JP2012214430A - Fat emulsion containing prostaglandin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a fat emulsion containing prostaglandin, which has improved stability of prostaglandin, excellent emulsion stability, excellent transparency, and long storage life.SOLUTION: A fat emulsion containing prostaglandin is a fat emulsion including a prostaglandin, an oil component, lecithin, a water-soluble acid having a dissociative group with a pKa of 4.0-6.0 or a salt thereof, and water, wherein the content of lecithin is 0.15 or more times the mass of the oil component, and having a pH of 4.5-6.0.

Description

  The present invention relates to a prostaglandin-containing fat emulsion that can be injected intravenously, a preparation for injection containing the prostaglandin-containing fat emulsion, and a method for producing a prefilled syringe preparation. Furthermore, it is related with the manufacturing method of a formulation for injection.

As a form of prostaglandin E1 (PGE ₁ ) formulation, fat emulsions for intravenous injection have been developed and marketed under the names “Ripple Injection” (Mitsubishi Tanabe Pharma), “Parks Injection” (Taisho Pharmaceutical), etc. Yes.
However, the prostaglandin E1 fat emulsion described above is prone to decompose prostaglandin E1, which is an active ingredient, so it is necessary to store it under shading at 5 ° C. or less. It has been established. Since such preparations increase the cost of drug management at the distribution stage and clinical site, development of preparations with a long effective period is eagerly desired.

So far, various studies have been made to increase the stability of prostaglandin E1.
For example, improvement in the stability of prostaglandins is recognized by using purified phospholipids (see Patent Document 1) and substantially not containing higher fatty acids (see Patent Document 2). However, in the method described in the above publication, the prostaglandin stability improvement effect cannot be said to be sufficient, and the emulsion stability of the fat emulsion may be lowered. Extension was required.
Patent Document 3 recognizes that the stability of prostaglandins is improved at a specific emulsifier / oil ratio.

On the other hand, since the prostaglandin E1 fat emulsion has a cloudy appearance, it is difficult to detect foreign matter contamination when opening an ampule, microbial contamination, and coarse particles generated during storage. Therefore, it can be said that it is a formulation that is extremely difficult to manage in the clinical field.
In the method described in Patent Document 3, the effect of improving the stability of prostaglandins is certainly observed, but since the excess lecithin is hydrolyzed, the effect of improving the storage period in a long period is not sufficient. I understood.
On the other hand, citric acid and specific amino acids are known as stabilizers for fat emulsions (Patent Document 4). However, although it is known that the stabilizer has an effect of suppressing discoloration of the fat emulsion, the stabilizing effect of the encapsulated drug has not been recognized. In particular, the pH is adjusted to 6.5 to 7.5, and the decomposition of prostaglandins cannot be suppressed at such a pH. Furthermore, since citric acid is easily accompanied by emulsion breakage, it is necessary to emulsify under conditions where the pH exceeds 6.0 in order to obtain stability of emulsification.
However, it is known that when the pH exceeds 6.0, the stability of prostaglandins is drastically lowered, and it is difficult to obtain a fat emulsion having high storage stability by the method described in Patent Document 4.

  In view of such a situation, development of a prostaglandin-containing fat emulsion excellent in stability and emulsification stability of an active ingredient (prostaglandin) and further in transparency is demanded.

Japanese Patent Publication No. 8-18989 JP-A-4-338333 International Publication No. 2009/93650 JP-A-8-81360

  The first object of the present invention is to provide a fat emulsion having a long shelf life, which improves the stability of prostaglandins and is excellent in emulsion stability. The second object is to provide a fat emulsion having high transparency. The third object is to provide an injectable preparation and a prefilled syringe preparation containing a prostaglandin-containing fat emulsion. Furthermore, it is providing the manufacturing method of the formulation for injection which can be sterilized easily.

