JPS63240938A - Liposome aqueous suspension - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides biocompatible surfaces.
Polymers derived from Lgsurfaces), i.e. surfaces suitable for prolonged contact with living tissues and body fluids;
and the production of Z polymers and the use of phospholipids and the use of said phospholipids and their polymers in the production of biocompatible surfaces and the long-term release of physiologically active compounds? The present invention relates to a composition for providing.

It is common practice to use biocompatible polymers to shape at least the surfaces of, for example, prosthetic devices and the groove base of hemodialysis machines. However, these materials are not perfect and their reaction with living tissue remains problematic. For example, surface-induced thrombosis may occur when large amounts of fluid are present in the oxygenator lung and artificial kidney 7J.
Foreign surfaces such as
It remains a major problem when contacting the cesium (Ces). Is the formation of clots in prosthetic organs an artificial surface? (break off) and adverse effects? affect Recently, surface agglomeration (surfac)
Ethrombgenicity Attempts to use Jfl-length J4A preserved artificial heart 1ak were thwarted. Many of the deaths that occur in animals are caused by artificial stones6.
The theory is that it is caused by mechanical damage, but not by clot formation. Dialysis membrane, blood substitute (blo
od 5ubstitutes) and artificial lungs are all M together with this @ title.

Materials used for pharmaceutical applications in the light of their general biological compatibility should preferably a) be renewable products as pure substances, and b) be subject to deterioration or adverse changes. c) have the necessary mechanical properties and permeability properties in light of the specific function, and d) can be sterilized without adversely changing the mechanical permeability or surface properties. e) not be acted upon in a harmful way by the biological environment; and f) preferably non-local.

There are limitations in applications involving direct contact with blood. Shouldn't lipids induce thrombosis to the extent that it becomes a problem?Is it normal for lipids to induce thrombosis? 11) Should not cause significant damage to the narrow elements or soluble components of the blood. Many attempts have been made to produce biocompatible surfaces that are blood compatible, ie, surfaces that do not activate the blood coagulation process and do not promote clot formation. Examples of attempts to achieve this goal include the development of negatively charged polymers such as anionic polymers or suitably oriented electret polymers.
Viewed surface, natural anticoagulant heparin or synthetic
Does the IJ imitation body have an inherently low surface free energy? It is thought that albumin is absorbed from the surface loaded with albumin, the surface has a small amount of albumin, and the surface of blood is absorbed (
■Polymethane-like surface? include. However, all have limitations r.

Considering the problem as a general matter of surface properties,
Is there an impression that there is a great intention that biological re is essential to all areas of the body? I received it.

Abe's life is still alive. The cannon has an outer membrane r! a@internally, various rI+iII organelles, such as mitochondria, nucleus and endoplasmic reticulum (endoplasmic rete).
(mi creticulum) There is a sense of smell that acts to divide the body into two categories. The membrane is composed of a matrix of polar lipids (for example, phospholipids). Red blood cells have a cell wall composed of a matrix of polar lipids (for example, a phospholipid bilayer). 〒Have. Lipids include the phospholipids lecithin (phosphatidylcoria) and sphingomyelin and R?7 on the outer surface of the cell wall. K, and on the inner surface of the wall 6 sphatin lucerine and phosphatin ethanolamine are arranged symmetrically. The latter has a net charge of 7 and is believed to cause blood (coagulation) on itself. The former has a mesoionic structure and is thin
Since phospholipids are essential constituents of biological membranes throughout the body, the present invention aims to improve the appearance of phospholipids on the surfaces of foreign objects that come into contact with living tissue. membrane 1; given fc coating surface imitations are those 7
This is indeed the case, and the essentials of the present authors' proposal are based on the concept of biological compatibility.
It has been found that it is possible to provide an artificial biologically compatible surface f; N''T article or object in which the ionic groups (oxy-acid)/-i are present on the outer surface of the molecular structure. .

