WO2011158237A1 - Phosphatidylcholine lipid liposomes as boundary lubricants in aqueous media - Google Patents
Phosphatidylcholine lipid liposomes as boundary lubricants in aqueous media Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/10—Materials for lubricating medical devices
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/24—Materials or treatment for tissue regeneration for joint reconstruction
Definitions
- Liposomes are vesicles whose membranes in most cases are based on phospholipid bilayers. They are generally biocompatible and, when modified with other molecules, are widely used in clinical applications, primarily as drug delivery vehicles, as well as in gene therapy and for diagnostic imaging.
- WO 08/038292 by some of the present inventors, disclosed, inter alia, multilamellar vesicles (LVs) of several phospholipids above their liquid-crystalline-phase to gel-phase transition temperature Tm as possible boundary lubricants in the articular cartilage environment.
- LVs multilamellar vesicles
- Boundary lubrication in aqueous media is often problematic as water on its own is not a good lubricant, while common surfaces or surface coatings in water frequently exhibit quite high friction (with friction coefficients ⁇ > 0.01 - 0.05), especially at high pressures .
- US 6,800,298 describes a lubricant composition comprising dextran-based hydrogel with lipids.
- gel-phase liposomes are known to transform from their gel (solid) phase to liquid crystalline phase at a characteristic temperature designated T m , defined as the temperature at which the maximal change in the excess heat capacity ( kcal/mol/deg) occurs.
- T m characteristic temperature
- the lubrication properties of gel phase liposomes, namely, liposomes applied onto surfaces at a temperature which is lower than their T m were tested and were found to be particularly good. It has been found that gel-phase liposomes are especially useful for lubricating surfaces that are subject to high pressure, up to 120 atmospheres (around 120 MPa) or more.
- the gel-phase liposomes may be used according to the invention for the treatment of joint dysfunction, wherein the pressure within the joint reaches values in the range of 30 to 120 atmospheres (3-12 MPa) .
- Characteristic pressures in joints are reported in the following references :
- gel-phase liposomes of different compositions and size characteristics can provide efficient lubrication in aqueous environments on solid surfaces on which they spontaneously adsorb to form surface coatings.
- the lubrication yielding, in most cases, values ⁇ ⁇ ca. lxlO "3 ) occurs under pressures of up to 120 atmospheres or more, and down to very low sliding velocities, with little apparent wear of the liposome surface coatings.
- the invention provides a method for lubricating one or more non-biological surfaces (in particular negatively charged solid surfaces) , comprising applying gel- phase liposomes onto said one or more surfaces, wherein the temperature of said surface (s) at the time of lubrication is below the phase transition temperature T m of said liposomes.
- the invention also provides a method for lubricating one or more surfaces of a biological tissue in a mammalian subject (for example, a cartilage surface within a joint capsule) , comprising applying gel-phase liposomes onto said one or more surfaces, wherein the temperature of said surface (s) at the time of lubrication is below the phase transition temperature T m of said liposomes.
- a mammalian subject for example, a cartilage surface within a joint capsule
- the use of gel-phase liposomes for lubricating surfaces having a surface temperature which is below the phase transition temperature T m of said liposomes constitutes another aspect of the invention.
- the invention also encompasses a therapeutic composition for lubricating the surface of a biological tissue in a mammalian subject, wherein said composition comprises gel-phase liposomes and an aqueous carrie .
- the invention provides the use of gel-phase liposomes in the preparation of a therapeutic composition for the treatment of joint dysfunction in a mammalian subject by means of the lubrication of cartilage surface (s) within the joint capsule, wherein the temperature of said surfaces at the time of lubrication is below the phase transition temperature T m of said liposomes.
- the invention also provides gel-phase liposomes for the treatment of joint dysfunction in a mammalian subject by means of the lubrication of surface (s) within the joint capsule, wherein the temperature of said surfaces at the time of lubrication is below the phase transition temperature T m of said liposomes.
- the maximal pressure within the joint is in the range of 30 to 120 atmospheres (3-12 MPa) .
- the carrier used for administering the liposomes to the mammalian subject is preferably an aqueous carrier (e.g., an aqueous-based buffer solution) free of organic co-solvents or extraneous organic compounds (other than of course the liposomes) .
- an aqueous carrier e.g., an aqueous-based buffer solution
- organic co-solvents or extraneous organic compounds other than of course the liposomes
- Gel-phase Liposomes to be used according to the invention are based on phosphocholine-containing lipids and mixtures thereof. However, it is possible to combine lipids having polar head groups other than phosphocholine in the gel-phase liposomes.
