JP3120461B2 - Fat body composition containing prostaglandins - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention aims at improving the rate of incorporation of prostaglandins (hereinafter referred to as "PGs") into fat bodies, improving the stability in a composition, and suppressing the release rate. The present invention relates to a fat body composition containing PGs.

[0002]

2. Description of the Related Art PGs have various physiological actions such as vasodilation, improvement of peripheral circulation, hypotension, antilipolysis, natriuresis, etc., and therefore have been applied to pharmaceuticals.
When this useful PG is applied as a drug, there are problems in that it is easily metabolized to an inactive substance in a living body and lesion selectivity. Therefore, the PG preparation generally requires frequent administration, which not only increases the pain of the patient but also may cause side effects due to the frequent administration. As a means for solving these problems, preparations containing PGs in fat bodies have been provided.

[0003]

However, even in the liposome preparation containing PGs, the incorporation (hereinafter also referred to as encapsulation) rate of PGs into the lipid bodies, the stability of the preparation itself, There are problems to be solved such as release of PGs, and various studies have been made. Tokushu 63-5035
No. 26 and Japanese Patent Publication No. 2-504027 have attempted to solve these problems by giving lipid bodies a membrane permeation concentration gradient such as an ion gradient and a pH gradient. However, even in the fat body described in the above publication, these problems cannot be said to be sufficiently improved.

[0004] An object of the present invention is to provide a composition containing PGs in fat bodies, which has solved the above-mentioned problems at once. That is, the incorporation of PGs into lipid bodies is improved, the stability of PGs in the lipoid composition incorporating PGs is improved, and P from lipid bodies is improved.
An object of the present invention is to provide a composition containing PGs contained in fat bodies, in which the release rate of Gs is suppressed.

[0005]

Means for Solving the Problems The present inventors have made various studies and found that the conditions for imparting a membrane permeation concentration gradient have a great effect on the properties of the PG-containing fat body composition. For the first time. That is, the present inventors adjust the pH of the extracorporeal solution to 2 to 6 and adjust the encapsulating solution to a pH of 7 to 11 with a weak acid and a strong base.
It has been found that a composition containing PGs in fat bodies, which has solved the above-mentioned problems, can be obtained. That is, the present invention provides a PG-containing fat body composition characterized in that the pH of the extracorporeal body fluid is adjusted to 2 to 6, and the fat body sealing solution is adjusted to pH 7 to 11 with a weak acid and a strong base. About.

In the present invention, lipid bodies (liposomes)
Has a multi-concentric bilayer, single-layer or multi-layer structure, and has the ability to incorporate various proteins and other physiologically active substances into the gaps.

[0007] The lipids for forming the lipid bodies include phospholipids, glycolipids, and derived lipids. Any lipid that is physiologically acceptable and can be metabolized is used in the present invention. Examples of phospholipids include phosphatidylcholine, phosphatidylserine, phosphatidic acid, phosphatidylglycerin, phosphatidylethanolamine, phosphatidylinositol, sphingomyelin, dicetyl phosphate,
Examples thereof include lysophosphatidylcholine (lysolecithin), and a mixture thereof such as soybean phospholipid and egg yolk phospholipid.

Examples of glycolipids include cerebroside, sulfatide, ganglioside and the like. Examples of the derived lipid include cholic acid and deoxycholic acid. In particular, preferred lipids include phosphatidylcholine. The lipid is generally blended in an amount of 10 to 3000 parts by weight, preferably 150 to 200 parts by weight, per 1 part by weight of the PG.

The PGs used in the present invention are arachidonic acid metabolites or structurally similar compounds thereof. Examples of arachidonic acid metabolites include, for example, prostaglandins, prostacyclins, thromboxanes, leukotrienes and the like. Examples of the arachidonic acid metabolite structure analogous compound include, for example, a 6-keto-PGE ₁ derivative, a carbacycline derivative, a PGD ₂ derivative, and the like, whose structure is modified using an arachidonic acid metabolite as a basic skeleton.