In its broadest aspect, the present invention provides a conjugate of the following formula:

CII 2- OB + where at least one of B and B2 -<Co)
-X, -C-=C-C=C-Y where p is O or 1, Xl is a direct or divalent aliphatic or truncated aliphatic group, Y1 H or - aliphatic or cycloaliphatic group, each B.

The total number of carbon atoms in X and Y in ) an aliphatic or cycloaliphatic group containing at least 8 carbon atoms, n = 0, m = 2.3 or = 4, each R independently having 1 to 41 carbon atoms; Carbon atom? The alkyl group contained in 7 is represented.

The purpose of the present invention is to provide an electrical assembly which is suited for constructing a conjugate geier as described above.

These electric combinations have the two symbols Z, , z2, Zs and Z4, and the seven symbols Zl, Z2, Z3 and Z4, respectively -x I. (c OJ p G7, where X and p are the above-mentioned through, and G is H2-
Q- represents pregnancy, where n, m and R are as described above,
The cross-linked chains are attached to the same or different G residues,
No/Child/Shi unit'? ! : Al-based, preferred.

The conjugated diynes of formula 1 are preferably groups in which the basic ionic group is a phosphate-loaded group of the natural phospholipids lecithin and sphingomyelin, i.e., a choline phosphate group: O○ or a related phosphine group. This is a military service in a certain place.

Divalent zwitterionic groups in which m is 2, but m can also be 3 or 4;
1, and each R group is preferably methyl, as in naturally occurring products, but can also be ester, propyl or butyl; The forming ionic group may also be asymmetrically substituted at the quaternary nitrogen.

In the conjugate of the present invention, 1'tQ B , and B2 are also all basic expressions of the 4-formula % formula % 1E-fL.

As a practical matter, symmetrical compounds are the easiest to synthesize, those in which plX and Yl are the same in B1 and B2. However, such symmetry is not essential for the purposes of the present invention, and if each X1 and Y are the same or different, p is O in one of 81 and B2, and B, and B2, p is 1
Is the compound proboscis? It is possible to use. It is extremely difficult to synthesize a substance that achieves η1 while at the same time.

As far as the theoretical basis of the invention is concerned, position 14 of the conjugated gene system in B1 and B2 is not important.

For example, Xl can be a direct bond such that the conjugated diyne is immediately adjacent to the carboxylic acid Nisdel or ether, and when Y.

would need to contain at least 8 carbon atoms. A conjugated di-yne system in which Y is hydrogen and X has at least 8 carbon atoms? It is also possible that the structure is modified from a carboxylic acid Nisder or ether group at its end of the hydrophobic chain. For reasons discussed in detail below, the conjugated N-Yin system has an internal force at the center of the hydrophobic group such that there are approximately the same number of carbon atoms in Xl and Y) It has been found out that the people who are most likely to be placed in such a way as to cry are the ones who are most likely to be 1-year-olds.

X and Y are each preferably an aliphatic or cycloaliphatic group. Although the inventor's early efforts focused on compounds in which the aliphatic or cycloaliphatic group is an unbranched hydrocarbon group, the aliphatic or cycloaliphatic group is a branched hydrocarbon group. The reason why there should not be a group on the hydrocarbon chain,
There is no reason why it should contain, for example, an alkoxy substituent or... For reasons that will become clear in the discussion below, the di-yne system has a carbon-to-carbon bond in the hydrophobic chain. However, if an 11 carbon bridge bond is desired, it is preferred that additional carbon-carbon bonds can be present in groups XI and Yl.

It is important that the total number of carbon atoms in each group B, and in Xl and Y in B2, is from 8 to 26 so that each strand contains a total of 12 to 30 carbon atoms.

If the group B and/or B2 contains 12 fewer carbon atoms, then what happens if the Yl quality is extremely low? Is it difficult or usu to have one go except for? Headline friend. As a practical matter, when there are 16 to 26 carbon atoms in 4B and/or B2, sometimes the chain is 22 or 24
It has been found that satisfactory results can also be obtained in the case where one carbon atom contains gold.

