KR20100053541A - Stable fat emulsion containing prostaglandin e1 - Google Patents

Abstract

Disclosed is a fat emulsion containing a compound having prostaglandin Eactivity, which fat emulsion is hermetically sealed in a glass container and then heat sterilized. The residual amount of prostaglandin Eactivity after 16-month storage at 5°C is not less than 65% but not more than 100% of the prostaglandin Eactivity at the beginning of storage.

Description

Stable fat emulsion containing prostaglandin E1

The present invention relates to a stable fat emulsion comprising prostaglandin E ₁ .

Prostaglandin E ₁ (hereinafter sometimes abbreviated as "PGE ₁ ") is the generic name "alprostadil", which has a potent vasodilating action and platelet aggregation inhibitory effect, and chronic arterial obstruction (burger disease). , Ulcers in obstructive atherosclerosis), improvement of resting pain, improvement of skin ulcers in progressive systemic sclerosis, etc., improvement of skin ulcers in diabetes, and the like are clinically used. As the prostaglandin E _1- containing preparations, so-called lipoic preparations (eg, "ripple injection", Mitsubishi Tanabe Pharma Corporation manufacture and sale) in which PGE ₁ is dissolved in fine fat particles are known. This formulation efficiently integrates PGE ₁ into the lesion site by devising a drug delivery system (DDS), using a fat particle used as a carrier of the drug, which has a property of being easily distributed to damaged blood vessels. As an agent which makes it hard to generate the inactivation of an active ingredient in an inside, the additive contains refined soybean oil, highly refined egg yolk lecithin, oleic acid, concentrated glycerin, and sodium hydroxide, and pH is adjusted to 4.5-6.0.

However, the Lipoic Chemistry formulations of the PGE ₁ is so easy a PGE ₁ of the active ingredient to decompose in the solution, it is necessary to preserve the frozen under avoid shading of less than 5 ℃, valid for all fixed in a short one years conventional formulation have. Since such preparations lead to an increase in drug management costs at distribution stages and clinical settings, development of long-lived preparations leading to a reduction in drug administration costs is urgently desired. In addition, a means for inhibiting inactivation due to pulmonary passage of prostaglandin E ₁ by fat emulsion is disclosed in Japanese Patent Laid-Open No. 58-222014 (Patent Document 1), which improves chemical stability by fat emulsion. Sudan is disclosed in Japanese Patent Application Laid-Open No. 60-149524 (Patent Document 2), and an angiography aid prepared as a fat emulsion is disclosed in Japanese Patent Application Laid-Open No. 4-66540 (Patent Document 3). . It is also known that the effect of pH on PGE ₁ in fat emulsions is most stable near pH 5.0 and destabilized at pH above or below (Pharmaceutical Research, 6, pp. 210-215, 1989; Non-Patent Document 1).

Patent Document 1: Japanese Patent Application Laid-Open No. 58-222014

Patent Document 2: Japanese Patent Application Laid-Open No. 60-149524

Patent Document 3: Japanese Patent Application Laid-Open No. 4-66540

Non Patent Literature 1: Pharmaceutical Research, 6, pp. 210-215, 1989

An object of the present invention is to provide a formulation containing a compound having prostaglandin E ₁ activity having a longer shelf life. More specifically, prostaglandins E lipoic screen agents on the market as a preparation containing ₁ to provide a means to prolong the lifetime of a (for example, "ripple injection", etc.).

In order to solve the above problems, the present inventors have studied intensively, and, in the final stage of the preparation process, the preparation (adjusting the pH to about 5.0 at the time of filling) in a glass ampoule is heated in an autoclave (125 ° C). Upon sterilization, the alkali component eluted from the inner surface of the glass ampoule, and the pH of the formulation was found to be higher than before sterilization. Based on this knowledge, the present inventors continued further research and adopted a means for suppressing the elution of the alkali component from the glass ampoule at the time of sterilization, thereby making it easy without being affected by the properties (materials) of the glass ampoule. It has been found that it can be prepared easily, and that a stable lipoforming agent can be provided over a long period of time.

That is, according to the present invention, a fat emulsion containing a compound having prostaglandin E ₁ activity, which is heat sterilized after being sealed in a glass container, and after the storage for 16 months at 5 ° C., the residual amount of prostaglandin E ₁ activity is at the start of storage. A fat emulsion of 65% or more and 100% or less is provided.

