JPH0347892B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to biocompatible surfaces, i.e. surfaces suitable for prolonged contact with living tissues and body fluids, and more particularly to novel phospholipids, their preparation, polymers derived therefrom, and The present invention relates to the production of polymers and the use of phospholipids and the use of said phospholipids and their polymers in the production of biocompatible surfaces and to compositions providing prolonged release of physiologically active compounds. It is common practice to use biocompatible polymers to form at least the surfaces of, for example, prosthetic devices and components of hemodialysis equipment. However, these materials are not perfect and their reaction with living tissue remains problematic. For example, surface-induced thrombosis remains a major challenge, especially when large volumes of blood come into contact with foreign surfaces, such as in artificial lungs and artificial kidneys. The formation of clots in prosthetic devices can be harmful or even catastrophic, including blockage of the blood flow path of the extracorporeal system and occlusion if the clots break off the artificial surface and become lodged within the host blood vessels. exert an effect. Recently, surface thrombogenicity has frustrated attempts to use long-term storage artificial hearts. Many of the deaths that occur in animals supported by artificial hearts are not caused by mechanical failure of the artificial heart, but by clot formation. Dialysis membranes, blood substitues, and artificial lungs all share this problem. Materials used for pharmaceutical applications with respect to general biological compatibility should preferably (a) be renewable products as pure substances, and (b) be free from deterioration or adverse change. (c) have the necessary mechanical and permeability properties for the specified function; and (d) are sterilizable without adverse changes in mechanical permeability or surface properties. (e) not be acted upon in a harmful manner by the biological environment; and (f) desirably not carcinogenic. There are limitations in applications involving direct contact with blood. The substance should not () induce appreciable thrombosis or interfere with normal clotting mechanisms, and () cause appreciable damage to cellular elements or soluble components of the blood. isn't it. Many attempts have been made to produce biocompatible, particularly blood compatible, surfaces, ie, surfaces that do not activate the blood coagulation process and do not promote thrombus formation. Examples of such approaches include negatively charged surfaces such as anionic polymers or appropriately oriented electret polymers, the natural anticoagulant heparin or synthetic heparin analogs, charged surfaces with inherently low surface free energies, These include surfaces such as albumin-coated surfaces and certain polymethanes that are believed to preferentially absorb albumin from blood. However, everything has its limits. Considering the problem as a general matter of surface properties, it struck me as of great significance that biological membranes are important in all areas of the body. All living cells have an outer membrane, and within the cell there are membranes that act to separate the various organelles, such as mitochondria, nucleus, and endoplasmic reticulum. Various cell membranes are composed of a matrix of polar lipids (eg, phospholipids). Thus, red blood cells, for example, have a cell wall organized on a matrix of phospholipid bilayer membranes. The lipids are arranged symmetrically with the phospholipids lecithin (phosphatidylcholine) and sphingomyelin on the outer surface of the cell wall, and symmetrically with phosphatidylserine and phosphatidylethanolamine on the inner surface of the cell wall. The latter has a net negative charge and is known to cause blood clotting on itself. The former has a zwitterionic structure and forms the outer surface of the cell wall. Since phospholipids are an essential component of biological membranes throughout the body, the present invention is directed to the surface mimicry imparted to these membranes by phospholipids on the surfaces of foreign objects that are to come into contact with living tissues. This is indeed the case, and the imperative of the applicant's proposal is based on the realization that (imitation) makes them biologically compatible. - It has been found that nitrogen zwitterionic groups are present on the outer surface of the molecular structure to provide articles or objects with an artificial biocompatible surface. In its broadest aspects, the present invention provides conjugated di-ins of the general formula: In the formula, at least one of B ₁ and B ₂ has the formula -(CO) _p -X ₁ -C≡C-C≡C-Y ₁ , where p is 0 or 1, and X ₁ is a direct bond or is a divalent aliphatic or cycloaliphatic group, Y ₁ is H or a monovalent aliphatic or cycloaliphatic group, and each
The total number of carbon atoms of X ₁ and Y ₁ in B ₁ and/or B ₂ is 8 to 26, and the other of B ₁ and B ₂ has the formula (a) -(CO) _p -X ₁ -C≡C- or (b) an aliphatic or cycloaliphatic group containing at _least 8 carbon atoms, where n is 0 or 1, m is 2, 3 or 4, each R independently representing an alkyl group containing 1 to 4 carbon atoms. Another aspect of the invention provides a polymer obtained by crosslinking a conjugated diyne as described above. These polymers have a structure In the formula, Z ₁ , Z ₂ , Z ₃ and Z ₄ are as described above.