- Liposomes operable in the invention have external (exposed at the outer liposome surface) polar head groups which are composed of at least 95 mole % phosphocholine groups, and of up to 5 mole % external non-phosphocholine head group having an unperturbed- end-to-end radius in aqueous medium equal to or smaller than about 1 nm, or cross-section parameter which is less than 0.8 nm 2 , (provided, of course that said liposomes are in their gel- phase and have a T m which is higher than the intended working temperature) .
- liposomes in which the up to 5 mole % external ' non- phosphocholine head group units have an unperturbed-end-to-end radius (in the aqueous medium) which is larger than about 1 nm are not suitable for use as lubricant compositions since the systems formed by incubating the solid surfaces therein have a high friction coefficient.
- liposomes in which the 5% of external non-phosphocholine head groups were the PEG groups of DSPE-PEG2000, having an unperturbed-end-to-end radius (in aqueous medium) of about 4 nm demonstrated poor lubrication properties, having friction coefficients of 0.05 to 0.1 (Example C7 , see below) .
- head groups other than phosphocholine units in the gel-phase liposomes is permitted, provided that the unperturbed-end-to-end radius of said non- phosphocholine groups is less than 1 nm, or their cross section is less than 0.8 nm 2 .
- unperturbed-end-to-end radius means the steric size of said head group when it is not subject to external constraints, and is used herein in order to estimate the radius of non-phosphocholine head groups which are polymer chains (such as PEG chain in the case of DSPE-PEG2000 lipid) and also for non-phosphocholine head groups which are molecular/cationic entities (such as the TAP group in the 1, 2-dimyristoyl -3- trimethylammonium-propane (DMATP) ) .
- non-phosphocholine head groups which are polymer chains (such as PEG chain in the case of DSPE-PEG2000 lipid) and also for non-phosphocholine head groups which are molecular/cationic entities (such as the TAP group in the 1, 2-dimyristoyl -3- trimethylammonium-propane (DMATP) ) .
- the size of the charged head-group on the D TAP is approximately 0.3 - 0.5 nm and its radius would be about half of that, say 0.2 nm.
- lipids which contain the TAP head group (and two hydrocarbon saturated chains) can be combined with phosphocholine-containing lipids to form liposomes which are suitable for use in the invention.
- thermodynamic phase behavior of cationic lipids calorimetric, infrared spectroscopic and X-ray diffraction studies of lipid bilayer membranes composed of 1,2- di-O-myristoyl-3-N, N, N-trimethylaminopropane (DM-TAP) . Biochim. Biophys. Acta. 1510:70-82, 2001].
- DM-TAP 1,2- di-O-myristoyl-3-N, N, N-trimethylaminopropane
- the gel-phase liposomes used according to the invention comprise one or more phosphatidylcholine lipids, with the T m values of the liposomes being not less than 40°C, preferably not less than 45°C.
- Mixtures of different phosphatidylcholine lipids can be used to form the liposomes, with the molar ratio between the components of the mixture being adjusted to produce liposomes having the desired T m value [see Scott et al., Biophysical Journal (28), p.117-132 (1979)].
- T m is not less than 50°C, e.g., from 50 to 60° C.
- the hydrocarbon tails of the phosphatidylcholine lipids are saturated and contain not less than 17 carbon atoms.
- liposomes comprising hydrogenated soy phosphatidylcholine (HSPC) , 1,2- distearoyl-sn- glycero-3-phosphocholine (DSPC) and dipalmitoylphosphatidylcholine (DPPC) and mixtures thereof may act as efficient lubricants in aqueous media even at physiologically high pressures of up to 120 atmospheres (85 % of the HSPC are DSPC and 15% are the sum of 1 stearoyl 2- palmitoyl PC plus 1-palmitoyl 2- steroyl PC) .
- HSPC hydrogenated soy phosphatidylcholine
- DSPC 1,2- distearoyl-sn- glycero-3-phosphocholine
- DPPC dipalmitoylphosphatidylcholine
- T m values for HSPC, DSPC and DPPC are 52.5°C, 55°C and 41.4°C, respectively.
- T m values of various PC-based lipids may be found in "Thermotropic Phase Transitions of Pure Lipids in Model Membranes and Their Modifications by Membrane Proteins", John R. Silvius, Lipid- Protein Interactions, John Wiley & Sons, Inc., New York, 1982, and also in the Lipid Thermotropic Phase Transition Data Base - LIPI DAT .
- the liposomes to be used are in the form of small unilamellar vesicles (SUV) .
