JPH04338333A - Prostaglandin e1 fat emulsion - Google Patents

Abstract

PURPOSE:To provide a prostaglandin E1 (PGE1) fat emulsion containing PGE1, an oil base, a phospholipid and water, free from higher fatty acid as an emulsifying assistant and having remarkably improved storage stability of PGE1. CONSTITUTION:The objective PGE1 fat emulsion contains (A) PGE1, (B) an oil base such as a vegetable oil (e.g. soybean oil or sesame oil) especially having a purity of >=98%, preferably >=99.8% as a glyceride, (C) a phospholipid, e.g. a refined phospholipid such as yolk lecithin or soybean lecithin and (D) water and is free from a higher fatty acid (e.g. oleic acid) or its salt as an emulsifying assistant. The amounts of the components A and B are 0.0001-0.001W/V% and 5-50W/V%, respectively, and the weight ratio of C/B is 1/100 to 1/2. The emulsion may be further incorporated with an emulsion stabilizer other than higher fatty acid and its salt, a polymeric substance, an isotonizing agent, an antioxidant, etc.

Description

Description: [0001] The present invention relates to a prostaglandin E1 fat emulsion having vasodilatory and antihypertensive effects, and more particularly, to a prostaglandin E1 fat emulsion that has vasodilatory and antihypertensive effects. Concerning high prostaglandin E1 fat emulsions. [Prior Art] Prostaglandin E1 (hereinafter referred to as "PG")
PGE (sometimes expressed as "E1") is known to exhibit a strong vasodilatory effect in many mammals, but PGE
Due to the low chemical stability of 1 itself, its administration method and formulation have been difficult. Conventionally, in order to improve the instability of PGE1, methods of stabilizing PGE1 by adding various compounds and α-cyclodextrin inclusion compounds of PGE1 have been studied. [0003]Recently, it has been recognized that PGE1 has the disadvantage that it is inactivated by 15-hydroxydehydrogenase present in the lungs, kidneys, liver, etc., and in order to solve this disadvantage, soybean oil was used as an oil base for PGE1. A fat emulsion for intravenous use has been developed (Japanese Patent Publication No. 1-57094) and is actually commercially available. [0004]Problems to be Solved by the Invention Generally, when preparing a fat emulsion using soybean oil, an emulsification adjuvant is required to assist emulsification. ,
Preferably, higher fatty acids having 12 to 20 carbon atoms or salts thereof are used. For example, the above-mentioned Special Publication No. 1-5709
No. 4 also indicates the use of higher fatty acids such as oleic acid, stearic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid, or their sodium salts, and oleic acid or its sodium salt is particularly preferred as an emulsification aid. listed as an agent. However, in conventional fat emulsion compositions, the chemical instability of PGE1 has not necessarily been improved, and the development of a PGE1 fat emulsion with an improved residual rate of PGE1 has been awaited. [Means for Solving the Problems] As a result of intensive research to solve the above problems, the present inventors unexpectedly found that higher fatty acids, which are emulsification aids, are involved in the chemical instability of PGE1. The inventors have discovered that by removing this from the PGE1 fat emulsion, the storage stability of PGE1 is significantly improved and the residual rate of PGE1 in the formulation is increased, leading to the completion of the present invention. That is, the present invention provides a PGE1 fat emulsion which contains PGE1, an oil base, a phospholipid, and water, and is substantially free of higher fatty acids or salts thereof. The prostaglandin E1 fat emulsion of the present invention can be prepared by a conventional method, except that it does not contain higher fatty acids or salts thereof as emulsification aids.
That is, it may be prepared by appropriately using an oil base, phospholipid, and water in addition to prostaglandin E1, which is the main drug. [0009] The amount of PGE1, which is the main ingredient, can be increased or decreased as appropriate depending on the form of the fat emulsion and its use, but generally it is sufficient to add an effective amount to the emulsion or emulsion composition, usually 100 to 0.2 μg/ml. It is sufficient to add a certain amount. The oil base used in the preparation of the PGE1 fat emulsion of the present invention includes vegetable oils such as soybean oil, sesame oil, cottonseed oil, safflower oil and corn oil, preferably soybean oil or sesame oil. used. The vegetable oil is preferably a highly purified vegetable oil, and specifically, impurities may be removed from refined soybean oil or refined sesame oil by steam distillation, column adsorption, etc., and glycerides (tri, di, monoglycerides) Those having a purity of 98% or more, preferably 99.8% or more are preferred. On the other hand, examples of phospholipids include purified phospholipids such as egg yolk lecithin and soybean lecithin.
These phospholipids can be prepared by a conventional fractionation method using an organic solvent. That is, for example, crude egg yolk lecithin is dissolved in cold n-hexane-acetone, and while stirring,