The fat body of the present invention has a pH of 2
-6, preferably pH 3-5. To achieve such a pH, a buffer is usually used , and hydrochloric acid, sulfuric acid, nitric acid, etc.
May be used . The buffer is not particularly limited as long as the object of the present invention can be achieved. Specific examples thereof include, for example, citrate buffer, acetate buffer, lactate buffer, and the like. Particularly preferred external solution is citrate buffer. Is mentioned. The concentration of the buffer is 5 to 500 mM, preferably 20 to 200 m
M. Further, sucrose or the like may be blended to adjust the osmotic pressure.

[0011] The fat body sealing solution of the present invention is adjusted to pH 7 to 11, preferably pH 9 to 10, with a weak acid and a strong base. Examples of the combination of a weak acid and a strong base, carbonate and sodium carbonate, boric acid and sodium borate, combinations of pyrophosphate and sodium pyrophosphate and the like, particularly preferred examples include a combination of carbonate and sodium carbonate. The concentration of the fat body sealing solution is usually 100
１０００1000 mM, preferably 500-600 mM.

The outline of the production of the fat body of the present invention is as follows. That is, a solvent is distilled off from a solution containing an appropriate lipid (the solution may be any solvent that does not denature lipid, for example, a solution such as chloroform), and a thin film of lipid is formed. A solution having the same composition as the body sealing solution is added, followed by freezing and thawing to prepare fat bodies. Freezing at the time of freezing and thawing is performed by a method of standing on dry ice or the like, and thawing is performed by a method of immersion in a warm bath at 30 to 40 ° C or the like.

After reducing the size to a uniform size distribution (about 200 nm) using a filter or the like, a solution having the same composition as the extracorporeal fat solution is added to form a pH gradient across the membrane. This is performed by ultracentrifugation at about 30,000 to 70000 rpm. For the exchange of the extracorporeal fluid, other known means such as gel filtration and ultrafiltration can be used.
Next, PGs are added to this aqueous suspension to obtain PGs-containing fat bodies. PGs can also be added before the formation of the membrane permeation pH gradient.

In preparing a lipid thin film, tocopherol (vitamin E), cholesterol, phosphatidic acid, dicetyl phosphate, fatty acid (palmitic acid, etc.)
May be blended as a stabilizer. In particular, cholesterol not only contributes to the stability of fat bodies, but also
This is also advantageous in forming an H gradient. Cholesterol is added in an amount of 0.5 to 1.0 mol per mol of lipid, more preferably about 0.8 mol.

The production method exemplified above is a freeze-thaw method (Pick
U .: Arch. Biochem. Biophys., 212, 186 (1986)), but not limited thereto, and an ultrasonic treatment method (Huang,
C .: Biochemistry, 8, 344 (1969)), a surfactant treatment method (Brunner, J. et al .: Biochem. Biophys. Acta, 4
55 , 322 (1976)), reverse phase evaporation method (Szoka, F. et al .: Pr
oc. Natl. Acad. Sci .: USA, 75 , 4194 (1978)), a method using an emulsifier (Talsma, H. et al .: Drug Dev. and In
d. Pharmacy, 15 , 197 (1989)).

The fat body of the present invention may contain, as a stabilizer, a polymer selected from albumin, dextran, a vinyl polymer, a nonionic surfactant, gelatin, and hydroxyethyl starch. . The polymeric substance stabilizer may be incorporated into the voids inside the fat body together with the PGs, or may be blended into the fat body incorporating the PGs (ie, blended outside the fat body). Good. Of course, it is needless to say that both inside and outside of the fat body may be blended. The amount of the stabilizing agent to be added is 0.1 to 1 part by weight of the lipid.
It is 5 to 10 parts by weight, preferably 1 to 5 parts by weight.

