JPH0429924A - Injection preparation containing fat-soluble drug - Google Patents

Abstract

PURPOSE:To obtain an injection preparation containing a fat-soluble drug, having high safety and suitable for the high-calorific transfusion in the case impossible to orally administer nutrients by compounding a fat-soluble drug to an emulsifier produced by bonding a polyethylene glycol to a functional group of a phospholipid. CONSTITUTION:A fat-soluble drug (e.g. vitamin A, D, E, etc., their derivative and coenzyme Q) is compounded to an emulsifier having a structure produced by bonding a polyethylene glycol to a functional group of a phospholipid. Amino group is used as the functional group of the phospholipid (e.g. phosphatidylethanolamine or hydrogenated natural phosphatidylethanolamine) and the average molecular weight of the polyethylene glycol is 1,000-10,000.

Description

[Detailed description of the invention] [Industrial application field 1 The present invention relates to formulations containing lipid-soluble drugs.

More specifically, the present invention relates to an injectable preparation containing fat-soluble vitamins suitable for use in addition to high-calorie infusions applied to patients who are unable to take in nutrients orally.

[Prior Art] In recent years, it has become common practice to administer high-calorie infusions containing various essential vitamins to patients who are unable to take oral nutrition immediately after surgery. Such high-calorie infusions are usually administered intravenously in the form of an aqueous solution. Therefore, when adding fat-soluble vitamins to high-calorie infusions, it is necessary to emulsify the fat-soluble vitamins using a surfactant.

Conventionally, polyoxene ethylene hydrogenated castor/oil derivatives and lecithin have been used as surfactants to emulsify fat-soluble vitamins. However, when a fat-soluble vitamin emulsion emulsified using polyoxyethylene hydrogenated castor oil is freeze-dried with excipients added for stabilization, it becomes cloudy when the resulting dry preparation is redissolved. There was a problem in that it caused In addition, although polyoxyethylene hydrogenated castor oil has a relatively strong emulsifying power, it cannot be used in large quantities because of the risk of hemolytic toxicity and shock when administered intravenously (Adverse Drug Reaction Information No. 78). There were also problems.

Furthermore, although lecithin is safe when administered to living organisms, it has a weak emulsifying power, so a special device called a pressure emulsifying machine is required to sufficiently emulsify fat-soluble vitamins using lecithin. The stability of the emulsion was not sufficient.

[Problem to be Solved by the Invention 1] The present invention solves the above problems, and provides an injectable preparation containing a fat-soluble drug that has low hemolytic toxicity and low toxicity when administered intravenously, and is sufficiently emulsified. The purpose is to provide.

[Means for Solving the Problems] In order to solve the above problems, the lipophilic drug-containing injection preparation according to the present invention has the following configuration.

(1) A lipophilic drug-containing injectable preparation that contains a lipophilic drug and an emulsifier formed by bonding polyethylene glycol to the functional group of a phospholipid.

(2) The functional group of the phospholipid is an amine group (1).
) The injectable preparation containing a fat-soluble drug.

(3) The lipophilic drug-containing injection preparation according to (2) above, wherein the phospholipid is phosphatidylethanolamine.

(4) The lipophilic drug-containing injection preparation according to (3) above, wherein the phospholipid is hydrogenated natural phosphatidylethanolamine.

(5) The average molecular weight of the polyethylene glycol is 1.
000 to 10,000, the injectable preparation containing a fat-soluble drug according to any one of (1) to 4) above.

(6) The injectable preparation containing a fat-soluble drug according to any one of (1) to 5) above, wherein the fat-soluble drug is a fat-soluble vitamin.

The fat-soluble drug in the present invention is a substance that has pharmacological or physiological activity and has low solubility in water, and includes, for example, fat-soluble vitamins, steroids, fat-soluble anticancer drugs, and the like. Specifically, vitamins A, D, and E,
, K2 and their derivatives, coenzyme Q1, ubidecarenone, ceftizoxime, nifedipine, N4-acylcytosine arabinoside, indomethacin, γ-oryzanolyl ampicillin, mefenamic acid, phenytoin, corticosteroids, ergosterol, superficial alkaloids, pleio- Examples include mycin and ftorafur.

In the present invention, the emulsifier that emulsifies a fat-soluble drug has a structure in which polyethylene glycol (PEG) is bonded to the parent tree of a phospholipid (hereinafter referred to as PEG-bonded phospholipid).
. The end of the PEG chain that is not bonded to the phospholipid may be a hydroxyl group, a short chain ether such as methyl or ethyl, or a short chain ester such as acetic acid or lactic acid.

