JPS63319046A - Coated fat emulsifier - Google Patents

Abstract

PURPOSE:To control directiveness of a medicine to a targeted internal organ and to decrease disappearance rate of the medicine from blood by coating fat emulsifier particles with native polysaccharide derivative of specified structure to form an emulsifier. CONSTITUTION:By mixing the fat emulsifier with the native polysaccharide derivative and stirring with a mixer, the fat emulsifier coated with the native polysaccharide derivative is obtd. The native polysaccharides is pullulan, amylose amylopectin, dextran or mannan, and one of the derivatives contains 0.5-5.0 saccharide units per 100 component saccharide units in the polysaccharid, prim. hydroxyl group on six-position carbon atom in these saccharide units being a group of formula I, where R1 is H or cholesteryloxycarbonyl group. Therefore, in the amylose, the 0.5-5.0 saccharide units per 100 component units are saccharide unit of formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a fat emulsion (hereinafter referred to as the fat emulsion of the present invention) in which fat emulsion particles are coated with a naturally occurring polysaccharide derivative (hereinafter referred to as the derivative according to the present invention).

PRIOR ART AND PROBLEMS Recently, in the pharmaceutical field, the use of fat emulsions, ie fat emulsions, in vivo through injection administration has been attracting a lot of attention. That is, emulsifying systems have conventionally been generally used as dosage forms for oral administration of oil-based substances or as dosage forms for topical administration to the skin. However, it has become known that emulsifying systems are also useful in so-called valentiral drug delivery systems.

Therefore, from this point of view, attempts have been made to use a dosage form that is different from liposomes and is aimed at increasing bioavailability in injection administration. The following literature is shown as a reference for explaining this tendency in detail.

S-3, Davis:F)nulsLon syst
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Optimization of drug
eliver7* Alfed Benzon Syh
>poaium 17. Editors ;Hans
Bundgaard et al, Copenh
Agen 1982 Reluctance [The major problem with fat emulsions is that the technology for arbitrarily controlling the directivity of drugs to so-called target organs has not yet been established. Furthermore, since drugs in fat emulsions generally disappear at a high rate from the blood, it is difficult to maintain a constant blood concentration for a certain period of time. For this reason, fat emulsions require a so-called delay technique to reduce the rate of disappearance, but this has not yet been established.

Solution Means As a result of conducting various studies in order to solve the above-mentioned problems in fat emulsions, we have learned that the object can be achieved by coating the particles of fat emulsion with the naturally-derived polysaccharide derivative according to the present invention, and the present inventors The invention was completed. That is, the present invention aims to control the directivity of the drug to the target organ and to delay the disappearance of the drug from the blood when administering the fat emulsion. The gist is a fat emulsion characterized by coating.

The present invention will be explained in detail below.

In the present invention, fat emulsion refers to vegetable oil and animal oil.
~30%%, emulsifiers [phospholipid surfactants, etc.] 0
．． It mainly consists of 1 to 10 vr/v%, an isotonizing agent, a pH adjusting agent, and an appropriate amount of water.

Other fatty acids 2 to 54%; Restyrol 3
W/% or less, phosphatidic acid 2X% or less, dicetyl phosphate 1%X or less, etc. can also be added.

The vegetable oil used in the present invention is not limited as long as it can be used for food or medicine, but soybean oil, sesame oil, cottonseed oil, olive oil, etc. are preferred. Moreover, eicosapentaenoic acid and the like are used as the animal oil.

Phospholipids are lecithin derived from egg yolks and soybeans, and are hydrogenated lecithin (iodination degree θ ~ 70).
can also be used.

The surfactants are mainly nonionic surfactants such as polyoxyethylene hydrogenated castor oil derivatives, such as HCO-
40, HCO-30, HCO-60, and polyoxyethylene polyoxypropylene ether derivatives such as Pluronic F-68 are mainly used.

Further, in the present invention, a phospholipid and a surfactant can be mixed and used as an emulsifier.

Glycerin, glucose, maltose, etc. can be used as an isotonic agent.

As a pH adjuster, hydrochloric acid, sodium hydroxide, trishydroxymethylaminomethane, etc. are used.

Fatty acids can be used as long as they have 10 to 22 carbon atoms and are linear or branched and can be used for food or medicine, such as stearic acid, palmitic acid, myristic acid, oleic acid, and linoleic acid. A window is used. Salts of these fatty acids can also be used, including sodium salts,
Potassium salts and the like can be used.

The fat emulsion in the present invention has a particle size of 1 μm or less, preferably 0.2 to 0.4 μm.