- SUV small unilamellar vesicles
- HSPC hydrogenated soy phosphatidylcholine
- the SUV liposomes have a mean diameter which is, smaller than 100 nm.
- Good to excellent lubrication between solid surfaces coated by SUVs of 1 , 2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and by SUVs of 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) has also been achieved at comparably high pressures as seen in Table 1 and described below.
- At least 95% of the external polar head groups of the gel-phase liposomes used in the method of the invention are phosphoryl choline head group, the liposomes being in the SUV form and having a. mean diameter which is smaller than 100 nm.
- these gel-phase SUV PC-based liposomes have a mean diameter ranging from about 60 nm to about 80 nm, more preferably ranging from about 65 nm to about 75 nm.
- the liposomes in the compositions described herein are in the form of multilamellar vesicles (MLVs).
- MLVs multilamellar vesicles
- these liposomes have a mean diameter larger than 200 nm, yet more preferably larger than 500 nm, and most preferably ' of about 1 micron and larger.
- Preferred liposomes to be used according to the invention for example for lubricating non-biological surfaces, consist of HSPC, DSPC or DPPC lipids. These PC-based liposomes exhibit good to excellent lubrication results under various conditions, as can be seen in Examples SI, S2, S3, S6, S10 and Sll.
- Another class of preferred liposomes to be used according to the invention is based on a mixture comprising a first lipid, which is phosphocholine-containing lipid (e.g., HSPC, DSPC or DPPC, or their mixtures) and a second lipid, which contains TAP hydrophilic head group, wherein the mole ratio between said first and second lipids is from 95:5 to 99.9:0.1.
- the second lipid namely, the TAP-eontaining lipid has two hydrocarbon chains which independently contain 14, 16 or 18 carbon atoms.
- the TAP-containing liposome is selected from the group consisting of 1, 2-ditetradecanoyl-3-trimethylammonium- propane (DMTAP) , 1 , 2-dipalmitoyl-3-dimethylammonium-propane and 1 , 2-disteraroyl-3-dimethylammonium-propane, which are also described as 14:0 TAP, 16:0 TAP and 18:0 TAP, respectively, indicating that the length of both chains of the lipid is the same (being 14, 16 and 18, respectively) .
- DMTAP 2-ditetradecanoyl-3-trimethylammonium- propane
- 2-dipalmitoyl-3-dimethylammonium-propane 1
- 2-disteraroyl-3-dimethylammonium-propane which are also described as 14:0 TAP, 16:0 TAP and 18:0 TAP, respectively, indicating that the length of both chains of the lipid is the same (being 14, 16 and 18, respectively) .
- the good lubrication was obtained also when the surface of the liposomes was positively charged (for example, when some of the zwiterionic HSPC molecules were replaced by charged DMTAP cationic lipids) .
- liposomes having positively charged surface showed improved lubrication with the negatively-charged solid surfaces in water at high salt concentrations (for example, not less than 0.05M of a 1:1 salt, e.g., not less than 0.15M), as compared to liposomes having positively charged surface used in water containing no added salt.
- the gel-phase liposomes to be used have positively charged surfaces.
- the liposomes used according to the present invention adsorb spontaneously onto negatively charged solid surfaces in water, to form close-packed boundary layers that provided uniquely efficient lubrication, resulting in friction coefficients down to 2xl0 ⁇ 5 at pressures of more than 100 atmospheres (above 10 MPa) . This extremely low friction at such high pressures makes these liposomes extremely suitable for providing efficient lubrication in aqueous media.
- the surfaces to be treated by the liposomes in accordance with the invention may be overall neutral, but having discrete positive and negative regions, such that the liposomes attach to the negatively-charged regions, or even to overall-positively charged surfaces if there are also negatively charged patches on them onto which the liposomes may attach.
- Positively-charged surfaces can also be treated with gel-phase phosphatidylcholine liposomes with up to 5 mole% of negatively-charged lipids such as phosphatidic acid (PA) , phopsphatidyl glycerol (PG) , phopsphatidyl inositil (PI) and phosphatidylserine (PS) .
- PA phosphatidic acid
- PG phopsphatidyl glycerol
- PI phopsphatidyl inositil
- PS phosphatidylserine
- a lubricant system comprising a plurality of liposomes being in their gel-phase and further being spontaneously adsorbed on at least one of two negatively charged solid surfaces, in an aqueous medium.
- the characteristics of the liposomes are as set forth above.
- Suitable negatively charged solid surfaces include, but are not limited to, glass, mica and cartilage.