Y ₁ and the other two Z ₁ , Z ₂ , Z ₃ and Z ₄ each represent -X ₁ -(CO) _p -G, where X ₁ and p are as described above, and G teeth , where n, m, and R are as defined above, and the crosslinked chains usually contain repeating units of linked to the same or different G residues. The conjugated diyne of the formula is preferably a group in which the zwitterionic group is attached to the phosphate of the natural phospholipids lecithin and sphingomyelin, i.e. the choline phosphate group: or related phosphine-linked groups: This is the conjugate G-in. Preferred zwitterionic groups are analogs of naturally occurring products where m is 2, but m can also be 3 or 4, and each R group is Methyl is preferred, but R can also be ethyl, propyl or butyl, and the zwitterionic group may be asymmetrically substituted at the quaternary nitrogen. In the conjugated G-in of the present invention, both B ₁ and
It is also preferred that each _B2 represents a group of the formula -(CO) _p - _X1 -C≡C-C≡C- _Y1 . As a practical matter, symmetrical compounds are those that are easiest to synthesize, i.e. p, X ₁ in B ₁ and B ₂
and Y ₁ are the same. However, such symmetry is not essential _according to the invention, and p is 0 in one of B _{1 and} B ₂ if each X ₁ and Y ₁ are the same or different; On the other hand it is possible to use compounds in which p is 1. However, it is more difficult to synthesize such materials. As far as the theoretical basis of the invention is concerned, B ₁ and B ₂
The position of the conjugated di-in system in is not important.
For example, X ₁ can be a direct bond such that the conjugated diyne is immediately adjacent to the carboxylic ester or ether, and in such case Y ₁
would need to contain at least 8 carbon atoms. It is also possible that the conjugated diyne system is at that end of the hydrophobic chain remote from the carboxylic ester or ether group such that Y ₁ is hydrogen and X ₁ contains at least 8 carbon atoms. However, for reasons discussed in more detail below, the conjugated diyne system is arranged such that there are approximately the same number of carbon atoms in X ₁ and Y ₁ toward the center of the hydrophobic group. is usually found to be the most convenient. X ₁ and Y ₁ are each preferably an aliphatic or cycloaliphatic group. Although the inventor's early experiments focused on compounds in which the aliphatic or cycloaliphatic group is an unbranched hydrocarbon group, Although there is no reason why an aliphatic or cycloaliphatic group should not be a branched hydrocarbon group or contain substituents on the hydrocarbon chain, such as an alkoxy substituent or a halogen. . For reasons that will become clear in the discussion below, the conjugated diyne system represents the only carbon-carbon unsaturation in the hydrophobic chain, but if additional cross-linking is desired, further carbon-carbon unsaturation can be added to the group X. ₁ and Y ₁ . It is important that the total number of carbon atoms in X ₁ and Y ₁ in each group B ₁ and B ₂ is from 8 to 26 so that each hydrophobic chain contains a total number of 12 to 30 carbon atoms. It has been found that if the groups B ₁ and/or B ₂ contain less than 12 carbon atoms, the resulting materials are difficult to polymerize except at very low temperatures. In practice, we find that the most satisfactory results are obtained when the groups B ₁ and/or B ₂ have 16 to 26 carbon atoms, especially when the chain contains 22 or 24 carbon atoms. I found it. The precise structural arrangement of the carbon atoms in X ₁ and Y ₁ is not critical to the invention; their primary function is to impart the correct degree of hydrophobicity to the compound;
and allow polymerization at a convenient temperature, although the carbon atoms may be in a linear or branched structure.
