JPH09136836A - Pge1-containing lyophilizing preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject pharmaceutical preparation having bacteriologically or thermally excellent stability or excellent stability with the lapse of time and useful for preparation of a high-quality medicine containing prostaglandin E1 (PGE1 ). SOLUTION: This preparation is obtained by lyophilizing a fat emulsion (preferably fat emulsion particles having preferably 5-70μm average particle diameter) containing (A) PGE1 , (B) oil component (preferably vegetable oil or triglyceride), (C) an emulsifier (preferably phospholipid or nonionic surfactant) and (D) water and having a liquid property (pH) in a neutral region (preferably pH 6.5-7.5). The content of the component B is preferably 0.1-30(W/V)% and the content of the component C is preferably 0.01-30(W/V)% and a weight ratio of the components B/C is preferably 0.8-1.2. The preparation contains further preferably 1-30(W/V)% saccharides (preferably maltose) and further contains preferably a fatty acid and/or cholesterol.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a freeze-dried preparation containing prostaglandin E ₁ (hereinafter referred to as “PGE ₁ ”).

[0002]

2. Description of the Related Art PGE ₁ is a useful drug for the treatment of chronic arterial occlusion (occlusive thrombosis (TAO), arteriosclerosis obliterans (ASO)) due to its strong vasodilatory effect and platelet aggregation inhibitory effect. Are known. However, since PGE ₁ is rapidly inactivated in the pulmonary circulation, continuous arterial therapy, intravenous continuous drip infusion, and large-dose administration, which are difficult to perform in clinical applications, have been attempted. Side effects such as lowering blood pressure were unavoidable.

In recent years, in order to overcome the above-mentioned drawbacks of PGE ₁ and bring out its excellent effects, various studies have been made on its fat emulsion formation (JP-A-58-222014, JP-A-4-69340, JP-A-4-69340, Kaihei 4-338333 publication, JP-A-4-338334 publication,
JP-A-4-338335, etc.). Actually, JP-A-58-22201
The PGE ₁ fat emulsion according to Japanese Patent No. 4 is commercially available.

The commercially available PGE ₁ fat emulsion is a PGE ₁
Since PGE ₁ is encapsulated in emulsion particles, there is little inactivation of PGE _{1 in} the lungs, and in combination with the targeting effect on damaged blood vessel sites based on the biodistribution peculiar to microemulsion particles, powerful and sustained vasodilation is achieved. It is an excellent PGE ₁ preparation which has an action and has reduced local side effects such as improvement of irritation. However, the fat emulsion contained about 20% of the indicated PGE ₁ content value immediately after the production of PGE ₁ degradation product, and the PGE ₁ decreased by about 2.5% in one month even under the condition of storage at 5 ° C. It has been reported that (Kazuo Mizuguchi et al.
Basic and clinical, 26, 1647-1653 (1992)), and it seems that there is room for improvement in quality and stability.

[0005] PGE ₁ lyophilized formulation containing fat emulsion is considered as a means to ensure the PGE ₁ in the storage stability of the fat emulsion, it has been studied actually respect lyophilized formulation of fat emulsion (PCT W092 / 07552 Publication, Unexamined Japanese Patent Publication
5-43450 and JP-A-6-157294, etc.) have not yet been developed.

By the way, each drug has a stable liquidity (p
Unless there are special circumstances, there is H) region, and in order to maintain the stability of the drug, a pharmaceutical product is usually developed in the stable liquid region of the drug. PGE ₁ is known to be stable in the weakly acidic region (Pharmaceutical Resea
rch, vol.5, No.8, 482-487 (1988). PharmaceuticalR
esearch, vol.6, No.3, 210-215 (1989)), the above-mentioned fat emulsion which is actually commercially available also has a weak acidic region (pH 4.5 to
It has been adjusted to 6.0).

[0007]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a preparation for a high quality PGE ₁ -containing fat emulsion having excellent bacteriological or heat or time-dependent stability. is there.

[0008]

Means for Solving the Problems The present invention intensively studied, the change in thinking that the liquid property of PGE ₁ containing fat emulsion release the stable liquid region of PGE ₁ is adjusted to a neutral region At the same time, by freeze-drying the fat emulsion, fortunately, it is possible to find a formulation suitable for the above purpose,
The present invention has been completed. That is, the present invention is a PG
PGE ₁ derived from a fat emulsion containing E ₁ , an oil component, an emulsifier, and water and having a liquidity (pH) within the neutral range
The present invention relates to a freeze-dried preparation contained therein. Such PGE ₁
The freeze-dried preparation containing water is adjusted to pH 7.0 (for example, distilled water,
When it is reconstituted (reconstituted) with purified water, its liquidity shows substantially the same pH as the liquidity of the fat emulsion before lyophilization, although there is some variation. Therefore, the present invention is characterized in that it contains PGE ₁ , an oil component, and an emulsifier, and the liquidity (pH) immediately after reconstitution (restoration) with water having a pH of 7.0 is within the range of the neutral region. In other words, it relates to a freeze-dried preparation containing PGE ₁ .

