Amidine derivatives and drug carriers comprising the same

Novel amidine derivatives of the formula (1); and drug carriers such as liposomes or emulsions comprising the derivatives, which can enclose genetic materials or drugs and transfer them to cells or affected sites efficiently and safely, ##STR1## wherein A is an aromatic ring, R.sup.1 and R.sup.2 are the same or different and independently represent an alkyl group having any one of 10 to 25 carbon atoms, and an alkenyl group having any one of 10 to 25 carbon atoms, X and Y are the same or different and independently represent --O--, --S--, --COO--, --OCO--, --CONH--, or --NHCO--, m is 0 or 1, and n is 0 or a natural number of 1 to 6.

TECHNICAL FIELD
 The present invention relates to a novel amidine derivative and a drug
 carrier comprising it.
 BACKGROUND ART
 Recently, studies have been actively made for applications of closed
 vesicles such as liposome, emulsion, and lipid microsphere as drug
 carriers have been activity made for drug delivery system (hereinafter
 referred to as DDS). These closed vesicles are usually prepared using
 phospholipids or their derivatives, sterols, or lipids except
 phospholipids as basic membrane-constituting materials. However, the
 closed vesicles composed of only these basic materials could not overcome
 various problems occurring in the practical use, such as mutual
 aggregation of closed vesicles and shortened retention time in
 circulation. Furthermore, it was practically difficult for them to drive
 drugs to their target sites.
 In order to improve a drug-loading and cell binding ability of the closed
 vesicles, an attempt has been made to charge the surface of the closed
 vesicles to cationic at physiological pH range by charging a small amount
 of a cationic lipid such as stearylamine. In particular, cationic
 liposomes containing DNA are well known to promote transfer of the DNA
 into cells, that is, transfection, and those liposomes having higher
 introduction efficiency, higher expression level, and higher safety level
 are strongly required. But, there are limited kinds of lipid available to
 use for cationic liposome, then it has been desired to develop cationic
 lipids usable for a drug carrier that are highly safe and exhibit high
 performance. Such cationic lipids have been reported so far in U.S. Pat.
 Nos. 4,897,355, 5,334,761, JP-A 2-292246, and JP-A 4-108391. However,
 their effects are not satisfactory.
 Therefore, it has been eagerly desired to develop a drug carrier that can
 transfect a DNA into cells efficiently and safely. And regarding other
 purpose in addition to the transfection of a DNA, the effective and safety
 carriers are also required for effective DDS therein to enable accurate,
 efficient, and safe targeting of a drug to such as injured sites in
 vascular endothelium and affected sites caused by nephritis, kidney
 cancer, pneumonia, lung cancer, hepatitis, hepatoma, pancreatic cancer,
 lymphoma, etc.
 DISCLOSURE OF THE INVENTION
 An objective of the present invention is to provide a drug carrier that
 enables transfection of nucleic acids, polynucleotides, genes, and their
 analogues into cells efficiently and safely, and to provide a cationic
 lipid capable of forming such drug carrier. Another objective of the
 present invention is to provide a drug carrier that effectively delivers a
 desired drug, peptide, or protein to target sites, and to provide a
 cationic lipid capable of forming such drug carrier.
 The above objectives are achieved by the present invention as described
 below.
 (1) An amidine derivative represented by the formula 1 or a salt thereof:
 ##STR2##
 wherein A is an aromatic ring, R.sup.1 and R.sup.2 are the same or
 different and independently represent an alkyl group having any one of 10
 to 25 carbon atoms, and an alkenyl group having any one of 10 to 25 carbon
 atoms, X and Y are the same or different and independently represent
 --O--, --S--, --COO--, --OCO--, --CONH--, or --NHCO--, m is 0 or 1, and n
 is 0 or a natural number of 1 to 6.
 (2) A drug carrier comprising the amidine derivative as described in (1) as
 a constituent.
 (3) The drug carrier as described in (2), wherein said carrier encloses a
 drug for diagnosis and/or therapy.
 (4) The drug carrier as described in (2) or (3), wherein said carrier has
 an external diameter of 0.02 to 250 .mu.m.
 (5) The drug carrier as described in (2) to (4), wherein said carrier is
 constituted by at least one of liposomes, emulsions, macromolecules, fine
 aggregates, fine particles, microspheres, and nanospheres.
