JPH04164024A - Production of drug substance-containing self-emulsifiable type fat emulsion composition - Google Patents

Abstract

PURPOSE:To obtain the title composition having fixed particle diameter without passing through a homogenizer by diluting a mixed solution of a vegetable oil, etc., a nonionic surfactant, a water-soluble nonaqueous solvent and a drug substance soluble in the solvent or the vegetable oil, etc., with water or transfusion. CONSTITUTION:A stock solution composed of a mixed solution comprising (A) 1-40V/V%, preferably 10-30V/V% vegetable oil and/or synthetic or semisynthetic mono-triglyceride, (B) 30-250 pts., preferably 50-80 pts. based on 100 pts. component A of a nonionic surfactant, (C) a proper amount of a water-soluble nonaqueous solvent and (D) a proper amount of a drug substance soluble in the component A or the component C is diluted with water or transfusion by about 10-50 times to give the title composition having fixed particle diameter without requiring operation of homogenizer. By changing the ratio of the component A:B to 1:0.3-1:2.5, the average particle diameter of fats of the final composition can be adjusted to a desired size of about 0.03-0.3mum.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a method for producing a self-emulsifying fat emulsion composition containing a pharmaceutical substance, a liquid mixture used for preparing the composition, and a method for using the composition. This relates to a preparation kit.

[Prior Art] Fat emulsion compositions containing pharmaceutical substances have been developed and commercially available for intravenous administration for the purpose of nutritional support and drug administration to patients who have difficulty in administering them orally.

Embodiments of this pharmaceutical substance-containing fat emulsion composition include: (a) one prepared by incorporating a pharmaceutical substance into a fat emulsion in advance in the industrial manufacturing process of the composition; (b) a fat emulsion and a pharmaceutical substance; Two types are known: one in which a solution of a substance is mixed and prepared when necessary.

Specific examples of (a) include steroid fat emulsion (Japanese Patent Application Laid-Open No. 57-1518), biphenylpropionic acid derivative fat emulsion (Japanese Patent Application Laid-open No. 60-16923), prostaglandin E, fat emulsion (Japanese Patent Application Laid-Open No. 58-1988), -222014), etc. Although these examples are very pharmaceutically useful formulations, they have several drawbacks.

Firstly, unstable medicinal substances cannot be stored in fat emulsions for long periods of time.Secondly, since this preparation method involves homogenizing the medicinal substance and fat, it is difficult to store medicinal substances that are sensitive to shock. In other words, it cannot be applied.

Regarding the composition (b), Japanese Patent Application No. 63-507076
It is detailed in the issue. That is, a fat emulsion composition containing a medicinal substance is prepared by mixing a fat emulsion and a solution of a medicinal substance when necessary.

The composition overcomes at least the drawbacks listed in (a).

However, what both embodiments (a) and (b) have in common is that a homogenization operation is required in advance.

That is, in order to prepare a fat emulsion - for boat fishing,
It requires adding an emulsifier such as lecithin to vegetable oil and mechanically emulsifying it using an emulsifier. In this case, in order to obtain particles with a desired particle size, it is necessary to repeatedly homogenize once to several times using a high-pressure homogenizer such as a Manton-Gorlin or microfluidizer.

Therefore, in order to obtain such a composition, an industrial emulsifying device is required, and time and labor are also required.

Furthermore, the fat emulsion prepared here has the limitation that it must be physically stable for a long time and maintain a constant particle size.

[Problems to be Solved by the Invention] The present inventors have proposed a method of mixing and dissolving a vegetable oil, etc., a nonionic surfactant, a water-soluble non-aqueous solvent, and a medicinal substance soluble in the vegetable oil, etc. or the water-soluble non-aqueous solvent. The inventors have discovered that a self-emulsifying fat emulsion composition containing a pharmaceutical substance with a constant particle size can be obtained by diluting the solution with water or an infusion solution, and has completed the present invention.

That is, according to the present invention, a self-emulsifying fat emulsion composition containing a pharmaceutical substance with a constant particle size can be obtained without undergoing a homogenization operation in advance.

[Means to solve the problem] The present invention is.

(1) ■ Vegetable oil and/or synthetic or semi-synthetic mono-, di-, or mono-liglycerides, ■ nonionic surfactants, ■ water-soluble non-aqueous solvents, ■■ or ■ pharmaceuticals soluble in ■ Method 1 for producing a self-emulsifying fat emulsion composition containing a pharmaceutical substance, which comprises mixing substances and (2) diluting the mixed solution with water or an infusion solution.
This is related to this.