Hereinafter, the present invention will be described in detail. Examples of the oil component according to the present invention include vegetable oils, animal oils, neutral lipids (mono-, di-, triglycerides), synthetic oils and fats, sterol derivatives, and the like. Specifically, soybean oil, cottonseed oil, as vegetable oils, Rapeseed oil, sesame oil, corn oil, peanut oil, safflower oil, etc., animal oil such as fish oil, neutral lipids such as triolein, trilinolein, tripalmitin, tristearin, trimyristin, triarachidonin, etc. as synthetic lipid. Examples of sterol derivatives of azone and the like include cholesteryl oleate, cholesteryl linoleate, cholesteryl myristate, cholesteryl palmitate, and cholesteryl arachidate. These may be two or more. Examples of preferable oil components include triglyceride and vegetable oils containing this as a main component. Practically preferred is soybean oil, and particularly preferred is refined soybean oil purified to high purity.

The content of the oil component in the fat emulsion before lyophilization and after re-dissolution varies depending on the type of the oil component and other constituents, but is preferably within the range of 0.1 to 30 w / v%. And is preferably in the range of 1 to 20 w / v%.

The emulsifier according to the present invention is not particularly limited as long as it is an emulsifier used in pharmaceutical preparations, and examples thereof include phospholipids and nonionic surfactants. Specific examples of phospholipids include phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, sphingomyelin and lecithin.
Also, hydrogenated phospholipids can be used.
Examples of the nonionic surfactant include polyalkylene glycol (e.g., polyethylene glycol having an average molecular weight of 1,000 to 10,000, preferably 4,000 to 6,000) and polyoxyalkylene copolymer (e.g., average molecular weight of 1,000 to 20,000, preferably 6,000 to 6,000). 10
000 polyoxyethylene-polyoxypropylene copolymer), hydrogenated castor oil polyoxyalkylene derivative (for example, hydrogenated castor oil polyoxyethylene- (20) -ether, the same- (40) -ether, the same- (100)) -Ether etc.) castor oil polyoxyalkylene derivative (for example, castor oil polyoxyethylene- (20) -ether, the same- (40)
-Ether, the same- (100) -ether and the like). These may be two or more. Preferable emulsifiers include egg yolk phosphatidylcholine, egg yolk lecithin and soybean lecithin. Practically preferred are egg yolk lecithin and soybean lecithin. In addition, in the present invention, commercially available phospholipids can sufficiently achieve the object of the present invention.

The content of the emulsifier in the fat emulsion before lyophilization and after re-dissolution varies depending on the type of emulsifier and other constituents, but is preferably in the range of 0.01 to 30 w / v%. , 0.1 to 20 w / v% is preferable.

The weight ratio of the oil component and the emulsifier (oil component / emulsifier) is preferably in the range of 0.1 to 20,
The range of 4 to 6.0 is preferable, and the range of 0.8 to 1.2 (particularly 1) is more preferable. The ratio is 1
The combination in the vicinity has an excellent DDS (drug delivery system) effect, and can obtain a fat emulsion in which the average particle size of emulsion particles is 70 nm or less and which can be sterilized by filtration. The ratio is substantially the same after reconstitution as before lyophilization, regardless of the amount of reconstitution solution.

The water according to the present invention serves as a medium for emulsion particles or maintains the form of a fat emulsion, and as such water, generally, water for injection (distilled water for injection) can be mentioned.

The fat emulsion before lyophilization according to the present invention is most characterized in that its liquidity is adjusted to a neutral region in order to increase the stability of PGE ₁ in the lyophilized preparation. Here, the neutral region refers to a generally considered liquid region of around pH 7, specifically, a liquid region of pH 6.5 to 7.5, preferably a liquid region of pH 6.7 to 7.3. The area can be mentioned. For adjusting the pH, a pH adjusting agent generally used in pharmaceutical preparations can be used.
Examples of pH adjusters include inorganic acids, inorganic bases, organic acids, organic bases, and buffers. Specific examples include hydrochloric acid, sulfuric acid, phosphoric acid, boric acid, citric acid, succinic acid, acetic acid, sodium hydroxide, potassium hydroxide, potassium hydrogen carbonate, sodium carbonate, triethanolamine, and phosphate buffer. You can However, depending on the type and content of the oil component, emulsifier, etc. used, it may be in the neutral range without the use of a pH adjuster, and in this case it is not necessary to adjust the pH. The liquidity immediately after reconstitution of the freeze-dried preparation according to the present invention with neutral water shows a pH substantially the same as the liquidity of the fat emulsion before freeze-drying, though there are some fluctuations. It shows a pH within the range, specifically, within the range of pH 6.5 to 7.5 or pH 6.7 to 7.3.