 (6) The drug carrier as described in (2) to (5), wherein said carrier
 contains phospholipids or their derivatives, and/or lipids other than
 phospholipids or their derivatives, and/or a stabilizer, and/or an
 antioxidant, and/or the other surface modifier.
 (7) The drug carrier as described in (2) to (6), wherein said drug for
 diagnosis and/or therapy is a nucleic acid, a polynucleotide, a gene, or
 their analogues.
 (8) The drug carrier as described in (2) to (6), wherein said drug for
 diagnosis and/or therapy is an antiinflammatory agent, a steroid agent, an
 anticancer agent, an enzyme agent, an enzyme inhibitor, an antibiotic, an
 antioxidant, a lipid-intake inhibitor, a hormone agent, an angiotensinase
 inhibitor, an angiotensin receptor antagonist, an inhibitor of
 proliferation and migration of smooth muscle cells, a platelet-aggregation
 inhibitor, an inhibitor of releasing a chemical mediator, an enhancer or
 inhibitor of proliferation of vascular endothelial cells, an aldose
 reductase inhibitor, a mesangial cell-proliferation inhibitor, a
 lipoxygenase inhibitor, an immunosuppressant, an immunpotentiator, an
 antiviral agent, or a radical scavenger.
 (9) The drug carrier as described in (2) to (6), wherein said drug for
 diagnosis and/or therapy is a glycosaminoglycan or its derivative.
 (10) The drug carrier as described in (2) to (6), wherein said drug for
 diagnosis and/or therapy is an oligo- and/or poly-saccharide or their
 derivatives.
 (11) The drug carrier as described in (2) to (6), wherein said drug for
 diagnosis and/or therapy is a protein or a peptide.
 (12) The drug carrier as described in (2) to (6), wherein said drug for
 diagnosis and/or therapy is an endogenous diagnostic agent including an X
 ray contrast medium, a radioisotopically labeled nuclear medical
 diagnostic agent, and an agent for diagnosis by nuclear magnetic
 resonance.
 The compounds of the present invention represented by the formula 1 are all
 novel. An example of their synthetic process is shown below. However, the
 present invention is not construed to be limited thereto.
 For example, the compounds can be produced by introducing thiourea to the
 moiety of Z of the compound represented by the following formula 2 when Z
 is a halogen atom or by converting Z to an amidino group when Z is --CN.
 ##STR3##
 In the formula 2, A is an aromatic ring, R.sup.1 and R.sup.2 are the same
 or different and independently represent an alkyl group having 10 to 25
 carbon atoms, an alkenyl group having 10 to 25 carbon atoms, X and Y are
 the same or different and independently represent --O--, --S--, --COO--,
 --OCO--, --CONH--, or --NHCO--, and n is 0 or a natural number of 1 to 6.
 Z is a halogen atom or --CN.
 The thus-produced amidine derivatives represented by the formula 1 can be
 isolated and recovered by per se known separation and purification methods
 (for example, chromatography and recrystallization).
 The carrier of the present invention preferably has a particle diameter of
 0.02 to 250 .mu.m, more preferably 0.05 to 0.4 .mu.m.
 Its structure can take various forms and does not have to be limited. The
 carrier is most preferably formed by at least one of macromolecules, fine
 aggregates, fine particles, microspheres, nanospheres, liposomes, and
 emulsions, which can potentially function to load drugs in a high
 concentration.
 In the present invention, compositions of the drug carrier are not
 particularly limited as long as they can take the above-described forms.
 In view of safety, in vivo stability, the compositions preferably contain
 phospholipids, their derivatives, lipids other than phospholipids, their
 derivatives, a stabilizer, an antioxidant, and some other surface
 modifier.
 Examples of phospholipids are natural or synthetic phospholipids including
 phosphatidylcholine (lecithin), phosphatidylglycerol, phosphatidic acid,
 phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine,
 phosphatidylinositol, sphingomyelin, cardiolipin, and their hydrogenated
 products obtained by usual methods.
 Examples of the stabilizers include sterols, such as cholesterol, which
 reduce membrane fluidity, glycerol, or saccharides such as sucrose.
 The antioxidants include tocopherol homologues, namely vitamin E. There are
 four tocopherol isomers, .alpha., .beta., .gamma., and .delta.. Any of
 them can be used in the present invention.