The present invention also provides the following: (1) ■ Vegetable oil and/or synthetic or semi-synthetic mono-, di-, or triglyceride; ■ Non-ionic surfactant; ■ Water-soluble non-aqueous solvent; (2) At the time of use, the mixture is mixed with water or infusion, etc.
The present invention relates to a ready-to-use kit for preparing a self-emulsifying fat emulsion composition containing a pharmaceutical substance.

The vegetable oil used in the present invention includes soybean oil, cottonseed oil, corn oil, sesame oil, olive oil, safflower oil, etc., but there is no restriction as long as it can be used for medicinal purposes, and soybean oil is particularly preferred. used for.

As the synthetic or semi-synthetic mono-, di-, or triglycerides, monocaprone, monocabrilin, monocaprin, cicabron, cicabrilin, cicapurin, tricaprone, tricabrilin, tricaprin, and mixed glycerides of these are used.

Nonionic surfactants include polyoxyethylene (hereinafter referred to as rPOEJ), sorbitan fatty acid ester, POE castor oil derivative oil conductor OE hardened castor oil conductor OE fatty acid ester, POE sterol ether,
POE-polyoxypropylene copolymer, polyglycerin fatty acid ester, etc. are used, but in particular, POE cured castor heavy oil polymer, OE sorbitan fatty acid ester, POE
OE-polyoxypropylene copolymer and the like are preferably used.

Examples of water-soluble nonaqueous solvents include N,N-dimethylacetamide (hereinafter referred to as rDMAJ), dimethyl sulfoxide (hereinafter referred to as rDMsOJ), polyalkylene glycols such as polyethylene glycol 200 or 400, propylene glycol, or glycerin. Polyhydric alcohols such as ethanol, alcohols such as propatool, etc. are used, and in particular, DMA, ethanol, polyethylene glycol 40
0 is preferably used.

The medicinal substance is not particularly limited as long as it is soluble in vegetable oil and/or synthetic or semi-synthetic mono-, di-, or triglycerides, or water-soluble non-aqueous solvents. Specific examples are described below.

Steroids include dexamethasone, dexamethasone palmitate, dexamethasone stearate, dexamethasone myristate, hydrocortisone, hydrocortisone palmitate, hydrocortiscin stearate, hydrocortisone myristate, prednisolone, prednisolone palmitate, prednisolone stearate, These include prednisolone myristate and progesterone.

As prostaglandins, prostaglandin A
I% prostaglandin E1, prostaglandin E1
, prostaglandin F1α, prostaglandin F,
α, prostaglandin I, derivatives thereof, etc. are used.

Fat-soluble vitamins include vitamin A1, vitamin A
2. Vitamin^3, vitamin island palmitate, vitamin C palmitate, vitamin 01, vitamin D, vitamin D1, vitamin 04, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, vitamin +, vitamin 2 , vitamin 1, vitamin 4, vitamin $, vitamin 6 and their derivatives may be used.

Anti-inflammatory drugs include ibuprofen, flufenamic acid,
Mefenamic acid, ketoprofen, indomethacin and derivatives thereof, etc. are used.

As antiviral drugs, acyclovir, interferon, azidothymidine, derivatives thereof, etc. are used.

Antibiotics include cephalosporins, penicillins, cephems, erythromycins, kixamycins, chloramphenicols, tetracyclines, streptomycins, kanamycins, and drugs that act on Durham-negative and Durham-positive bacteria. Oleandomycin-based, colistin-based, gentamicin-based, 2-dipekacin-based, lincomycin-based, lincomycin-based drugs and their derivatives are used, and amphotericin B and its derivatives are used as drugs that act on molds and protozoa. .

Anticancer drugs include hexamethylmelamine, daunorubicin, doxorubicin, daunomycin, ftorafur,
5-FU, pleomycin, methotrexate, actinomycin D, mitomycin C, chlorambucil, rhizoxin and derivatives thereof, etc. are used.

Anti-ulcer drugs include cimetidine, gefarnate and their derivatives.

Medications for arrhythmia include propranolol, ajmaline,
Verapamil, alprenolol, their derivatives, etc. are used.

As cardiotonic drugs, digoxin, desnoraside, G-strophanthin, isoproterenol, etilefrine, dopamine, ubidecarenone, and derivatives thereof, etc. are used.

As the vasodilator, oxyphethrin, carbochromene, dividamole, nitroglycerin, and their derivatives are used.

Dehydrocholic acid and its derivatives are used as choleretic agents.

