JPH0543450A - Lyophilized formulation - Google Patents

Abstract

(57) [Summary] [Purpose] An object is to provide a stabilized preparation of a fat emulsion useful as a drug carrier. [Structure] A freeze-dried preparation of a fat emulsion containing a drug, an oil component, an emulsifier and water. The freeze-dried preparation of the present invention is excellent in storage stability, and has an effect that it can be stored at room temperature, unlike conventional liquid-type fat emulsions.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a freeze-dried preparation, and more particularly to a freeze-dried preparation of a drug-containing fat emulsion.

[0002]

2. Description of the Related Art Conventionally, a drug carrier has been used for accumulating and retaining a drug administered to a living body at a specific site. Fat emulsions consisting of vegetable oils, phospholipids and water have also been used as unique drug carriers. The characteristics of fat emulsions as drug carriers are that they have a specific affinity for the onset site, reticuloendothelial system, especially phagocytic cells (macrophage, liver parenchymal cells, etc.). There is a point to blame. That is, it has been proved that the drug is taken up and accumulated in a site where many phagocytic cells are present such as an inflammatory site or a cancer site, and that the effect is retained and the effect is retained for a long time.

[0003]

The drug-containing fat emulsion is supplied in a liquid state, and in order to stabilize the fat emulsion,
Usually, the storage is required to be performed at a cold temperature. Therefore, it is necessary to control the temperature during transportation and storage, and there is a problem that handling is complicated. From such a problem, a drug-containing fat emulsion which has excellent storage stability and can be stored even at room temperature has been desired.

[0004]

Means for Solving the Problems The present invention has been made to solve the above problems, and the inventors of the present invention have made diligent studies to improve the storage stability of drug-containing fat emulsions. The present invention has been completed by finding that lyophilization of the product significantly improved the stability, could be stored at room temperature, and had no particular problem when redissolved at the time of use. That is, the freeze-dried preparation of the present invention is a freeze-dried preparation obtained by freeze-drying a fat emulsion consisting of a drug, an oil component, an emulsifier and water.

In the present invention having the above-mentioned constitution, the drug is not particularly limited as long as it can be applied to a fat emulsion, and various various drugs can be used. More specifically, for example, prostaglandins (PG) (for example, PGE ₁ , PGE ₂ , PGF ₁ α,
PGF ₂ α, PGA ₁ , PGI ₂ , PGB ₁ , PGD
₂ etc.), steroidal anti-inflammatory agents (for example, dexamethasone, hydrocortisone, prednisolone, betamethasone, triamcinolone, methylprednisolone, etc.), non-steroidal anti-inflammatory agents (for example, indomethacin, acemethacin, flurbiprofen, aspirin, ibuprofen, Flufenamic acid, ketoprofen, etc.), anticancer drug (eg, 5-fluorouracil, adriamycin,
Spadicomycin, benzoylurea compounds, daunomycin, bleomycin, etc.), vitamins (eg, vitamin A, vitamin K, vitamin E, vitamin D, CoQ ₁₀ etc.), antibiotics (eg, cephalosporins, penicillins, etc.) ), Immunosuppressants (for example, cyclosporin, etc.) and their derivatives.

In the present invention, the fat emulsion is mainly composed of
An oil component, an emulsifier, a drug and water are exemplified, and the content of each component in this example is, for example, 1 to 50 (W / V%) oil component, an emulsifier relative to 100 parts of the oil component 1
~ 500 parts, preferably 5-30 parts, and an appropriate amount of water.
The content of the drug in the fat emulsion can be appropriately increased or decreased depending on the form of the emulsion, the intended use, the dose, the administration form and the like. Further, if necessary, an emulsification aid [for example, a fatty acid having 6 to 22, preferably 12 to 20 carbon atoms in an amount up to 0.3 (W / V%) or a physiologically acceptable salt thereof, etc.], a stabilizer [For example,
0.5 (W / V%), preferably 0.1 (W / V%) or less cholesterol, or 5 (W / V%), preferably 1 (W / V%) or less phosphatidic acid etc.] , Polymeric substances (for example, 0.5 to 5 parts by weight, preferably 0.5 to 1 parts by weight of albumin, dextran, vinyl polymer, gelatin, hydroxyethyl starch, etc., per 1 part by weight of drug), particle stabilizers (for example, , Non-reducing sugars such as xylitol, sucrose, raffinose)
Etc. can also be added.