It is not essential that X ₁ and Y ₁ can also include cycloaliphatic residues containing 3 to 8 or even more carbon atoms in the cycloaliphatic configuration. For reasons that will become clear from the following explanation regarding the polymerization of conjugated diynes, both B ₁ and B ₂ do not contain a conjugated diyne system so that the conjugated diyne system can participate in intra- and intermolecular polymerization. preferable. However, a sufficient degree of crosslinking can be obtained simply by intermolecular polymerization, in which case it is only essential that one of the groups B ₁ and B ₂ contains a conjugated diyne system. When only one of B ₁ and B ₂ contains a conjugated di-yne system, B ₁ and
The other of B ₂ can be an aliphatic or cycloaliphatic residue, preferably a hydrocarbon residue, which may be saturated or conjugated with an isolated or conjugated diyne system or an olefin or May contain perhaps a single acetylenic unsaturation.
Such groups are also linked to the glycerol residue via an ester or ether group and should also contain at least 12 carbon atoms. The conjugated di-yne of the present invention can be produced by a method known per se. Therefore, the zwitterionic group can be prepared by reacting a suitable phosphonic or phosphinic acid or an esterifiable derivative thereof with glycerol or an esterifiable derivative thereof, thereby reacting the α-hydroxy group of glycerol. It can be introduced by forming a phosphorus ester group. The groups B ₁ and B ₂ are carboxylic acids B ₁ COOH or alcohols B ₁ OH or the corresponding B ₂ COOH or BOH substances or esters of one of the above carboxylic acids or alcohols with glycerol or its ether-forming or ester-forming derivatives. Alternatively, it can be introduced into the molecule by esterification or etherification using an ether-forming derivative. These reactions can be carried out simultaneously or sequentially in either order between glycerol or its derivatives on the one hand and carvone or alcohol and phosphorus ester on the other hand. For the production of symmetrical phospholipids, which are the preferred compounds of the present invention, we in practice form the required glycerol monoester with a chosen phosphoric acid or phosphoric acid and then use this mono-phosphoric ester of choice. the anhydride of a conjugated diynecarboxylic acid (obtained by treating the above acid with dicyclohexyl-carbodiimida) and then react the glycerol monoester with the anhydride in an organic solvent and in the presence of an organic base. I found it convenient to react with Other known methods for the formation of ester groups can equally be used. If it is desired to prepare compounds in which p is 0, corresponding conventional ether-forming processes can be used. The conjugated di-ynes of the present invention can be polymerized by exposing them to actinic radiation, typically ultraviolet radiation at wavelengths in the <300 nm range. Such irradiation creates crosslinks between conjugated diyne systems of adjacent chains. This results in a polymer containing repeating units of the following structure. In the formula, Z ₁ , Z ₂ , Z ₃ and Z ₄ are as described above. The conjugated diyne systems involved in crosslinking are asymmetrically substituted diynes. The bridge involves C ₁ and C ₄ of the chain of four carbon atoms of the conjugated diyne,
Since C ₁ and C ₄ are not equivalent to each other due to the asymmetric substitution, the bridge can be between C ₁ and C ₁ of each chain or between C ₁ and C ₄
Depending on whether the crosslinking occurs between C ₄ and C ₄ , different crosslinked products can result. For example, if the crosslinking occurs between C ₁ and C ₄ , the repeating unit It is. Although our structural studies on polymers have not yet established whether crosslinked polymers contain one or more possible crosslinked products, it is possible that they are present in all crosslinked structures. Conjugate systems that are common It was established that it contains If B ₁ and B ₂ both contain conjugated diyne systems, there will be both intramolecular and intermolecular crosslinking, which is desirable for most uses of the polymers of this invention. For this reason, it is preferred that B ₁ and B ₂ both contain conjugated di-yne systems, and in order to optimize intramolecular cross-linking, the relative positions of the conjugated di-yne systems of B ₁ and B ₂ are approximately the same. In other words, it is preferred that the carbon chains connecting the conjugated diyne system to the glycerol residue should not differ in length by more than two carbon atoms. In view of the intended biomedical use of the polymers of the invention, polymerization is best induced by exposure to chemically active radiation, usually having a wavelength shorter than that of visible radiation; Any method known in principle to be able to induce the polymerization of conjugated diyne systems can be used for the preparation of the polymers of the invention. Conjugated diynes can be polymerized in various states, for example as a monolayer on water, as multilayers on hydrophobic substrates such as Teflon, as liposomes or in the solid state in KBr discs. One of the main uses of the polymers of the present invention is for substrates,