According to a preferred embodiment of the present invention, the fat containing 5 µg or more of a compound having prostaglandin E ₁ activity at the start of storage, and the remaining amount of the compound having prostaglandin E ₁ activity after storage at 5 ° C. for 16 months is 4 µg or more. emulsion; A fat emulsion containing 10 μg or more of a compound having prostaglandin E ₁ activity at the start of storage and having a residual amount of a compound having prostaglandin E ₁ activity after storage at 5 ° C. for 16 months is provided. Moreover, the said fat emulsion with the pH at the time of the start of storage after heat sterilization is provided in the range of 4.9-5.3.

According to a further preferred aspect, the glass container is the fat emulsion wherein the glass container is a coat coated on an inner surface thereof; The fat emulsion, wherein the glass container is a glass ampoule with an overcoat coated on an inner surface thereof; The fat emulsion wherein the coat is a silicon oxide coat; The fat emulsion wherein the glass container is a container in which the alkali component on the glass surface is removed by chemical treatment; The fat emulsion is provided wherein the glass container is a glass ampoule in which the alkali component on the glass surface has been removed by chemical treatment. In addition, the above fat emulsion is provided which contains 5-50 w / v% vegetable oil with respect to the whole fat emulsion amount.

In another aspect, the present invention provides a method for producing a fat emulsion containing a compound having prostaglandin E ₁ activity, wherein the fat emulsion containing a compound having a prostaglandin E ₁ activity has a pH adjusted in the range of 4.8 to 5.2. The method includes sealing the container by heat sterilization, and preferably, the container is provided with a means for suppressing the pH increase of the fat emulsion after heat sterilization.

According to a preferred aspect of the invention, the glass container is a glass ampoule, and the means for suppressing the pH increase is a coating coat on the inner surface of the glass ampoule, preferably a silicon oxide coating coat; The said glass container is a glass ampoule, The said method which suppresses pH raise is provided by the said chemical treatment of the alkali component of a glass surface. Moreover, the said method whose pH of the fat emulsion after heat sterilization is the range of 4.9-5.3; And the above standard method wherein the relative standard deviation of the amount of the compound having PGE ₁ activity remaining in the fat emulsion in each glass ampoule after heat sterilization is 1.0% or less. In addition, where the amount of a compound having PGE ₁ activity is, as an active ingredient, the amount of "PGE _1", which is In the active ingredient to the fat emulsion containing "PGE _1", an as an active ingredient PGE ₁ activity of the "non-PGE ₁ in the compound having "a fat emulsion containing means an amount of a compound" having an active ingredient, the "PGE ₁ activity than PGE _1.

The fat emulsion of the present invention has improved stability of a compound having prostaglandin E ₁ activity compared to a conventional fat emulsion, and has a feature that the content of the active ingredient does not decrease even if stored for a long time. Moreover, the manufacturing method of this invention has the characteristic that the product which is not influenced by the characteristic (material) of the glass container with respect to the amount of PGE ₁ after sterilization can be provided.

The fat emulsion of the present invention is a fat emulsion containing a compound having prostaglandin E ₁ activity, which is heat sterilized after being sealed in a container, and the remaining amount of PGE ₁ activity after storage at 5 ° C. for 16 months is at least 65% at the start of storage. It is characterized by being 100% or less. As the compound having an active PGE _1, PGE ₁ has an activity, as long as suitable as the active ingredient of the medicament may be used any compound. For example, PGE ₁ derivatives disclosed in Japanese Patent Laid-Open No. 59-206349, Japanese Patent Laid-Open No. 59-216820, and the like are preferably used. Among them, for example, 7-{(1R, 2R, 3R) -3-hydroxy-2-[(1E, 3S) -3-hydroxyoct-1-en-1-yl] -5-oxo Cyclopentyl} heptanoic acid (general name "Alprostadyl") is particularly preferable.

Particularly preferred as a compound having prostaglandin E ₁ activity in the present invention is 7-{(1R, 2R, 3R) -3-hydroxy-2-[(1E, 3S) -3-hydroxy as described above. Oct-1-en-1-yl] -5-oxocyclopentyl} heptanoic acid (alprostadyl), but the compound is dehydrated by 7-{(1R, 2S) -2-[(S, E ) -3-hydroxyoct-1-enyl] -5-oxocyclopent-3-enyl} heptanoic acid (prostaglandin A1). It is thought that the pharmacological activity of the fat emulsion in this invention will fall by the change to prostaglandin A1. In this invention, it is preferable that the amount of prostaglandin A1 in 1 ml of the fat emulsions of this invention after storage at 5 degreeC for 16 months is 3.0 micrograms or less. Particularly preferred are 0 µg or more and 1.5 µg or less.