Examples of physiologically active peptides that can be used include insulin, calcitonin, glucagon, ribocortin, atrial natriuretic peptide, erythroboetin, renin, angiotensin, kallikrein, various cytotoxic compounds, and fat-soluble derivatives thereof.

As the antioxidant, butylated hydroxytoluene, butylated hydroxyanisole, propyl corticate, salicylic acid, etc. are used.

(1) ■ Vegetable oil and/or synthetic or semi-synthetic mono-, di-, or triglyceride (hereinafter referred to as "■ liquid") ■ Nonionic surfactant containing phospholipid as necessary (hereinafter referred to as "■Liquid J") ■Water-soluble non-aqueous solvent (hereinafter referred to as "■Liquid") ■■ or ■mix a soluble pharmaceutical substance in ■; (2) the mixed liquid (hereinafter referred to as Diluting the stock solution (referred to as "stock solution") with water or an infusion solution is performed in the following manner.

The stock solution is 1 to 40 V/V%, preferably 10 to 30 V/V% of solution (1), and 30 to 250 parts, preferably 50 to 80 parts of solution (2) per 100 parts of solution (2), and an appropriate amount of (2). ) night, and consists of an appropriate amount of ■ medicinal substance.

If necessary, it is also possible to add phospholipids, emulsification aids, stabilizers, antioxidants, etc.

As the phospholipid, egg yolk lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidic acid, etc. are used.

Then, adjust the ratio of the above ■liquid:■liquid to 1:0.3 to 1:2.
．． 5, the average particle size of the fat in the final composition can be adjusted to a desired size of about 0.03 μm to 0.3 μm.

In the case of a heat-stable drug, the stock solution is dispensed into ampoules or vials and then heat sterilized by a conventional method.

When targeting heat-labile drugs, the stock solution should be diluted with 0.2
It is aseptically filtered using a μm membrane filter (Millibore FG, manufactured by Millibore), and prepared by aseptically subdividing into ampoules or vials.

By diluting these stock solutions approximately 10 to 50 times with water or an infusion solution such as 5% glucose solution or physiological saline before use, a self-emulsifying fat emulsion composition containing a pharmaceutical substance with a constant particle size can be obtained. can get things.

This composition does not need to be stable over long periods of time (
It serves its purpose if it is stable at least within the administration time.

The ready-to-use kit of the self-emulsifying fat emulsion composition containing a pharmaceutical substance of the present invention is used, for example, as follows.

As a pre-operation, the liquids (1), (2), (2) and the medicinal substances (3) are thoroughly mixed using a magnetic cooler or other suitable stirring device.

After mixing, the product is sterilized according to the method described above and sold as a stock solution, and when used, it is mixed with water or infusion according to the method described above to produce a self-emulsifying fat emulsion containing a pharmaceutical substance, which is the object of the present invention. A composition can be obtained.

The present invention will be explained in more detail below using Examples and Test Examples, but the present invention is not limited thereto.

Octyldecyl triglyceride (hereinafter referred to as ゛,
5 to 40 ml of "ODO") and POE 40 hydrogenated castor oil (trade name: Niracol HCO40, manufactured by Nikko Chemicals ■) as a nonionic surfactant. 12.
5g, dissolved in N,N-dimethylacetamide (hereinafter referred to as rDMAJ) as a water-soluble non-aqueous solvent, total amount 10
0 ml (hereinafter referred to as "undiluted solution ■").

1 ml of these various stock solutions with different ODO concentrations was
When added to +nl of water, fat emulsion compositions of various particle sizes were obtained.

Table 1 lists the compositions of the various stock solutions prepared. Table 1 Components\Stock solution A+ At Ax A4A
SOPO5ai115+nl 25ff1135+nl
40m1) IGO4012,5g Same left Same left Same left Same left DMA Total 100m1 Same left Same left Same left Same left 000:H(:040 1:2.5 1:0.
81:0.51:0.361:0.3100033.3
3.5g egg yolk lecithin, nilacol) 1cOIO
12g, nilacol) l(,0403g, and DMA
Various pharmaceutical substances soluble in DMA were dissolved in DMA, and the total amount was 100
ml (hereinafter referred to as "undiluted solution ■").

This stock solution 01ffi1 containing various medicinal substances was made in 2011.
When added to water, fat emulsion compositions of various particle sizes were obtained.

Table 2 lists the medicinal substances and amounts of the various stock solutions 0 prepared.