In particular, it is intended to provide surface coatings on these substrates which are subsequently brought into direct contact with blood or other body fluids or internal body surfaces. Such surface coatings are, in effect,
It is usually best introduced by coating a substrate with the conjugated di-ynes of the present invention and then polymerizing the conjugated di-ynes in situ by exposure to actinic radiation. The conjugated diynes of the present invention are colorless materials, but as the polymerization proceeds, there is a pronounced color change that first progresses through the blue range as the conjugated diynes are first converted to the intermediate carbene, and then this transition state. The carbene intermediate is converted to a final polymer molecule with a red or purple coloration. As a result, polymerization on the substrate can be followed visually. The substrate can be, for example, polymeric, metal, glass, ceramic and many others;
Examples of polymers are cellophane, polyvinyl chloride, polycarbonate, polymethyl methacrylate, polyethylene, polytetrafluoroethylene and silicone rubber. Such coated substrates can be used for prosthetic implants, eye implants and contact lenses, diagnostic devices, lung machines, artificial kidneys, sutures, artificial lenses, optional tissues, culture vessels and other surgical instruments, gloves, catheters, permanent entry ports, drug delivery systems,
It can be used in contraceptive devices, including syringes, intrauterine devices, and bandages. The present invention deals with corneal endothelial damage.
It is particularly suitable for providing a surface coating on intraocular lenses to reduce damage. Initial implantation of an intraocular lens can problematically increase endothelial cell loss and damage associated with cataract extraction. This damage appears to be caused by the instantaneous adhesion of the lens material, polymethyl methacrylate (PMMA), to the endothelial surface if the lens contacts the corneal endothelium. Using an electron microscope, Kaufmann (Kauf-
(1999) and Katz (2003) showed that even momentary contact between lenses made from PMMA and corneal endothelial cells caused the cell membrane to detach from its attachment to the IOL surface. Studies on the surface modification of polymethyl methacrylate to reduce or prevent such cellular damage at occasional lens-endothelial contacts have shown that this polymer is well tolerated within the eye without exhibiting significant short- or long-term degradation. This appears to be a practical method as it has already been shown to be resistant. Variations that introduce new substances will similarly require repeated extensive safety and efficacy testing. Previous research in this field was based on the idea that the attachment between the lens and the endothelium is an interaction between hydrophobic polymethyl methacrylate and hydrophilic intraocular tissue. Polyvinylpyrrolidone (PVP) prior to grafting the polymethyl methacrylate surface
Alternatively, rendering the polymethyl methacrylate surface hydrophilic by immersion in a methylcellulose solution has been shown to reduce the clinical incidence of endothelial damage. Immersion solutions of PVP, silicone oil, and serum have been used in similar attempts to temporarily alter the surface of these intraocular lenses. However, soaking these lenses in a solution immediately prior to surgery is cumbersome and inconvenient, and introduces new problems of sterility and reproducibility. The substances of the invention are used to coat intraocular lenses in such a way that their polar groups of the substances of the invention face extracellular fluids. This will make it suitable for short or long contact with living tissues and body fluids and will reduce tearing of intradermal cell membranes. The conjugated diine is then stabilized to form a polymeric coating that is hydrophilic at the surface and at the same time biologically compatible with living tissue. Intraocular lenses or other support surfaces can be coated in a variety of ways, such as solution or emulsion coating or Langmuir-Blodgett.