- the gel -phase liposomes to be used according to the invention proved as efficient lubricants when coated on one or two mica surfaces, having friction coefficients lower than 1x10 2 and even lower than 5xl0 ⁇ 3 and 15xl0 ⁇ 4 .
- the lubricant system described herein has a coefficient of sliding friction between the above-described surfaces which is less than about lxlO "2 under a pressure of at least 1 Mpa, in the aqueous medium.
- liposomes described herein may reduce friction between surfaces onto which they spontaneously adsorb, up to the maximal pressures pertaining in mammalian joints, to levels that are even lower than between healthy sliding articular cartilage. Such low friction between surfaces in aqueous media at these high pressures has not hitherto been attained by any physically-attached boundary lubricant system.
- a method of decreasing the friction coefficient between two negatively charged solid surfaces in aqueous medium to below about IxlCT 2 under a pressure of at least 1 MPa comprising incubating one or both of the surfaces in a lubricant comprising a plurality of liposomes being in their gel-phase and dispersed in an aqueous medium.
- the characteristics of the liposomes are as set forth above .
- the method can decrease the coefficient of sliding friction to below about 5xl0 ⁇ 3 , and even to below about 5xl0 ⁇ 4 .
- the liposome used is as described in detail hereinabove.
- the incubation is preferably conducted for at least 0.5 hours, for example from 1.5 to 2 hours.
- the surfaces can be left under incubation for prolonged periods of time (for example several days) without ' adversely effecting the adsorption of the liposomes to the surfaces.
- the gel-phase liposomes can also be used for the treatment of joint dysfunction in a mammalian subject by means of the lubrication of surface (s) within the joint capsule, wherein the temperature of said surfaces at the time of lubrication is below the phase transition temperature T m of said liposomes.
- the gel-phase liposomes may be used to treat, alleviate, retard, prevent, manage or cure any articular disorder or symptoms arising there from which is associated with joint dysfunction.
- articular disorder shall be held to mean any affliction (congenital, autoimmune or otherwise) , injury or disease of the articular region which causes degeneration, pain, reduction in mobility, inflammation or physiological disruption and dysfunction of joints.
- the disorder may be associated with reduced joint secretion and lubrication as well as from complications of knee and hip replacement .
- the joint in accordance with the invention may be any one of the knee, hip, ankle, shoulder, elbow, tarsal, carpal, interphalangeal and intervertebral .
- Specific articular disorders include, but are not limited to, deficiencies of joint secretion and/or lubrication arising from arthritis, including conditions of joint erosion in rheumatoid arthritis, osteoarthritis, osteoarthritis in rheumatoid arthritis patients, traumatic joint injury (including sports injury) , locked joint (such as in temporomandibular joint (TMJ) ) , status post arthrocentesis , arthroscopic surgery, open joint surgery, joint (e.g. knee or hip) replacement in mammals, preferably humans.
- a specific disorder to be treated or prevented by the method of the invention is osteoarthritis ..
- the method of the present invention could be used as a prophylactic measure to prevent future damage or degeneration.
- the gel-phase liposomes could be administered intra-articularly to athletes intermittently throughout their career to minimize the risk of stress related injury or cartilage degeneration .
- the method of the present invention may be used exclusive of, or as an adjunct to, anti-inflammatory agents, analgesic agents, muscle relaxants, anti depressants, or agents that promote joint lubrication commonly used to treat disorders associated with joint stiffness, such as arthritis.
- ⁇ combined therapeutic approach is beneficial in reducing side effects associated with agents, such as non-steroidal, anti-inflammatory drugs (NSAIDs), commonly used to prevent, manage, or treat disorders such as osteoarthritis associated with reduced joint lubrication.
- NSAIDs non-steroidal, anti-inflammatory drugs
- a combined therapeutic approach may also be advantageous in increasing efficacy of treatment .
- the administration of the liposomes into an articular cavity of a patient may be by a method chosen from the group consisting of intra-articular injection, arthroscopic administration or surgical administration.
- the liposomes are administered to the mammalian subject using a physiologically acceptable carrier, such as histidine buffer (HB) .
- HB histidine buffer
- composition according to the invention is preferably in a form suitable for administration by a route selected from intraarticular injection, arthroscopic administration or surgical administration .
- W is preferably in a form suitable for administration by a route selected from intraarticular injection, arthroscopic administration or surgical administration .
- the amount of liposomes to be administered will vary depending on the liposome's composition, the disease, its severity and treatment regimen, as well as on the age, weight, etc., of the mammal to be treated. The amount for purposes herein is determined by such considerations as may be known in the art .