PGE ₁ is an active ingredient of the preparation according to the present invention, and the content of PGE ₁ in the fat emulsion before lyophilization and after reconstitution is the same as the constituents of the fat emulsion according to the present invention and PGE.
₁ , 0.1 to 500 μg / m, depending on the application
The range of 1 is suitable, and the range of 1 to 100 μg / ml is preferable.

In the present invention, an excipient (freeze-drying aid) can be added as necessary to protect the freeze-dried cake and the like. Examples of such excipients include sugars, amino acids, inorganic salts and the like. As sugars, monosaccharides,
Disaccharides, polysaccharides, sugar alcohols can be mentioned, specifically, glucose, fructose and the like as monosaccharides, maltose, lactose, sucrose, trehalose and the like as disaccharides, dextran, starch, malto as polysaccharides. Examples of sugar alcohols such as triose include mannitol, sorbit, glycerin, and the like.
Monosaccharides and disaccharides are preferable, and maltose is particularly preferable. When maltose is contained, it can be almost restored to a fat emulsion having the average particle size and particle size distribution of emulsion particles before lyophilization by re-dissolution. As an amino acid,
Examples thereof include glycine, and examples of the inorganic salt include sodium chloride and potassium chloride. These excipients are not limited to one type, and may be used in combination of several types at appropriate times. The inorganic salt, especially sodium chloride, can also suppress aggregation and fusion of the fat emulsion.

The content of the saccharide in the fat emulsion before lyophilization and after re-dissolution varies depending on the saccharide and other constituents, but is preferably in the range of 1 to 30 w / v% and 3 to 2
The range of 0 w / v% is preferable. The content of the amino acid in the fat emulsion before lyophilization and after re-dissolution varies depending on the amino acid and other constituents, but is appropriately in the range of 1 to 30 w / v%, and 3 to 20 w / v%. The range of is preferable. The content of the inorganic salt in the fat emulsion before lyophilization and after re-dissolution varies depending on the inorganic salt, other constituents, etc., but is preferably within the range of 0.5 to 5 w / v%.

Further, in the present invention, an emulsification aid or an emulsion stabilizer can be added if necessary. As these emulsification aids and emulsion stabilizers, linear or branched saturated or unsaturated fatty acids having 6 to 22 carbon atoms, specifically, stearic acid, oleic acid, linoleic acid, palmitic acid,
Linolenic acid, myristic acid and salts thereof (for example, alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, etc.), etc., having 2 to 22 carbon atoms
Primary aliphatic amine or secondary aliphatic amine, specifically, ethanolamine, propylamine, octylamine, stearylamine, oleylamine, etc., lysine,
Examples thereof include basic amino acids such as histidine, ornithine and arginine, sterols such as cholesterol and cholestanol, and charged substances such as phosphatidic acid, ganglioside and stearylamine. These are not limited to one type, and may be used in combination of several types as appropriate.

The content of these additives in the fat emulsion before lyophilization and after re-dissolution varies depending on the purpose, but is usually 2 w / v% or less, preferably 1 w / v% or less.
The object of the present invention can be sufficiently achieved without containing these additives.

In addition, additives such as antioxidants, preservatives, isotonicity agents, buffers, stabilizers and the like, auxiliary substances, nutritional substances and the like which can be used in pharmaceutical preparations can be added as required. . Specific examples include benzoic acid, ascorbic acid, tocopherol and the like. These can usually be contained in appropriate amounts, and 10 w / v% or less is sufficient.

The fat emulsion before lyophilization and after re-dissolution according to the present invention is composed of emulsion particles containing an oil component and an emulsifier as a main component, and PGE ₁ is considered to be included in the emulsion particles. . The emulsion grains are extremely fine,
The average particle size is in the range of 5 to 500 nm. However, those having an average particle diameter of 250 nm or less are preferable, and the average particle diameter is in the range of 5 to 70 nm, particularly 5 to 50 nm.
Those in the range of nm are more preferable. Those having an average particle size in the range of 5 to 70 nm can pass through a 0.2 μm membrane filter substantially 100%, and filtration sterilization can be sufficiently performed without using heat sterilization. When filter sterilization is adopted, the production of decomposed products derived from heat sterilization can be suppressed, and a formulation containing few impurities can be obtained. Since the sterilization power of filter sterilization is inferior to that of heat sterilization, the growth of bacteria is concerned, but the growth of bacteria can be sufficiently suppressed by using a freeze-dried preparation.