The addition of a saccharide is advantageous in adjusting the osmotic pressure and preparing a lyophilized preparation described later.
Preferred examples of such saccharides include monosaccharides (glucose, mannose, galactose, fructose, etc.), disaccharides (sucrose, maltose, lactose, etc.) and sugar alcohols (mannitol, sorbitol, xylit, etc.). ,
It is not limited to these. The amount added is 1 lipid
0.5 to 10 parts by weight, preferably 1 to 5 parts by weight per part by weight
Parts by weight.

The diameter of the fat body of the present invention is usually 20 to 5
00 nm, preferably 100-250 nm, with such a particle size being less susceptible to lung inactivation.
Since the incorporation rate of PGs into the fat body of the present invention is close to 100%, it is not necessary to carry out further purification treatment and it can be used as a pharmaceutical as it is. However, if necessary, further molecular sieving treatment, impurities, free Any at least one treatment such as a gel filtration treatment for removing substances can also be performed.

Fat bodies incorporating PGs can be recovered as a precipitate. For example, a medium containing fat bodies can be subjected to ultracentrifugation, and the fat bodies can be recovered as a precipitate. This is then washed, if necessary, with a physiologically acceptable aqueous solution to prepare a pellet or suspension. Formulation is in accordance with widely known methods in the production of pharmaceuticals.

The PG-containing fat body composition thus obtained has a very high incorporation rate of PGs into lipids, and its particle diameter is uniform and extremely small, so that it is preferable as a medical preparation. The lipid body of the present invention is also provided as a lyophilized preparation by freezing the liquid preparation and then drying it under reduced pressure. The preparation method may be in accordance with a known method.

The preparation of the lipid body composition of the present invention is generally used as an oral drug or an injection, and its dosage is 1 to 50 μg / kg / time as PGs for an adult, preferably in the case of an adult. It is administered in an amount of 0.02 to 1 ng / kg / dose. The lyophilized preparation is generally used by dissolving or diluting it with a physiologically acceptable aqueous solvent (for example, distilled water for injection) at the time of use. In addition, the freeze-dried preparation may be tableted, encapsulated, or enteric-encapsulated by devising the preparation.

[0022]

Examples and Experimental Examples The following Examples and Experimental Examples were performed in the following manner unless otherwise specified. 1. Production of PGs-containing fat bodies: 70 mg of phosphatidylcholine (hereinafter abbreviated as EPC) from egg yolk and 30 mg of cholesterol (mole ratio 55:45) are mixed. After dissolving this mixture in 1 ml of chloroform, put it in a 25 ml pear-shaped flask,
Chloroform was distilled off using a rotary evaporator to prepare a lipid thin film. The flask in which the lipid thin film was formed on the inner wall was placed in a desiccator and sucked for one hour with a vacuum pump. Next, 1 ml of the first buffer solution (same composition as the fat body sealing solution) was added to the flask, and stirred with a vortex mixer to prepare a lipid suspension (MLV).

Next, the procedure of freezing on dry ice and thawing in a 37 ° C. warm bath was repeated five times to prepare fat bodies (LUV). Next, a 0.2 μm Nucle
pore filter (Costar Corporation)
10), and the particle diameter was made uniform. Next, to a sample obtained by adding 100 μl of fat bodies to 3 ml of the same buffer solution used in the above preparation, a second buffer solution [20 mM citric acid (pH 3.0) containing 800 mM sucrose and having the same composition as the extra-fat body solution] was added. Use) and ultracentrifugation (5
(0000 rpm, 30 minutes) twice to prepare lipid bodies having a transmembrane pH gradient. Next, the fat bodies were added to the air-dried PGs and incubated at 25 ° C. for 1 hour. By the above steps, PG-containing fat bodies were prepared. Note that MLV indicates multilamellar vesicles, and LUV indicates single-layer lamellar vesicles having a large particle diameter.