The precise placement of carbon atoms in However, although the carbon atoms are in a straight chain or branched structure, Words that can also include family members are not mandatory.

For reasons that become clear from the following explanatory power regarding the JF combination of conjugated di-ynes, both B7 and B2 conjugated di-yne systems can be 87 IO in the molecule and in the molecular real 11 combination. Containing words are preferred. 711) 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 B1 and B2 contains a conjugated dianyl group. It is. B, and B2 may be one or more hydrocarbon residues, which may be saturated or may be olefinic or possibly combined with isolated or conjugated di-one systems. It may contain a single acetylene compound.

Sword ≧ Sword) Ru base is Yabori Ester Matabo Needle base? and at least one
The sound of two carbon atoms is also included.

The co-injector of the present invention can be manufactured by methods known per se. In addition, s1 bioionic group rr1
It can be introduced by reacting with a normal phosphonic acid or phosphinic acid or the α-hydroxy group of engineered glycerol to form the necessary phosphorus ester group. Group B
, and B2, carbo7y4B, CoOH or alcohol B, OH or the corresponding B2C0OH or BO
H substances or esters or needle-forming derivatives of alcohols with glycerol or other ether-forming or ester-forming derivatives? It can be introduced into the molecule by modifying the esterification or etherification used. These reactions can be carried out between glycerol or its derivatives on the one hand and carvone or alcohols and phosphorus esters on the other hand simultaneously or sequentially in any order. For the preparation of the symmetrical phospholipids, which are the preferred compounds of the present invention, we form the required glycerol monoester with a selected phosphoric acid or phosphoric acid and then this mono-phosphoric acid. Reacting the selected conjugated di-ynecarboxylic anhydride (obtained by treatment with dicyclohexyl-carbodiimide above) with the anhydride (obtained by treatment with Mx dicyclohexyl-carbodiimide above) and then reacting dalicerol monoester kW in a bath medium and in the presence of an organic base. It turns out that it is convenient to react with anhydride.

Other known methods for the formation of ester groups can equally be used. Compound where p is O? If it is desired to produce them, they can be used with the corresponding conventional ether base processes.

The conjugated diynes of the present invention can be polymerized by exposure to actinic radiation, typically ultraviolet radiation in the wavelength range <30 Qnm. Irradiation produces crosslinks between conjugated di-yne systems of adjacent chains. Is this the 4-return unit of the structure below? Containing polymer r is produced.

In the formula, Zl, Z2, Z3 and Z4 are as described above. The conjugated N-Yin system involved in cross-linking is asymmetric, but C1 and C4 are not equivalent to each other due to asymmetric substitution, so cross-linking occurs between C8 and 01 of each class, or between C1 and C4, or between C4 and C41) Depending on the furnace, different crosslinked products may result, for example, if crosslinking occurs between C1 and C4
If it occurs in between, the repeating unit is.

Our structural studies on polymers have shown that cross-linked polymers contain one or more possible cross-linked products (71), although it has not yet been established that they are all possible cross-linked products. Conjugate system that is common to the groove path → C-C three c-c, c-c= c-c4=tl
II 1? It has been established that it contains 7.

Are B and B2 both conjugate no-in 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 preferable that B1 and B2 are conjugated di-yne systems, and in order to optimize intramolecular crosslinking, the relative positions of the conjugated di-yne systems of BI and B2 (almost the same) are preferred. In other words, the carbon chain connected to the conjugated diyne glycerol residue has 2' carbon atoms in length.
Preferably, they should not differ by more than 1IIA.

Indicating the intended biomedical use of the polymers of the invention, λ et al.
Polymerization is best induced by exposure to chemically active radiation, usually a chemically active radiation with a wavelength that is higher than or shorter than the wavelength of the radiation, but in principle it is possible to induce polymerization of a conjugated N-Yin system. Any process known to be possible can be used to prepare the polymers of the invention. Conjugated materials can be used in various ways, such as as a layer on water, as a multilayer on a substrate, or as a liposome (
It can be polymerized as a tiposome or in the solid state in rHKBr disks.

