JP4092507B2 - Products containing prostaglandins - Google Patents

Description

  The present invention provides an aqueous solution containing a prostaglandin derivative that is easily adsorbed to a container and hardly soluble in water, by storing it in a resin container molded using a polymer alloy of polyethylene terephthalate and polyarylate. The present invention relates to a prostaglandin-containing product that suppresses a decrease in the content of the prostaglandin derivative in a liquid.

  Prostaglandins are substances having physiological activity, and many prostaglandin derivatives have been researched and developed. For example, Patent Document 1, Patent Document 2, and Patent Document 3 disclose prostaglandin derivatives useful as therapeutic agents for glaucoma and ocular hypertension.

  However, some prostaglandin derivatives are easily adsorbed on containers and have poor water-soluble properties. For aqueous liquids containing prostaglandin derivatives having such properties, adsorption to containers There is a need to improve the solubility and solubility in water. On the other hand, as materials for resin containers for storing aqueous liquids such as eye drops, for example, polyethylene, polypropylene, polyethylene terephthalate, polyvinyl chloride, acrylic resin, polystyrene, polymethyl methacrylate, nylon 6 and the like are known.

Patent Document 4 discloses that a prostaglandin product containing a prostaglandin and a surfactant is more stable when stored in a polypropylene resin container than when stored in a polyethylene resin container. Patent Document 5 discloses that prostaglandins can be stably stored in a resin container containing polypropylene. Patent Document 6 improves the solubility of prostaglandin derivatives in water and the adsorptivity to resin containers by adding a nonionic surfactant such as polysorbate 80 or polyoxyethylene hydrogenated castor oil 60 to an aqueous liquid. However, the resin container for storing the aqueous liquid agent itself has not been studied.
Japanese Patent No. 2721414 Japanese Patent Laid-Open No. 2-108 JP 11-71344 A Japanese translation of PCT publication No. 2002-520368 International Publication No. 02/22106 Pamphlet JP 2002-161037 A

  Prostaglandin, which is an active ingredient in aqueous liquids, focusing on the material of resin containers in order to stably store aqueous liquids that contain prostaglandin derivatives that are easily adsorbed to containers and are hardly soluble in water It is an important issue to suppress a decrease in the content of the derivative.

  Therefore, the present inventor conducted earnest research on the material of a resin container suitable for preserving an aqueous solution containing a prostaglandin derivative that is easily adsorbed to a container and hardly soluble in water. Polyethylene terephthalate It was found that the content of the prostaglandin derivative in the aqueous liquid can be remarkably suppressed when stored in a resin container molded using a polymer alloy of styrene and polyarylate.

That is, the present invention
(1) An aqueous liquid preparation containing a prostaglandin F2α derivative having a fluorine atom in the molecule is obtained by using polyethylene terephthalate and polyarylate having a polyethylene terephthalate / polyarylate ratio of 1/2 to 2/1. A prostaglandin-containing product that suppresses a decrease in the content of the prostaglandin F2α derivative in the aqueous liquid by storing it in a resin container molded using an arylate polymer alloy;
(2) The prostaglandin-containing product according to (1), wherein the prostaglandin F2α derivative having a fluorine atom in the molecule is a difluoroprostaglandin F2α derivative,
(3) A prostaglandin F2α derivative having a fluorine atom in its molecule is 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranor prostaglandin F2α, 16- (3 -Chlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin F2α, 16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro- The prostaglandin-containing product according to (1), which is 17,18,19,20-tetranorprostaglandin F2α, or an alkyl ester thereof, or a salt thereof;
(4) An aqueous liquid preparation containing a prostaglandin F2α derivative having a fluorine atom in the molecule thereof, wherein the ratio of polyethylene terephthalate to polyarylate is polyethylene terephthalate / polyarylate = 1/2 to 2/1. A method for suppressing a decrease in the content of the prostaglandin F2α derivative in an aqueous liquid by storing it in a resin container molded using a polymer alloy of arylate,
(5) The method according to (4) above, wherein the prostaglandin F2α derivative having a fluorine atom in the molecule is a difluoroprostaglandin F2α derivative, and
(6) A prostaglandin F2α derivative having a fluorine atom in the molecule is 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranor prostaglandin F2α, 16- (3 -Chlorophenoxy) -15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin F2α, 16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro- The method according to the above (4), which is 17,18,19,20-tetranorprostaglandin F2α, or an alkyl ester thereof, or a salt thereof.
About.

  The prostaglandin derivative that is the subject of the present invention is not particularly limited as long as it is a prostaglandin derivative that is easily adsorbed on a container and is hardly soluble in water (hereinafter referred to as “the present prostaglandin derivative”). Preferred examples include prostaglandin F2α derivatives having fluorine atoms in the molecule disclosed in JP-A-11-71344 or JP-A-10-251225, more preferably difluoro disclosed in JP-A-11-71344. A prostaglandin F2α derivative is exemplified, and particularly preferred is a difluoroprostaglandin F2α derivative having two fluorine atoms at the 15-position disclosed in JP-A-11-71344. As a particularly preferred specific example, 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin F2α, 16- (3-chlorophenoxy) -15-deoxy-15, 15-difluoro-17,18,19,20-tetranorprostaglandin F2α, 16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18,19,20-tetranorprosta Glandin F2α, or an alkyl ester thereof, or a salt thereof. Specific examples of the alkyl ester include lower alkyl esters such as methyl ester, ethyl ester, propyl ester, isopropyl ester, tert-butyl ester, pentyl ester and hexyl ester.