2. Measurement of entrapment efficiency of PGs: It was measured by an ultrafiltration method using tritium-labeled PGs. That is, P captured on an ultrafiltration membrane (AP-1 manufactured by Amicon)
Gs were PGs incorporated into fat bodies, and PGs that passed through the ultrafiltration membrane were free PGs. Then, the ratio of the supplemented PGs to the total PGs is calculated as PG
And encapsulation efficiency. That is, the encapsulation efficiency of PGs is shown in FIG.
The radioactivity of the ultrafiltration membrane and the radioactivity of the filtrate were respectively measured through the methods shown in (1) and (2) and were determined by the following equation. (Radioactivity of ultrafiltration membrane) ÷ (Radioactivity of ultrafiltration membrane +
(Radioactivity of filtrate) × 100 (Measurement of radioactivity) 100 μl of sampled liquid was added to liquid scintillator 1
After adding 0 ml and stirring well, the radioactivity was measured.

3. Quantification of phospholipid (PC): Measurement was performed using a reagent (enzyme) for measuring phospholipid (manufactured by Denka Seiken Co., Ltd.).

Example 1 / Experimental Example 1 PGE when the pH of the encapsulating buffer was adjusted to 7.0 to 10.0
₁ Encapsulation efficiency: Fat bodies produced using PGE ₁ as PGs and according to the method described in the section of the above-mentioned method for producing fat bodies, and having an enclosing buffer pH of 7.0 and 8 .0,
PG of 1 and 9.0 and 10.0
The E ₁ encapsulation efficiency was examined, and the results are shown in FIG. In addition,
In this example, the amount of PC was changed with respect to 5 μg of PGE ₁ . The following were used as the internal buffer. That is, as the fat body of the present invention, pH 7.0 is 500 m
M phosphoric acid, pH 8.0 and 9.0 is 500 mM Tris, pH 10.0 is 500 mM carbonic acid. As a control fat body, 20 mM citric acid was used at pH 3.0. On the other hand, the PC amount of fat body is set to 0.
0075mg, 0.075mg and 0.75mg 3
Steps were used (same in the following examples). PGE
_{1 The} encapsulation efficiency is proportional to the amount of fat bodies,
0 was the highest, followed by phosphoric acid at pH 7.0.

Example 2 / Experimental Example 2 Influence of pH and Concentration of Encapsulated Carbonate Buffer on PGE ₁ Encapsulation Efficiency: a) PGE ₁ was used as PGs and produced according to the production of the above-mentioned fat body. The PGE ₁ encapsulation efficiency was examined for the fat bodies obtained by changing the pH of the carbonate buffer (500 mM), and the results are shown in FIG. As a control fat body (control), pH 3 was adjusted with 20 mM citric acid.
0 was used (the same applies to the following examples). As is clear from the results in FIG.
At 0.0, the encapsulation efficiency was somewhat lower than at pH 9.0. However, pH 9.0 in carbonic acid showed much higher PGE ₁ encapsulation efficiency than pH 9.0 in Tris. As b) PG compounds, using PGE _1, wherein the fatty corpuscles according to the method described in the item of preparation a fat bodies manufactured, 250 mM concentration of carbonate buffer (pH 10.0), 500 mM, and measuring the PGE ₁ encapsulation efficiency when changing the 1000 mM, and the results are shown in FIG. As is clear from the results shown in FIG. 4, the higher the carbonic acid concentration, the higher the PGE ₁ encapsulation efficiency. In the above a) and b) of Experiment, PGE ₁ 5
The amount of PC was changed with respect to μg.

Example 3 / Experimental Example 3 Influence of pH change of encapsulated phosphate buffer on PGE ₁ encapsulation efficiency: Fat produced using PGE ₁ as PGs according to the production of the above-mentioned fat body In the body, the pH of the phosphate buffer (500 mM) was adjusted to pH 7.0, pH 8.
0, pH 9.0, is changed to pH10.0 was examined PGE ₁ encapsulation efficiency (all concentrations are 500 mM). The result is shown in FIG. As is clear from the results of FIG.
The higher the H, the higher the encapsulation efficiency.