- the amount must be effective to achieve an improvement in the lubrication of the treated joint, namely, to reduce friction between the cartilages forming the joint, the improvement may be exhibited by clinical tests as well as by an improvement in the well-being of the subject undergoing said treatment (e.g. reduced pain in the afflicted joint, improvement in mobility) .
- the effective amount is typically determined in appropriately designed clinical trials (dose range studies) and the person versed in the art will know how to properly conduct such trials in order to determine the effective amount.
- the concentration of the liposomes in the aqueous carrier may be between 30 and 150 mM.
- Table 1 summarizes the lubricant compositions prepared according to preferred embodiments of the invention, and adsorbed on one or two molecularly smooth mica surfaces, as well as the lubrication properties of the obtained systems:
- System SI composed of two mica surfaces coated by small unilamellar vesicles (SUVs) of hydrogenated soy phosphatidylcholine (HSPC) liposomes in pure water.
- System S2 composed of a bare mica and a mica coated with SUV HSPC liposomes in pure water. This system showed, for regular high surface coverage, very good levels of lubrication, ⁇ 3 ⁇ 4 IO -4 , up to pressures of ca. 6 Mpa .
- Liposomes lubrication efficiency was scored by the inventors according to the shear reduction measured in the experimental system - the surface force balance. Value of 5 was given to the best lubrication capability as 1 to the worst.
- MMVs Multilamellar vesicles
- the MLVs were downsized to form SUVs at a HSPC concentration of 30 mM, by stepwise extrusion through polycarbonate membranes from 400-nm to 50-nm- pore-sizes at 65°C, using a Lipex 100 mL extruder system (Northern Lipids, Vancouver, Canada.
- Water used (also for the SFB experiments) was purified (Milli-Q ® Gradient A10 or Barnsted NanoPure systems) to 18.2 ⁇ cm resistance with total organic content levels of 3 - 4 ppb (Milli-Q) or ⁇ ca.l ppb (Barnstead) .
- the pH of the water was 5.8 due to ions leached from glassware and dissolved atmospheric C0 2 .
- Liposomes were characterized for size distribution by dynamic light scattering using an ALV-NIBS High Performance Particle Sizer (Langen, Germany) at a scattering angle of 173°. Over 98% of the freshly-prepared liposomes were 65+3 nm in diameter.
- AFM N-MDT, Integra;- topography images were taken in water in tapping mode using silicon nitride tips of 3 ⁇ height, spring-constant 0.5 N/m (Olympus, OMCL-TR800PSA) .
- cryo-SEM cryo-scanning-electron-microscopy
- Lubrication Normal and shear forces, F n (D) and F s (v s , D) respectively, between the interacting, liposome-coated mica surfaces as a function of their closest separation D and sliding velocity v s , were determined in the SFB.
- F n (D) profiles are shown in Figure 2. At large separations the forces decayed exponentially with D, and are attributed to double-layer electrostatic repulsions arising from the residual charge on the interacting surfaces.
- Example S2 Coating of one solid mica surface with liposomes :
- SUV-HSPC liposomes were adsorbed to a ⁇ single mica sheet which was brought into contact with an atomically smooth mica sheet, while measuring the force as a function of the distance between the surfaces.
- Two different surface coverages were obtained due to a different washing technique after the adsorption procedure.
- a more vigorous wash which left large areas of bare mica - is referred as x b'
- a gentle wash procedure that lead to a dense surface is referred as A a' .
- This system showed, for high surface coverage, very good levels of lubrication, ⁇ * 1CT 4 , up to pressures of ca. 6 Mpa, and for the low surface coverage (namely after extensive washings) showed high friction at pressures higher than 1 MPa.
- Liposomes were characterized for size distribution by dynamic light scattering using an ALV-NIBS High Performance Particle Sizer (Langen, Germany) at a scattering angle of 173°. Over 98% of the freshly-prepared liposomes were 75 ⁇ 3 nm in diameter. Coating of solid mica surfaces with liposomes prepared by example S3 :
- HSPC-SUV were adsorbed on a.tomically smooth mica surface by placing freshly cleaved mica in 10 ml 150 mM Na 0 3 and then adding 360+10 of the liposome dispersion (of concentration of 30 mM) for 1.5-2 hours of incubation. Then mica surfaces were washed to remove excess, non-adsorbed liposomes by placing the adsorbed surfaces in a beaker filled with 150mM NaNC>3 for a few minutes along with a delicate shake motion. All preparations were done in a laminar hood to prevent contamination. Results
- MLV small unilamellar vesicles
- Liposomes were characterized for size distribution by dynamic light scattering using an ALV-NIBS High Performance Particle Sizer (Langen, Germany) at a scattering angle of 173°. Over 98% of the freshly-prepared liposomes were 75+3 nm in diameter . The zeta potential of liposomes in pure water was 36.5 mV.