Fat emulsions containing compounds having PGE ₁ activity are disclosed in, for example, Japanese Patent Application Laid-Open No. 58-222014, Japanese Patent Application Laid-Open No. 60-149524, and Japanese Patent Application Laid-Open No. 4-66540. And the like, and those skilled in the art can easily prepare a fat emulsion. Fat emulsions can be formulated to include, for example, vegetable oils, phospholipids, water, and compounds having PGE ₁ activity. Moreover, it is also possible to add an emulsification adjuvant, a stabilizer, a polymeric substance, an isotonicity agent etc. as needed.

Fat emulsions can be prepared by various methods, for example, can be prepared by the following method. A predetermined amount of vegetable oil (preferably soybean oil), phospholipids, compounds having PGE ₁ activity, and other such additives are mixed, heated as necessary, and then used as a homogenizer (for example, pressurized). A water-in-oil dispersion is prepared by homogenizing with a spray homogenizer, an ultrasonic homogenizer, etc., and then the required amount of water is added to the dispersion, homogenized with a homogenizer and converted into an oil-in-water emulsion. Can be prepared. You may add additives, such as a stabilizer and an isotonicity agent, after preparation of a fat emulsion. The fat emulsion is adjusted to have a pH in the range of 4.8 to 5.2 before heat sterilization. What is necessary is just to use a suitable quantity of basic substances, such as sodium hydroxide, for adjustment of pH. The penetration ratio can be adjusted to be about 1 as the ratio to the saline solution.

The average particle diameter of the fat emulsion in this invention can be measured using the particle diameter measuring device based on the dynamic light scattering method. Preferable average particle diameters of the fat emulsion in this invention are 0.1 micrometer or more and 0.4 micrometer or less.

The fat emulsion of the present invention can be produced, for example, by sealing the fat emulsion prepared as described above in a glass container and then heat sterilizing. As the glass container, any glass container can be used as long as it is suitable for sealing and does not elute an alkali component in the fat emulsion filled inside in the heat sterilization treatment. For example, the fat after heat sterilization can be used. The glass container provided with the means which suppresses the pH rise of an oil agent is preferable, and the glass ampoule provided with the said means is especially preferable.

The means for suppressing the pH rise of the fat emulsion after heat sterilization is not particularly limited. For example, the means for preventing the elution of an alkali component in the fat emulsion during heat sterilization or the acid in the fat emulsion during heat sterilization. Means for eluting the component may be employed. Means for preventing the elution of the alkali component in the fat emulsion during heat sterilization are preferable. As a means for preventing the elution of an alkali component in a fat emulsion at the time of heat sterilization, the means for film-coating a container inner surface is mentioned, for example. Preferably, a means for film coating a silicon oxide on the inner surface of the glass ampoule can be employed. Alternatively, it is also possible to employ means for removing the alkali component on the glass surface by chemical treatment as a means for suppressing the pH rise. Such a technique is described, for example, in Japanese Patent Laid-Open No. Hei 2-175630 and the like and can be easily employed by those skilled in the art.

The fat emulsion of the present invention can be prepared by sealing the fat emulsion in which the pH is adjusted in the range of 4.8 to 5.2 in a container and heat sterilizing it. Although heat sterilization can be performed at 125 degreeC for several minutes-about 10 minutes in an autoclave, for example, temperature and time are not specifically limited, Any process can be employ | adopted as long as it can achieve sufficient sterilization. The pH of the fat emulsion after heat sterilization is preferably in the range of 4.9 to 5.3. The increase in pH before and after heat sterilization is preferably less than 0.3, more preferably less than 0.2, and particularly preferably less than 0.1. Regarding the amount of PGE ₁ after sterilization, it is preferable that the relative standard deviation of the amount of PGE ₁ (μg) is 1.0% or less, more preferably 0.5% or less, for each ampoule.

Fat emulsions containing a compound having prostaglandin E ₁ activity in the present invention can be provided by filling into an ampoule, for example, as a formulation containing 5 μg or 10 μg as the weight of a compound having prostaglandin E ₁ activity. have. In this invention, it is preferable that the said compound of the weight of 80%-125% of the quantity is filled in 5 micrograms filled ampoules. That is, it means that the compound is filled with 4 µg or more and 6.25 µg or less in the ampoule. Or in this invention, it is preferable that the said compound of 80 weight-125% of the quantity is filled in the 10 microgram filled ampoule. That is, it means that the compound is filled with 8 µg or more and 12.5 µg or less in the ampoule.

In addition, about the applied disease of the fat emulsion of this invention, a usage method, etc., it describes in detail in the attached document (Mitsubishi Tanabe Pharma Corporation, revision of April 2008, 16th edition) of "Ripple injection 5 micrograms", for example. It is.