The present invention has the following configuration.
[1]
A fat emulsion comprising a prostaglandin, an oil component, lecithin, a water-soluble acid having a dissociation group having a pKa of 4.0 to 6.0 or a salt thereof, and water,
A prostaglandin-containing fat emulsion in which the content of the lecithin is 0.15 times by mass or more of the oil component and the pH is 4.5 to 6.0.
[2]
The prostaglandin-containing fat emulsion according to [1], wherein the water-soluble acid or salt thereof is contained in an amount of 0.01 mmol / L to 5 mmol / L.
[3]
The prostaglandin-containing fat emulsion according to [1] or [2], wherein the water-soluble acid is citric acid.
[4]
The prostaglandin according to any one of [1] to [3], wherein the content of lecithin in the fat emulsion is 0.3 mass times or more with respect to the content of the oil component. Contains fat emulsion.
[5]
The prostaglandin-containing fat emulsion according to any one of [1] to [4], wherein a content of an oil component in the fat emulsion is 0.01 to 5% by mass in the fat emulsion.
[6]
The prostaglandin-containing fat emulsion according to any one of claims [1] to [5], wherein the lecithin is egg yolk lecithin containing 98% by mass or more of phosphatidylcholine.
[7]
The prostaglandin-containing fat emulsion according to any one of [1] to [6], wherein the oil component is soybean oil.
[8]
[1] to [7], wherein the fat emulsion further contains a higher fatty acid, and the content of the higher fatty acid in the fat emulsion is 0.06 mass times or less with respect to the content of lecithin. The prostaglandin-containing fat emulsion according to any one of the above.
[9]
The prostaglandin-containing fat emulsion according to any one of [1] to [8], wherein an average particle size of the fat emulsion measured by a light scattering method is 30 to 150 nm.
[10]
The prostaglandin-containing fat emulsion according to any one of [1] to [9], wherein the prostaglandin is prostaglandin E1.
[11]
The prostaglandin-containing fat emulsion according to any one of [1] to [10], wherein the prostaglandin-containing fat emulsion is a filter sterilized prostaglandin-containing fat emulsion.
[12]
[1] An injectable preparation comprising the prostaglandin-containing fat emulsion according to any one of [11].
[13]
A prefilled syringe preparation, wherein the prostaglandin-containing fat emulsion according to any one of [1] to [11] or the injection preparation of [12] is filled in a syringe.
[14]
The method for producing an injectable preparation of [12] or [13], comprising a step of filter sterilizing the prostaglandin-containing fat emulsion of [12] or [13].

  The constitution of the present invention not only improved the emulsion stability of the fat emulsion, but also found an unexpected effect that the stability of the prostaglandin was greatly improved and the coarse particles were reduced. That is, according to the configuration of the present invention, it is possible to provide a prostaglandin-containing fat emulsion, an injectable preparation, and a prefilled syringe preparation that can be intravenously injected with a significantly improved shelf life compared to conventional products. In addition, since the present fat emulsion has improved transparency, it is possible to easily detect contamination of foreign substances, and it is a preparation that can be effective for drug management in clinical settings.

The intravenously administrable prostaglandin-containing fat emulsion of the present invention comprises a prostaglandin, an oil component, lecithin, a water-soluble acid having a dissociation group having a pKa of 4.0 to 6.0, or a salt thereof, and water. The lecithin content is at least 0.15 times the oil component, and the pH is 4.5 to 6.0.
Conventionally, it has been widely known that the presence of fatty acids reduces the stability of prostaglandins in fat emulsions. However, the present inventors have found an unexpected effect that the presence of a specific water-soluble acid significantly improves the stability of prostaglandins in fat emulsions.
Here, “mass fold” represents how many times the mass is increased.

<Water-soluble acid>
The fat emulsion of the present invention contains a water-soluble acid having a dissociation group having a pKa of 4.0 to 6.0 or a salt thereof. Here, the acid dissociation constant pKa is in water at 25 ° C. In the case of a polyfunctional acid, any of a plurality of acid dissociation constants may be in the range of 4.0 to 6.0.
As such a water-soluble acid, an organic acid is preferable, and carboxylic acids having 2 to 10 carbon atoms are more preferable. Specific examples of water-soluble acids include acetic acid (pKa = 4.76), butyric acid (pKa = 4.63), benzoic acid (pKa = 4.00), citric acid (pKa1 = 3.15, pKa2 = 4.77, pKa3 = 6.40), succinic acid (pKa1 = 4.00, pKa2 = 5.24), tartaric acid (pKa1 = 3.2, pKa2 = 4.8), phthalic acid (pKa1 = 2) .94, pKa2 = 5.41), fumaric acid (pKa1 = 2.85, pKa2 = 4.10), maleic acid (pKa1 = 1.75, pKa2 = 5.83), malic acid (pKa1 = 3.40). PKa2 = 5.13) and the like. Of these, acetic acid and citric acid are preferred, and citric acid is particularly preferred.
A plurality of water-soluble acids may be used in combination.
The water-soluble acid may be contained in the form of a salt or may be a buffer system. Although the kind of salt is not specifically limited, A salt with an alkali metal or an alkaline earth metal etc. are mentioned, A salt with sodium, potassium, or calcium is preferable.

  The water-soluble acid or salt thereof is preferably contained in the fat emulsion in an amount of 0.001 mmol / L to 50 mmol / L, more preferably 0.005 mmol / L to 10 mmol / L, and 0.01 mmol / L to 5 mmol / L. It is particularly preferred that By setting it in this range, the stability effect of prostaglandins can be sufficiently obtained, and the emulsion stability can be maintained, which is preferable.