It can be coated by a multilayer dipping method to obtain oriented layers and makes it possible to treat irregular surfaces. Attachment of the coating can be achieved, for example, by using lipids which have groups within or at the end of the chain of the fatty acid that are reactive with the polymer or substance to be coated or with the substances absorbed by it, for example after solvent treatment. can be improved by covalent bonding to the surface. Alternatively, physical attachment of the coating may occur, for example, by swelling the polymeric substrate with a low molecular weight solvent, resulting in subsequent absorption of the fatty chains of the fatty acid residues into the polymeric structure. Another important use of the conjugated diynes of the present invention is in the production of liposomes. Such liposomes support physiologically active substances and can therefore provide biocompatible formulations for sustained release of non-metabolizable drugs or enzymes into the body, for example. Such liposomes are prepared by dispersing the conjugated diine in an aqueous medium and adjusting the temperature of the dispersion to the lipid or chapman trancision temperature, which is the temperature at which liposome formation occurs.
It can be prepared by raising the temperature of the dispersion to a higher temperature and then cooling the dispersion to ambient temperature. If a physiologically active substance is present in the aqueous medium during liposome production,
Liposomes contain the active substance and slowly release the active substance over a long period of time as a result of the metabolism of the liposome membrane structure. One of the practical advantages of such a combination is that in this way water-soluble and water-insoluble active substances can be formulated, or if desired, water-soluble and water-insoluble substances in the same formulation and water-insoluble substances in fat. This means that it can be formulated by first blending the ingredients. It is often found that the conjugated diine phospholipids of the invention or their polymers forming the membranes of liposomes act as adjuncts to many physiologically active substances introduced into the liposomes. Incorporation of aluminum hydroxide or other adjuvants into these formulations to enhance the activity of physiologically active substances by introducing aluminum hydroxide or other adjuvants into the aqueous medium during the liposome formation period. It is also possible. Liposome formation can be carried out by known methods to produce multilamellar structures. Small diameter unilamellar liposomes can be generated by subjecting multi-lamellar liposomes to ultrasonic vibrations. Larger unilamellar liposomes can be generated by dissolving the conjugated diine in alcohol and then injecting this solution through a syringe into an aqueous medium. These single lamellar materials are sometimes known as microvesicles. The resulting liposomes, which may be unilamellar or multilamellar and usually contain physiologically active substances and optionally adjuvants, can be cross-linked with the conjugated diine system by exposure to chemically active radiation as described above. It can be stabilized by Such irradiation occurs intermolecularly and, depending on the structure of the conjugated diine, possibly intramolecular crosslinking, provides a liposomal dispersion comprising the polymer of the invention. It is also possible to include liposomes of other phospholipids in the liposome dispersion of the invention before or after crosslinking of the conjugated diynes of the invention. Although it is usually most convenient to formulate the polymers of the invention in liposomal form, it is also possible to polymerize the conjugated diynes in large quantities and then extrude the polymer to provide phospholipid polymer capsules. Alternatively, the phospholipid polymers of the invention can be included within other phospholipid-based liposome systems. A wide variety of physiologically active substances can be formulated into the liposome dispersions of the present invention, including pharmaceuticals such as antigenic substances, hormones, enzymes, and anti-inflammatory agents. The incorporation of influenza virus or fragments thereof in liposomes, diphtheria toxin, tetanus toxin and other antigenic substances derived from viral or bacterial sources in liposomes may include hormones such as insulin, anti-inflammatory steroids such as corticosteroids, e.g. Cortisone, cortisol and their Δ'-dehydro- and 9-fluoro derivatives; anti-inflammatory non-steroids such as peptides, immunosuppressive compounds such as methotrexate, salicylates,
Phenylbutazone, as well as inhibitors of hydrolytic enzymes, are now well described in the literature. How these and other physiologically active substances can be incorporated into liposomal compositions is described, for example, in U.S. Pat.
No. 4199565 and West German Publication No. 2249552, no.
No. 2528411, No. 2643641, No. 2712030 and No.