Example 4 / Experimental Example 4 Influence of Buffer Type on PGE ₁ Encapsulation Efficiency When Enclosure Buffer pH was set to 9.0: PGE ₁ was used as PGs to produce the above-mentioned fat body. Fat body produced according to
5 types of buffers: Tris buffer, glycine buffer,
Phosphate buffer, for those using borate buffer and carbonate buffer, examine the PGE ₁ encapsulation efficiency in the pH 9.0, and the results are shown in Figure 6. The properties of these buffers are as shown in Table 1.

[0030]

[Table 1]

As is apparent from the results shown in FIG. 6, among these buffers, the carbonate buffer exhibited the highest PGE ₁ encapsulation efficiency.

Example 5 / Experimental Example 5 Release rate of PGE ₁ from fat bodies: PGs
Using the E _1, the fat fat was prepared analogously to the preparation of bodies bodies, and stored at 10 ° C. or less in a refrigerator, free PGE ₁ from over time fat corpuscles, ultrafiltration Investigated by. The results are as shown in Table 2, and the release was slight even after storage for 90 hours. From this, it can be seen that in the fat body of the present invention, the release of PGs is suppressed, that is, it is persistent. The internal buffer used was a 500 mM carbonate buffer.

[0033]

[Table 2]

Example 6 / Experimental Example 6 Stability of PGE ₁ encapsulated in fat bodies: PGE ₁ (5 μg) was used as PGs, and the PC amount was 0.75 m.
g, and using a 500 mM carbonate buffer solution as an encapsulating solution, the fat body produced according to the above-mentioned method for producing the fat body is stored in a refrigerator at 10 ° C. or less, and the PGE which changes over time is not changed.
The ratio of ₁ to decomposed PGE ₁ (ie, PGB ₁ ) was determined by a post-column method using an octadecylsilylated packed column. The result is as shown in FIG.
From these results, PGE ₁ in the fat body of the present invention is
It turned out to be very stable.

[Analytical Method by HPLC] PGE ₁ and PGB ₁ were quantified by the HPLC post-column method. That is, PG was separated by a column, and the separated eluate was reacted with a 1N potassium hydroxide solution. Next, PGE
After quantitatively converted to ₁ PGB _1, it was it quantified detected by ultraviolet absorption photometer. The measurement conditions are as follows. Separation conditions Mobile phase: 1/150 M phosphate buffer (pH 6.3) / for liquid chromatography Internal standard: Acetonitrile mixed solution (3/1) β-naphthol Column: Octadecylsilylated silica gel packed column Column temperature: 60 ° C. Flow rate: 1 3 ml / min. Post-column reaction conditions Reaction solution: 1N KOH Reaction coil: Teflon tube (inner diameter 0.5 mm, length 1)
0 m) Coil temperature: 60 ° C. Flow rate: 0.5 ml / min. Analysis condition Measurement wavelength: 278 nm

Example 7 / Experimental Example 7 Release of PGE ₁ encapsulated in fat bodies: a) Fat body of the present invention containing 500 mM carbonate buffer (pH 10.0) and 20 mM citrate buffer ( pH3.
Using a fat body (control) in which 0) was encapsulated, the effect of dilution with a buffer having the same pH as that of the extralipidal solution or a neutral buffer was examined by ultrafiltration. PGE ₁ 5 μg,
Fat body 50 consisting of 7.5 mg of phosphatidylcholine
0 μl was diluted 10-fold. The result is shown in FIG. As is clear from the results, the control fat body was p
The PGE ₁ was liberated simply by dilution with H3.0 citrate buffer, more in Hepes buffer pH7.4 liberated the PGE ₁ in the most. On the other hand, in the fat body of the present invention, PG
E ₁ of the free suppression was observed.