Example

Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited to the following Examples.

Example 1

To refined soybean oil, egg yolk lecithin from which alprostadyl (PGE ₁ ), oleic acid, and phosphatidylethanolamine (PE) have been dissolved is dissolved, a mixture of separately prepared glycerin and distilled water for injection is added, followed by stirring with a homomixer. It prepared. The obtained suspension was emulsified with a Manton Gaulin homogenizer (manton highlin agent), and the pH was adjusted to 4.90 using sodium hydroxide and hydrochloric acid. The prepared emulsion is filled into a silicate ampoule (manufactured by Fuji Glass, a glass ampoule with a silicon oxide film coated with a thickness of 70 to 100 내부 inside the ampoule), and sealed by nitrogen-substituting the air gap in the ampoule. It was. The resulting ampoule was sterilized at 125 ° C. for 2.2 minutes using a high pressure steam sterilizer to obtain the fat emulsion of the present invention.

Example 2

The emulsion was prepared in the same manner as in Example 1, the pH was adjusted to 5.01 using sodium hydroxide, and then, in the same manner as in Example 1, the silicate ampoules were filled and sealed, and sterilized to obtain the fat emulsion of the present invention.

Example 3

The emulsion was prepared in the same manner as in Example 1, the pH was adjusted to 5.15 using sodium hydroxide, and then charged and sealed in a silico ampoule in the same manner as in Example 1 to be sterilized to obtain the fat emulsion of the present invention.

Example 4 (comparative)

The emulsion prepared in Example 1 was filled into an ordinary glass ampoule (glass ampoule not coated with a silicon oxide film), and sealed by nitrogen substitution of the ampoule portion and sealing. The resulting ampoule was sterilized at 125 ° C. for 2.2 minutes using a high pressure steam sterilizer to obtain a fat emulsion.

Example 5

The emulsion was prepared in the same manner as in Example 1, the pH was adjusted to 5.09 to 5.15 with sodium hydroxide, and then 9 samples were prepared and sterilized in the same manner as in Example 1, and filled and sealed in the silicate ampoules. The fat emulsion of the present invention was obtained.

Example 6 (comparative)

In the same manner as in Example 5, 10 samples filled in ordinary glass ampoules were produced, and sterilized in the same manner as in Example 5 to obtain a fat emulsion.

In Table 1, the result of the stability test of PGE _{1 in} the case where the fat emulsion which changed the pH before heat sterilization is preserve | saved at 25 degreeC is shown. The residual ratio of PGE ₁ was measured by high performance liquid chromatography using a post column reaction (it was measured according to the method described in JP Forum, 15 (3), pp. 233-235, 2006). In Table 2, the result of the stability test of PGE _{1 in} the case of storing at 30 degreeC and 40 degreeC is shown. As apparent from these results, even when stored at 30 ° C. and 40 ° C., the PGE ₁ stability of the fat emulsion of the present invention sealed-filled in the silica coat ampoule was higher than that of the fat emulsion of Example 5 sealed-filled in a conventional glass ampoule. Excellent. Using the above results, the PGE ₁ stability at 5 ° C. when the fat emulsion prepared near pH 5.0 was used was calculated by Arrhenius Plotting. As shown in Table 3, in the fat emulsion of the present invention sealed-filled in the silica coat ampoule, the content of 65% or more was maintained at the start of the 16th month.

Table 4 shows the amount of PGE ₁ remaining in each sample after sterilization, their average value, standard deviation value and relative standard deviation value. The standard deviation value of the residual amount of fat emulsion of the present invention sealedly filled in the silica coat ampoule is smaller than the relative standard deviation value of the amount of fat emulsion of Example 7 sealed and filled in a normal glass ampoule, and is a uniform product having a small variation for each sample. Is shown.

Example 7

1 ml of the emulsion prepared in the same manner as in Example 2 was collected, and 1 ml of internal standard solution (50 mg of 1-naphthol was dissolved in 20 ml of 99.5% ethanol, and the mobile phase was added to 3 ml of the solution to make 100 ml). ) Was added and mixed to obtain a sample solution. Separately, the alprostadyl standard solution was dried with a desiccator, weighed 10 mg, accurately weighed, dissolved in 99.5% ethanol to 100 ml to give a standard stock solution (E1). In addition, the prostaglandin A1 standard solution was dried with a desiccator, weighed 10 mg, dissolved in 99.5% ethanol to make 100 mL to obtain a standard stock solution (A1). 2.5 ml of E1 and A1 were collected, the mobile phase was added to 50 ml, and 1 ml of this mixed solution was taken and mixed with 1 ml of the internal standard solution to obtain a standard solution. Liquid chromatography was performed on 40 µl of the sample solution and the standard solution, respectively.