<Prostaglandins>
Among the components constituting the fat emulsion of the present invention, prostaglandins include prostaglandin E1 (PGE ₁ ), prostaglandin A2 (PGA2), prostaglandin D2 (PGD2), and prostaglandin E2 (PGE). ₂ ), prostaglandin F1α (PGF1α), prostaglandin I2 (PGI2), and derivatives thereof. Of these, the present invention is preferably prostaglandin E1 (PGE ₁ ), which is highly demanded as a fat emulsion, and is particularly effective in PGE ₁ .
A plurality of prostaglandins may be used in combination.
The prostaglandin-containing fat emulsion of the present invention contains prostaglandins. Specifically, the content of prostaglandins in the fat emulsion of the present invention is preferably 0.00001 to 0.01% by mass, more preferably 0.0001 to 0.005% by mass, More preferably, it is 0.0003-0.001 mass%.

<Lecithin>
The fat emulsion of the present invention contains lecithin.
Here, lecithin is phosphatidylcholine itself or a mixture containing at least phosphatidylcholine.
The mixture containing phosphatidylcholine is generally phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, N-acylphosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, lysophosphatidylcholine, lysophosphatidic acid, sphingomyelin, sphingoethanol It is a mixture that may contain an amine or the like.
Lecithin may be a synthetic product or a natural product, and generally includes egg yolk lecithin (lecithin derived from egg yolk, hereinafter the same), soybean lecithin, cottonseed lecithin, rape lecithin, corn lecithin and the like. As lecithin in the present invention, egg yolk lecithin and soybean lecithin are preferable, and egg yolk lecithin is more preferable. Purified egg yolk lecithin obtained by purifying egg yolk lecithin is preferable, and highly purified egg yolk lecithin is more preferable. The lecithin in the present invention contains phosphatidylcholine, preferably yolk lecithin having a phosphatidylcholine content of 96% or more, more preferably egg yolk lecithin having a phosphatidylcholine content of 98% or more, and is preferably used for a fat emulsion for intravenous injection. be able to.
As the yolk lecithin having a phosphatidylcholine content of 98% or more, those listed in the Pharmaceutical Additives Dictionary 2007 (Pharmaceutical Daily) can be used. Is PC-98N (manufactured by Kewpie Co., Ltd.).

  The content of lecithin in the fat emulsion of the present invention is preferably 100 to 20000 times by mass, more preferably 500 to 10000 times by mass, and 1000 to 5000 times by mass the content of the prostaglandins. It is particularly preferred. The lecithin content is preferably 0.1% by mass or more, more preferably 0.2% by mass or more, and more preferably 0.3% by mass or more based on the fat emulsion. It is still more preferable that it is 0.5 mass% or more, and it is especially preferable that it is 1.2 mass% or more. Moreover, it is preferable that it is 3 mass% or less, and it is more preferable that it is 2 mass% or less. When the content of lecithin is within this range, the emulsion stability is high, and prostaglandins that are liberated in water in the fat emulsion are reduced, and a high medicinal effect is obtained.

<Oil component>
The fat emulsion of the present invention contains an oil component.
As the oil component used in the present invention, fatty acid glycerides (monoglyceride, diglyceride, triglyceride, and a mixture of these) can be preferably used.
As the fatty acid glyceride, both medium chain fatty acid glycerides and long chain fatty acid glycerides can be used.
Here, the medium chain fatty acid glyceride is a condensate of a fatty acid having 6 to 12 carbon atoms and glycerin, for example, TCG-M (Higher Alcohol Industry), Kurodamol GTCC (Crowda Japan), Coconut MK (Kao), Coconut. RK (Kao), Sunfat MCT-7 (Taiyo Kagaku), Derios (Cognis Japan), Panacet (Nippon Oil & Fats), Miglyol 810 (Mitsuba Trade), Miglyol 812 (Mitsuba Trade), Myrritol 318 (Cognis Japan), Panacet 810 (Oilization industry).
Long chain fatty acid glycerides are condensates of fatty acids having 14 or more carbon atoms and glycerin, such as soybean oil, olive oil, sesame oil, rapeseed oil, peanut oil, sunflower oil, corn oil, safflower oil, cottonseed oil and the like. It is done. Of these, soybean oil, olive oil, and sesame oil are preferable, and soybean oil is particularly preferable.
These fatty acid glycerides may be further purified by steam distillation or the like.
The content of the oil component in the present invention is preferably 0.01 to 10% by mass in the fat emulsion from the viewpoint of preventing hydrolysis of lecithin and maintaining the emulsification stability and transparency. -5% by mass is more preferable, and 0.01-2% by mass is particularly preferable. On the other hand, from the viewpoint of further reducing coarse particles generated in a range that can be injected intravenously, the content of the oily component is preferably 0.01 to 10% by mass, preferably 0.01 to 5% by mass in the fat emulsion. More preferably, it is particularly preferably 2 to 5% by mass.