Purified phospholipids can be obtained by gradually adding acetone, filtering and collecting insoluble matter, repeating this operation once more, and then distilling off the solvent. It mainly contains phosphatidylcholine, but may also contain other phospholipids. [0012] In the present invention, the higher fatty acids excluded from the formulation composition are emulsification adjuvants that are present or added when preparing conventional PGE1 fat emulsions; Fatty acids having about 12 to 20 carbon atoms that may contain saturated bonds, such as oleic acid, stearic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid, and the like, particularly oleic acid. In addition, in the present invention, the use of these salts should also be avoided, such as alkali metal salts (sodium salts, potassium salts, etc.) of higher fatty acids, alkaline earth metal salts (calcium salts, etc.), etc. Acceptable salts should also be excluded. In this way, in order to substantially not contain higher fatty acids in the PGE1 fat emulsion,
Specifically, higher fatty acids as emulsification aids may not be added during the preparation of the PGE1 fat emulsion. [0013] As an example of the blending amount of each component for preparing the PGE1 fat emulsion of the present invention, prostaglandin E1, which is the main drug, is added in an effective amount, usually 0.001 to 0% of the total amount.
．． About 0001W/V%, oil base is usually 1 to 30W/V
%, preferably about 5 to 50 W/V%, and phospholipids are blended at about 1/100 to 1/2 of the oil base by weight, and an appropriate amount of water and optional ingredients described below are blended. be done. The fat emulsion of the present invention may contain various optional ingredients within the range that does not impair the effects of the present invention, such as emulsion stabilizers other than higher fatty acids and their salts, polymeric substances, isotonic agents,
Antioxidants can also be added. [0015] Examples of emulsion stabilizers include cholesterol and phosphatidic acid, which can be used as long as they are medicinally usable. Usually cholesterol is contained in an amount of 0.5 W/V% or less based on the total amount; Preferably, it is sufficient to add the amount of 0.1 W/V% or less, and phosphatidic acid is usually added in an amount of 5 W/V% or less, preferably 1 W/V%.
The following amounts may be added. [0016] Also, examples of high molecular substances include albumin,
Dextran, vinyl polymer, nonionic surfactant,
Gelatin, hydroxyethyl starch, etc. are exemplified, and these are usually 0.1 to 5 parts by weight per 1 part by weight of PGE1.
Preferably, 0.5 to 1 part by weight may be added. Among these, human-derived albumin is preferable from the viewpoint of antigenicity, and specific preferable examples of the vinyl polymer include polyvinylpyrrolidone. In addition, as a nonionic surfactant, polyalkylene glycol (for example, an average molecular weight of 1,000 to 10,000
, preferably 4000-6000 polyethylene glycol), polyoxyalkylene copolymers (e.g. average molecular weight 1000-20000, preferably 6000-10
000 polyoxyethylene-polyoxypropylene copolymer), hydrogenated castor oil polyoxyalkylene derivative (
For example, hydrogenated castor oil polyoxyethylene (20) ether, (40) ether, (100) ether, etc.),
Examples include castor oil polyoxyalkylene derivatives (eg, castor oil polyoxyethylene (20) ether, castor oil polyoxyethylene (40) ether, castor oil polyoxyethylene (100) ether, etc.). [0017] Furthermore, examples of isotonizing agents include glycerin, glucose, etc.
An appropriate amount that can be adjusted to mOsm may be added; for example, in the case of glycerin, about 1.7 to 2.7 W/V%, preferably about 2.2 to 2.6 W/V% is exemplified. . Examples of the antioxidant include vitamin C, benzoic acid, citric acid and its salts, dibutylhydroxytoluene, dibutylhydroxyanisole, α-tocopherol, and D-sorbitol. In producing the fat emulsion of the present invention, for example, a predetermined amount of an oil base (eg, highly purified sesame oil), PGE1, phospholipids, and, if necessary, the various other additives mentioned above (eg, An emulsion may be prepared by adding appropriate amount of water (glycerin, etc.), further adding an appropriate amount of water, and performing homogenization using a commonly used homomixer or homogenizer, such as a pressure injection type homogenizer or an ultrasonic homogenizer. . When adding PGE1, PGE1 may be dissolved in a trace amount of a non-toxic anhydrous organic solvent (preferably absolute ethanol, etc.) and then added. [0020] As another production method, phospholipids etc. are added to an oil base, an appropriate amount of water is added, an emulsion is made by the above method, and then the emulsion is mixed with a non-toxic anhydrous organic solvent (preferably anhydrous ethanol etc.). By adding and mixing a predetermined amount of dissolved PGE1 to this emulsion and removing the organic solvent, the PGE of the present invention can be obtained.
Examples include methods for producing GE1 fat emulsions. In this case, it is also possible to first prepare a water-in-oil dispersion by adding a small amount of water to the oil phase and then phase invert this into the oil-in-water emulsion of the present application. Furthermore, depending on the convenience and purpose of production, additives such as stabilizers and tonicity agents may be added after the production of the fat emulsion. The PGE1 fat emulsion thus obtained can be formed into particles having an appropriate particle size, but as a medicine, the average particle size should be 50% to prevent the occurrence of side effects.