[0023]

BEST MODE FOR CARRYING OUT THE INVENTION The freeze-dried preparation according to the present invention comprises P
Liquid (p ₁₎ containing GE ₁ , oil component, emulsifier, water, etc.
It can be produced by freeze-drying a fat emulsion in which H) is within the neutral range by a conventional method. In addition,
The oil component, emulsifier, water, neutral region, fat emulsion and the like are as defined above. Hereinafter, a method for producing the freeze-dried preparation according to the present invention will be described in detail. First, a PGE ₁ -containing fat emulsion before lyophilization is prepared. Such a fat emulsion is prepared, for example, by adding PGE ₁ , emulsifier,
And other additives, etc. are appropriately added, for example, heated to homogenize, and an appropriate amount of water is added to the mixture to add a regular homomixer, homogenizer, ultrasonic homogenizer, microfluidizer (trade name), nanomizer (trade name). The emulsification treatment may be carried out by an emulsifying machine such as a Ultimaizer (trade name), a Manton-Gaulin type high-pressure homogenizer or the like until emulsion particles having a desired average particle diameter within the above range are obtained. After production of the fat emulsion, components other than PGE ₁ , the oil component, the emulsifier, the emulsification aid, and the emulsification stabilizer (for example, an excipient or a pH adjuster) may be produced depending on the production convenience.
May be added. The pH adjustment may be performed before or after the emulsification treatment as long as it is after addition of components other than the pH adjusting agent.

Then, the obtained fat emulsion is freeze-dried by a conventional method, whereby the freeze-dried preparation according to the present invention can be prepared. The freeze-drying treatment can be performed by a conventional method. For example, after sterilizing the fat emulsion, a predetermined amount is dispensed into a vial. Pre-freeze for about 2 hours under conditions of about -40 to -20 ° C, perform primary drying under reduced pressure at about 0 to 10 ° C, and then secondary dry under reduced pressure at about 15 to 25 ° C and freeze. dry. Then, generally, the inside of the vial is replaced with nitrogen gas, and the vial is stoppered to obtain a freeze-dried preparation.

The freeze-dried preparation according to the present invention can be re-dissolved very easily by adding any appropriate solution (re-dissolving solution) and can be reconstituted into a fat emulsion before freeze-drying.
Such redissolved solutions include water for injection, physiological saline,
Other general infusions can be mentioned. The amount of the redissolved liquid varies depending on the use and the like and is not particularly limited, but 0.5 to 2 times the amount before the freeze-drying, or 500 ml or less is suitable.

The lyophilized preparation of the present invention which has been redissolved in water for injection or the like can be parenterally administered by injection or the like. Intravenous administration is particularly preferable. The administration form varies depending on the purpose of treatment and the like, but may be one shot once a day, divided administration such as three times a day, continuous intravenous infusion and the like.

The freeze-dried preparation according to the present invention can be used within the range of efficacy of PGE ₁ . For example, it can be used as a therapeutic agent for chronic arterial occlusive disease, progressive systemic sclerosis, systemic lupus erythematosus, diabetes, vibration disease and the like.

[0028]

The present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited to these.

Example 1 10 g of purified soybean oil, 1.8 g of purified egg yolk lecithin, PGE
₁ 0.5 mg was heated and mixed at about 40 ° C., about 80 ml of an aqueous solution containing 10% maltose was added thereto, and the mixture was stirred with a homogenizer to give a crude dispersion. 1 in the resulting crude dispersion
A 0% maltose-containing aqueous solution was further added, the pH was adjusted to 7.0 with sodium hydroxide, and the volume was adjusted to 100 ml.
This crude dispersion liquid was cooled with water using a Manton-Gaulin homogenizer under a total pressure of 500 kg / cm ³ under a pressure of 1
The mixture was passed 0 times and emulsified. PGE homogenized by this
_{A 1-} containing fat emulsion was obtained. The average particle size of this emulsion was 203 nm as measured by a light scattering photometer (DLS-700, manufactured by Otsuka Electronics Co., Ltd., hereinafter). Then, the obtained emulsion was dispensed in 1 ml portions into 1 ml vials and freeze-dried to obtain a freeze-dried preparation according to the present invention. The freeze-drying is performed by a Kyowa freeze-dryer (RL-20
MB, manufactured by Kyowa Vacuum Co., Ltd.), pre-freezing at −40 ° C. for 2 hours, and then primary drying at 0 ° C. under reduced pressure for 10 hours.
It was carried out by secondary drying for 5 hours under reduced pressure at ℃. The freeze-dried state was extremely good and no defects such as chipping, cracking and shrinkage were observed. When water for injection was added and re-dissolved (reconstituted into 1 ml of fat emulsion), the dissolution was completed very quickly, and there was almost no change in the average particle size and particle size distribution of the emulsion particles after re-dissolution, and freeze-drying was performed. The previous fat emulsion was almost restored. The average particle size of the emulsion particles after re-dissolution was 210 nm. Immediately after reconstitution to 1 ml of fat emulsion with distilled water of pH 7.0, the liquid property of the fat emulsion was pH 6.9.