- HSPC/DMTAP liposomes in pure water showed that liposome adsorbed on a mica surface in not close-packed coverage.
- Shear measurements of 2 HSPC/DMTAP coated mica surfaces in pure water show no response to shear up to pressures of 25 ⁇ 6 atm.
- a shear trace test demonstrated the low Fs as P ⁇ 30 atm.
- Shear measurements of 1 HSPC/DMTAP coated surface vs. bare mica in pure water showed rigid coupling already in pressures of ⁇ 10 atm.
- Example S5 Preparation of HSPC/DMTAP liposome mixtures in salt environment: The same process described above (S4) was repeated with the modification that the liposomes were prepared in 150 itiM NaN0 3 (Fluka, >99.999% purity) rather than in pure water using four dialysis steps at 4°C.
- Liposomes were characterized for size distribution by dynamic light scattering using an ALV-NIBS High Performance Particle Sizer (Langen, Germany) at a scattering angle of 173°. Over 98% of the freshly-prepared liposomes were 61.9 nm in diameter.
- the zeta potential of liposomes was 4.18mV after replacing the external medium with 150 mM NaN0 3 .
- HSPC/DMTAP SUV were adsorbed on atomically smooth mica surface by placing freshly cleaved mica in 10 ml 150 mM NaNC>3 salt solution and then adding 720 ⁇ 20 ⁇ i of the liposome dispersion for 1 hour of incubation. After 1 hour the mica surfaces were placed in 400 ml beaker of 150 mM NaN0 3 for 1-2 minutes in order to remove excess, non-adsorbed liposomes.
- Cryo-SEM samples (mica surfaces covered with HSPC:DMTAP 95:5 liposomes) were prepared as described above, with additional rinsing step by placing the sample in pure water for few seconds in order to remove salt. Samples were frozen by plunging into liquid ethane and transferred to a BAF 60 freeze fracture device (BAl-Tec AG, Liechtenstein) . Water was sublimed in the BAF 60 at a temperature of -100 degrees for 1 hour. Pt cover of the samples by rotary shadowing of 1.5 nm followed by 1.5 nm of Pt in an angle of 45 degrees.
- Example S6 preparation of MLV HSPC liposomes in water, characterization thereof and solid surfaces coated by it:
- 0.9145gr HSPC were dissolved in hot ethanol to a concentration of 0.45 w/v. This solution was injected into pure water at temperature of 62°C (above the gel-to-liquid crystalline phase transition temperature, Tm, of HSPC, 52.5°C) in order to hydrate the lipids and form a 40ml dispersion of multilamellar liposomes, MLV at final concentration of 30mM phospholipids (PL) . Water was treated with a Barnstead Nanopure system.
- the resistance of water was 18.2 ⁇ cm with total organic compound (TOC) ⁇ ca .1 ppb (Barnstead) .
- MLV HSPC mean radius size of 1.24 ⁇ 0.57 ⁇ was measured with particle size analyzer LS 13 320 equipped with the PIDS unit which can determine particle size at the range of 40 nm to 2.0 mm (Beckman Coulter) .
- Shear force measurements between a mica surface covered with HSPC MLVs liposomes in opposing to a bare mica surface in pure water at different surface separation D and applied normal force (pressure) show that a similar shear force was measured during the first approach to a contact point and on during the second approach.
- the MLVs were downsized to form SUVs at a final concentration of 15 mM, by stepwise extrusion through polycarbonate membranes from 400-nm to 50-nm-pore-sizes at 65°C, using a Lipex 100 mL extruder system (Northern Lipids, Vancouver, Canada.
- Water used (also for the SFB experiments) was purified (Barnsted NanoPure systems or milli-Q gradient A10) to 18.2 ⁇ cm resistance with total organic content levels of 3 - 4 ppb (Milli-Q) or ⁇ ca .1 ppb (Barnstead) .
- the pH of the water was 5.8 due to ions leached from glassware and dissolved atmospheric C0 2 .
- Liposomes were characterized for size distribution by dynamic light scattering using an ALV-NIBS High Performance Particle Size (Langen, Germany) at a scattering angle of 173°. Over 98% of the freshly- prepared liposomes were 65 ⁇ 10 nm in diameter.
- the normal force profiles were similar in range and magnitude to those described for HSPC-SUV in example SI above (e.g. fig. 2).
