JPS60239417A - Preparation of freeze-dried emulsion drug - Google Patents

Abstract

PURPOSE:To obtain the titled drug consisting of an easily soluble freeze-dried cake and containing redispersed oil droplets having sufficiently small size to enable the administration by intravenous injection, by dissolving a vehicle and a specific water-soluble polymer in the aqueous phase of an O/W-type emulsion, and freeze-drying the solution. CONSTITUTION:A vehicle (e.g. saccharide, urea, etc.) and a water-soluble polymer selected from PVA, polyvinyl pyrrolidone, low-molecular weight gelatin, PEG, etc. are dissolved in the aqueous phase of an O/W-type emulsion. The obtained aqueous solution is mixed with an oil (e.g. soybean oil, linoleic acid, etc.) preferably at a ratio of (30-15):1, emulsified, and freeze-dried to obtain the objective drug preparation. The dissolution of the water-soluble polymer in the aqueous phase is effective to prevent the coagulation of the emulsion particles in the freeze-drying process, and accordingly, the obtained cake has excellent appearance and solubility and gives an emulsion having oil particle diameter of <=2-3mum.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a preparation that is easily dissolved in a bath when redissolved and can reproduce an emulsion in which the diameter of oil droplets is several μm or less.

It is also known that emulsion oil droplets have characteristics such as lymphatic tropism and sustained release properties as drug storage. Utilizing this feature, any oil-soluble drug, including anticancer drugs, can be dissolved in O/W containing it in oil droplets.
Emulsions can be prepared into effective formulations.

As described above, the importance of O/W type emulsions in the pharmaceutical field has particularly increased in recent years. However, O/W emulsions themselves have poor physical stability, the chemical stability of the active ingredient contained in the oil droplets is poor, and furthermore, the emulsion structure may be destroyed when freezing occurs. It has its drawbacks. Therefore, it is expected that the above-mentioned drawbacks can be improved if a preparation that can reproduce a sufficiently fine emulsion by redissolving with water can be prepared. From this point of view, a powder product is known that easily becomes an emulsion upon reconstitution by freeze-drying an emulsion in which a skin-forming agent is dissolved in an aqueous phase (%Open 111852-12
No. 5615).

However, the emulsion obtained by re-emulsifying all products manufactured by this method has the disadvantage that its particle size is quite large, up to 500 pm, and furthermore, the solubility during re-emulsification is not necessarily good.

In other words, the particle size of emulsions for injection should generally be 7 μm or less (see Japanese Pharmacopoeia), and large oil droplets pose a serious risk of embolizing blood vessels, especially when used for intravenous injection. have.

Therefore, emulsion freeze-dried preparations prepared by conventionally known methods have limited applications, such as being unable to be used intravenously.

As a result of various studies on freeze-dried emulsion preparations, the present inventors discovered a method for producing a preparation in which the freeze-dried cake dissolves easily and the redispersed oil droplets are small enough to be used for intravenous administration, and have completed the present invention. did.

The feature of the present invention is that a specific water-soluble polymer is dissolved in the aqueous phase of the emulsion and then freeze-dried to prevent excipients forming a dry cake and agglomeration of emulsion particles during the freeze-drying process. . As a result, it is possible to obtain a freeze-dried product in which the appearance and solubility of the cake are improved by the excipient and the specific water-soluble polymer, and in which fine oil droplets can be redispersed.

Next, the manufacturing method of this JIIJ will be described. Excipients and water-soluble polymers are dissolved in advance in the aqueous phase, which is the continuous phase of the emulsion. The excipient used is not particularly limited as long as it can be administered to the human body and has physical properties that facilitate freeze-drying. Such excipients include sugars (
This is a good example. 5 to 4 of these excipients
It is made into an aqueous solution at a concentration of 0 w/w, preferably 18-20 w/w. The excipient aqueous solution thus obtained is further added to the water-soluble polymers such as polyvinyl alcohol (molecular Ji 300 to 3000), polyvinylpyrrolidone (
molecular weight 10000-1200000), low molecular weight gelatin (molecular weight 5000-20000), hydroxyprobyl cellulose (molecular weight 20000-100000)
), polyethylene glycol (molecular weight 4000-2
0000), dextran (molecule H1ooo.

~100000), methoxyethylene maleic anhydride copolymer (molecular weight 200000~150000G)
or cyclodextrin (molecule i1972~1zsy
) is dissolved at a concentration of 0.5 to SW/W%, preferably 1.2 to 2.5 W/V%.