Example 2 A fat emulsion consisting of emulsion particles having an average particle size of 195 nm was obtained by the same procedure as in Example 1 except that 0.24 g of oleic acid was added. From this, a freeze-dried preparation according to the present invention was obtained. It was The freeze-dried state is extremely good, with no chips, cracks,
No defects such as shrinkage were recognized. When water for injection was added and re-dissolved (reconstituted into 1 ml of fat emulsion), the dissolution was completed very quickly, and there was almost no change in the average particle size and particle size distribution of the emulsion particles after re-dissolution, and freeze-drying was performed. The previous fat emulsion was almost restored. The average particle size of the emulsion particles after re-dissolution was 201 nm. Immediately after reconstitution to 1 ml of fat emulsion with distilled water of pH 7.0, the liquid property of the fat emulsion was pH 6.7.

Example 3 5 g of purified soybean oil, 5 g of purified egg yolk lecithin, and PGE ₁
0.5 mg was heated and mixed at about 40 ° C., about 80 ml of an aqueous solution containing 10% maltose was added thereto, and the mixture was stirred with a homogenizer to give a crude dispersion. 1 in the resulting crude dispersion
A 0% maltose-containing aqueous solution was further added, the pH was adjusted to 7.0 with sodium hydroxide, and the volume was adjusted to 100 ml.
This crude dispersion was water-cooled and Nanomizer (LA-31 type,
High-pressure emulsification with Nanomizer Co., Ltd. to obtain a homogenized fat emulsion containing extremely fine PGE ₁ . The average particle diameter of the emulsion particles was 33 nm as measured by a light scattering photometric device. The obtained emulsion was sterilized by filtration through a 0.2 μm membrane filter, then dispensed in 1 ml aliquots and freeze-dried to obtain a freeze-dried preparation according to the present invention. The freeze-drying was performed by pre-freezing at −40 ° C. for 2 hours using a Kyowa-type freeze dryer (RL-20MB, manufactured by Kyowa Vacuum Co., Ltd.), then primary drying was performed at 0 ° C. under reduced pressure for 10 hours, and at 25 ° C. It was carried out by secondary drying under reduced pressure for 5 hours. The freeze-dried state is extremely good, with no chipping,
No defects such as cracking and shrinkage were observed. When water was re-dissolved by adding water for injection (reconstitution into 1 ml of fat emulsion), the dissolution was completed very quickly, and there was almost no change in the average particle size and particle size distribution of the emulsion particles after re-dissolution The fat emulsion before drying was almost restored. The average particle size of the emulsion particles after re-dissolution was 34 nm. pH
Immediately after reconstitution to 1 ml of fat emulsion with 7.0 distilled water, the liquid property of the fat emulsion was pH 7.0.

Example 4 A fat emulsion consisting of emulsion particles having an average particle diameter of 38 nm was obtained by the same procedure as in Example 3 except that 0.24 g of oleic acid was added, from which a freeze-dried preparation according to the present invention was obtained. It was The freeze-dried state is extremely good, with no chips, cracks,
No defects such as shrinkage were recognized. When water was re-dissolved by adding water for injection (reconstitution into 1 ml of fat emulsion), the dissolution was completed very quickly, and there was almost no change in the average particle size and particle size distribution of the emulsion particles after re-dissolution The fat emulsion before drying was almost restored. The average particle size of the emulsion particles after re-dissolution was 40 nm. Immediately after reconstitution to 1 ml of fat emulsion with distilled water of pH 7.0, the liquid property of the fat emulsion was pH 6.9.

