JP2004339231A - Method for producing drug-containing fat emulsion - Google Patents

Abstract

[PROBLEMS] To provide a method for producing a drug-containing fat emulsion which is particularly excellent in stability.
The drug is dexamethasone palmitate, prostaglandin E1, a derivative having prostaglandin E1 activity or 1-acetoxyethyl 2- (2-fluoro-4-biphenylyl) propionate, and the fat emulsion is vegetable oil or medium. It consists of chain fatty acid triglyceride, phospholipid, and water (however, only phospholipid is used as an emulsifier). 10 to 40 parts of phospholipid is used as an emulsifier for 100 parts of an oil component, dispensed into an ampoule or a vial, and rotated in an autoclave. A method for producing a drug-containing fat emulsion having an average particle diameter of 0.5 μm or less, which is performed by sterilization using the above method.
[Selection diagram] None

Description

  The present invention relates to a method for producing a drug-containing fat emulsion having excellent stability.

Conventionally, a fat emulsion composed of vegetable oil, phospholipid and water has been used as a unique drug carrier (drug carrier). This drug carrier has specific affinity for inflammatory sites, vascular endothelial system, atherosclerotic site, reticuloendothelial system, especially tissues with developed phagocytic cells (liver, spleen, etc.), and macrophages, and should be taken up by them. Is characterized in that the effect of the drug is maximized locally in those areas. That is, it has been proved that the effect is exhibited by the drug being taken up and accumulated in a site where a large number of phagocytic cells such as an inflammatory site and a cancer site exist, and the effect is maintained by the retention (Patent Document 1).
U.S. Pat.No. 4,073,943

  An object of the present invention is to provide a method for producing a drug-containing fat emulsion, which is particularly excellent in stability.

The above object is achieved by the present invention described below. That is, the present invention is as follows.
(1) The drug is dexamethasone palmitate, prostaglandin E1, a derivative having prostaglandin E1 activity or 1-acetoxyethyl 2- (2-fluoro-4-biphenylyl) propionate, and the fat emulsion is vegetable oil or medium chain It is composed of fatty acid triglyceride, phospholipid and water (however, only phospholipid is used as emulsifier). 10 to 40 parts of phospholipid are used as emulsifier for 100 parts of oil component, dispensed into ampoules or vials, and rotated autoclave A method for producing a drug-containing fat emulsion having an average particle size of 0.5 μm or less, wherein the emulsion is subjected to a sterilization treatment.
(2) The method for producing a drug-containing fat emulsion according to the above (1), wherein the volume is 5 to 10 mL.
(3) A drug-containing fat emulsion having an average particle size of 0.5 μm or less prepared by the production method described in (1) above.
(4) The drug-containing fat emulsion according to the above (3), which has a volume of 5 to 10 mL.

  The drug-containing fat emulsion of the present invention has substantially no oil droplets after the sterilization treatment. In particular, even in the case of a large volume of 5 mL or more in which oil droplets are easily formed after the sterilization treatment, this characteristic is remarkably exhibited. Things. Therefore, according to the present invention, a drug-containing fat emulsion having particularly excellent stability can be clinically provided.

  Examples of the fat emulsion according to the present invention include those mainly composed of medicinal ingredients, oil components (eg, vegetable oils such as soybean oil, sesame oil, cottonseed oil, and safflower oil), phospholipids, and water. More specifically, an effective amount of a medicinal ingredient, an oil component (eg, soybean oil) of 1 to 50% (w / v), preferably 5 to 20% (w / v), and a phospholipid with respect to 100 parts of the oil component Those mainly composed of 1 to 50 parts (preferably 10 to 40 parts) and an appropriate amount of water are exemplified.

  In addition, if necessary, an emulsifying aid [for example, a fatty acid having 6 to 22 carbon atoms, preferably 12 to 20 carbon atoms or a pharmacologically acceptable salt thereof in an amount of up to 0.3% (w / v), Alternatively, 0.0001 to 0.1% (w / v) aliphatic amine or the like], a stabilizer [for example, 0.5% (w / v) or less, preferably 0.1% (w / v)] Cholesterol in the following amount, or phosphatidic acid in an amount of 5% (w / v) or less, preferably 1% (w / v) or less]; 1 to 5 parts by weight (preferably 0.5 to 1 part by weight) of albumin, dextran, vinyl polymer, nonionic surfactant, gelatin, hydroxyethyl starch and the like], tonicity agent (for example, glycerin, Glucose, etc.) can also be added.