Next, the naturally derived polysaccharide derivative according to the present invention will be explained as follows.

First of all, naturally occurring polysaccharides are pullulan, amylose, amylopectin, dextran, and mannan. One of the derivatives according to the present invention has a polysaccharide content of 0.5 to 5.0 per 100 sugar units constituting these polysaccharides. The primary hydroxyl group at the 6th carbon position of each sugar unit has the formula -〇〇HzCON
1 (CHtCHtNHRt (in the formula, R8 represents H or; restyryloxycarbonyl group). Therefore, for example, in amylose,
The sugar units of 0.5 to 5.0 per 100 are shown as follows. Here, further in the derivative, R
The sugar unit in which 1 is a cholesteryloxycarbonyl group is 0
．． The number is 5 to 4.5. The cholesteryloxycarbonyl group is represented by the structural formula below.

Another derivative according to the present invention is 0.5 to 10.0% per 100 sugar units constituting the polysaccharide.
The 0 sugar units are naturally occurring polysaccharide derivatives in which the primary hydroxyl group at the 6th carbon position is represented by the formula (in the formula, R1 represents a linear acyl group having 12 to 200 carbon atoms), and is particularly preferably Valmitic acid.

There is a report, and the description therein is referred to. Although these derivatives are known to be used to coat the surface of liposomes, their use in fat emulsions as shown in the present invention is not known at all.

The fat emulsion of the present invention is produced as follows.

That is, a predetermined amount of vegetable oil or animal oil, an emulsifier, an isotonic agent, a lipophilic drug, and other additives are mixed and heated, an appropriate amount of water is added to the mixture, and the mixture is roughly emulsified using a homomixer.Then, pressurized injection is performed. The mixture is emulsified using a type homogenizer (Manton-Gorlin homogenizer) or an ultrasonic homogenizer to obtain a homogeneous fat emulsion.

A naturally derived polysaccharide derivative coated fat emulsion can be obtained by mixing the thus obtained fat emulsion and a naturally derived polysaccharide derivative, and stirring the mixture with a stirrer or subjecting it to ultrasonication. 1. Naturally derived polysaccharide derivative coated fat emulsion of the present invention. is the average particle size 1. It is extremely fine, less than θμ wet.

Whether the fat emulsion particles are coated with the derivative according to the present invention can be determined by aggregation of the fat emulsion particles by concanavalin A, which is a type of lectin.

That is, concanavalin A has the property of binding to mannose and glucose, and has multiple binding sites. Therefore, if the fat emulsion is coated with a naturally occurring polysaccharide derivative, concanavalin A will bind to the naturally occurring polysaccharide derivative, causing aggregation of the fat emulsions. On the other hand, unless the fat emulsion is coated with the naturally occurring polysaccharide derivative, concanavalin A will not cause the aggregation of the fat emulsion.

These details will be explained in experimental examples.

The drug compounded in the fat emulsion must be a lipophilic substance, specifically a drug that has an affinity for vegetable oils and animal oils. −
To, vitamin 1, vitamin, % Ilobrost (P
GIz) and other plastaglandins, indomethacin farnesol ester, and the like.

Furthermore, the naturally occurring polysaccharide derivative according to the present invention to be blended into the fat emulsion preferably has a
Although it is 9 to 50'q, there is no particular restriction.

Effects and Effects The effects of the present invention are that by appropriately selecting and coating the type of naturally-derived polysaccharide derivative according to the present invention, it is possible to control the directionality of the drug to the target organ, and also to prevent drug release from the blood. The point is that it can slow down the rate of disappearance of .

Examples Example 1 6 tons of purified egg yolk lecithin was dispersed at 60 to 90° C. in 400 Mt of water containing 12.5 F of glycerin.

To this liquid, 50 f of soybean oil, which had been heated in advance at 60 to 90°C, was gradually added and emulsified for 30 minutes using a homomixer to obtain a rough emulsion. Next, purified water was added and the mixture was strained at 500°C, and this liquid was emulsified using a Manton-Gorlin homogenizer (1st stage 100 Kf/d, total pressure 500 Kg/d).
L. A very fine fat emulsion was obtained. The average grain size of this emulsion was 0.2 to 0.4 μm, and it did not contain any grains larger than 1 μm.