[0037] b) the free PGE ₁ from adipose corpuscles in the present invention the fat bodies about 5% human serum albumin (pH7.4 Hepes buffer) were studied at sucrose density gradient centrifugation. The result is shown in FIG. As is clear from the results, PGE ₁ is released in 5% human serum albumin (Hepes buffer at pH 7.4), but 60% of PGE ₁ is released.
Was held. In the experiment of b), PGE ₁
Is 5 μg and phosphatidylcholine is 0.75 mg in 5% human serum albumin.

[Sucrose density gradient centrifugation] A liposome is added to a sucrose having a density gradient, and PGs encapsulated in the liposome and free PGs are separated. By applying this method, the effect of a protein (for example, human serum albumin (HSA)) on the PGE ₁ holding ability of liposomes that cannot be analyzed by ultrafiltration can be examined. This method is specifically as follows. In an ultracentrifuge tube, add 50 μl of the liposome sample to be analyzed to 800 μl of buffer containing 0.8 M sucrose. 50 μl of the liposome sample is added to 800 μl of the buffer to be analyzed to which the pH has been changed or HSA has been added to adjust the final sucrose concentration to 800 mM. This solution was placed in a tube for ultracentrifugation, and 20 mM containing 500 mM sucrose was added from above.
Gently overlay 4.15 ml of citrate buffer. Next, ultracentrifuge at 230,000 g for 16 hours at 4 ° C. After the completion of ultracentrifugation, fractionate 1 ml / fraction from the bottom. The ratio of the PGs in the upper layer of 3 ml to the total PGs was defined as the PG encapsulation efficiency.

[0039] Excretion of Examples 8 - Experimental Example 8 rat plasma: Rat plasma concentrations of free PGE ₁ and the present invention PGE ₁ contains fat corpuscles (fat small body sealing buffer sodium 500mM carbonate, pH 10.0) Was compared. Using ¹ H-labeled PGE ₁ as a tracer, the change in radioactivity was examined. The dosage _PGE 1 _20μg / PC30mg /
The blood was administered from the tail vein and blood was collected from a cannula provided in the carotid artery. After the collected blood sample was dried, the radioactivity was measured, and the percentage of dose was calculated. The results are shown in FIG. Blood levels of free PGE ₁ is rapidly decreases after administration, became almost zero at 2 min after Zoletile injection after administration. In contrast, it decreased PGE ₁ was fat bodies encapsulated is slow, after administration, and remained at 10% or more at 5 min after Zoletile injection. Example 9 / Experimental Example 9 After dissolving 100 mg of EPC in 1 ml of chloroform,
Put in a 25 ml pear-shaped flask,
Chloroform was distilled off with a filter to prepare a lipid thin film. Inside
Put the flask with the lipid film on the wall in a desiccator
Suction was applied for 1 hour with a vacuum pump. Next, 500 mM, carbonate
Add 1 ml of buffer (pH 10.0) to prepare lipid suspension
did. This is a polycarbonate filter with a pore size of 0.2 μm.
The mixture was filtered ten times using a filter to make the particle diameter uniform. Next
0.8M sucrose without buffer in 1ml of liposome solution
3.5 ml of a liquid (pH 4.5), and ultracentrifuged (5000).
(0 rpm for 15 minutes) three times to collect the liposome fraction.
PH adjusted to 4.5 with 0.1N hydrochloric acid.
A lipid body with a gradient was prepared. PGE as PGs
₁ and the fat produced according to the production of the fat body
The PGE ₁ encapsulation efficiency in the body was examined. Measurement of ability to retain PGs (sucrose density gradient centrifugation): (Test sample) Fat body A of the present invention: As described above, carbonate buffer (pH 10.0) was added to fat body.
Liquid and adjust the pH to 4.5 with 0.1N hydrochloric acid to reduce fat
PGE ₁ fat body A as extracorporeal fluid . Fat body B of the present invention: 0.1 mM citrate buffer (pH
Fat body B similar to 4.5 except using 4.5). Control fat body C: 0.1 mM citric acid as both fat body fluid and external fluid
Fat body C using buffer (pH 4.5). (Test method) The retention rate of PGE _{1 in} fat bodies was determined as follows.
Examined. That is, 0.1 ml of each fat body of
And the following buffer solution of HSA (-) and HSA (+) 0.4m
and heated at 37 ° C. for 30 minutes as needed
Then, 0.2M HEPES [including: 1.6M sucrose] (pH
7.4) 0.5 ml was mixed. 0.2M HEP
2. ES buffer solution (including 0.5M sucrose) (pH 7.4)
Overlay 8 ml and centrifuge at 5 ° C, 50,000 rpm for 2 hours
Was. After centrifugation, 5 fractions of about 1 ml each from the lower layer
Separated into to quantify PGE ₁ concentration of each fraction.
Lower 2 fractions were free PGE ₁ , upper 3 fractions
The retention rate was calculated assuming that PGE ₁ was retained in the fat body
Issued. The results are as shown in Table 2. Human serum albumin (-) buffer: 0.2 M HEPE
S buffer (pH 7.4) human serum albumin (+) buffer: 0.2 M HEPE
S buffer (including 10.0% human serum albumin) (pH
7.4)