As the above-mentioned oil component, any of various oil components used in the preparation of medical fat emulsions can be used. For example, vegetable oil (eg, soybean oil, cottonseed oil, safflower oil, corn oil, etc.) can be used. ), Fish oil (for example, cod liver oil, etc.), medium-chain fatty acid triglyceride [triglyceride of constituent fatty acid having 8 to 10 carbon atoms (also referred to as MCT), for example, panacetate (trade name), ODO (trade name), etc.] And two or more of these may be used in combination. Preferred oil components include vegetable oils, especially soybean oil.
As soybean oil, highly purified refined soybean oil is preferably used,
More preferably, high-purity purified soybean oil (purity: 99.9% as triglyceride, diglyceride and monoglyceride) obtained by further refining purified soybean oil by, for example, a steam distillation method.
The above content) is used. It may also be a mixture of soybean oil and MCT.

As the emulsifier, any emulsifier can be used as long as it is an emulsifier used in pharmaceutical preparations. Examples thereof include phospholipids and nonionic surfactants, which may be used alone or in combination. Good. Phospholipids are preferably used. As phospholipids, egg yolk lecithin,
A purified phospholipid such as soybean lecithin is suitable, and can be prepared by a conventional fractionation method using an organic solvent.
That is, for example, crude egg yolk phospholipids are dissolved in cold n-hexane-acetone, acetone is gradually added with stirring, unnecessary substances are collected by filtration, and this operation is repeated once more, and then the solvent is distilled off. Purified phospholipid can be obtained by removing. It is mainly composed of phosphatidylcholine and phosphatidylethanolamine, and also contains phosphatidylinositol, phosphatidylserine, sphingomyelin and the like as other phospholipids.

As the phospholipid, one containing no phosphatidylethanolamine may be used. This product can be obtained by subjecting commonly available phospholipids such as egg yolk and soybean to organic solvent fractionation by a conventional method and then purifying with an inorganic adsorbent such as silica gel or alumina. The phospholipid thus obtained is mainly composed of phosphatidylcholine, and may contain phosphatidylinositol, phosphatidylserine, and sphingomyelin as other phospholipids. Furthermore, phosphatidylcholine itself may be used.

As the nonionic surfactant, a polyalkylene glycol (for example, an average molecular weight of 1000 to 10) is used.
000, preferably 4000-6000 polyethylene glycol), polyoxyalkylene copolymer (e.g., polyoxyethylene-polyoxypropylene copolymer having an average molecular weight of 1000-20000, preferably 6000-10000), hydrogenated castor oil polyoxy Alkylene derivatives [eg hydrogenated castor oil polyoxyethylene- (40) -ether, same- (20) -ether, same- (100) -ether, etc.], castor oil polyoxyalkylene derivative [eg castor oil polyoxyethylene -(20) -ether, same- (40) -ether, same- (100)
-Ether and the like] can be used.

If the above emulsifier is insufficiently emulsified, an emulsification aid is used. 6 to 22 carbon atoms as emulsification aid
Any of these fatty acids can be used as long as they can be added to pharmaceutical products. This fatty acid may be linear or branched, but linear stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid, etc. are preferably used. As these salts, physiologically acceptable salts such as alkali metal salts (eg sodium salt, potassium salt etc.), alkaline earth metal salts (eg calcium salt etc.) and the like can be used.

Further, an aliphatic amine may be used as an emulsification aid. Specifically, those having 2 to 22 carbon atoms are exemplified. Any of these aliphatic amines can be used as long as they can be added to pharmaceutical products. This aliphatic amine is linear,
Although it may be branched, it is preferable to use linear ethanolamine, propylamine, octylamine, stearylamine, oleylamine or the like. The amount added is, for example, about 0.0001 to 0.01 (W / V%).
Further, when the emulsification is insufficient, various known emulsification aids can be used.

Any stabilizer can be used as long as it can be used as a medicine. The following are preferred as albumin and vinyl polymer used as the polymer substance. That is, as the albumin, human-derived albumin is preferable from the viewpoint of antigenicity. Examples of the vinyl polymer include polyvinylpyrrolidone.

The freeze-dried preparation of the present invention is produced, for example, by the following method. First, a fat emulsion is prepared. That is, a predetermined amount of an oil component (preferably soybean oil), an emulsifier (preferably phospholipid), a drug, and the other additives described above are mixed, heated to form a solution, and a conventional homogenizer is used. After homogenization treatment, water containing a necessary amount of a tonicity agent / stabilizer and the like is added thereto, and homogenization is performed again by a homogenizer or ultrasonic treatment to obtain an oil-in-water emulsion. Depending on the production convenience, additives such as a stabilizer and a tonicity agent may be added after the fat emulsion is produced. The fat emulsion thus obtained is extremely fine, and the average particle size of its fat particles is about 0.05 to 0.5 μm or less.