No. 2712031 may be referred to. These substances are typical of physiologically active substances that can be incorporated into the liposomes of the invention. The following examples illustrate the invention. Example 1 Production of conjugated diine phospholipid (a) Synthesis of diacetylenic acid The outline of this synthesis is shown below. (1) H ₂ C=CH (CH ₂ ) ₈ CO ₂ H 1.+Br ₂ ―――――→ 2.−2HBr HC≡C (CH ₂ ) ₈ CO ₂ H (A) (2) H ₂ C =CH (CH ₂ ) _o CH ₃ 1.+Br ₂ --------→ 2.-2HBr HC≡C (CH ₂ ) _o CH ₃ n=9, 11 +CH ₃ CH ₂ MgBr --- ---→ BrMgC≡C(CH ₂ ) _o CH ₃ +I ₂ ---→ IC≡C(CH ₂ ) _o CH ₃ (B) (3) (A)+(B)CuCl, HON ⁺ H ₃ Cl ^- ――――――――――――→ CH ₃ CH ₂ NH ₂ CH ₃ (CH ₂ )C≡C-C≡C -(CH ₂ ) ₈ CO ₂ H (C) Alkenes and alkenoic acids were brominated in petroleum ether by slowly adding one molar equivalent of bromine. The dibro derivative was immediately dehydrobrominated by refluxing the dibromo derivative with excess KOH in ethanol. After distilling off the alcohol and adding dilute HCl, the alkyne was isolated by ether extraction and vacuum distillation (10 ^-3 mm
Hg). Due to the asymmetric Chodokiewicz coupling, one of the reaction components must be iodinated. Therefore, 1-alkynes can be converted into dry diethyl ether (CaH ₂ -treated).
and a slight excess of ethylmagnesium bromide in the solution. The resulting acetylenic Grignard reagent was reacted directly with added I ₂ to yield the desired halo derivative. The contents of the reaction flask were poured into excess dilute acetic acid and the acetylene iodide was extracted into diethyl ether. Unreacted I ₂ was removed by a thiosulfate wash and purification was achieved by vacuum distillation after evaporation of diethyl ether. The details of the acetylene coupling reaction have been extensively studied. To the acid dissolved in dilute KOH solution was added trace amounts of hydroxyl hydrochloride and 0.25 molar equivalents of Cu ₂ Cl ₂ dissolved in aqueous ethylamine. The alkyne iodide (1 molar equivalent) was then added portionwise at a time. The initially yellow solution turned green. Recovery was achieved by adding a few drops of 10% hydroxylamine solution before the next addition of alkyne.
Finally, the reaction mixture was made acidic and the product was extracted into diethyl ether. Diynic acid 40−
Recrystallized from petroleum ether at 60°C. The acid polymerized easily. Ultraviolet and infrared spectroscopy showed the presence of conjugated triple bonds and carboxylic acid groups, respectively. (b) Synthesis of phospholipids The acid was dissolved in methylene chloride and converted to the anhydride by adding 0.55 molar equivalents of dicyclohexylcarbodiimide. The anhydride was identified by infrared spectroscopy. Phospholipids were synthesized using the method of Gupta et al. Glycerophosphatidylcholine- _CdCl2 complex (1.0 molar eq.) was dissolved in dry chloroform (treated with _P2O5 ) for 30 h with anhydride ( _2.5 molar eq.) and 4-N,N-dimethylaminopyridine (2.0 eq.) and stirred. After removing the solvent, methanol/chloroform/water (5:
Rexin I-
300 (Rexyn I-300) resin was passed down. Now the CdCl ₂ and amino-pyridine-free product was added to Cephadex LH-20.
It was purified by chromatography on (Cephadex LH-20). The overall yield is 5% based on the starting alkene. Products and dipalmitoylphosphatidylcholine (puriss grade)
Fluka] was compared by thin layer chromatography (Merck silica gel plates; solvent, chloroform/methanol/water (65:35:4, V/V)) and infrared spectroscopy. The R _f values and spectra were the same. The product gave a positive test (turned blue) when sprayed with Dittmer reagent.