One of the main uses of the polymers of the present invention is to use them as substrates, as well as other body fluids or internal body surfaces. I
! It is to bestow upon these men a great deal of destruction. (Katana) Is the conjugate of the present invention the basis of the conjugate of the present invention? It is usually best introduced by in situ conjugate polymerization by irradiation and exposure to chemically active radiation. The conjugated diynes of the present invention are colorless and chlorinated, but as the polymerization proceeds, there is a pronounced color change that first progresses through the red range as the conjugated diynes are first converted to the intermediate carbene, and then this transition state carbene. The intermediate is converted to the final polymer molecule having a red or purple coloration. As a result, the Togane on the base can be seen with the naked eye. Basic -1/:1
．． For example, it can be a polymer, metal, glass, ceramic and many others; examples of polymers are cellophane, polyvinyl chloride, polycarbonate, polymethyl methacrylate, polyethylene, polytetrafluoroethylene and silicone coams. . sword) to sword. It is repeated and constant substrate (Guhae organ transplant, ■ #ic (prosthet
ic implants), eye, transplant 1 tissue (ey
e implantants J and contact lenses, diagnostic equipment, oxygenator machine 1 to 11, sutures, artificial lenses, tissue that can be changed at will, culture medium and surgical instruments, + bags , Permanent Entry Port Medication Delivery System, Syringe, Intrauterine Device, Contraceptive Device Including 7.
And a toilet knife can be used as a bandage.

The present invention relates to M membrane endothelial fjjf3 (corneal e
It is particularly suitable for giving a 1'3V7 surface to the 1'3 V7's.

The brightest four implants of the intraocular lens are associated with cataract oil production and endothelial cell loss.
1oss) and damage? 711].

This damage can cause damage to the lens material, polymethyl methacrylate (P), to the endothelium surface if the lens absorbs into the corneal endothelium.
This appears to be caused by the instantaneous adhesion of MMA).

Kauf-man (Kauf-man)
) and 'h Noah (K (L tZ ) iq P
hf M A 7Jk The momentary contact between the lens and the endothelium causes the membrane to attach to the IOL flame surface. thing? Show friend.

Studies on the surface modification of polymethyl methacrylate to reduce or prevent cell damage caused by occasional lens-endothelial contact have shown that this polymer exhibits short- or long-term deterioration (C). This appears to be a practical method as it has already been shown to be well tolerated in the eye. Modifications that introduce new substances similarly require extensive repeated safety and efficacy testing. Will.

Previous research in this field has been based on the idea that the adhesion between the lens and the endothelium is an interaction between hydrophobic polymethyl methacrylate and the phthalate.

Polymethyl methacrylate surface? Prior to implantation, the 4-polymethyl methacrylate surface was immersed in a polyvinylpyrrolidone (P'VPJ) methylcellulose bath.
nicαtincidence) f was shown to decrease. (In similar attempts to temporarily alter these intraocular lens surfaces, immersion solutions of FVP, silicone oil, and serum have been used.) It is cumbersome and inconvenient to pre-immerse in a bath solution and creates two problems: sterility and reproducibility.

The substance of the present invention is characterized in that the polar groups of the substance of the present invention are
, ids) How to use an intraocular lens? It is used for being criticized. This makes it suitable for short or long contact with living tissue and the environment.
Tearing of the B cyst membrane? will decrease. The conjugated polymer is then stabilized to form a polymeric coating whose surface is hydrophilic and at the same time biologically compatible with living tissue.

The long surface of the intraocular lens or other support can be coated by a variety of methods, such as bath or emulsion coating or the Langmuir-Blodgett multilayer dipping method to form oriented layers. Obtain and irregular surface? Processing can be done with care.

Attachment of the coating, e.g. groups which are reactive with the polymer or other substance to be coated or with the substances absorbed by it after e.g. bath treatment? Lipids with fatty acids in the eye or at the end of the chain can be used to improve covalent attachment to the surface. Alternatively, for example ■ the combined substrate r small molecule @ swelled by a solvent and the fatty chains of the fatty residues are subsequently absorbed into the polymer structure? As a result, physical adhesion of the coating may occur.