 The other surface modifiers include derivatives of hydrophilic polymers and
 water-soluble polysaccharides such as glucuronic acid, sialic acid, and
 dextran.
 Examples of the hydrophilic polymers include polyethylene glycol, dextran,
 pullulan, Ficoll, polyvinyl alcohol, styrene-maleic anhydride alternating
 copolymer, divinyl ether-maleic anhydride alternating copolymer, synthetic
 polyamino acid, amylose, amylopectin, chitosan, mannan, cyclodextrin,
 pectin, and carrageenan. Among them, polyethylene glycol remarkably
 prolongs residency in blood.
 The hydrophilic Polymers can form derivatives by combining with hydrophobic
 compounds such as long-chain aliphatic alcohols, sterols, polyoxypropylene
 alkyls, and glycerol fatty acid esters. Hydrophobic compound moieties of
 the derivatives can be stably inserted into membranes of drug carriers
 (for example, liposome). Thus, hydrophilic polymers can be allowed to
 exist on the surface of the drug carrier. Such a hydrophilic polymer
 derivative that can be specifically used in the present invention is
 exemplified by polyethylene glycol-phosphatidylethanolamine and the like.
 The drugs to be enclosed in the drug carriers can be pharmacologically
 active compounds, physiologically active compounds, or diagnostic
 substances, which are pharmaceutically acceptable, depending on the
 diagnostic and/or therapeutic purpose.
 Basically the properties of the drug to be loaded are not limited to any
 particular substances, electrically neutral or anionic substances can be
 loaded in good efficiency because the surface of the carrier has
 characteristically the positive charge.
 The kind of the therapeutic drug to be entrapped is not particularly
 limited as long as it does not affect the formation of the drug carrier.
 Specific examples of the drug include nucleic acids, polynucleotides,
 genes and their analogues, an antiinflammatory agent, a steroid agent, an
 anticancer agent, an enzyme agent, an enzyme inhibitor, an antibiotic, an
 antioxidant, a lipid-intake inhibitor, a hormone agent, an angiotensinase
 inhibitor, an angiotensin receptor antagonist, an inhibitor of
 proliferation and migration of smooth muscle cells, a platelet-aggregation
 inhibitor, an inhibitor of releasing a chemical mediator, an enhancer or
 inhibitor of proliferation of vascular endothelial cells, an aldose
 reductase inhibitor, a mesangial cell-proliferation inhibitor, a
 lipoxygenase inhibitor, an immunosuppressant, an immunpotentiator, an
 antiviral agent, or a radical scavenger, proteins, peptides and the like.
 The kind of the diagnostic drug to be entrapped is not particularly limited
 as long as it does not affect the formation of the drug carrier.
 Specifically, such drugs includes X ray contrast mediums,
 radioisotopically labeled nuclear medical diagnostic agents, and agents
 for diagnosis by nuclear magnetic resonance.
 The drug carriers of the present invention can be readily obtained by any
 suitable method in the art. An example thereof is described below. The
 amidine derivative represented by the formula 1, phospholipid, and the
 other components are mixed in an organic solvent such as chloroform in a
 flask. After the organic solvent is removed by evaporation, the residue is
 dried under vacuum to form a thin film on the inner wall of the flask. A
 drug is added to the flask and vigorously stirred to obtain a liposome
 suspension. The resulting liposome suspension was centrifuged and the
 supernatant containing the drug that has not been loaded is removed by
 decantation. Thus, the drug carrier suspension can be obtained.
 Alternatively, the drug carrier can be obtained by discharging the mixture
 of the above-described components under high pressure with a high-pressure
 discharging emulsifier.

BEST MODE FOR CARRYING OUT THE INVENTION
 The following examples and test examples illustrate the present invention
 in more detail, but are not to be construed to limit the scope of the
 present invention.
 (EXAMPLE 1)
 Synthesis of 3,5-dipentadecyloxybenzamidine
 3,5-dihydroxybenzonitrile (0.50 g), 1-bromopentadecane (2.70 g), potassium
 carbonate (2.56 g), and 30 ml of acetone were mixed and the mixture was
 heated overnight under reflux. After water was added, the mixture was
 extracted with methylene chloride. The extract was washed with water and
 dried over anhydrous magnesium sulfate. The solvent was removed by
 evaporation to obtain 0.33 g of 3,5-dipentadecyloxybenzonitrile as
 colorless crystals. This product was dissolved in a mixed solvent of 20 ml
 of methanol and 35 ml of benzene and hydrogen chloride gas was allowed to
 flow into the mixture for 1 hour under ice-cooling. The solvent was
 removed by evaporation under reduced pressure and the thus-obtained
 crystals were recrystallized from chloroform and hexane to obtain 0.28 g
 of 3,5-dipentadecyloxy-.alpha.-methoxy-.alpha.-iminotoluene hydrochloride.