Examination by ultraviolet spectroscopy showed the presence of conjugated triple bonds. The products are phospholipids 1,2-ditricosanoyl (C ₂₃ )- and 1,2
-Pentacosanoyl ( _C25 )-10,12-diyne-
It was sn-glycero-3-phosphorylcholine. These diacetylene phospholipids ( _C23 and
The transition temperature and enthalpy for _C25 ) are shown below:

Table: Example 2 The method used in Example 1 was modified to produce conjugated triyne analogs of _C23 phospholipids. The alkynoid carboxylic acid HC≡C-( _CH2 ) _8COOH was prepared as described in Example 1. Stage 1. Bis-
Diacetylene HC≡ is obtained by reacting (chloromethyl)-acetylene with 3 moles of butyl-lithium in tetrahydrofuran and hexamethylphosphoramide.
The lithium salt of C-C≡CLi was obtained which was then reacted with n-octyl bromide to form dodecadiyn-1,3 in about 40% yield. Dodecadiin-1,3 was then reacted with NaOI to give the 1-iodo derivative _CH3- ( _CH2 ) ₇ -C≡C-C≡C-I, which was then subjected to the conditions shown in Example 1 step 3. A conjugated triyne _CH3- ( _CH2 ) _7- C≡C-C≡C-C=C is obtained by reacting with the alkinoic acid described below.
( _CH2 ) _8COOH was obtained. This conjugated triacetylenic acid shows a higher peak in the UV spectrum than the conjugated diacetylenic acid obtained in step 3 of Example 1, indicating its higher degree of conjugation. Converting the conjugated triacetylenic acid to its anhydride by the method described in step 4 of Example 1 and then reacting the anhydride with the CdCl ₂ complex of glycerophosphatidylcholine as described in step 5 of Example 1. Forms conjugated triacetylene phospholipids, which polymerize upon exposure to actinic radiation. Conjugated triacetylene phospholipids convert triacetylene carboxylic acid into a ketone in tetrahydrofuran.

Amide by reacting with [formula]

[Formula] and then convert this amide into CdCl ₂ of the phospholipid in dimethyl sulfoxide.
It was also produced by reacting with a complex to obtain a conjugated triacetylene phospholipid. Conjugated triacetylenic acid is an acid HC=C,
(CH ₂ ) ₈ COOH is iodinated at the acetylene bond, and iododecinoic acid is converted into diine CH ₃ .
It was also produced by a method comprising reacting ( _CH2 ) ₇ -C≡C-C≡CH with the coupling method described above. Example 3 The diacetylene phosphate lipid of Example 1 was used to coat an intraocular lens made from polymethyl methacrylate using the Langmire-Prodget method. In this method, a surface layer of lipids is formed at the air-water interface. A final lipid layer with a hydrophilic polar surface is required. The phospholipid monolayer was soaked in pure water containing _CdCl2 (1 g/,
CdCl ₂ , water resistance 15 MΩ/cm (undetectable organic contaminants). Lenses were cleaned by soaking for 2 hours in detergent solution (RBS35) at ~60°C and then thoroughly rinsed in pure water. The monolayer has a relatively high velocity (free falling or ~73
Transfer is effected by repeatedly dipping downward through the monolayer at 100 cm/min). Deposition occurs only during periods of upward movement. When the coated object is drawn into the air, it is drawn off at a speed of 0.3 cm/min or less so that the final layer has an outer hydrophilic surface. The coated lens is then exposed to an energy output of 1200 μw/cm ² 15.2 cm from its surface.
Irradiation was performed for 10 seconds at room temperature with a UV lamp with peak radiation intensity at 254 nm. Alternatively, to produce the desired hydrophilic polar surface as the final outer surface, the polymerization by irradiation of the lipid layer during coating (of the desired number of monolayers) can be carried out under water, and the lens is placed on the water surface. can be extracted after being thoroughly cleaned. The surface pressure of lipid layers is close to the fracture pressure of these layers
chosen to be 35 dynes/cm and the temperature between 20 and 22
℃ (room temperature). subphase (1g/) to minimize the influence of impurities.