<Mass ratio of lecithin to oil component>
In the fat emulsion of the present invention, the content of lecithin is preferably 0.15 to 50 times by mass of the content of the oil component from the viewpoints of suppression of particle size change over time and emulsion stability. It is more preferably 5 to 20 times by mass, particularly preferably 0.7 to 10 times by mass, and most preferably 0.7 to 6 times by mass. On the other hand, from the viewpoint of further reducing coarse particles generated in a range that can be injected intravenously, the content of the lecithin is preferably 0.15 to 50 times by mass of the content of the oil component. 2-10 mass times is more preferable, it is especially preferable that it is 0.3-1 mass times, and it is most preferable that it is 0.3-0.7 mass times.

<Higher fatty acid>
In the fat emulsion of the present invention, a higher fatty acid may be blended for the purpose of improving the emulsion stability.
Here, the higher fatty acid is a fatty acid having 10 or more carbon atoms, and may be either a saturated or unsaturated fatty acid. In the present invention, the higher fatty acid functions as an emulsification aid and has a function of improving the emulsion stability of the fat emulsion. Preferred examples of the higher fatty acid used in the present invention include oleic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid and the like, and oleic acid is particularly preferred.
The fat emulsion contains a higher fatty acid, and the content of the higher fatty acid is preferably 0.06 times by mass or less, more preferably 0.0001 to 0.06 times by mass with respect to the content of lecithin. The amount is preferably 0.0001 to 0.03 times by mass, more preferably 0.0001 to 0.01 times by mass, and most preferably not substantially added.
Here, “substantially not added” means that it is not added for the purpose of blending. For example, free higher fatty acids generated by decomposition of oil components or phospholipids, or free higher fatty acids contained by unintentional contamination. Fatty acids are excluded.

<Emulsifier and dispersant>
In the fat emulsion of the present invention, an emulsifier or a dispersant may be further added for the purpose of improving the emulsion stability.
Examples of the emulsifier include poloxamer (polyoxyethylene-polyoxypropylene copolymer), polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan mono Palmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monooleate, 12-hydroxystearic acid polyoxyethylene ester, d-alpha-tocopheryl polyethylene glycol succinate, sorbitan fatty acid Examples include esters and sorbitan sesquioleate.
Examples of the dispersant include human serum albumin, purified gelatin, polyvinyl pyrrolidone, ursodeoxycholic acid, ursodeoxycholic acid salt, desoxycholic acid, desoxycholic acid salt and the like.
The amount of these emulsifiers and dispersants is not particularly limited as long as it does not affect the stability of the fat emulsion, but when added, it is generally at least 0.1 mass times the oil component and 20 masses. It is preferably 2 times or less, more preferably 10 times or less, and still more preferably 5 times or less.

<Other ingredients>
In the fat emulsion according to the present invention, an isotonic agent (for example, glycerin, glucose, sodium chloride), an antioxidant (for example, dibutylhydroxyanisole, dibutylhydroxytoluene, α-tocopherol, D-sorbitol), pH, if necessary. A preparation agent (sodium hydroxide, hydrochloric acid, phosphoric acid) may be contained.

<Grain size of fat emulsion>
The average particle size (immediately after emulsification) of the fat emulsion of the present invention measured by a dynamic light scattering method is preferably 30 to 150 nm, more preferably 30 to 120 nm, and particularly preferably 30 to 100 nm. preferable. By setting the particle size within the above range, the transparency of the fat emulsion is improved, so that it is easy to find foreign substances and microbial contamination, and it is possible to easily find a formulation that has a problem in use in clinical settings. It becomes. Furthermore, since filtration sterilization becomes possible, it is preferable also from the viewpoint of reduction of decomposition products. When the fat emulsion of the present invention is sterilized by filtration, it can pass through the filter for sterilization by filtration without clogging if the particle size of the fat emulsion is within the above range.

The particle size can be achieved by controlling the processing pressure and the number of processing using an emulsifying device to be described later.
Here, the particle size of the fat emulsion can be measured with a commercially available particle size distribution meter or the like. Particle size distribution measurement methods include optical microscopy, confocal laser microscopy, electron microscopy, atomic force microscopy, static light scattering, laser diffraction, dynamic light scattering, centrifugal sedimentation, and electrical pulse measurement. Methods, chromatographic methods, ultrasonic attenuation methods and the like are known, and devices corresponding to the respective principles are commercially available.
In the particle size measurement in the present invention, it is preferable to apply a light scattering method, more preferably a dynamic light scattering method or a laser diffraction method, from the particle size range and ease of measurement. As a commercially available measuring device using dynamic light scattering, Nanotrac UPA (Nikkiso Co., Ltd.), dynamic light scattering type particle size distribution measuring device LB-550 (Horiba, Ltd.), a concentrated particle size analyzer FPAR-1000 (Otsuka Electronics Co., Ltd.) etc. are mentioned.
In particular, the particle diameter of the fat emulsion in the present invention is a value measured using FPAR-1000, and specifically, the median diameter of the scattering intensity distribution obtained by the Contin method is defined as the particle diameter.