There is no particular limitation on the medicinal component according to the present invention, and a wide variety of medicinal components can be used. Specifically, prostaglandin _{(E 1, E 2, F} 1 α, F 2 α, A 1, I 2, B 1, D 2 , etc.), steroidal anti-inflammatory agents (dexamethasone, hydrocortisone, prednisolone, Betamethasone, triamcinolone, methylprednisolone, etc.), non-steroidal anti-inflammatory drugs (indomethacin, acemetacin, flurbiprofen, aspirin, ibuprofen, flufenamic acid, ketoprofen, etc.), anticancer drugs (5-fluorouracil, adriamycin, spadicomycin, benzoylurea) system compound, daunomycin, bleomycin, etc.), vitamins (A, K, E, D , CoQ 10 , etc.), radioactive isotopes ^(99m Tc, etc.), antibiotics (cephalosporins, penicillins and the like), antiviral agents ( Interferon, etc.), immunosuppressants (cyclocross poly) Etc.) and derivatives thereof.

Particularly preferred in the context of the present invention are the PGE ₁ classes. While PGE ₁ compounds is not particularly limited as long as it has the PGE ₁ activity, it may be a large derivative lipophilic than PGE _1. The PGE _1, such (see JP 58-222014 Laid) PGE _1, (see JP-A-59-216820) PGE ₁ alkyl esters, PGE ₁ alkoxycarbonylalkyl esters or PGE ₁ acyloxyalkyl esters ( JP-A-59-206349; 7-thia PGE ₁ (see JP-A-58-110562); 9-enol acylate type (JP-A-58-39660; JP-A-3-204853) Gazette, JP-A-5-213682).

  The content of the medicinal component in the fat emulsion can be appropriately increased or decreased depending on the kind of the medicinal component, the form and use of the emulsion, and the like.

  As the oil component according to the present invention, vegetable oil, generally high-purity refined soybean oil, preferably high-purity refined soybean oil obtained by further purifying refined soybean oil by a steam distillation method or the like (purity: triglyceride, diglyceride and monoglyceride) 99.9% or more) or medium-chain fatty acid triglyceride (MCT).

  Examples of the phospholipids according to the present invention include egg yolk phospholipids, soybean phospholipids, and those obtained by subjecting these phospholipids to a hydrogenation treatment. In particular, these purified phospholipids are preferably used. This purified product can be prepared by a conventional method by a fractionation method using an organic solvent. It is mainly composed of phosphatidylcholine and phosphatidylethanolamine, and also contains other phospholipids such as phosphatidylinositol, phosphatidylserine, sphingomyelin and the like. Further, a phospholipid containing no phosphatidylethanolamine may be used.This is a method using a phospholipid such as egg yolk and soybean, and after performing an organic solvent fractionation by a conventional method, an inorganic adsorbent such as silica gel and alumina is used. And purified by The thus obtained phospholipid mainly consists of phosphatidylcholine (see JP-A-60-149524). Further, phosphatidylcholine itself can be used as the phospholipid.

  In the present invention, a known emulsifying aid in this field can be added, if necessary. For example, up to 0.3% (w / v) of a fatty acid having 6 to 22, preferably 12 to 20 carbon atoms or a pharmaceutically acceptable salt thereof, or 0.0001 to 0.1% (w / v). w / v) aliphatic amines and the like can also be added. The fatty acid is not particularly limited as long as it can be added to pharmaceuticals, and may be linear or branched.Specifically, linear stearic acid, oleic acid, linoleic acid, palmitic acid, It is preferable to use linolenic acid, myristic acid and the like. Examples of these salts include pharmacologically acceptable salts such as alkali metal salts (sodium salt, potassium salt, etc.) and alkaline earth metal salts (calcium salt, magnesium salt, etc.). The aliphatic amine as an emulsifying aid according to the present invention is not particularly limited as long as it can be added to a drug, and is, for example, a linear or branched primary amine having 2 to 22 carbon atoms, a secondary amine. Amines are exemplified, and specifically, ethylamine, propylamine, octylamine, stearylamine, oleylamine and the like are exemplified as preferred.