Another important application of the conjugated diine of the present invention is the ribosome (
liposome) and blue. Liposomes support physiologically active 'P/Q' properties and are therefore biologically compatible for the release of, for example, non-metabolized drugs or enzymes. Because you can give.

The 71" ribosomes in the sword are dispersed in an aqueous medium, and the temperature of the dispersion is determined to cause the generation of ribosomes.
Lipid quality or Chapman transition 1 degree (tipid)
or chapman trancitio,
Temperature) Is the temperature of the temperature dispersed at a higher temperature? The dispersion can be heated and then cooled to the same temperature as the dispersion. If a physiologically active substance is present in the aqueous medium during liposome formation, the liposomes contain active lipids and the active substance remains for a long time as a result of the metabolism of the liposome membrane.
I recommend releasing it slowly.

One of the practical advantages of such a combination is thus the water-soluble and water-insoluble activities'! Or, if desired, aqueous and aqueous substances in the same formulation,
This means that it is possible to formulate water-insoluble substances by first incorporating them into fats.

The conjugated di-yne phospholipids or liposome membrane-forming polymers of the present invention are often found to act as adjuvants for many physiologically active substances introduced into the liposomes.

Liposomal form 5y, during which aluminum hydroxide or other adjuvants are introduced into the aqueous medium, these formulations are formulated with water, aluminum hydroxide or other auxiliary agents that are physiologically active'; f: It is also possible to enhance the activity 7 of the substance and to obtain a 0° liposomal ashes multilayered lamellar structure 7, which can be done by known methods. Single-lamellar liponomes with small diameters are replaced by multilamellar ribonomes (mrbt t
i-lame 1iar 1iposornes
)? It can be generated by subjecting it to ultrasonic vibration. Larger single lamellar liposomes are dissolved in conjugated di-alcohol and then this solution is injected into a syringe 7.
It can be specifically injected into an aqueous medium through injection. These single lamellar materials are known as micro-5icles.

The resulting liposomes, which are single-lamellar or multi-lamellar, and which usually contain physiologically active substances and adjuvants, can be cured by exposure to active radiation as described above. It can be stabilized by having a relationship. Such irradiation occurs intermolecularly,
And depending on the structure of the conjugated diine, possibly intramolecular cross-linking, dispersion of liposomes comprising the polymers of the invention is achieved. The preamble to the crosslinking of the uninvented conjugated diynes may later include the inclusion of liposomes of other phospholipids in the liposome dispersion of the invention.

Although it is usually most convenient to formulate the conjugate of the present invention in liposomal form, it is possible to combine large amounts of the conjugated di-ynes.
Next, polymers? It is also possible to provide phospholipid polymer capsules by extrusion. Alternatively, the phospholipid polymers of the present invention may be included in a liposome system in which other phospholipids are also present.
+! : Mekoto can also do it.

Medicines such as antigenic substances, hormones, fermentation agents and anti-inflammatory agents? A wide variety of physiologically active substances can be incorporated into the liposomal dispersion of the present invention. The combination of influenza virus or fragments of influenza virus, diphtheria toxin, tetanus toxin and other antigenic substances from viral or bacterial sources in the liposomes can be used to treat hormones such as insulin, anti-inflammatory drugs, etc. steroids, such as corticosteroids, such as cortisol, Δ'-dehydro and 9-fluoro derivatives thereof; anti-inflammatory non-steroids, such as peptides, immunosuppressive compounds, such as methotrexate, salicylates, phenylbutacin, and Hydrolytic enzyme 1'-like inhibitors are now well described in the literature.

How these and other physiologically active substances can be introduced into ribbon ash compositions by cutting is discussed, for example, in US Pat. Nos. 4.177.113 and 44,199.
No. 565 and West German Publication No. 22/19552,
No. 2528411, No. 2643641, No. 2712
No. 030 and No. 2712031. These substances are a class of physiologically active substances that can be incorporated into the glue bombs of the present invention.