Example 5 A fat emulsion consisting of emulsion particles having an average particle diameter of 42 nm was obtained in the same manner as in Example 3 except that the amount of purified egg yolk lecithin was changed to 3 g to obtain a freeze-dried preparation according to the present invention. .
The freeze-dried state was extremely good and no defects such as chipping, cracking and shrinkage were observed. When water was re-dissolved by adding water for injection (reconstitution into 1 ml of fat emulsion), the dissolution was completed very quickly, and there was almost no change in the average particle size and particle size distribution of the emulsion particles after re-dissolution The fat emulsion before drying was almost restored. The average particle size of the emulsion particles after re-dissolution was 41 nm. Immediately after reconstitution to 1 ml of fat emulsion with distilled water of pH 7.0, the liquid property of the fat emulsion was pH 6.8.

Example 6 A fat emulsion consisting of emulsion particles having an average particle size of 43 nm was obtained in the same manner as in Example 3 except that soybean lecithin was used as the purified egg yolk lecithin, from which a freeze-dried preparation according to the present invention was obtained. It was The freeze-dried state was extremely good and no defects such as chipping, cracking and shrinkage were observed. When water for injection was added and redissolved (reconstituted into 1 ml of fat emulsion),
The dissolution was completed very quickly, and there was almost no change in the average particle size and particle size distribution of the emulsion particles after re-dissolution, and the fat emulsion before lyophilization was almost restored. The average particle size of the emulsion particles after re-dissolution was 45 nm. pH 7.
Immediately after reconstitution to 1 ml of fat emulsion with 0 distilled water, the pH of the fat emulsion was 7.3.

Example 7 A fat emulsion consisting of emulsion particles having an average particle diameter of 35 nm was obtained in the same manner as in Example 3 except that the pH was adjusted to 6.5.
From this, a freeze-dried preparation according to the present invention was obtained. The freeze-dried state was extremely good and no defects such as chipping, cracking and shrinkage were observed. Redissolve by adding water for injection (1 ml
Reconstitution into the fat emulsion), the dissolution was completed very quickly, and there was almost no change in the average particle size and particle size distribution of the emulsion particles after re-dissolution, and the fat emulsion before lyophilization was almost restored. The average particle size of the emulsion particles after re-dissolution was 35 nm. 1 ml with distilled water of pH 7.0
The liquid properties of the fat emulsion immediately after reconstitution into the fat emulsion of
The pH was 6.5.

Example 8 A fat emulsion consisting of emulsion particles having an average particle diameter of 34 nm was obtained in the same manner as in Example 3 except that the pH was adjusted to 7.5. From this, the freeze-dried preparation according to the present invention was obtained. It was The freeze-dried state was extremely good and no defects such as chipping, cracking and shrinkage were observed. Add water for injection to redissolve (1
When reconstituted into a fat emulsion of ml), the dissolution was completed very quickly, and there was almost no change in the average particle size and particle size distribution of the emulsion particles after re-dissolution, and the fat emulsion before lyophilization was restored. The average particle size of the emulsion particles after re-dissolution was 36 nm. 1 ml with distilled water of pH 7.0
The liquid properties of the fat emulsion immediately after reconstitution into the fat emulsion of
The pH was 7.4.

Comparative Example 1 A fat emulsion consisting of emulsion particles having an average particle diameter of 35 nm was obtained by the same procedure as in Example 3 except that the pH was adjusted to 6.0, from which a freeze-dried preparation was obtained. The liquid property of the fat emulsion immediately after reconstitution into 1 ml of the fat emulsion with pH 7.0 distilled water was pH 6.1. Comparative Example 2 A fat emulsion consisting of emulsion particles having an average particle diameter of 34 nm was obtained by the same treatment as in Example 3 except that the pH was adjusted to 5.0, and a freeze-dried preparation was obtained therefrom. The liquid property of the fat emulsion immediately after reconstitution into 1 ml of fat emulsion with pH 7.0 distilled water was pH 5.1. Comparative Example 3 A fat emulsion consisting of emulsion particles having an average particle diameter of 36 nm was obtained by the same treatment as in Example 3 except that the pH was adjusted to 8.5, and a freeze-dried preparation was obtained from this. The liquid property of the fat emulsion immediately after reconstitution into 1 ml of the fat emulsion with pH 7.0 distilled water was pH 8.4.

Test Example 1 Storage stability test (1) With respect to the freeze-dried preparations of Examples 3, 7 and 8 and Comparative Examples 1, 2 and 3, the residual rate of PGE ₁ after storage at 40 ° C. for 1 month was examined. . Table 1 shows the results. The residual rate of PGE ₁ was examined after adding the water for injection to each freeze-dried preparation and re-dissolving it (reconstructed into 1 ml of fat emulsion) after the storage period.