The thickness is preferably 0 nm or less, particularly about 100 to 400 nm. For example, when water or acid acts on a container made of borosilicate glass or soda lime glass, the pH of the aqueous solution composition may change due to external factors such as elution of alkaline components from the surface of the container. Fluctuations may occur. In such cases, if the container is filled into a dealkalized container that has been selectively cleaned and removed from the alkaline components on the surface of the container,
The PGE1 fat emulsion of the present invention can be made into an extremely stable formulation. A preferred example of the dealkalization treatment container is a container made of glass or the like that has been subjected to a dealkalization treatment, and more specifically a glass ampoule that has been subjected to a dealkalization treatment. An example of this method is to contact the glass surface in a state with a water-soluble sulfur oxide such as sulfur dioxide gas or ammonium sulfate to convert the alkaline component on the surface into fine sulfate crystals, followed by washing. [0023] The fat emulsion of the present invention is preferably administered by parenteral routes such as injection, particularly by intravenous administration.
Preferred administration of the fat emulsion of the present invention is, for example, about 1 to 100 μg of PGE1, 0.02 to 0.2 ng
It is a continuous intravenous infusion once a day at a rate of /kg/min. [Examples] Specific examples, comparative examples, and test examples relating to the present invention are listed below, but the present invention is not limited by these in any way. Example 1 2 mg of prostaglandin E1 was added to absolute ethanol (
Wako Pure Chemical Industries, Ltd., reagent special grade) was dissolved in 200 μl of Japanese Pharmacopoeia sesame oil (Kosakai Pharmaceutical Co., Ltd.) 40 g, and purified egg yolk lecithin (Asahi Kasei Co., Ltd.) 4.8 g, concentrated glycerin (
10 g of Wako Pure Chemical Industries, Ltd., reagent special grade) was added thereto, and distilled water was further added to bring the total amount to 400 g. This was coarsely emulsified at 5°C using an autohomogen mixer at 10,000 rpm for 20 minutes, and then emulsified using a pressure injection homogenizer (product name: Manton-Gourin) at 30°C or lower, 460 kg/cm2, and 20 passes. Fine emulsification was performed under the following conditions to obtain 300 g of a white fat emulsion with an average particle size of 227 nm. Dispense 1 ml of the fat emulsion into an ampoule (dealkalization treatment container) whose inner surface has been treated with sulfur, seal the ampoule,
An ampoule formulation was obtained. Example 2 Prostaglandin E1 2m was prepared in the same manner as in Example 1.
g was dissolved in 200 μl of absolute ethanol, mixed with 40 g of sesame oil in the Japanese Pharmacopoeia, and purified egg yolk lecithin (phosphatidylethanolamine content based on the total phospholipids; 4%
), 10 g of concentrated glycerin was added, and distilled water was added to bring the total amount to 400 g. The procedure was repeated in the same manner as in Example 1 to prepare a transparent white prostaglandin E1 fat emulsion (average particle size 227 nm). 300g was obtained and made into an ampoule formulation. Comparison Example In the same manner as in Example 2, prostaglandin E1 2m
g was dissolved in 200 μl of absolute ethanol and mixed with 40 g of Japanese Pharmacopoeia sesame oil. To this, purified egg yolk lecithin (phosphatidylethanolamine content; 4%) 4.8
g, 10 g of concentrated glycerin and 1 g of oleic acid (manufactured by NOF Corporation, purity 99%), and further added distilled water to make a total amount of 400 g. 300 g of Grandin E1 fat emulsion (average particle size 227 nm) was obtained and made into an ampoule formulation. Test Example Ampoule preparations of the PGE1 fat emulsion of Example 2 and the PGE1 fat emulsion of Comparative Example were stored at 40°C for one week, and then the amount of remaining PGE1 was measured and compared. The results are shown in Table 1.
Shown below. The content of PGE1 was measured by high performance liquid chromatography (HPLC) under the following conditions after extracting PGE1 from a fat emulsion using a known method. Detection wavelength: 200nm column
; Dicrosolve ODS column (inner diameter 4.6 m
m, length 150 mm) Elution solvent; 1/150M phosphate buffer (pH
6.5) -Acetonitrile = 3.3:1 mixture elution rate
; 1 ml/min [0031] As is clear from these results, the PGE1 residual rate of the PGE1 fat emulsion of Example 2 was clearly higher than that of the comparative example. [0032] Effect of the invention: The PGE1 fat emulsion of the present invention has PGE1
Since it has high storage stability and is not inactivated by 15-hydroxydehydrogenase, it can be advantageously used as a PGE1 preparation having vasodilatory and hypotensive effects. that's all

Claims (3)

[Claims] 1. A prostaglandin E1 fat emulsion, which contains prostaglandin E1, an oil base, a phospholipid, and water, and is substantially free of higher fatty acids or salts thereof. 2. The prostaglandin E1 fat emulsion according to claim 1, which does not contain oleic acid or a salt thereof. 3. At least an effective amount of prostaglandin E1, 5 to 50% w/v of an oil base, and 1/1/2 of the oil base.
2. The prostaglandin E1 fat emulsion according to claim 1, which contains 100 to 1/2 weight of phospholipids and an appropriate amount of water, and is substantially free of higher fatty acids or salts thereof. .