The present invention will be explained with reference to Examples 1 and 11 below.

Example l (α) Synthesis of diacetylene throat HC-EC(CH2)8C02H(A)HC=C(CH
2) rLCH3 n=9, 11 3, +Cti3CH2MgBr Br MgC=C(CH,)nCH3 4, +I 2 1 C=C(CH2) n CH
3(B)CH5(CH2) C=-C-C=C-<
CH2), Co2HfJ 2 (C) RN=C
=N-RCH5(to CH28C=C-C-=C-(
CH2n.

t51 (D)4- CH20H 0-CdCl2 Alkenes and alkonic acids? Bromination was carried out in a stone and needle solution by slowly adding 1 mol of bromine. Excessive KO in dibromo-induced 4-body ethanol
The dibro derivative is immediately dehydrobrominated by refluxing with H. Alcohol 'c' + M removed and H added
After the C1=zt river was extracted, the alkyne was subjected to ether extraction and then subjected to vacuum distillation (10-1 to 1-1 t).

Chod
okiewicz coupling) (Dfla!
'), one of the reaction components must be iodized. Therefore, the 1-alkyne was added to MJI's ethylmagnesium bromide in dry diethyl needle (CaH2-embedded). The resulting acetylene was immediately reacted with I2 added to Grignard's reagent to form the desired...
I got r. The contents of the reaction flask were poured into an excess of dilute acetylene and extracted into ethyl ether. I2 of the reaction? Eliminate with thiosulfate wash,
And diethylneedle? ! - After evaporation, purification was achieved by true nitrogen distillation.

The details of the acetylene coupling reaction have been extensively studied. 0.25 molar equivalents of Cu2Cl22 dissolved in dilute KOH and trace amounts of hydroxyl hydrochloride and gold dust in aqueous ethylamine were added.

Then, a small amount of alkyne dioxydide (1 mol equivalent = -) was impregnated at a time. The yellow solution in the beginning sword 1 turned green. Next to the alkyne, 471[1g of 10% hydroxylamine, which is a few quotient in 1@? He recovered by digging.

Finally, the reaction mixture is made ↑7 acidic, and the product? Oil leaked into the diethyl needle. Ninj Shun 740150℃
The petroleum ether sword 1 and others were re-launched.

The acid polymerized easily. Are ultraviolet and infrared spectroscopy the presence of conjugated triple bonds and carboxylic acid groups, respectively? Indicated.

b) Synthesis of phospholipids: 710 mol of cyclohexylcarbodiimide dissolved in methylene chloride and 0.55 mol equivalent of cyclohexyl carbodiimide, -
It was converted to the anhydride by The anhydride was subjected to infrared spectroscopy.

Phospholipids are from Gupta et al.
the method of? It was synthesized by repeating the procedure once. Glycerophosphatidylcholine-CdCl2 complex (■, 0 molar equivalents) was purified in anhydrous (Z
5 molar equivalent] and 4-N,N-methylaminobirine (2-O equivalent) for 1 mol. After removal of the solvent, methanol/chloroform/water (5:4:1, V/VIK soluble fraction 2v#Syn I-300 (Rexyn I-3
00) Resin Tukaram? Passed it down. Next time CdC1
, and amino-pyridine 7-containing raw material, Sephadex LH-20 (Cephadex LH-20)
It was purified by chromatography. The total yield is 5% based on If1 primary alkene 7.

Products and dipalmitoylphosphatidylcholine [Puriss grade (Puriss grad and λFlu)
kα] Basin thin layer chromatography [Merck silica gel
Brate; @'4K, Taloloform/methanol/water (65:35:4, V/VI) and Eli ratio for infrared spectroscopy. The Rf range and spectra were identical. D it tme'r
recL qent ) T”Gt g t, *
4-K positive test
(#changed color) τ gave. Examination by ultraviolet spectroscopy showed the presence of conjugated triple bonds. The products are phospholipids 1,2-ditricosanoyl<C25)- and 1,2-pentacosanoyl(C25)-10,12
-diyne-5n-glycero-3-phosphorylcholine.