 This product was dissolved in 10 ml of chloroform, ammonia gas was allowed
 to flow into the solution for 40 minutes under ice-cooling, then the
 mixture was heated for 4.5 hours under reflux. After the solvent was
 removed by evaporation under reduced pressure, the materials insoluble in
 chloroform were removed from the resulting solid to obtain 0.20 g of
 3,5-dipentadecyloxybenzamidine as colorless crystals. The data obtained by
 instrumental analysis of this compound support the structure represented
 by the following formula 3.
 .sup.1 H-nmr (CDCl.sub.3) .delta. (ppm): 6.92 (s, 2H), 6.65 (s, 1H), 3.99
 (t, 4H, J=6.4 Hz), 1.77-1.22 (m, 52H), 0.88 (t, 6H, J=6.8Hz). melting
 point: 149-150.degree. C.
 ##STR4##
 (EXAMPLE 2)
 Synthesis of 3,5-dihexadecyloxybenzamidine
 The method of Example 1 was repeated except for using 1-bromohexadecane in
 place of 1-bromopentadecane to produce a desired compound whose structure
 is represented by the following formula 4 and whose properties are shown
 below.
 .sup.1 H-nmr (CDCl.sub.3) .delta. (ppm): 6.93 (s, 2H) , 6.64 (s, 1H) , 3.98
 (t, 4H, J=6.5 Hz), 1.78-1.70 (m, 4H), 1.47-1.15 (m, 52H), 0.88 (t, 6H,
 J=6.8 Hz). melting point: 109-110.degree. C.
 ##STR5##
 (EXAMPLE 3)
 Synthesis of 3,5-dioctadecyloxybenzamidine
 The method of Example 1 was repeated except for using 1-bromooctadecane in
 place of 1-bromopentadecane to produce a desired compound whose structure
 is represented by the following formula 5 and whose properties are shown
 below.
 .sup.1 H-nmr (CDCl.sub.3) .delta. (ppm): 6.91 (s, 2H), 6.65 (s, 1H), 3.99
 (t, 4H, J=6.5 Hz), 1.80-1.70 (m, 4H), 1.47-1.18 (m, 60H), 0.88 (t, 6H,
 J=6.8 Hz). melting point: 146-148.degree. C.
 ##STR6##
 (EXAMPLE 4)
 Synthesis of 3,5-didecyloxybenzamidine
 The method of Example 1 was repeated except for using 1-bromodecane in
 place of 1-bromopentadecane to produce a desired compound whose structure
 is represented by the following formula 6 and whose properties are shown
 below.
 .sup.1 H-nmr (CDCl.sub.3) .delta. (ppm): 6.96 (s, 2H) , 6.58 (s, 1H) , 3.96
 (t, 4H, J=6.5 Hz), 1.77-1.66 (m, 4H), 1.44-1.19 (m, 28H), 0.88 (t, 6H,
 J=6.8 Hz). melting point: 127-128.degree. C.
 ##STR7##
 (EXAMPLE 5)
 Synthesis of 3,4-didecyloxybenzamidine
 The method of Example 1 was repeated except for using
 3,4-dihydroxybenzonitrile in place of 3,5-dihydroxybenzonitrile and using
 1-bromodecane in place of 1-bromopentadecane to produce a desired compound
 whose structure is represented by the following formula 7 and whose
 properties are shown below.
 .sup.1 H-nmr (CDCl.sub.3 --CD.sub.3 OD) .delta. (ppm): 7.43-7.28 (m, 2H) ,
 7.01-6.95 (m, 1H), 4.12-4.01 (m, 4H), 1.91-1.78 (m, 4H), 1.54-1.12 (m,
 28H), 0.94-0.84 (m, 6H).
 ##STR8##
 (EXAMPLE 6)
 Liposomes containing the amidine derivatives synthesized in Examples 1 to 5
 as a membrane component were prepared in the following manner.