[Table 2]

[0040]

It has been found that the PG-containing fat body composition of the present invention has the following characteristics. High encapsulation amount of PGs: Encapsulation amount per fixed amount of lipid is about 1 of control liposome.
00 times. The PGs in the fat bodies were stable: even if stored in liquid form at 4 ° C. for 20 hours, the leakage rate was 4% or less, and PGA ₁
Alternatively, the decomposition into PGB ₁ was 7% or less. The release of PGs was greatly suppressed: the release inhibitory effect was observed even in the presence of albumin. The PGs concentration in the rat blood was high: the blood concentration in the early stage of administration was significantly higher than free.

[Brief description of the drawings]

FIG. 1 is a principle diagram of ultrafiltration used for analysis.

FIG. 2 is a graph showing the effect on the PG encapsulation efficiency by a change in pH of a buffer solution for enclosing a fat body.

FIG. 3 is a graph showing the PG encapsulation efficiency when the pH of the encapsulated carbonate buffer is changed.

FIG. 4 is a graph showing the PG encapsulation efficiency when the concentration of the encapsulated carbonate buffer was changed.

FIG. 5 shows the PG when the pH of the encapsulated phosphate buffer was changed.
It is a graph which shows class encapsulation efficiency.

FIG. 6 is a graph showing the PG encapsulation efficiency when the pH of the encapsulation buffer is 9.0.

FIG. 7 is a graph showing the stability of PGs encapsulated in fat bodies.

FIG. 8 is a graph showing the release of PGs from fat bodies.

FIG. 9 is a graph showing the release of PGs from fat bodies.

FIG. 10 is a graph showing excretion of PGs from rat plasma.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Yasuo Ueda 2-1-1180 Sumida Otani, Hirakata City, Osaka Prefecture 1 Inside Midori Cross Research Institute, Inc. (72) Inventor Koichi Yamauchi 2-1-1180 Sumida Otani, Hirakata City, Osaka Prefecture (1) Inside the Midori Cross Research Laboratory Co., Ltd. (56) References Special Table 63-503526 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/557, 9/127

Claims (1)

(57) [Claims] The pH of the extracorporeal solution is 2 to 6, and the pH of the encapsulating solution is 7 to 1 by a combination of a weak acid and a strong base.
A prostaglandin-containing fat bodies composition characterized by comprising adjusted to 1, the weak acid and strong base pairs
The combination is with carbonic acid and sodium carbonate or boric acid
A composition that is a combination of sodium borate .