The transition temperatures and enthalpies for these diacetylene phospholipids (C23 and C25) are shown below. A sudden imitation? generated. Alkynoid carboxylic acid HC3C-(C1i, ToriC0OHKeikugougAJ
It was manufactured as described in 1. Step 10 Bis-(chloromethylnoacetylene r reacted with 3 moles of butyl-lithium in detrahydrofuran and hexamethylphosphoramide to form diacetylene II C=C-C=-COL
Get the lithium term of i■, then this? Reaction with n-octyl bromide gave dodecadiyn-
1 and 3 basins were formed.

Reacting with dodecadi-yn-1,37zNaOI to form the 1-iodo-pruritic compound C1l, -(CH,) 7-C=C
-C=C-12 obtained, this? Next, the reaction with the above-mentioned alkinoic acid as shown in Example 1 [Product 3] was carried out to form a conjugated triyne CH3-(CH2), -C=C-C=C-C.
=C(CH2)8COOII? Obtained.

Does this conjugated triacetylenic acid have a high peak in the UV spectrum as does the conjugated diacetylenic acid obtained in Step 3 of Example 1? and its higher degree of conjugation is shown. Military triacetylene phosphorus is converted to its anhydride by the method described in step 4 of Example 1 and then reacted with the CdCl2 complex of glycerophosphatidylcholine as described in step 5 of Example 1 to obtain military triacetylene phosphorus. Lipid r is formed, which polymerizes upon exposure to actinic radiation.

Conjugated triacetylene phospholipids were also prepared by reacting triacetylene carboxylic acid with CdCl2 complexes of phospholipids in ketone ketone methyl sulfoxide in tetrahydrofuran to yield conjugated triacetylene phospholipids.

Conjugated triacetylenic acid has pHc=c, (CH2)a
CoOH is iodinated at the acetylene bond to form iodo-decynoic acid? Gin CH3゜<Cf12), -C=C
It was also produced by a method consisting of reacting with -C═CH using the coupling method described above.

Example 3 Diacetylene phosphate lipid of Example 1? The Langmire-Prodget method was used to coat intraocular lenses made from polymethyl methacrylate. In this method, a superficial UfJ layer of lipids is formed at the air-water interface. A final lipid layer with an aqueous polar surface is essential.

Pure water containing phospholipid monolayer CdC12 (Ijj/l.

CdCl2, water resistance 15AfΩ/tan organic contaminants? Undetectable] Expand above. V's? ~60℃ detergent bath solution (
Cleaned by soaking for 2 hours in RBS 35) and then thoroughly rinsed in Pure. The monolayer is transferred by dipping in four sections downward through the monolayer at a relatively high rate (free-falling speed ~73 α/min). Deposition occurs only during periods of upward movement. When the coated object is drawn out into the air, the final layer will have an outer hydrophilic surface of approximately 0.3□□□/
It is extracted at a speed of 1 minute or less. The refracted lens is then 1.200 u w/brd from that surface.
Peak radiation intensity at 254nm with energy output of 15.2m? The room temperature was irradiated with an ultraviolet lamp for 10 seconds. Alternatively, in order to produce the desired hydrophilic polar surface as the final outer surface, the coating (applied to the irradiation of the lipid layer between two of the desired number of monolayers) can be carried out under water. After the surface of the lentil ice has been thoroughly cleaned, it is removed and prayed.

The surface pressure of the lipid layer was chosen to be 35 dynes/α, close to the fracture pressure of these +i, and the temperature was 20-22°C (room temperature). C in phase (5ubphas e) (l evening/l)
For use with only one spray layer of dC1, double and fr.
It is necessary to Water is Millipore
are) Eri-loaded to the water hole system, used immediately after manufacturing, and then re-decontaminated? Minimize.