 Three .mu.M of an amidine derivative, 21 .mu.M of
 dipalmitoylphosphatidylcholine (DPPC), and 6 .mu.M of cholesterol were
 weighed and put into a 10-ml round bottom flask and completely dissolved
 in 1 ml of chloroform. Chloroform was removed by evaporation with an
 evaporator under reduced pressure to form a thin lipid film on the inner
 wall of the flask. One ml of 10 mM Tris-HCl buffer containing 0.5 .mu.M of
 calcein was added to the flask and stirred by vigorous shaking to obtain a
 suspension of calcein-entrapping liposomes (MLV).
 (Test Example 1) Measurement of Calcein Entrapping Ratio
 The ratio of entrapping calcein in liposomes was determined as follows.
 Forty .mu.l of a 50-fold diluted liposome suspension was added to 2.0 ml
 of 10 mM Tris-HCl buffer. Fluorescent intensity of the mixture was
 measured (exitation wavelength: 490 nm, fluorescent wavelength: 530 nm).
 The fluorescent intensity measured at this time is referred to as Ft.
 Twenty .mu.l of a 10 mM CoCl.sub.2 solution was added to the mixture and
 calcein that was not entrapped into the liposomes was allowed to quench.
 The fluorescence of calcein entrapped in the liposome was measured. The
 fluorescent intensity measured at this time is referred to as Fin. Twenty
 .mu.l of a 20% Triton X-100 solution was added thereto to destroy the
 liposomes and bind calcein to Co.sup.2+ for quenching. The fluorescent
 intensity measured at this time is referred to as Fq. The retention
 efficiency of the liposome was calculated by the following equation.
EQU Retention efficiency (%)=(Fin-Fq.times.r)/(Ft-Fq.times.r).times.100
 In the formula, r is a value by calibrating volume changes of the reaction
 mixture brought about by adding the liposome suspensions and the drug. In
 this example, r =(2.0+0.04+0.02+0.02)/2.0=1.04. The results are shown in
 Table 1.
 TABLE 1
 Ratio of entrapping into liposomes
 Entrapping
 Liposome suspension ratio (%)
 Liposome suspension containing the amidine 26.77
 derivative of Example 1
 Liposome suspension containing the amidine 26.60
 derivative of Example 2
 Liposome suspension containing the amidine 27.31
 derivative of Example 3
 Liposome suspension containing the amidine 25.75
 derivative of Example 4
 Liposome suspension containing the amidine 24.89
 derivative of Example 5
 (EXAMPLE 7)
 DNA-entrapping liposomes containing the amidine derivatives synthesized in
 Examples 1 to 5 as membrane components were prepared in the following
 manner.
 Ten .mu.M of an amidine derivative, 20 .mu.M of
 dilauroylphosphatidylcholine (DLPC), and 20 .mu.M of
 dioleoylphosphatidylethanolamine (DOPE) were weighed and dissolved in 1 ml
 of chloroform to obtain chloroform solution A.
 Twenty .mu.l of the chloroform solution A was put into a 10-ml round bottom
 flask and 1 ml of chloroform was added. The solvent chloroform was removed
 with a rotary evaporator to form a lipid thin film on the inner wall of
 the flask. The film was hydrated by vigorously mixing in 1 ml of steile
 water containing 20 .mu.m of plasmid pcDNA/Amp (manufactured by
 Invitrogen) in which a .beta.-galactosidase gene was incorporated to
 produce DNA-entrapping liposomes.
 (Test Example 2) Preparation of Cells and Transfection
 Cells: Cos-1 cells (ATCC No. CRL-1650) purchased from Dainippon
 Pharmaceutical Co., Ltd. were subcultured in an Iscove's modified
 Dulbecco's medium (IMDM) containing 10% fetal calf serum (FCS) in an
 incubator under 5% CO.sub.2 and 95% O.sub.2 at 37.degree. C.