- the shear traces and resulting load vs. friction data are shown in figs 5A and 5B, revealing excellent lubrication up to high pressures (> 100 atms) .
- Cryo-SEM micrographs of the DSPC-SUV on mica revealed close-packed layers on the surface.
- Example Sll Preparation of SUV-DPPC liposomes in. pure water, characterization thereof and solid surfaces coated by it:
- the MLVs were downsized to form SUVs at a final concentration of 15 mM, by stepwise extrusion through polycarbonate membranes from 400-nm to 50-nm-pore-sizes at around 60°C, using a Lipex 100 mL extruder system (Northern Lipids, Vancouver, Canada.
- Water used (also for the SFB experiments) was purified (Barnsted NanoPure systems or milli-Q gradient A10) to 18.2 ⁇ cm resistance with total organic content levels of; 3 - 4 ppb (Milli-Q) or ⁇ ca .1 ppb (Barnstead).
- the pH of the water was 5.8 due to ions leached from glassware and dissolved atmospheric C0 2 .
- Liposomes were characterized for size distribution by dynamic light scattering using an ALV-NIBS High Performance Particle Size (Langen, Germany) at a scattering angle of 173°. Over 98% of the freshly- prepared liposomes were 65 ⁇ 10 nm in diameter.
- Comparative Example C7 preparation of SUV HSPC/PEG liposome mixtures in wate , characterization thereof and solid surfaces coated by it
- SUV HSPC/PEG liposome mixtures in water were prepared as a comparative example, since the PEG external head groups have an end-to-end radius which is larger than lnm (being 4 nm) .
- the HSPC/PEG liposomes were prepared and characterized as described in Langmuir 21, 2560 (2005) .
- Comparative Example C8 preparation of SUV POPC liposomes in water, characterization thereof and solid surfaces coated by it
- SUV POPC liposomes in water were prepared as a comparative example, since the obtained liposome has a Tm which is smaller than the measuring temperature, being smaller than about 15 °C (being -3°C) .
- POPC l-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
- This solution was injected into pure water at temperature of 250°C (above the gel- to-liquid crystalline phase transition temperature, Tm, of POPC, -3°C) in order to hydrate the lipids and form a dispersion of multilamellar liposomes, MLV at final concentration of 30mM phospholipids (PL) .
- Water was treated with a Barnstead Nanopure system. The resistance of water was 18.2 ⁇ cm ' with total organic compound (TOC) ⁇ ca .1 ppb (Barnstead).
- MLV were downsized to form small unilamellar vesicles (SUV), ca.
- Liposomes were characterized for size distribution by dynamic light scattering using Malvern Zetasizer - nano series (Malvern Instrument Limited - UK) at a scattering angle of 173°. 100% of the liposomes were 68.8 nm in diameter.
- Example Tl Testing in biological systems
- Lipids Table 1 describes the lipids (>98% pure) used in this experiment .
- Hyaluronic Acid HA
- Multilamellar vesicles composed of pure Phosphatidylcholines (PCs) : POPC, DMPC and HSPC, were prepared by hydrating the lipids in at least 5 °C above the lipid T M .
- MLVs small unilamellar vesicles (SUV, ⁇ 100 nm)
- SUV small unilamellar vesicles
- MLVs were downsized by stepwise extrusion through polycarbonate membranes starting with a 400-nm and ending with 50-nm-pore-size membrane, using a Lipex 100 mL extruder system (Northern Lipids, Vancouver, Canada) , heated at least 5 °C above the lipid T M .
- MLVs liposomes concentration was of 130+10 mM
- SUVs liposomes concentration was of 35 ⁇ 5 mM.
- Cartilage Articular cartilage from freshly slaughtered and healthy bovine was used for friction tests. Specimens of cartilage (approximately thickness of 3-4 mm) were removed from the surface using a scalpel. Samples were kept at -20 °C until used. For each test two samples were glued: one on the lower surface and the other on the upper surface. Size of the lower surface was ⁇ 0.8 cm 2 and size of the upper surface was 0.14 ⁇ 0.02 cm 2 . The cartilage samples were glued to their holders using a cyanoacrylate-based glue.
- Friction testing was carried out using a CETR ® tribometer, UMT model with high sensor which enables high normal loads.
- the system configuration was of a cartilage on a cartilage setup, in which two samples of bovine cartilage are immersed in HB, saline (0.9% w/v) or in synovial fluid (SF, obtained from the fresh bovine joints) .