To the thus obtained fat emulsion 10-, a cholesterol group-introduced mannan aqueous solution (24N9/+j) was added and gently sonicated to obtain a naturally-derived polysaccharide derivative-coated fat emulsion. The average particle diameter of this fat emulsion coated with a naturally derived polysaccharide derivative was 0.2 to 4 μm.
15 f was added and heated to 60-90°C to dissolve. Add to this 40 liters of purified water that has been preheated to 60-90°C.
0ti, then 12.5 f of glycerin,
Further, purified water was added to bring the total volume to 500 -, and rough emulsification was performed for 50 minutes using a homomixer. This was emulsified using a Manto/Gorlin type homogenizer (first stage 1001 g/m, total pressure 500/4/i) to obtain an extremely fine fat emulsion.

The average grain size of this emulsion was 0.2 to 0.4 μm, 1
It did not contain particles larger than μm.

Cholesterol group-introduced amylopectin (60wI9/d) was added to the fat emulsion 10 thus obtained, and the mixture was gently stirred with a stirrer to obtain a fat emulsion coated with a naturally occurring polysaccharide derivative. The average particle diameter of this fat emulsion coated with a naturally occurring polysaccharide derivative was α2 to 0.4 μm.

Example 5 An unedited fat emulsion was obtained in the same manner as in Example 1, except that 0.32% cholesterol was added to soybean oil in advance. The average particle diameter was 0.2 to 0.4 μm, and no particles larger than 1 μm were contained.

To the thus obtained fat emulsion 10-3, an aqueous solution of cholesterol group-introduced pullulan (6 µ/, t) was added and gently sonicated to obtain a fat emulsion coated with a naturally-derived polysaccharide derivative. The average particle diameter of this fat emulsion coated with a naturally occurring polysaccharide derivative was 0.2 to 0.4 μm.

Example 4 CoQ at t25f. CoQ, in the same manner as in Example 1, except that CoQ was added to the soybean oil in advance. A fat-containing emulsion was obtained. The average particle diameter was 0.2 to 0.4 μm, and no particles larger than 1 μm were contained.

10 dK of the thus obtained fat emulsion and 3 d of a cholesterol group-introduced mannan aqueous solution (24 q/d) were added and gently sonicated to obtain a naturally derived polysaccharide derivative coated fat emulsion.

This CoQ. The average particle diameter of the fat emulsion coated with the naturally derived polysaccharide derivative containing the naturally occurring polysaccharide derivative was α2 to 0.4 μm.Example 5 ct- A tocopherol-containing fat emulsion was obtained. Average particle size is 0.2-0.4
To the thus obtained fat emulsion 10, which did not contain any particles larger than 1βm in μm, a cholesterol group-introduced mannan aqueous solution (24t+y/d) was added and gently sonicated to coat the fat emulsion with a naturally derived polysaccharide derivative. Example 6 The average particle diameter of the obtained fat emulsion coated with a C0Q1o-containing naturally derived polysaccharide derivative was 0.2 to 0.4 μm! A fatty emulsion was obtained in the same manner as in Example 1, except that 5.0 cape of Airobrost was added to soybean oil in advance. Contains no.

To the thus obtained fat emulsion 10 times, 3 times an aqueous solution of cholesterol group-introduced mannan (24/-) was added and gently sonicated to obtain a fat emulsion coated with a naturally derived polysaccharide derivative. The average particle diameter of this fat emulsion coated with two naturally occurring polysaccharide derivatives was 0.2 to α4 μm.

Experimental Example 1 The following specimen sample a-1 was prepared in the same manner as described in Sample Example 1 and Examples 4 to 6.