<PH of fat emulsion>
The pH of the fat emulsion of the present invention is preferably in the range of 4.5 to 6.0, more preferably in the range of pH 4.8 to 5.8, and preferably in the range of pH 5.0 to 5.5. Particularly preferred. When the pH is within this range, the stability of the prostaglandin can be further increased. Below pH 4.5, not only does the stability of the prostaglandin decrease, but the emulsion stability of the fat emulsion may also decrease. On the other hand, if the pH exceeds 6.0, the stability of prostaglandins decreases as the pH increases.
The hydrogen ion exponent pH is at 25 ° C.

<Method for producing fat emulsion>
The fat emulsion of the present invention can be produced, for example, by emulsifying a mixture of prostaglandins, an oil component and lecithin by adding water as necessary. The production method of the fat emulsion of the present invention is not particularly limited, but after emulsification using a normal emulsifier using a shearing action such as a stirrer, impeller stirring, homomixer, continuous flow type shearing device, etc., a high pressure homogenizer is used. It is particularly preferable to use two or more types of emulsifiers together by a method such as passing through. By using a high-pressure homogenizer, the emulsion can be arranged into even more uniform droplets of fine particles.

Examples of the high-pressure homogenizer include a chamber-type high-pressure homogenizer having a chamber in which a flow path for processing liquid is fixed, and a homogeneous valve-type high-pressure homogenizer having a homogeneous valve. Among these, the homogeneous valve type high-pressure homogenizer can easily adjust the width of the flow path of the processing liquid, so the pressure and flow rate during operation can be set arbitrarily, and the operation range is wide. In particular, it is widely used in the emulsification field such as food and cosmetics. On the other hand, although the degree of freedom of operation is low, a chamber type high-pressure homogenizer is used for applications that require ultra-high pressure because a mechanism for increasing pressure is easy to make.
Examples of the chamber type high-pressure homogenizer include a microfluidizer (manufactured by Microfluidics), a nanomizer (manufactured by Yoshida Kikai Kogyo Co., Ltd.), an optimizer (manufactured by Sugino Machine Co., Ltd.), and the like.
As the homogeneous valve type high-pressure homogenizer, Gorin type homogenizer (manufactured by APV), Lanier type homogenizer (manufactured by Lanier), high-pressure homogenizer (manufactured by Niro Soabi), homogenizer (manufactured by Sanwa Machinery Co., Ltd.), high-pressure homogenizer ( Izumi Food Machinery Co., Ltd.), ultra-high pressure homogenizer (manufactured by Ika), and the like.

  Dispersion by the high-pressure homogenizer is considered to be due to a large shear force generated when the liquid passes through a very narrow (small) gap at a high speed. The magnitude of this shearing force is approximately proportional to the pressure, and the higher the pressure, the stronger the shearing force applied to the particles dispersed in the liquid, that is, the dispersion force. However, since most of the kinetic energy when the liquid flows at high speed is converted to heat, the higher the pressure, the higher the temperature of the liquid, which may promote the deterioration of the dispersion components and the reaggregation of the particles. . Therefore, there is an optimum point for the pressure of the high-pressure homogenizer, and it is considered that the optimum point varies depending on the object to be dispersed and the particle size to be aimed. In the present invention, the homogenizer pressure is preferably 50 MPa or more, more preferably 50 to 250 MPa, and still more preferably 100 to 250 MPa. It is possible to control the particle size by performing dispersion under a high pressure condition in this range. preferable. The emulsion is preferably cooled through some cooler within 30 seconds, preferably within 3 seconds immediately after passing through the chamber.

  Another effective method for obtaining a fine emulsion is the use of an ultrasonic homogenizer. Specifically, a method of irradiating ultrasonic waves at a frequency of 15 to 40 kHz after emulsification using a normal emulsification apparatus using a shearing action as described above has been known. Examples of high-power ultrasonic homogenizers include ultrasonic homogenizers US-1200T, RUS-1200T, and MUS-1200T (above, manufactured by Nippon Seiki Seisakusho), ultrasonic processors UIP2000, UIP-4000, UIP-8000. , UIP-16000 (above, manufactured by Heelscher). By using these high-power ultrasonic irradiation devices, fine emulsification can be achieved by setting the energy density of the dispersion part to 100 W / cm 2 or more, preferably 120 W / cm 2 at a frequency of 25 kHz or less, preferably 15 to 20 kHz. Is possible.