 Transfection: The Cos-1 cells were cultured after inoculated at a density
 of about 2 .times.10.sup.4 cells per each well of a 6-well multi-well
 plate supplemented with 1 ml of the IMDM containing 10% FCS. After about
 24-hour of incubation, the medium was replaced with a fresh medium free
 from FCS and the liposome suspension containing 0.2 .mu.g of DNA was added
 thereto. After 16-hour of transfection, the medium was replaced with a
 fresh IMDM containing 10% FCS and the cell were further incubated 48
 hours. The cells were then fixed with formaldehyde, and then
 5-bromo-4-chloro-3-indolyl-.beta.-galactopyranoside (X-gal) which is a
 substrate of .beta.-galactosidase was added to identify the cells that
 expressed .beta.-galactosidase. To determine the percentage of transfected
 cells, the stained cells were image analyzed. The results are shown in
 Table 2.
 TABLE 2
 Ratio of incorporated cells
 Ratio of
 Samples incorporated cells
 Liposome containing the amidine derivative of 32.3 .+-. 3.8
 Example 1
 Liposome containing the amidine derivative of 28.3 .+-. 2.2
 Example 2
 Liposome containing the amidine derivative of 20.5 .+-. 3.8
 Example 3
 Liposome containing the amidine derivative of 33.5 .+-. 4.5
 Example 4
 Liposome containing the amidine derivative of 30.0 .+-. 5.5
 Example 5
 Lipofectin (Life Technology) 5.9 .+-. 0.91
 Gene transfer (Wako Pure Chemical Industries, 15.0 .+-. 0.67
 Ltd.)
 (EXAMPLE 8)
 Rhodamine-labeled liposomes containing the amidine derivative synthesized
 in Example 1 as a membrane component were prepared in the following
 manner.
 A chloroform solution of lipid consisting of soybean
 lecithin/cholesterol/amidine derivative (total lipid content: 120 mM,
 7/2/1 (molar ratio)) was added to a round bottom flask. The solution was
 evaporated to dryness with a rotary evaporator under reduced pressure and
 dried overnight at room temperature under vacuum to form a lipid thin film
 on the inner wall of the flask. The film was hydrated by vortexing in a
 vortex mixer at 65.degree. C. in physiological saline (4 ml) to form
 liposome suspension.
 The particle size of the suspension was adjusted by filtering the
 suspension through a polycarbonate film. An ethanol solution of
 rhodamine-labeled phosphatidylethanolamine (Avanti) was added to the
 suspension and allowed to stand at 37.degree. C. for 30 minutes. The
 mixture was then fully dialyzed against physiological saline using a
 cellulosic dialysis membrane at 4.degree. C.
 (Test Example 3) Accumulation test Using Experimental Nephritis Animal
 Model.
 SD rats (5-week-old, male) was previously bleeded for a week and
 anti-Thy1.1 antibody (OX7, Serotec) was administered to the caudal vein to
 induce nephritis. In three to four days after the administration of the
 antibody, a protein content in urine accumulated for one day was measured
 to confirm onset of nephritis. The rhodamine-labeled amidine liposomes
 (the total lipid content of 10 mg/ml of physiological saline) were
 administered to the caudal vein in a dose of 1 ml/kg. One, six, and
 twenty-four hours after the administration, the rats were sacrificed by
 removing blood. Systemic perfusion was performed with heparinized
 physiological saline, then, liver, spleen, and kidney were excised. Tissue
 homogenate for each organ was prepared. Rhodamine pigment was extracted
 from the tissue homogenate with chloroform to determine the concentration
 of the liposomes in the tissue. The results are shown in Table 3.
 As shown in Table 3, the liposomes containing the amidine derivative of the
 present invention as a membrane component rapidly disappeared in the liver
 and the spleen of the nephritis induced rats, while the liposomes were
 outstandingly accumulated in the kidney and the accumulation was continued
 for 24 hours or longer.
 TABLE 3
 Dynamics of the amidine liposomes in rats
 Accumulation of liposomes
 Hours after the (.mu.g lipid/g tissue)
 administration liver kidney spleen
 1 43 21 75
 6 17 18 20
 24 2 10 1
 [Acute Toxicity]
 Acute toxicity test was performed by orally or intravenously administering
 the amidine derivatives of the present invention to ICR male mice
 (5-week-old). As a result, LD .sub.50 of the amidine derivatives was not
 less than 320 mg/kg. High safety of the derivatives was confirmed as
 compared with their effectiveness.
 APPLICATION
 The present invention provides novel amidine derivatives. The drug carrier
 such as liposomes or emulsions comprising the amidine derivative of the
 present invention can enclose genetic materials or drugs and transfer them
 to cells or affected sites efficiently and safely.