The aqueous solution thus obtained was mixed with oil at a ratio of 50:1-10.
: 1, preferably 30:1 to 15:1 and emulsified. The oil used is not particularly limited as long as it is an injectable oil, and examples thereof include vegetable oils (soybean oil, sesame oil, olive oil, coconut oil, etc.), vegetable fatty acids (linoleic acid, oleic acid, etc.), and the like. Dissolve the drug in oil in advance. Drugs can be of any type as long as they are soluble in oil and poorly soluble in water; examples include control agents, antibiotics,
Examples include anti-inflammatory agents, antihistamines, agents for treating peptic fk wounds, and vitamin preparations.

Surfactants, which are emulsifiers, make O/W emulsions fA.
There is no particular choice as to the type as long as it is hydrophilic and suitable for #. Examples of such emulsifiers include holoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxycastor oil derivative, polyoxyethylene higher alcohol, polyoxyethylene di-noline derivative, holoxypropylene polyoxyethylene alkyl ether, Examples include polyoxyethylene alkyl phenyl ether and lecithin.

Emulsification is carried out to such an extent that the diameter of oil droplets in the emulsion is 1 μm or less. This is aliquoted into freeze-drying containers and freeze-dried using a normal freeze-drying program. A normal program is a program that can freeze-dry an aqueous solution containing only excipients.

The appearance of the completed freeze-dried cake was good, and the amount of liquid that was subdivided before freezing and f'! 1. When you add the same amount of water and mix gently, it dissolves quickly and becomes an emulsion toner. The diameter of the oil droplets in this emulsion is less than 2-3 μm.

The present invention will be explained in more detail with reference to Examples below.

Example 1 The formulations shown in Table 1 were mixed and emulsified using a Manton-Gorlin emulsifier at a pressure of about soO#/d. The emulsion particle size was 1 μm or less.

This emulsion was divided into 2 portions (liquid thickness 70) into vials. This was freeze-dried using a program that raised the temperature from -40℃ to +30℃ in about 15 hours (degree of vacuum = 0.0
A freeze-dried cake with a good quality of 2 torr) was obtained. When two tablespoons of water were added to this and the mixture was gently shaken, it was dissolved gently, and the emulsion particle size was uniform at 2 to 3 μm or less.

Example λ In Example 1, 2 vol of the anticancer drug ACNU was dissolved in advance in linoleic acid, and the other operations were the same. As a result, a product containing ACNU in the oil droplets and having the same results as in Example 1 was obtained.

Example 3゜In Example 1, 0.1% vitamin A was added to linoleic acid.
were mixed in advance, and the other operations were the same. As a result, a product containing vitamin A in the oil droplets and having the same results as in Example 1 was obtained.

Example 4 The same operation as in Example 1 was carried out for the formulation 11 [1] shown in Table 2. The external ml and quality of the product were the same as in Example 1.

Dioctyldodecyl triglyceride (fractionated from coconut oil) Reference Example 1 The same procedure as in Example 1 was carried out except that the low molecular weight gelatin was replaced with sodium carboxymethylcellulose in the formulation shown in Table 1. Although the appearance and solubility of the freeze-dried cake were good, the oil droplets of the redispersed emulsion had poor dispersibility and were unable to agglomerate.

Reference Example λ The same operation as in Example 1 was carried out except that the low molecular weight gelatin was replaced with gum arabic. The appearance and solubility of the freeze-dried cake are good, but the emulsion oil droplets have a particle size of 10 to 20.
Large ones of 1tm were mixed in.

Reference Example 3゜The low molecular weight gelatin of Example 1 was replaced with gelatin (molecular weight approximately 40
000) and the same operation was performed.

Although the appearance of the freeze-dried cake was good and the particle size of the redispersed emulsion was 2 to 3 μm or less, the solubility was poor.

Claims (1)

[Claims] In the method for producing emulsion freeze-dried preparations, excipients and polyvinyl alcohol, polyvinylpyrrolidone, low molecular weight gelatin, hydroxypropyl cellulose, polyethylene glycol, dextran, methoxyethylene, maleic anhydride copolymer are added to the aqueous phase of the 0/W emulsion. A method for producing a freeze-dried preparation, characterized by combining or dissolving two types of water-soluble molecules selected from cyclodextrins.