  An ultrasonic homogenizer may be used in combination with the ultrahigh pressure homogenizer. That is, after emulsification using a normal emulsifier using a shearing action, ultra-high pressure homogenizer dispersion is performed to increase the efficiency of ultra-high pressure homogenizer dispersion, thereby reducing the number of passes and reducing coarse particles. A high-quality emulsion can be obtained. Moreover, after carrying out ultrahigh pressure homogenizer emulsification, coarse particles can be reduced by further irradiating with ultrasonic waves. Also, these steps can be repeated in an arbitrary order such as alternately performing ultra-high pressure dispersion and ultrasonic irradiation.

<Form of preparation>
The invention also relates to an injectable formulation comprising a prostaglandin-containing fat emulsion.
The preparation form of the fat emulsion is not particularly limited as long as it is suitable as an injection preparation. Specific examples include preparations filled in containers such as ampule tubes, vials, prefilled syringes, bags and the like.
The capacity, material and shape of the container can be appropriately selected from the viewpoint of the filling amount of the prostaglandin-containing fat emulsion and ease of use. Further, it is preferable to reduce the gas in the voids during filling or to substitute with nitrogen because the stability is further improved.
Further, the inside of these containers is preferably subjected to a surface treatment such as a silicote treatment.

Among the above preparations, ampule tube preparations or prefilled syringe preparations are preferable, and prefilled syringe preparations are more preferable.
The present invention also relates to a prefilled syringe formulation in which a prostaglandin-containing fat emulsion or injectable formulation is filled in a syringe.
Prefilled syringe preparations are prefilled in syringes at the concentration and amount used to prevent dilution errors during preparation, mistakes in drug mixing, bacterial contamination and decreased activity due to divided use and storage, reducing the risk of infection It is also preferable from the viewpoint of improving labor productivity of medical workers.

The syringe used for the injectable preparation and the prefilled syringe preparation is not particularly limited, and a conventionally known one can be suitably used.
The syringe of the present invention can be composed of a syringe (syringe) and a gasket. The syringe is a cylindrical body having a gasket fitted in an opening on one end (base end open portion) side and a discharge port for discharging the prostaglandin-containing fat emulsion by pushing the gasket on the other end (tip open portion) side. It is preferable. A cap is usually fitted to the discharge port before use, and the chemical solution can be held together with the gasket. In addition, a plunger rod may be connected to the gasket. The length from the proximal end of the syringe to the distal end of the cap and the inner diameter of the syringe can be appropriately determined depending on the volume of the chemical solution (prostaglandin-containing fat emulsion) to be filled.

Examples of the material of the syringe and plunger rod used in the present invention include ordinary plastic or glass. Examples of the plastic include polyolefin (eg, polyethylene, polypropylene), cyclic polyolefin, and the like. The volume can be appropriately determined according to the clinical use amount of this preparation. Specifically, those having a volume of 1 to 20 mL are exemplified.
If necessary, a glass or plastic syringe can be treated with silicon or the like by baking or coating to reduce the sliding resistance of the gasket and facilitate the movement of the gasket in the syringe. It is preferable from the viewpoint of easy connection with the injection needle or the vascular catheter that the open end portion where the discharge port is formed has a luer tip shape corresponding to the shape of the device to be connected.
The cap used in the present invention is not particularly limited, but is preferably an elastic cap made of rubber or a thermoplastic elastomer. The gasket may preferably be provided with means to which the plunger rod is coupled, for example a screw part. Moreover, the plunger rod and the gasket may be integrally formed.
In the administration of this preparation, the fat emulsion of the present invention may be intravenously injected as it is as an injection preparation, or may be administered by infusion after appropriately diluting with an infusion solution such as physiological saline.

  Examples of the method for sterilizing the fat emulsion include high-pressure steam sterilization and filter sterilization. From the viewpoint of inhibiting the decomposition of the drug during sterilization and inhibiting the emulsion breakage, the fat emulsion is preferably sterilized by filtration. It is also preferred to sterilize the liquid component itself or the liquid component and / or solid component solution before preparing the fat emulsion.

The present invention also relates to a method for producing an injectable preparation comprising a step of filter sterilizing a prostaglandin-containing fat emulsion.
Filter sterilization can usually be performed after preparing a prostaglandin-containing fat emulsion.
As a filter used for filter sterilization, a filter having a pore size of 0.01 to 0.22 μm is preferable, and a filter for filter sterilization having a 0.1 to 0.22 μm is more preferable. Commercially available products can be used as the filter for filter sterilization. Specific examples of filters for filter sterilization include Zaltopore 2, Zaltoblanc (Sartorius Stedim Japan), Durapore (Nihon Millipore), Fluorodyne II, Superpore, Fluorodyne EX, Ultipor N66, and Podyne (Nihon Pole). Can be mentioned.
Further, when sterilizing by filtration, a differential pressure can be applied with a pressure filter, and the differential pressure is preferably 0.01 MPa to 1 MPa, more preferably 0.05 MPa to 0.3 MPa. Here, the differential pressure refers to a difference in pressure between the primary side (inlet side) and the secondary side (outlet side) of filtration. The pressure on the secondary side is usually atmospheric pressure.
These conditions can be appropriately selected depending on the concentrations of prostaglandins, oil components, and lecithin used, and the types and concentrations of additives that can be included.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.
In this specification, “%” means “% by mass” unless otherwise specified.