Then, the fat emulsion obtained above is subjected to freeze-drying treatment to prepare a freeze-dried preparation. The freeze-drying treatment can be carried out according to a conventional method.For example, after the fat emulsion is filled in a suitable container and frozen, it is placed in a freeze-dryer which has been cooled to about -40 to -50 ° C in advance. It can be performed by vacuum freeze-drying for about 24 to 48 hours. The freeze-dried preparation thus obtained has very good storage stability and can be stored at room temperature. At the time of use, the lyophilized preparation of the present invention is dissolved in water for injection or the like and administered parenterally such as by injection, preferably intravenous administration.

[0016]

The freeze-dried preparation of the present invention has excellent storage stability, and unlike conventional liquid-type fat emulsions,
It can be stored at room temperature. In addition, re-dissolution at the time of use is relatively easy, and there is no particular problem with the emulsifying property of the emulsion after dissolution. Therefore, the present invention can provide a clinically useful preparation.

[0017]

EXAMPLES Examples will be given to explain the present invention in more detail, but the present invention is not limited thereto. Example 1 To 3 g of purified soybean oil, 0.6 g of egg yolk lecithin and 1.5 mg of PGE ₁ were added, and 25.7 g of sucrose was added thereto, and the total amount was made up to 300 ml with distilled water for injection. The mixture was homogenized using a homomixer as needed, and then emulsified using a Manton-Gaulin homogenizer under a pressure of 400 to 500 kg / cm ² . This gave a homogenized fat emulsion containing very fine PGE ₁ . The average grain size of this emulsion is 0.1-0.2 μm
Met. The emulsion thus obtained was filtered through a 0.45 μm membrane filter, then dispensed into a container and instantly frozen in a dry ice-ethanol bath. Then, it was freeze-dried in a pre-cooled freeze dryer at -40 ° C for 24 hours, at -20 ° C for 24 hours and at 0 ° C for 24 hours to prepare a freeze-dried preparation. When the thus obtained preparation was stored at room temperature for 3 months and then redispersed in distilled water for injection, it was easily redissolved and the emulsified state was good.

Example 2 After dissolving 100 g of egg yolk phospholipid in 600 ml of a chloroform-methanol (1: 1) mixed solvent, 600 g of alumina was added with stirring. After stirring for 5 minutes, suction filtration was performed with a G4 glass filter, and the separated alumina was washed with 400 ml of a chloroform / methanol mixed solvent. To the combined filtrate and washing solution, 200 g of alumina was newly added with stirring. After stirring for 5 minutes, suction filtration with a G4 glass filter was performed and the separated alumina was 200 ml of a chloroform / methanol mixed solvent.
Washed with. After combining the filtrate and washing solution, 10,000 rpm at 4 ℃
Centrifuged at m for 10 minutes. The supernatant was suction filtered with a Millipore filter (pore size 1.0 μ), and the solvent was distilled off to obtain 60 g or more of phospholipids free of phosphatidylethanolamine (phosphatidylethanolamine content was 0.4% or less. ). Refined soybean oil as oil phase 3
g, PGE ₁ 1.5 mg and oleic acid 0.024 g, sucrose 25.7 g and distilled water for injection 100 g as an aqueous phase, and the purified phospholipid 0.6 g obtained above as an emulsifier are mixed, and the total amount is 300 ml, and a homomixer is prepared. Was used for rough emulsification.
Furthermore, this was emulsified for 10 minutes using a Manton-Gaulin homogenizer under a total pressure of 500 kg / cm ² . This gave a homogenized, very fine fat emulsion containing PGE ₁ . The average grain size of this emulsion is 0.1-0.2 μm
Met. Then, it was freeze-dried in the same manner as in Example 1 to obtain a freeze-dried preparation.

Example 3 A fat emulsion was prepared in the same manner as in Example 1 except that 12 mg of dexamethasone palmitate was used in place of PGE ₁ in Example 1 and 3 g of egg yolk phospholipid was used. This gave a homogenized very fine fat emulsion. The average grain size of this emulsion was 0.1 to 0.2 μm. Then, it was freeze-dried in the same manner as in Example 1 to obtain a freeze-dried preparation.

Example 4 1-acetoxyethyl = 2- (2 instead of PGE ₁ in Example 1
A fat emulsion was prepared in the same manner as in Example 1 except that 1 mg of -fluoro-4-biphenylyl) propionate and 3 g of egg yolk phospholipid were used. Then, it was freeze-dried in the same manner as in Example 1 to prepare a freeze-dried preparation.

Claims (2)

[Claims] 1. A freeze-dried preparation obtained by freeze-drying a fat emulsion consisting of a drug, an oil component, an emulsifier and water. 2. The freeze-dried preparation according to claim 1, wherein the oil component is soybean oil and the emulsifier is phospholipid.