It is necessary to add _CdCl2 to and use only a new spray monolayer. Water is Millipore
pore) water purification system and used only after production to minimize recontamination. The hydrophilicity of each surface is assayed by measuring the ``water contact angle,'' defined as the degree of surface spreading of a water droplet.Water forms beads on a standard (hydrophobic) PMMA surface, but is not coated. On a covered surface, it spreads out for about 10 seconds and rolls off very slowly. This behavior changes if the coated perspex is stored on air after several weeks or immersed in water for several days. No. Stability can be seen from the fact that sterilization methods involving immersion in 70% NaOH solution for several days do not change the surface properties. Permanentization of lipid polymers onto intraocular lenses using R-ray irradiation Grafting results in successful hydrophilic modification of the lens surface.The water contact angle for unmodified PMMA is 72°, and after grafting this angle decreases (spreading increased).These lenses were tested in clinical trials. The coated lenses were introduced into humans without causing intradermal damage or any adverse effects on patients over a two-month study period. Example 4 Lenses were wrapped in a flexible Teflon sheet 0.1 mm thick. The coating method described in Example 3 was repeated by substituting . The coated sheet was polymerized in air as described in Example 3. The flexible sheet was then formed into a tube and the blood was poured into the tube. An in vitro fibrinopeptide A generation assay was used as a measure of the surface's ability to induce thrombin activity.The surface showed little tendency to initiate blood clotting, and in this respect untreated EXAMPLE 5 The coating method of Example 3 was repeated by replacing the lens with a silicone contact lens, a glass sheet and a cellulose acetate dialysis membrane (Cuprophane). Testing showed the formation of a polymeric film on each of these three substrates. Contact angle measurements on the coated substrates showed that a hydrophilic outer surface was formed in each case. Example 6 1 di-C ₂₃ -di-conjugated phospholipid at 50°C.
was introduced into the water. This was above its liposome formation temperature, and the dispersion was then cooled to room temperature if electronic suspension showed the presence of multilamellar liposomes. This dispersion was then irradiated with ultraviolet rays, and if a change in color was observed, this indicates polymerization due to crosslinking of the conjugated diyne system. The spectral changes also identified were consistent with increased conjugation paths of this organic material. This procedure is repeated to obtain the enzymatically active intrinsic protein Ca ₂ ²⁺ ATPase (Ca 2 2+ ATP-ase).
Conjugated phospholipids were introduced into an aqueous medium containing Ca ²⁺ ATP-ase). Subsequent examination of the resulting liposomes showed that the liposomes exhibited enzymatic activity indicating that some enzyme had been incorporated within the liposomes. The above method was repeated using the di- _C25 conjugated phospholipid of Example 1, but the temperature of the aqueous medium into which it was introduced was raised to 60°C to be higher than the liposome formation temperature of the di- _C25 material. Ta. Again, in this case,
It was found that enzyme activity was detected in the liposomes.

Claims (1)

[Claims] 1 (A) General formula In the formula, at least one of B ₁ and B ₂ has the formula -(CO) _p -X ₁ -C≡C-C≡C-Y ₁ , where p is 0 or 1, and X ₁ is a direct bond. or a divalent aliphatic or cycloaliphatic group,
Y ₁ is H or _a monovalent aliphatic or cycloaliphatic group, and _{X 1 and}
Y ₁ is a group in which the total number of carbon atoms is 8 to 26, and the other of B ₁ and B ₂ is a group of the formula (a) -(CO) _p -X ₁ -C≡C-C≡C-Y ₁ In the formula, X ₁ , Y ₁ or p is as described above,
or (b) an aliphatic or cycloaliphatic group containing at least 8 carbon atoms, n is 0 or 1, m is 2,
3 or 4, and each R independently represents an alkyl group containing 1 to 4 carbon atoms, or (B) a polymer obtained by crosslinking the above conjugated di-ynes. An aqueous dispersion of liposomes characterized by: 2 The above polymer (B) has the formula In the formula, two of Z ₁ , Z ₂ , Z ₃ and Z ₄ represent Y ₁ as described in claim 1, and Z ₁ , Z ₂ ,
The other two Z ₃ and Z ₄ each represent −X ₁ −(CO) _p −G, where X ₁ and p
is as stated in claim 1,
G is , in which n, m and R are as described in claim 1, and the crosslinked chains are repeating units that are bonded to the same or different G residues. The aqueous dispersion according to claim 1, which is a coalescent.