  Cholesterol, phosphatidic acid and the like as stabilizers according to the present invention are not particularly limited as long as they can be used for medicine.

  As the albumin as the polymer substance according to the present invention, a human-derived one is preferable from the viewpoint of antigenicity.

  Examples of the vinyl polymer as the polymer substance according to the present invention include polyvinyl pyrrolidone and polyvinyl alcohol.

  Examples of the nonionic surfactant as the polymer substance according to the present invention include polyalkylene glycol (for example, polyethylene glycol having an average molecular weight of 1,000 to 10,000, preferably 4,000 to 6,000), polyoxyalkylene. Copolymer (for example, polyoxyethylene-polyoxypropylene copolymer having an average molecular weight of 1,000 to 20,000, preferably 6,000 to 10,000), hydrogenated castor oil polyoxyalkylene derivative [for example, hydrogenated castor Oil polyoxyethylene- (20) -ether,-(40) -ether,-(100) -ether, etc.), castor oil polyoxyalkylene derivative [for example, castor oil polyoxyethylene- (20) -ether, -(40) -ether,-(100) -ether, etc.] It can be.

  The fat emulsion according to the present invention is prepared by a known method (such as the method described in JP-A-58-222014). An example is shown below. That is, a predetermined amount of an oil component (for example, soybean oil), phospholipids and other additives described above are mixed by heating or at room temperature using a conventional homogenizer (for example, a high-pressure injection homogenizer, an ultrasonic homogenizer, etc.). By doing so, a homogeneous oil phase is prepared. Then, a necessary amount of water is added, and the mixture is homogenized again with the homogenizer to prepare an oil-in-water emulsion. Depending on the production convenience, additives such as a stabilizer and a tonicity agent may be added after the formation of the fat emulsion. Depending on the solubility of each drug, water-soluble drugs can be added by dissolving in an aqueous phase, and fat-soluble drugs can be added by suspending or dissolving in an oil phase.

  The drug-containing fat emulsion thus produced is extremely fine, and the average particle size of fat particles is 0.5 μm or less.

  After the emulsification treatment, a sterilization treatment by a high-pressure heat treatment method is performed. Even by such treatment, the drug in the emulsion of the present invention is stable and the particle size is constant.

The drug-containing fat emulsion of the present invention is characterized in that substantially no oil droplets are formed after the sterilization treatment by the high-pressure heat treatment method (or no oil droplets are formed after the sterilization treatment). Such a drug-containing fat emulsion can be obtained by carrying out the production thereof preferably under the following conditions 1) and / or 2).
1) A rotary autoclave is used for sterilization by the high-pressure heat treatment method.
2) The heat treatment is performed at 100 to 130 ° C (preferably 115 to 128 ° C) for about 1 to 30 minutes (preferably 2 to 20 minutes).

  In addition, since fat emulsions tend to form oil droplets after sterilization treatment and are inferior in stability to large-capacity fat emulsions, the present invention relates to fat emulsions having such a large capacity, specifically, those having a volume of 5 mL or more. Is particularly useful when

  The drug-containing fat emulsion according to the present invention is administered parenterally by injection or the like (for example, intravenous administration, intraarticular administration, or intramuscular administration), particularly preferably intravenous administration.

Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.
Example 1
Take 30 g of refined soybean oil and 240 mg of dexamethasone palmitate as the oil phase, 7.5 g of glycerin Japanese Pharmacopoeia and 100 g of distilled water for injection as the aqueous phase, mix 3.6 g of egg yolk phospholipid as an emulsifier, and use a homomixer. To perform coarse emulsification. Further, this was emulsified using a Manton-Gaurin type homogenizer under a total pressure of 500 kg / cm ² to obtain a homogenized extremely fine fat emulsion, and an appropriate amount of distilled water for injection was added. The total volume was 300 mL. Then, after adjusting the pH to 6.5 to 8.5, 5 mL was dispensed into ampoules or vials, and subjected to high-pressure steam sterilization at 125 ° C. for 2 minutes using a rotary autoclave (4 rpm). The emulsion had substantially no oil droplets and had an average particle size of 0.5 μm or less.