Phospholipids that bind to polyethylene glycol include
It is preferable to use hydrogenated natural phospholipids because of their low toxicity and excellent safety. As the natural phospholipid, it is preferable to use soybean lecithin, egg yolk lecithin, phosphatidylethanolamine, or the like.

For purposes of the present invention, the molecular weight of PEG in the PEG-conjugated phospholipid molecule is preferably between 1,000 and 10,000, more preferably between 4,000 and 8,000. P.E.
If the molecular weight of G is less than 1,000, toxicity during intravenous administration increases, and if it exceeds 1o, ooo, the weight of PEG-bonded phospholipid required to emulsify a fat-soluble drug increases, resulting in The viscosity of injectable preparations containing soluble drugs increases, making them difficult to administer intravenously.

In order to covalently bond PEG and phospholipid, a reactive functional group is required in the polar part of the phospholipid. This functional group includes the amino group of phosphatidylethanolamine,
Examples include the hydroxyl group of phosphatidyl sericerol and the carpoxyl group of phosphatidyl serine, and the amine group of phosphatidylethanolamine is preferably used.

In order to covalently bond the functional group of phospholipid and PEG, there are methods using cyanuric chloride, methods using carbodiimide,
There are methods using acid anhydrides, methods using glutaraldehyde, etc. To bond the amino group of phosphatidylethanolamine and PEG, cyanuric chloride (2,4
, 6-)dichloros-triazine) is preferred.

For example, by combining monomethoxypolyethylene glycol and cyanuric chloride using a known reaction procedure, 2-
O-methoxypolyethylene glycol-4,6-dichloro-8-triazine (activated PEGI) or 2,4-his(0-methoxypolyethylene glycol)-6-chloro-5 triazine (activated PEG2) is obtained. By bonding these and amino groups through a dehydrochloric acid condensation reaction, PE is attached to the polar head of phos-7 atidylethanolamine.
A phospholipid to which G is covalently bonded is obtained. Here, when activated PEGI is used, the phospholipid in the molecule contains one PEG chain, and when activated PEG2 is used, it contains two PEG chains. In addition, by reacting monomethoxy PEG with succinic anhydride to introduce a carboxyl group to the PEG terminal, and reacting this with phosphatidylethanolamine in the presence of carbodiimide,
A PEG-linked natural phospholipid via an amide linkage is obtained.

The appropriate blending ratio of the fat-soluble drug and PEG-bonded phospholipid varies depending on the type of fat-soluble drug, but usually 1 to 100 parts by weight of the PEG-bonded phospholipid is used for 1 part by weight of the fat-soluble substance. .

The lipophilic drug-containing injection preparation of the present invention may optionally include:
Saccharides and/or sugar alcohols such as glucose, xylit, sorbitol, mannitol, etc., which are commonly used as tonicity agents, may be added. Further, if necessary, a buffer, a solubilizing agent, a flavoring agent, a preservative, a stabilizer, a specific gravity adjuster, etc. can be added.

To obtain the lipophilic drug-containing injectable preparation of the present invention, the lipophilic drug and the PEG-bonded phospholipid are dissolved in a solvent that can dissolve both, mixed uniformly, the solvent is removed, and then dispersed in water. Bye. If the solvent used is one that is acceptable for administration to living organisms, such as ethanol or propylene glycol, these do not need to be removed. Furthermore, the lipophilic drug-containing injectable preparation of the present invention can be made into a dry powder by freeze-drying, spray-drying, or the like, and then redispersed in water immediately before use.

Next, the present invention will be explained in further detail by showing Examples and Comparative Examples.

〔Example〕

Monomethoxypolyethylene glycol 5,000 (P
1.2 of 100g (manufactured by Union Carbide) to EG5
-Dissolved in 500 m4 of dichloroethane, further added 10 g of succinic anhydride and 8 m4 of pyridine, and refluxed at boiling point for 3 days under a nitrogen stream. After filtration and evaporation, 20
After dissolving in 0 mA distilled water and washing the aqueous phase with ether, it was extracted with 200 m chloroform (2). After evaporation, it was dissolved in 400 m ethanol (2) and hexane 9
A was purified by reprecipitation. The residue was collected by filtration and dried under vacuum to obtain 85.6 g of one-end carboxy PEG 5K. 30 g of this, 7 g of hydrogenated soybean phosphatidylethanolamine, and 1.8 g of dicyclohexylcarbodiimide were dissolved in 50 m of chloroform (2) immediately after distillation by heating and reacted overnight at 50°C. After filtering, evaporation was carried out. Dissolved in ethanol, filtered off insoluble matter, and reprecipitated the solution in hexane. Filtered and vacuum-dried to obtain 34 g of PEG-bonded hydrogenated soybean phospholipid (H5PE-PEG5K). Obtained H
When a physiological saline solution of 3PE-PEG5 was administered intravenously to mice and its LD50 was determined by Purohit's method, it was found to be 11 g/kg body weight, indicating extremely low toxicity.

