48. The pharmaceutical composition of Claim 47 wherein said compound(s) is/are selected from the group consisting of POPC, PLPC, DLPC, DOPC, SLPC and SAPC.

49. The pharmaceutical composition of Claim 47 or 48 wherein said compound does not form crystals in the diluent.

50. The pharmaceutical composition of Claim 49 wherein said compound does not form does not form crystals in the diluent at any temperature above 0°C.

51. The pharmaceutical composition of any one of Claims 48 to 50 wherein said pharmaceutical composition comprises one or more compound(s) at a total concentration of 200 mg/ml in propylene glycol.

52. The pharmaceutical composition of any one of Claims 48 to 51 wherein the composition is in the form of eye drops.

53. A contact lens coated with the pharmaceutical composition of Claim 47.

54. An industrial composition comprising the compound of general Formula (I) alone or in combination with a saturated phosphatidylcholine.