Example 2
The procedure was substantially the same as that of Example 1 except that 1.5 mg of PGE ₁ was used instead of dexamethasone palmitate of Example 1 and 5.4 g was used instead of 3.6 g of yolk phospholipid. As a result, a very fine fat emulsion homogenized (adjusting the pH to 4.5 to 6.0 and dispensing 5 mL each) was obtained. The emulsion had substantially no oil droplets and had an average particle size of 0.5 μm or less.

Example 3
The procedure of Example 1 was followed except that 1 g of 1-acetoxyethyl 2- (2-fluoro-4-biphenylyl) propionate was used instead of dexamethasone palmitate of Example 1. As a result, a very fine fat emulsion homogenized (adjusting the pH to 4.5 to 6.5 and dispensing 10 mL each) was obtained. The emulsion had substantially no oil droplets and had an average particle size of 0.5 μm or less.

Example 4
After dissolving 100 g of egg yolk phospholipid in 600 mL of a mixed solvent of chloroform-methanol (1: 1), 600 g of alumina was added with stirring. After stirring for 5 minutes, suction filtration was performed using a G4 glass filter, and the separated alumina was washed with 400 mL of a mixed solvent of chloroform and methanol. 200 g of alumina was newly added to the combined filtrate and washing solution with stirring. After stirring for 5 minutes, suction filtration was performed using a G4 glass filter, and the separated alumina was washed with a chloroform-methanol mixed solvent (200 mL). After combining the filtrate and the washing solution, the mixture was centrifuged at 4 ° C. at 10,000 rpm for 10 minutes. The supernatant was suction-filtered with a 1.0 μmillipore filter, and the solvent was distilled off to obtain 60 g or more of phospholipid (substantially no phosphatidylethanolamine was contained). The method of Example 2 was followed except that the purified phospholipid obtained as described above was used instead of the egg yolk phospholipid of Example 2. As a result, a very fine fat emulsion homogenized (adjusting the pH to 4.5 to 6.0 and dispensing 10 mL each) was obtained. The emulsion had substantially no oil droplets and had an average particle size of 0.5 μm or less.

Example 5
According to the method of Example 2, the PGE ₁ was prepared fat emulsion of the following composition was added 50μg per ampoule.
PGE ₁ 50 μg
Refined soybean oil 1000mg
Highly purified egg yolk phospholipid 180mg
Oleic acid 24mg
Concentrated glycerin 221mg
Distilled water for injection qs 10ml
The emulsion had substantially no oil droplets, and had a pH of 4.5 to 6.0 and an average particle size of 0.5 μm or less.

Example 6
According to the method of Example 2, the PGE ₁ was prepared fat emulsion of the following composition was added 25μg per ampoule.
PGE ₁ 25 μg
500mg refined soybean oil
Highly purified yolk phospholipid 90mg
Oleic acid 12mg
Concentrated glycerin 110.5mg
Distilled water for injection qs 5ml
The emulsion had substantially no oil droplets, and had a pH of 4.5 to 6.0 and an average particle size of 0.5 μm or less.

Claims (4)

  The drug is dexamethasone palmitate, prostaglandin E1, a derivative having prostaglandin E1 activity or 1-acetoxyethyl 2- (2-fluoro-4-biphenylyl) propionate, and the fat emulsion is vegetable oil or medium-chain fatty acid triglyceride; It is composed of phospholipid and water (however, only phospholipid is used as an emulsifier). 10 to 40 parts of a phospholipid is used as an emulsifier for 100 parts of an oil component, dispensed into ampoules or vials, and sterilized using a rotary autoclave. A method for producing a drug-containing fat emulsion having an average particle size of 0.5 μm or less, characterized by performing a treatment.   The method for producing a drug-containing fat emulsion according to claim 1, wherein the volume is 5 to 10 mL.   A drug-containing fat emulsion having an average particle size of 0.5 μm or less, prepared by the production method according to claim 1.   The drug-containing fat emulsion according to claim 3, having a volume of 5 to 10 mL.