Table 2 Stock solution Pharmaceutical substance Compounding amount C%) B1
Dexamedasone acetate 0.582 Cefmetazole 1.0B, Rhizoxin
1.0B4 Chloramphenicol
1.0 Palmitate Bo Additive-free ~ Soybean oil 25g
, chive: l-71,) 20g of lcO20, and D
Various pharmaceutical substances soluble in MA were dissolved in DMA, and the total amount was 10
0ml (hereinafter referred to as "undiluted solution OJ").

20a+1 of this stock solution Q1m+1 containing various medicinal substances.
When added to water, fat emulsion compositions of various particle sizes were obtained.

Table 3 lists the medicinal substances and amounts of the various stock solutions O prepared.

Table 3 Stock solution Pharmaceutical substance Compounding amount C%) C3 prednisolone 1. OC2 Vitamin C Palmitate 1.0C1 Cefmetazole 1.
0C4 chloramphenicol/1.0 palmitate C0-free ~ 00025g, POE-polyoxypropylene copolymer (Pluronic F68: manufactured by Asahi Denka ■) 30g, and cefmetazole Ig or chloramphenicol as a DMA-soluble pharmaceutical substance 2 g of coal palmitate was dissolved in DMA to make a total volume of 100 ml.

When 1 ml of this stock solution was added to 20 ml of water, a fat emulsion composition was obtained.

Futachi■1 00025g, Ni: I-le HCO6017.5g
, 15 g of polyethylene gelicol 400 (Macrogol 400: manufactured by Nihon Yushi Sangyo ■) and 2 g of cefmetazole Ig or chloramphenicol as a medicinal substance were dissolved in DMA, and the total amount was dissolved in 1. I made it ooml.

When 1 ml of this stock solution was added to 20 ml of water, a fat emulsion composition was obtained.

The particle size of each composition prepared in Example 1 was determined by dynamic light scattering method (
Based on Otsuka Electronics Aji: DLS700. ).

Table 4 shows the results.

Table 4 Stock solution average particle size (nII+) distribution (stop)
A, 28 20-40A,
62 40~90A,
120 90-150A4247
100-450 A, 340 250-700 The average particle size shows linearity depending on the composition of the stock solution, and the distribution is also constant, so by changing the composition of the stock solution, it is possible to create a fat emulsion with a desired particle size. It was possible to obtain a composition.

Furthermore, the average particle size of the composition used in practical use is 200
nm or less, the stock solution A, ~A, (00,0
:HCO40=1.25-0.5) was shown to be useful.

The particle size of each composition prepared in Example 2 was measured in the same manner as in Test Example 1.

Table 5 Average particle size (nm) Stock solution Immediately after preparation 1 day after preparation B+
101 105Bz 12
2 120B, 100
100B4100 to.

8, 102 105 These results showed that a fat emulsion composition with a constant particle size could be obtained regardless of the presence or absence of the drug and the type, and that the particle size remained constant even after -8. .

Since the composition of the present invention is a ready-to-use type, its practicality was concluded from the fact that the particle size remained stable for days.

Trial 1 The particle size of each composition prepared in Example 3 was measured in the same manner as in Test Example 1. The results are shown in Table 6.

Table 6 Average particle size (nm) Stock solution Immediately after preparation One day after preparation C, 14114
0 C,196200 C,125125 C4125125 C,126126 Similarly to Test Example 2, a fat emulsion composition with a constant particle size can be obtained regardless of the presence or absence of the drug and the type, and -
It was shown that the particle size remained constant even after 8 hours.

Claims (1)

[Claims] 1. (1) [1] Vegetable oil and/or synthetic or semi-synthetic mono-, di-, or triglyceride, [2] Non-ionic surfactant, [3] Water-soluble non-aqueous A self-emulsifying fat emulsion composition containing a pharmaceutical substance, which comprises mixing a soluble pharmaceutical substance in a solvent, [4] [1] or [3], and (2) diluting the mixture with water or an infusion solution. manufacturing method. 2. (1) [1] Vegetable oil and/or synthetic or semi-synthetic mono-, di-, or triglyceride, [2] Non-ionic surfactant, [3] Water-soluble non-aqueous solvent, [4] [ A stock solution consisting of a medicinal substance soluble in [1] or [3]. 3. (1) [1] Vegetable oil and/or synthetic or semi-synthetic mono-, di-, or triglyceride, [2] Non-ionic surfactant, [3] Water-soluble non-aqueous solvent, [4] [ A self-emulsifying fat emulsion containing a medicinal substance is made by mixing (1) and (2) at the time of use, and (2) water or an infusion solution. A ready-to-use kit for preparing the composition.