- the cartilage samples were subjected to relative sliding over a wide range of loads of 1 to 12 kg (10 to 120 N) , equivalent to physiological pressures in joints (0.73+0.1 MPa to 8.75+1.25 MPa) .
- the testing parameters were the following: Sliding velocity of 1 mm/sec, sliding amplitude of 1.5 mm and dwell time of 5 sec. Experiments were at room temperature (ca. 25 ⁇ 1C)
- the static friction coefficient is obtained from the maximum value from the shear trace, and the kinetic friction coefficient is calculated as the average value at the sliding region.
- the data summaries are based o the mean of 2 - 3 independent experiments (i.e. 2 - 3 fresh pairs of cartilage surfaces) in each case, except for the synovial fluid control (1 experiment), and 40 back-and-forth cycles per measurement.
- the cartilage surfaces were incubated for 30 mins in the liposome solutions prior to friction measurements.
- Figure 1 Cryo-SEM image of the HSPC-SUV adsorbed on freshly cleaved mica as described in Methods section;
- the inset compares profiles on a first approach (full symbols) and second approach (corresponding empty symbols) from different contact positions.
- Figure 3 Typical shear (or friction) force Fs vs. time traces between HSPC-SUV coated mica surfaces taken directly from SFB;
- Figure 4 4A: Friction forces Fs vs. applied loads Fn between two HSPC-SUV-coated mica surfaces, based on traces such as in figure 3.
- 4B Friction forces F s variation with sliding velocity for different compressions (O 74 atm; ⁇ 1 94 atm; B 107 atm; ⁇ 118 atm) of HSPC-SUV coated mica surfaces showing little variation within the scatter over nearly 3 decades in v s .
- FIG. 5A Shear traces between two mica surfaces coated with SUV-DSPC liposomes in pure water, measured using the surface force balance showing the shear force Fs vs. time. The traces demonstrate the shear force at different surface separations under various applied pressures.
- FIG. 5B Friction force vs. the applied normal load between two SUV-DSPC coated mica surfaces, based on traces such as in 5A.
- FIG. 6 Dynamic (6A) and Static (6B) Friction coefficients vs. load (N) according to preferred embodiments of the invention for bovine articular cartilage surfaces following incubation in HSPC-MLV, DMPC-MLV, and POPC-MLV liposome solutions in histidine buffer.
- Figure 7 Dynamic and Static friction coefficients for different systems (both controls and with liposomes) for a 30N load (Fig. 7A) and for a 120N load (Fig. 7B) between sliding bovine cartilage surfaces according tb preferred embodiments of the invention.
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US13/704,866 US20130142863A1 (en) | 2010-06-17 | 2011-06-16 | Phosphatidylcholine lipid liposomes as boundry lubricants in aqueous media |
BR112012032153A BR112012032153A2 (en) | 2010-06-17 | 2011-06-16 | method for lubricating one or more non-biological surfaces, method for lubricating one or more surfaces of a biological tissue in a mammalian subject, use of gel phase liposomes and mixed liposome |
EP11743371.4A EP2582406B1 (en) | 2010-06-17 | 2011-06-16 | Phosphatidylcholine lipid liposomes as boundary lubricants in aqueous media |
CA2803034A CA2803034A1 (en) | 2010-06-17 | 2011-06-16 | Phosphatidylcholine lipid liposomes as boundary lubricants in aqueous media |
IL223518A IL223518A (en) | 2010-06-17 | 2012-12-09 | Phosphatidylcholine lipid liposomes as boundary lubricants in aqueous media |
US16/809,816 US11541008B2 (en) | 2010-06-17 | 2020-03-05 | Phosphatidylcholine lipid liposomes as boundary lubricants in aqueous media |
US17/984,761 US20230080018A1 (en) | 2010-06-17 | 2022-11-10 | Phosphatidylcholine lipid liposomes as boundary lubricants in aqueous media |
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US16/809,816 Division US11541008B2 (en) | 2010-06-17 | 2020-03-05 | Phosphatidylcholine lipid liposomes as boundary lubricants in aqueous media |
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EP (1) | EP2582406B1 (en) |
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US20230080018A1 (en) | 2023-03-16 |
IL223518A (en) | 2016-07-31 |
US20200338001A1 (en) | 2020-10-29 |
EP2582406B1 (en) | 2018-03-14 |
US20130142863A1 (en) | 2013-06-06 |
EP2582406A1 (en) | 2013-04-24 |
US11541008B2 (en) | 2023-01-03 |
CA2803034A1 (en) | 2011-12-22 |
BR112012032153A2 (en) | 2017-08-08 |
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