[0039]

[Table 1]

As shown in Table 1, the freeze-dried pre-lyophilized fat emulsion was adjusted to a weakly acidic region (pH 5.0, 6.0) or a weakly alkaline region (pH 8.5), and then the freeze-dried preparation was prepared. compared to PGE _1, PGE ₁ stability of the present invention a lyophilized formulation prepared with the pre-lyophilization fat emulsion, adjust the neutral region (pH 6.5-7.5) was significantly higher.

Test Example 2 Storage stability test (2) The freeze-dried preparation according to the present invention obtained in Example 3 was used together with a commercially available fat emulsion (Ripple (registered trademark)).
The residual rate of PGE ₁ after storage for 1 week at 40 ° C. was examined. Table 2 shows the results. The residual rate of PGE _{1 of the} freeze-dried preparation of the present invention in Example 3 was examined after redissolving (reconstructing into 1 ml of fat emulsion) water for injection after the storage period.

[0042]

[Table 2]

As shown in Table 2, the stability of PGE ₁ contained in the freeze-dried preparation of the present invention of Example 3 is remarkably higher than that of PGE ₁ contained in the commercially available fat emulsion. it was high.

[0044]

PGE ₁ containing freeze-dried preparation according to the present invention is, of PGE _1, as compared to PGE ₁ containing lyophilized formulations led humoral before lyophilization fat emulsion from a fat emulsion not adjusted to the neutral region Remarkably high stability. In the present invention,
Since the liquidity of the fat emulsion before lyophilization is in the neutral range,
The increase in free fatty acids due to hydrolysis in the fat emulsion can be suppressed, and the stability of the fat emulsion particles (maintaining the particle size and particle size distribution) is high. The freeze-dried preparation of the present invention derived from a fat emulsion in which the average particle size of the emulsion particles is 5 to 70 nm, does not contain water (hydrolysis of PGE ₁ etc., as compared with the commercially available liquid type fat emulsion). Control) and sterilization by filtration before freeze-drying (control of unnecessary thermal decomposition of PGE ₁ due to heat sterilization) and so on, the storage stability and stability are extremely excellent, and impurities (decomposed products) are remarkable. Very few. As described above, according to the present invention, a high-quality PGE ₁ -containing drug can be provided.

Claims (33)