The ratio of the peak area of prostaglandin A1 to the peak area of the internal standard was determined. The area ratio of prostaglandin A1 in the sample solution was QT, and the area ratio of prostaglandin A1 in the standard solution was QS. Using these area ratios, the amount of prostaglandin A1 converted to alprostadyl was determined by the following equation.

For emulsions prepared in the same manner as in Example 2, the exact weighing of prostaglandin A1 was 10.05 mg, the ratio of the peak area of prostaglandin A1 to the peak area of the internal standard of the sample solution was 0.180931, the internal standard of the standard solution. The ratio (QS) of the peak area of prostaglandin A1 to the peak area of was 0.778099. Applying this to the above formula, the calculated amount of prostaglandin A1 in the emulsion was 1.23 µg.

The fat emulsion of the present invention is very useful as a prostaglandin E _1- containing preparation because the stability of a compound having prostaglandin E ₁ activity is improved compared to a conventional fat emulsion, and the content of the active ingredient does not decrease even if stored for a long time. .

Claims (17)

Fat emulsion containing a compound having prostaglandin E ₁ activity, which is heat sterilized after being sealed in a glass container, and has a residual amount of prostaglandin E ₁ activity after storage at 5 ° C. for 16 months at 65% or more and 100% or less at the start of storage emulsion. The method of claim 1,
A fat emulsion containing 5 µg or more of a compound having prostaglandin E ₁ activity at the start of storage and having a residual amount of a compound having prostaglandin E ₁ activity after storage at 5 ° C. for 16 months. The method of claim 1,
A fat emulsion containing 10 µg or more of a compound having prostaglandin E ₁ activity at the start of storage and having a residual amount of a compound having prostaglandin E ₁ activity after storage at 5 ° C. for 16 months. The method according to claim 2 or 3,
A fat emulsion in which a compound having prostaglandin E ₁ activity, which corresponds to 80.0-125.0% of 5 μg or 10 μg of a compound having prostaglandin E ₁ activity after 16 months of storage at 5 ° C., remains. The method according to any one of claims 1 to 4,
A fat emulsion whose pH at the start of storage after heat sterilization is in the range of 4.9 to 5.3. The method according to any one of claims 1 to 5,
Fat emulsion, wherein the glass container is a container in which a coat is coated on an inner surface. The method of claim 6,
Fat emulsion in which the glass container is a glass ampoule. The method according to claim 6 or 7,
Fat emulsions wherein the coat is a silicon oxide coat. The method according to any one of claims 1 to 5,
Fat emulsion, wherein the glass container is a container in which the alkali component on the glass surface is removed by chemical treatment. 10. The method of claim 9,
Fat emulsion in which the glass container is a glass ampoule. The method according to any one of claims 1 to 10,
Fat emulsions containing 5-50 w / v% vegetable oils relative to the total amount of fat emulsions. The method according to any one of claims 1 to 11,
A fat emulsion containing 5 μg of a compound having prostaglandin E ₁ activity in 1 mL of fat emulsion, 100 mg of refined soybean oil, 18 mg of highly refined egg yolk lecithin, 2.4 mg of oleic acid, and 22.1 mg of concentrated glycerin. The method according to any one of claims 1 to 11,
A fat emulsion containing 10 µg of a compound having prostaglandin E ₁ activity in a 2 mL fat emulsion, 200 mg of refined soybean oil, 36 mg of highly refined egg yolk lecithin, 4.8 mg of oleic acid, and 44.2 mg of concentrated glycerin. The method according to any one of claims 1 to 13,
Compounds having prostaglandin E ₁ activity were identified as 7-{(1R, 2R, 3R) -3-hydroxy-2-[(1E, 3S) -3-hydroxyoct-1-en-1-yl] -5- Fat emulsions which are oxocyclopentyl} heptanoic acid. The fat emulsion according to any one of claims 1 to 14, wherein the fat emulsion containing a compound having prostaglandin E ₁ activity in a range of 4.8 to 5.2 is sealed in a glass container and heat sterilized. How to include. 16. The method of claim 15,
The said container is a container provided with a means which suppresses the pH rise of the said fat emulsion after heat sterilization. 16. The method of claim 15,
And a relative standard deviation of the amount of the compound having prostaglandin E ₁ activity remaining in the fat emulsion in each glass ampoule after heat sterilization is 1.0% or less.