a, uncoated fat emulsion, naturally derived polysaccharide derivative coated fat emulsion, provided that the naturally derived polysaccharide derivative is mannan with a cholesterol group introduced (molecular jk 200,000, degree of cholesterol group recognition 2).
．． 5) C6 naturally derived polysaccharide derivative coated fat emulsion, provided that the naturally derived polysaccharide derivative is cholesterol group-introduced amylopectin (molecule -ji 112,000, degree of cholesterol group substitution t8) d, naturally derived polysaccharide derivative coated fat emulsion, provided that naturally derived polysaccharide derivative is valmitoyl thread-introduced amylopectin/(molecular fi 112,000, degree of valmitoyl group substitution 8.
0) e, Naturally derived polysaccharide derivative coated fat emulsion, provided that the naturally derived polysaccharide derivative is cholesterol group-introduced pullulan (molecular weight 50,000. Degree of cholesterol group substitution 1)
9) f, Fat emulsion coated with a naturally occurring polysaccharide derivative containing ubidecarenone, however, it contains 2.5 W/- of ubidecarenone, and the naturally occurring polysaccharide derivative is mannan with a cholesterol group introduced (molecule i 200.ODD, degree of cholesterol group substitution 2.3) g, ct-) Co-7erol-containing naturally occurring polysaccharide derivative suspended fat emulsion, however, it contains 10/- of a-tocopherol, and the naturally occurring polysaccharide derivative is cholesterol group-introduced mannan (molecular weight 200,000, degree of cholesterol group substitution 2
．． 6) h, d-) Fat emulsion coated with a naturally occurring polysaccharide derivative containing copheryl acetate, however, it contains 5 rays/- of α-tocopheryl acetate, and the naturally occurring polysaccharide derivative is a cholesterol group-introduced pullulan (molecular weight 65,000, cholesterol group Degree of substitution: 1.7)i, a fat emulsion coated with naturally derived polysaccharide derivatives containing vitamins, but with vitamins,
The naturally occurring polysaccharide derivative is cholesterol group-introduced amylopectin (molecular weight 112,000, degree of cholesterol group substitution 2.
0)j, fat emulsion coated with a naturally occurring polysaccharide derivative containing 2 vitamins, but containing 5197 at of vitamins, and the naturally occurring polysaccharide derivative being mannan with a cholesterol group introduced (molecular weight 20 to 000, degree of cholesterol group substitution 2.3)
) k, fat emulsion coated with a naturally occurring polysaccharide derivative containing Airobrost, provided that it contains 10μ2/- of Airobrost, and the naturally occurring polysaccharide derivative is mannan with a cholesterol group introduced (molecular 1200,000, degree of cholesterol group substitution 2.3) L Indomesacin farnesol ester-containing A fat emulsion coated with a naturally occurring polysaccharide derivative, however, it contains 10 kg/- of indomethacin farnesol ester, and the naturally occurring polysaccharide derivative contains cholesterol group-introduced mannan (molecules - [200,000, degree of cholesterol group substitution 2
．． 3) Method Measurement of average particle diameter Average particle diameter of fat emulsion before and after coating with naturally derived polysaccharide derivative (
diameter) was measured using a submicron analyzer.

A vM recognition sample a-1 of a naturally occurring polysaccharide derivative coated on the surface of a fat emulsion was mixed with a 20mM Tris-HCt buffer (pH 7,
2) was diluted to 1/1000, concanavalin A, an agglutinin that recognizes the a residue, was added, and the coverage of the naturally occurring polysaccharide derivative was assayed from the aggregation of the fat emulsion.

The aggregation of the fat emulsion was determined by the change in absorbance at 620 nm.ResultsThe average particle diameter of the fat emulsion coated with the naturally occurring polysaccharide derivative is shown in Table 1.

Table 1 ■ Amount of naturally derived polysaccharide derivative added to 1 ml of 10 fat emulsion Explanation of Table 1 As shown in Table 1, the average particle size of the fat emulsion before and after coating depends on the type and amount of the coated naturally derived polysaccharide derivative. No major changes in diameter are observed.

Figure 1 shows the aggregation of a fat emulsion coated with a naturally occurring polysaccharide derivative by the addition of concanavalin A.

Description of Figure 1 1) to 5) are the following samples: 1); Sample b-i in Table 1, 2): Sample b-2 in Table 1, 3); Sample b-5 in Table 1, 4): Sample a of Table 1, 5): Only cholesterol group-introduced mannan.

The arrow indicates the time point when concanavalin A (250 μf 10.1 ml buffer) was added to the measurement sample.

The horizontal axis of the figure shows time (minutes), and the vertical axis shows the change in absorbance at 620 nm. Abs-1 is the absorbance of 620 fractions at time t, Abs. indicates the absorbance at 620 nm without the addition of concanavalin A.

As shown in Figure IK, the aggregation ability increases depending on the amount of the natural polysaccharide derivative coated, and therefore the amount of the naturally occurring polysaccharide derivative coated also increases depending on the amount added. The uncoated fat emulsion has no aggregation ability at all, and only a slight increase in absorbance is observed with only mannan introduced with a cholesterol group.

Experimental Example 2 CoQ, as described in Sample Example 4. Instead of K% 1
4C<^.

The following test samples a to c were prepared in the same manner as in Example 4 except that the following samples were used.

a, "C-CoQ," containing fat emulsion, "C-
CoQ,. Naturally derived polysaccharide derivative-coated fat emulsion containing, however, the naturally derived polysaccharide derivative is mannan with a cholesterol group introduced (molecular weight 200,000, degree of cholesterol group substitution 2.
3) The amount of naturally-derived polysaccharide derivative coated is 12 capes c-"C-CoQ per 1 tnt of fat emulsion. Naturally-derived polysaccharide derivative-coated fat emulsion containing, however, the naturally-derived polysaccharide derivative is a cholesterol group-introduced acropectine/(molecular weight 112,000, degree of cholesterol group substitution 1.
8) The amount of naturally derived polysaccharide derivative coated is 7.2'Iq per ml of fat emulsion. 14C-CoQ. is radiolabeled ubidecarenone represented by the structural formula below.