[Claims] 1. A PGE ₁ -containing freeze-dried preparation derived from a fat emulsion containing prostaglandin E ₁ (PGE ₁ ), an oil component, an emulsifier, and water and having a liquidity (pH) within a neutral range. . 2. The content of the oil component is 0.1 to 30 w / v%.
And the emulsifier content is 0.01 to 30 w /
The PGE ₁ -containing freeze-dried preparation according to claim 1, which is derived from the fat emulsion according to claim 1, which is in the range of v%. 3. The fat emulsion particles have an average particle size of 5 to 70 n.
The lyophilized preparation containing PGE _{1 according to} claim 1 or 2, which is derived from the fat emulsion according to claim 1 or 2, which is within the range of m. 4. The PGE _{1 according} to claim 3, which is derived from the fat emulsion according to claim 3, wherein the weight ratio of the oil component and the emulsifier (oil component / emulsifier) is in the range of 0.8 to 1.2. Freeze-dried formulation containing. 5. The claim 1 to 4 derived from the fat emulsion according to any one of claims 1 to 4, wherein the oil component is a vegetable oil or triglyceride and the emulsifier is a phospholipid or a nonionic surfactant. A freeze-dried preparation containing PGE ₁ . 6. The freeze-dried preparation containing PGE _{1 according to} claim 5, which is derived from the fat emulsion according to claim 5, wherein the vegetable oil is soybean oil and the phospholipid is egg yolk lecithin. 7. The freeze-dried preparation containing PGE _{1 according} to any one of claims 1 to 6, which is derived from the fat emulsion according to any one of claims 1 to 6, having a liquidity within the range of pH 6.5 to 7.5. . 8. The freeze-dried preparation containing PGE _{1 according to} claim 1, which is derived from the fat emulsion according to any one of claims 1 to 7, which further contains a saccharide. 9. The freeze-dried preparation containing PGE _{1 according} to claim 8, which is derived from the fat emulsion according to claim 8, wherein the saccharide content is in the range of 1 to 30 w / v%. 10. The freeze-dried preparation containing PGE _{1 according to} claim 8 or 9, which is derived from the fat emulsion according to claim 8 or 9, wherein the saccharide is maltose. 11. The PGE ₁ -containing freeze-dried preparation according to any one of claims 1 to 10, which further comprises a fatty acid and / or cholesterol and is derived from the fat emulsion according to any one of claims 1 to 10. 12. A liquid having a prostaglandin E ₁ (PGE ₁ ), an oil component, and an emulsifier, and having a liquidity (pH) within a neutral range immediately after reconstitution (restoration) with water having a pH of 7.0. And a lyophilized preparation containing PGE ₁ . 13. The content of the oil component after re-dissolution is 0.1 to 10.
Within the range of 30 w / v%, the content of emulsifier is 0.0
The PG according to claim 12, which is in the range of 1 to 30 w / v%.
Freeze-dried preparation containing E ₁ . 14. The freeze-dried preparation containing PGE _{1 according to} claim 12 or 13, wherein the average particle size of the fat emulsion particles after re-dissolution is in the range of 5 to 70 nm. 15. The freeze-dried preparation containing PGE _{1 according to} claim 14, wherein the weight ratio of the oil component and the emulsifier after re-dissolution (oil component / emulsifier) is in the range of 0.8 to 1.2. 16. The freeze-dried preparation containing PGE _{1 according} to claim 12, wherein the oil component is a vegetable oil or triglyceride, and the emulsifier is a phospholipid or a nonionic surfactant. 17. The freeze-dried preparation containing PGE _{1 according to} claim 16, wherein the vegetable oil is soybean oil and the phospholipid is egg yolk lecithin. 18. The liquidity immediately after reconstitution with water having a pH of 7.0 is within the range of pH 6.5 to 7.5.
7. The freeze-dried preparation containing PGE _{1 according} to any of 7. 19. The freeze-dried preparation containing PGE _{1 according} to claim 12, which further contains a saccharide. 20. The saccharide content after re-dissolution is 1 to 30 w.
A lyophilized preparation containing PGE ₁ derived from the fat emulsion according to claim 19, which is in the range of / v%. 21. The PGE ₁ -containing freeze-dried preparation according to claim 19 or 20, wherein the saccharide is maltose. 22. The PGE _{1 according} to any one of claims 12 to 21, which further contains a fatty acid and / or cholesterol.
Freeze-dried formulation containing. 23. A fat emulsion containing prostaglandin E ₁ (PGE ₁ ), an oil component, an emulsifier, and water having a liquidity (pH) within a neutral range is freeze-dried. Process for producing freeze-dried preparation containing PGE ₁ . 24. The oil component content is 0.1 to 30 w / v.
%, And the emulsifier content is 0.01 to 30 w.
24. The PGE according to claim 23, wherein the fat emulsion according to claim 23 is freeze-dried in the range of / v%.
Preparation of _1- containing freeze-dried preparation. 25. The average particle size of the fat emulsion particles is 5 to 70.
25. The fat emulsion according to claim 23 or 24, which is in the range of nm, is freeze-dried.
4. The method for producing a freeze-dried preparation containing PGE _{1 according to} 4. 26. A weight ratio of an oil component and an emulsifier (oil component /
The method for producing a freeze-dried preparation containing PGE _{1 according to} claim 25, characterized in that the fat emulsion according to claim 25 is freeze-dried, wherein the emulsifier is in the range of 0.8 to 1.2. 27. The fat emulsion according to any one of claims 23 to 26, wherein the oil component is a vegetable oil or triglyceride and the emulsifier is a phospholipid or a nonionic surfactant, which is freeze-dried. A method for producing the freeze-dried preparation containing PGE _{1 according to} claim 23. 28. The method for producing a freeze-dried preparation containing PGE _{1 according to} claim 27, characterized in that the vegetable oil is soybean oil and the phospholipid is egg yolk lecithin, and the fat emulsion according to claim 27 is freeze-dried. 29. The fat emulsion according to any one of claims 23 to 28, which has a liquidity in the range of pH 6.5 to 7.5, is freeze-dried. Process for producing freeze-dried preparation containing PGE ₁ . 30. The method for producing a freeze-dried preparation containing PGE _{1 according} to any one of claims 23 to 29, characterized in that the fat emulsion according to any one of claims 23 to 29, which further contains a saccharide, is freeze-dried. 31. The freeze-dried preparation containing PGE _{1 according to} claim 30, characterized in that the fat emulsion according to claim 30 having a saccharide content in the range of 1 to 30 w / v% is freeze-dried. Manufacturing method. 32. The method for producing a freeze-dried preparation containing PGE _{1 according to} claim 30 or 31, wherein the fat emulsion according to claim 30 or 31, wherein the saccharide is maltose, is freeze-dried. 33. The fat emulsion according to any one of claims 23 to 32, which further contains a fatty acid and / or cholesterol, is freeze-dried, and the fat emulsion according to any one of claims 23 to 32.
A method for producing the freeze-dried preparation containing PGE ₁ described.