Example 1
Prostaglandin E1 (Alprostadil, manufactured by Daiichi Fine Chemical Co., Ltd.) was dissolved in ethanol at a concentration of 10 mg / ml. Of these, 42 μl (420 μg as prostaglandin E1), 0.252 g of soybean oil (manufactured by Kaneda Corp.), and 0.504 g of highly purified egg yolk lecithin PC-98N (manufactured by Kewpie Corp.) were mixed. Separately, a 2.5 mass% glycerin aqueous solution obtained by mixing Japanese pharmacopoeia concentrated glycerin (manufactured by Kao Corporation) and purified water was added to this mixture so as to be 60 ml in total and stirred. This was roughly dispersed with a homomixer (15000 rpm, 12 min), and further emulsified with a chamber type high-pressure homogenizer. Dispersion 1 was prepared by adding a citric acid / sodium citrate buffer solution having a final concentration of 0.5 mM to the emulsion and adjusting the pH to 5.0.

(Examples 2-11, Comparative Examples 1-4)
In the same manner as in Example 1, dispersions 2 to 15 having the compositions shown in Table 1 were prepared. In addition, the quantity of hydrochloric acid of Comparative Examples 1-3 is the quantity added so that it may become pH described in a table | surface as mentioned above.

(Comparative Example 5: equivalent to existing drugs)
Although it was the same as that of Example 1, the dispersion liquid 16 was produced with the composition of Table 1. The oleic acid was preliminarily dissolved in soybean oil and emulsified, and then the pH was adjusted to 5.3 with sodium hydroxide.

(Evaluation of fat emulsion)
<Particle size measurement>
The dispersions (fat emulsions) prepared in the examples and comparative examples shown in Table 1 were diluted 10 to 100 times with purified water immediately after emulsification, and a light scattering particle size distribution analyzer (FPAR-1000, Otsuka). The median diameter of the scattering intensity distribution obtained by the Contin method was recorded as the particle diameter.

<PH>
About the dispersion liquid prepared by the Example and comparative example of Table 1, pH was measured with the compact pH meter (made by HORIBA) with the undiluted | stock solution, and was recorded as pH.

<Change in particle size>
Dispersions 1 to 16 were dispensed into 2 ml silicoat vials (CS-10, manufactured by Fuji Glass), and sealed with rubber stoppers and aluminum seals. The particle size measurement described above was performed on the dispersion after storage at 40 ° C. for 14 days. The change with respect to the particle size immediately after the preparation is evaluated according to the following criteria, and the results are shown in Table 1.
◎: No increase in particle size was observed ○: Increase in particle size was 10 nm or less △: Increase in particle size was more than 10 nm and less than 20 nm ×: Increase in particle size was 20 nm or more

(Examples 12-20, Comparative Examples 6-8)
<PGE ₁ remaining rate evaluation>
Dispersion liquids 1-7, 10, 11 and comparative dispersion liquids 13, 14, and 16 were dispensed in 2 ml portions into silicoat vials (CS-10, manufactured by Fuji Glass Co., Ltd.) with rubber stoppers and aluminum seals. . The prostaglandin E1 was quantified by high performance liquid chromatography in the dispersion after storage at 40 ° C. for 7 days and 14 days. At this time, 1-naphthol was used as an internal standard for quantification. The residual rate (%) of PGE ₁ was calculated by the following formula. The results are shown in Table 2.
PGE ₁ remaining rate (%) = (PGE ₁ concentration after time / initial PGE ₁ concentration) × 100

As shown in the examples of Table 1, in the dispersions 1 to 11 and 16 to which citric acid was added, it was found that the increase in the particle size with time was within an allowable range or was not recognized, and the emulsions were stable. It was. On the other hand, in dispersions 12 to 15 using an acid having a small pKa (lactic acid has a pKa of 3.79 at 25 ° C. of 3.79), an increase in particle size over time is observed, and stability over time is obtained. There wasn't.
Furthermore, as shown in the examples of Table 2, the dispersions 1 to 7, 10 and 11 to which citric acid was added found an unexpected effect that the stability of the prostaglandin itself was improved. From comparison with the dispersion 16 corresponding to the existing drug, it can be estimated that the shelf life is about three times or more that of the existing drug. On the other hand, in the dispersions 13 and 14 using hydrochloric acid having a small pKa, the prostaglandin residual rate is higher at the initial stage of storage than the dispersion 16 corresponding to the existing drug, but after 14 days, the prostaglandin residual rate is Was found to be significantly reduced.