0.25 wt% aqueous solution of H3PE-PEG5 0.8
After adding 0.2 mff of washed domestic rabbit red blood cells with a hemoglobin concentration of 2.5% to m(l) and leaving it for 37°C for 24 hours,
After centrifugation at 3,000 r, p, m for 10 minutes, hemoglobin in the supernatant was quantified using the cyanmeth method to determine the hemolysis rate, which was 7%.

Retinol palmitate (vitamin A derivative) 50mg
, tocopherol acetate (vitamin E derivative) 300mg
, fetnadione (vitamin Kl) 40 mg, and H
2 g of 3PE-PEG5 was dissolved in 20 ml of ethanol, 80 ml of distilled water was added, and the mixture was mixed uniformly. The powder obtained by freeze-drying this was dispersed in 100 m4 of physiological saline.

The average particle size of this dispersion was measured using a dynamic light scattering particle size measuring device (Oita Denshi DLS-700) and was found to be 160 nm. It has passed.

[Comparative Example 1] Polyoxyethylene hydrogenated castor oil (trade name HCO-60
Physiological saline (manufactured by Nikko Chemicals Co., Ltd.) was intravenously administered to mice, and its LD50 was determined by the probit method, and was found to be 7 g/Kg body weight.

HCO-6C11O, 25% by weight physiological saline 0.8m (
2, rabbit washed red blood cells with a hemoglobin concentration of 2.5% and 0.
After adding 2 m12 and standing for 37°024 hours, 3
．． After centrifugation at 000 r, p, m for 10 minutes, hemoglobin in the supernatant was quantified and the hemolysis rate was determined using the cyanmeth method, and it was found to be 95%.

[Comparative Example 2] Retinol palmitate (vitamin A derivative) 50 mg
, tocopherol acetate (vitamin E derivative) 300mg
, 40 mg of fetnadione (vitamin Kl) and 2 g of hydrogenated egg yolk lecithin were dissolved in 20 mff of ethanol, and 80 mff of distilled water was added and mixed uniformly. The powder obtained by freeze-drying this was dispersed in 100 m4 of physiological saline.

The average particle size of this dispersion was measured using a dynamic light scattering particle size measuring device (Hibakuden DLS-700), and it was found to be 2200 nm, and this dispersion could not pass through a sterile membrane filter with a pore size of 0.2 μm. There wasn't.

[Effects of the Invention 1] As detailed above, in the lipophilic drug-containing injection preparation according to the present invention, the lipophilic drug that is difficult to dissolve in water is finely emulsified so that it can be administered into the blood vessels of a living body. In other forms of administration, fat-soluble drugs that are not absorbed by the body or require administration in large amounts can quickly exert their medicinal effects with a small amount of administration.

In addition, the polyethylene glycol-bound phospholipid used as an emulsifier in the present invention has low hemolytic toxicity and low toxicity when administered intravenously, so the lipophilic drug-containing injectable preparation according to the present invention does not require conventional surfactants. It is safer than the injectable preparation used.

Claims (6)

[Claims] (1) An injectable preparation containing a fat-soluble drug, which is a combination of a fat-soluble drug and an emulsifier formed by bonding polyethylene glycol to the functional group of a phospholipid. (2) Claim 1, wherein the functional group of the phospholipid is an amino group.
An injectable preparation containing a lipophilic drug as described above. (3) The lipophilic drug-containing injection preparation according to claim 2, wherein the phospholipid is phosphatidylethanolamine. (4) The lipophilic drug-containing injection preparation according to claim 3, wherein the phospholipid is hydrogenated natural phosphatidylethanolamine. (5) The average molecular weight of the polyethylene glycol is 1,
5. The injectable preparation containing a fat-soluble drug according to any one of claims 1 to 4, which has a molecular weight of 000 to 10,000. (6) The injectable preparation containing a fat-soluble drug according to any one of claims 1 to 5, wherein the fat-soluble drug is a fat-soluble vitamin.