1 - The hydrophilicity of each surface is assayed by measuring the "water contact angle r" defined as the degree of surface spreading of a water droplet.
Shaped, but on a coated surface, it spreads out for about 10 seconds and is swept away very slowly (roll
lsoff I. This behavior does not change if the exposed perspex is stored on air after several weeks or immersed in water for several days. Sterilization method using immersion in NaOH solution for several days 703 surface characteristics? The fact that it doesn't change can be used as a sword.

Does permanent grafting of lipid polymers onto intraocular lenses used for gamma irradiation result in confusing hydrophilic modification of the lens surface? arise.

The water contact angle on unmodified PMMA is 72°, and after grafting this angle decreases (7°C with increased spreading).

These lenses were submitted to clinical trials. The coated lenses were introduced into humans without causing skin lesions or any adverse effects on patients over a two-month trial period.

Example 4 Lens W Flexible DEFRON sheet 01 What is the coating method described in Eri Jitsune vAJ 3 to be replaced by scrap thickness? repeated. 1) Polymerized in the air using a covered sheet as described in 3.Then, it was formed into a flexible sheet tube and placed in a blood clot tube.Thrombin activity was induced. An in vitro fibrinopeptide A generation test was used as a measure of the surface's ability to induce blood clotting.

Example 5 Lenska silicone contact lens, glass'/-
and Unrll cellulose dialysis membrane [cuprophane (Cu
How to cover actual gun example 3 by placing CF) on prophane)? It was dry. Visual transverse strain after irradiation indicated the formation of polymeric films 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 G-C7,-G conjugated phospholipid of Example 1? When introduced into water at 50°C, the temperature at which ribosomes form is higher than that of the dispersion. , What if the electron@microscope has a multilamellar ribonome? Cooled to room temperature where indicated. Next, when this dispersion liquid is irradiated with ultraviolet rays, a change in color is observed, indicating polymerization due to crosslinking of the conjugated diyne system. The spectral changes also identified were consistent with an increased recruitment pathway of this organic material.

This method? Measuring the enzymatically active intrinsic protein Ca
22+ATP-ase (1ntrinsicpr
Conjugated phospholipid 7 was introduced into an aqueous medium containing otein Ca'ATP-ase) 2. Subsequent examination of the resulting ribosomes showed that the HIJ ponomes exhibited enzymatic activity indicating that some enzyme had been introduced into the ribosomes.

The above method using the G-C2 conjugated phospholipid of Example 1? I repeated this, but the temperature of the water poured by 74 people was G-C.
7. 60 to raise the temperature higher than the ribosome formation temperature of the substance
Raised to ℃. Again, it was found that enzymatic activity was detected in the liposomes.

Claims (1)

[Claims] 1. (A) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ In the formula, at least one of B_1 and B_2 is the formula -(CO
) p-X_1-C≡C-C≡C-Y_1 where p is 0 or 1, X_1 is a direct bond or a divalent aliphatic or cycloaliphatic group, and Y_1 is H or a monovalent is an aliphatic or cycloaliphatic group, and the total number of carbon atoms of X_1 and Y_1 in each of B_1 and/or B_2 is 8 to 26
, and the other of B_1 and B_2 is (a)
In the formula -(CO)p-X_1-C≡C-C≡C-Y_1,
X_1, Y_1 or p are the same or different groups as defined above, or (b) are aliphatic or cycloaliphatic groups containing at least 8 carbon atoms, and 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) bridging the above conjugated di-ynes. An aqueous liposome dispersion comprising a polymer obtained by: 2. The above polymer (B) has the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, two of Z_1, Z_2, Z_3 and Z_4 represent Y_1 as described in claim 1, Z_
1, Z_2, Z_3 and Z_4 each represent -X_1-(CO)p-G, where X_1 and p are as described in claim 1, and G is represented by the formula ▲ , chemical formula, table, etc. ▼ , where n, m and R are as described in claim 1, and the crosslinked chains have the same or different G The aqueous dispersion according to claim 1, which is a polymer bonded to residues.