*14C-label location method Animal experiment 0.76 ml of 14C-CoQ was injected into the left femoral vein of a male guinea pig (weight 280-550F) and sutured. Thereafter, the guinea pigs were left in the breeding cage, and blood was collected from the ear vein at predetermined intervals.

The radioactivity concentration in the collected blood was measured by the method described below.

30 minutes and 24 hours after administration, the animals were sacrificed by exsanguinating the animals with a syringe under anesthesia, and each organ was removed.Measurement of radioactivity in the blood 20 μt or 50 μt of blood was collected from the ear vein.
, solubilized with 75 rJ of 5oluene 350/Inglovir alcohol (1 L, volume ratio), decolorized by adding a few drops of hydrogen peroxide, and instagel/0.5N.
HCl (chopsticks, volume ratio) 5- was added, and radioactivity was measured using a liquid scintillation/counter.

Measurement of intra-organ radioactivity: 0.5-5oluene 550
After solubilizing the organ by incubating at room temperature for about 12 hours, add 5-inatagel/0.5 N
HCt (volume ratio) was added, and radioactivity was measured using a liquid scintillation counter.

result FIG. 2 shows the change in radioactivity concentration in blood after administration of the specimen sample.

FIG. 5 and FIG. 4 compare and show the organ distribution between the samples at 30 minutes and 24 hours after administration.

Explanation of Figure 2: The O-marked line is the case when sample a was administered, the ・marked line is the case when sample S was administered, and the Δ-marked line is the case when sample C was administered (average value of 5 cases). Each is shown below.

Figure 2 shows that "C-C" in the fat emulsion coated with naturally derived polysaccharide derivatives.
o Ql. The disappearance from the blood of "C-" in the uncoated fat emulsion
It can be seen that the disappearance of CoQlo is also slow in the early period after administration.

3 and 4, columns 0, 9 and W indicate the amounts transferred to organs when sample a1 and sample C were administered, respectively.

Coating the fat emulsion with cholesterol group-introduced mannan significantly increased its transport to the lungs 7 and to the liver. On the other hand, the transfer to the heart and adrenal glands was significantly reduced. In addition, fat emulsions coated with amylopectin containing cholesterol groups tended to have increased transfer to the liver.

[Brief explanation of drawings]

FIG. 1 is a graph showing the relationship between the added amount of the naturally-derived polysaccharide derivative and the flocculating ability in the fat emulsion coated with the naturally-derived polysaccharide derivative of the present invention. FIG. 2 is a graph showing the change in radioactivity concentration in blood after administration of a specimen sample. FIG. 6 and FIG. 4 compare and show the organ distribution between samples at 30 minutes and 24 hours after administration.

Claims (3)

[Claims] (1) In pullulan, amylose, amylopectin, dextran and/or mannan, 0.5 to 5.0 sugar units per 100 constituent sugar units have a primary hydroxyl group at the 6-position carbon of the formula - OCH_2CONHCH_2CH_2NHR_1 (in the formula, R_1 represents H or a cholesteryloxycarbonyl group), and when R_1 in the formula is a cholesteryloxycarbonyl group, the number of sugar units is 0.5 to 4.5 naturally occurring In polysaccharide derivatives, or pullulan, amylose, amylopectin, dextran and/or mannan, 0.5 to 10.0 sugar units per 100 sugar units constituting the polysaccharide derivative have a primary hydroxyl group at the 6-position carbon of the formula A fat emulsion characterized in that fat emulsion particles are coated with a naturally occurring polysaccharide derivative represented by -OR_2 (in the formula, R_2 represents a linear acyl group having 12 to 20 carbon atoms). (2) Iupidecarenone, tocopherol, in the fat emulsion,
tocopheryl acetate, tocopheryl ecotinate,
The fat emulsion according to claim 1, characterized in that vitamin K_1, vitamin K_2, iloprost and other prostaglandin, and indomesacin farnesol ester are blended. (3) The amount of naturally derived polysaccharide derivative is 1 ml per 1 ml of fat emulsion.
Claim 1 or 2, which is mg to 50 mg.
Fat emulsion as described in section.