  Furthermore, as shown in Table 1, all of the dispersions 1 to 11 of the present invention have a particle size of 150 nm or less and are semitransparent in appearance. Therefore, the prostaglandin-containing fat emulsion of the present invention can be expected not only to extend the storage period but also to facilitate drug management such as contamination with foreign substances because of its high transparency.

<Visual evaluation of the coarse particles of the diluted solution>
Dispersions 1, 7, 10, and 11 were collected in appropriate amounts in 5 ml vials (colorless and transparent) and diluted 1 to 6 times with purified water. A vial was placed between the fluorescent lamp and the naked eye 1 m or more away, and the diluted solution was visually observed from the side of the vial. At this time, coarse particles were visually evaluated according to the following criteria to the extent that visible particles can be seen in the liquid, and the results are shown in Table 3.
× Precipitation is clearly visible △ Some fine particles are visible ○ Very few fine particles are visible ◎ No visible particles

<Stability evaluation of ampoule preparation and prefilled syringe preparation>
The dispersion 10 was stored at 40 ° C. for 7 days in the same manner as in Example 19 except that the container shown in Table 4 was used, and the PGE ₁ residual rate was determined. The results are shown in Table 4.

<Sterilization of dispersion>
10 mL of the dispersion 10 was dispensed into a silicoat vial (CS-10, manufactured by Fuji Glass), and a rubber stopper and an aluminum seal were provided. This was autoclaved using an autoclave (Autoclave SP200, Yamato Scientific Co., Ltd.) with a holding time at 121 ° C. of 1 minute. When the appearance of this liquid was observed, separation of oil droplets was observed.
Using 500 ml of the dispersion 10 as a sterilizing filter, Sartopore 2 (diameter 47 mm, pore diameter 0.2 μm, Sartorius Stedim Japan) was applied with a differential pressure of 0.2 MPa with a pressure filter, and sterilized by filtration. . The entire dispersion could be sterilized by filtration without clogging. When the appearance, particle size, pH, and PGE ₁ amount were measured in the same manner as described above, no significant change was observed before and after filtration.

Claims (14)

A fat emulsion comprising a prostaglandin, an oil component, lecithin, a water-soluble acid having a dissociation group having a pKa of 4.0 to 6.0 or a salt thereof, and water,
A prostaglandin-containing fat emulsion having a lecithin content of 0.15 times by mass or more of the oil component and a pH of 4.5 to 6.0.   The prostaglandin-containing fat emulsion according to claim 1, wherein the water-soluble acid or a salt thereof is contained in an amount of 0.01 mmol / L to 5 mmol / L.   The prostaglandin-containing fat emulsion according to claim 1 or 2, wherein the water-soluble acid is citric acid.   The prostaglandin-containing fat according to any one of claims 1 to 3, wherein the content of lecithin in the fat emulsion is 0.3 mass times or more with respect to the content of the oil component. emulsion.   The prostaglandin-containing fat emulsion according to any one of claims 1 to 4, wherein the content of the oil component in the fat emulsion is 0.01 to 5% by mass in the fat emulsion.   The prostaglandin-containing fat emulsion according to any one of claims 1 to 5, wherein the lecithin is egg yolk lecithin containing 98% by mass or more of phosphatidylcholine.   The prostaglandin-containing fat emulsion according to any one of claims 1 to 6, wherein the oil component is soybean oil.   The fat emulsion further contains a higher fatty acid, and the content of the higher fatty acid in the fat emulsion is 0.06 mass times or less with respect to the content of the lecithin. The prostaglandin-containing fat emulsion according to one item.   The prostaglandin-containing fat emulsion according to any one of claims 1 to 8, wherein the average particle diameter of the fat emulsion measured by a light scattering method is 30 to 150 nm.   The prostaglandin-containing fat emulsion according to any one of claims 1 to 9, wherein the prostaglandin is prostaglandin E1.   The prostaglandin-containing fat emulsion according to any one of claims 1 to 10, wherein the prostaglandin-containing fat emulsion is a filter-sterilized prostaglandin-containing fat emulsion.   The formulation for injection containing the prostaglandin containing fat emulsion as described in any one of Claims 1-11.   A prefilled syringe preparation, wherein the prostaglandin-containing fat emulsion according to any one of claims 1 to 11 or the injection preparation of claim 12 is filled in a syringe.   The method for producing an injectable preparation according to claim 12 or 13, comprising a step of filter sterilizing the prostaglandin-containing fat emulsion according to claim 12 or 13.