  Prostaglandin derivatives are likely to be adsorbed in a container when the prostaglandin derivative is stored in a container as an aqueous solution (the content is the amount of the prostaglandin dissolved in the aqueous solution). For example, the concentration of the aqueous solution of the prostaglandin derivative is 0.001% (% indicates mass% unless otherwise specified). In the case of.), After storage in a polyethylene container or a polypropylene container at 60 ° C. for one week, 10% or more of the same compound is adsorbed on the container.

  In addition, a prostaglandin derivative hardly soluble in water means a substance that requires 1000 ml or more of water to dissolve 1 g of the prostaglandin derivative (13th revision Japanese Pharmacopoeia Manual A-51 (1996) )).

  In the present invention, a resin container molded using a polymer alloy of polyethylene terephthalate and polyarylate refers to a resin container obtained by polymerizing polyethylene terephthalate and polyarylate. Examples include copolymerization, graft copolymerization, and polymer blends. Polyethylene terephthalate is a condensate of ethylene glycol and terephthalic acid or terephthalic acid diester, and polyarylate is a condensate of bisphenol A with terephthalic acid, isophthalic acid or esters thereof. The polyethylene terephthalate and polyarylate of the present invention may be obtained by any condensation method.

  The polymer alloy of polyethylene terephthalate and polyarylate according to the present invention may be obtained by any of block copolymerization, graft copolymerization, and polymer blend techniques. For example, a mixture of polyethylene terephthalate and polyarylate is mixed with an alkali metal salt or a heat stabilizer. It can obtain by adding an additive etc. and heating. Examples of commercially available polymer alloys of polyethylene terephthalate and polyarylate include U-8000 and U-8400H manufactured by Unitika.

  The ratio of each component in the polymer alloy of polyethylene terephthalate and polyarylate is not particularly limited, but is preferably polyethylene terephthalate / polyarylate = 1/4 to 4/1, more preferably polyethylene terephthalate / polyarylate = 1 / 3 to 3/1, more preferably polyethylene terephthalate / polyarylate = 1/2 to 2/1.

  A resin container molded using a polymer alloy of polyethylene terephthalate and polyarylate is obtained by molding a polymer alloy of polyethylene terephthalate and polyarylate, and examples of the molding process include injection blow It is done. The shape of the container is not limited.

  In the present invention, a nonionic surfactant may be blended in the aqueous liquid preparation, and the nonionic surfactant is added to the present prostaglandin in the aqueous liquid preparation by improving the water solubility of the present prostaglandin derivative. Suppressing a decrease in the content of gin derivatives. Specific examples of the nonionic surfactant include polysorbate 80 [polyoxyethylene sorbitan monooleate], polysorbate 60 [polyoxyethylene sorbitan monostearate], polysorbate 40 [polyoxyethylene sorbitan monopalmitate], polyoxyethylene Polyoxyethylene fatty acid esters such as sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65 [polyoxyethylene sorbitan tristearate], polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene Hardened castor oil 50, polyoxyethylene hardened castor oil such as polyoxyethylene hardened castor oil 60, polyoxyethylene (160) polyoxypropylene (30) Recall [Pluronic F68], Polyoxyethylene (42) Polyoxypropylene (67) Glycol [Pluronic P123], Polyoxyethylene (54) Polyoxypropylene (39) Glycol [Pluronic P85], Polyoxyethylene (196) Polyoxy Polyoxyethylene polyoxypropylene glycols such as propylene (67) glycol [Pluronic F127], polyoxyethylene (20) polyoxypropylene (20) glycol [Pluronic L-44], stearic acid polyoxyl 40, sucrose fatty acid esters, etc. Preferred examples include polysorbate 80 [polyoxyethylene sorbitan monooleate], polyoxyethylene hydrogenated castor oil 60, and polyoxyl 40 stearate. That. These nonionic surfactants can be used alone or in combination of two or more. Particularly preferred nonionic surfactants include polysorbate 80 [polyoxyethylene sorbitan monooleate] or polyoxyethylene hydrogenated castor oil 60, which is widely used as an additive for eye drops.

  The prostaglandin-containing product of the present invention is desirably present in a state in which the prostaglandin is dissolved in water, and the blending amount of the prostaglandin may be appropriately selected in consideration of the use of an aqueous liquid preparation and the like. . For example, in the case of an eye drop, the compounding amount (concentration) of the present prostaglandin derivative in the eye drop can be appropriately selected according to the target disease, symptom, etc., but is preferably 0.00005 to 0.05%. In addition, when a nonionic surfactant is added to the ophthalmic solution, the amount of the nonionic surfactant can be appropriately increased or decreased depending on the amount of the prostaglandin derivative. From the viewpoint of improving water solubility, the concentration of the nonionic surfactant is preferably set to 5 times or more of the concentration of the present prostaglandin derivative, and when it is necessary to further increase the water solubility, it is set to 10 times or more. It is particularly preferable to do this.

  When the prostaglandin-containing product of the present invention is an eye drop, in addition to the above nonionic surfactant, an antioxidant such as ethylenediaminetetraacetic acid and dibutylhydroxytoluene, sodium chloride, potassium chloride, calcium chloride, glycerin, Isotonic agents such as propylene glycol, buffers such as boric acid, borax, citric acid, disodium hydrogen phosphate, ε-aminocaproic acid, benzalkonium chloride, chlorhexidine gluconate, benzethonium chloride, sorbic acid, sorbic acid Various pharmaceutically acceptable additives such as preservatives such as potassium, ethyl paraoxybenzoate, butyl paraoxybenzoate and the like can be blended. The method for preparing the ophthalmic solution containing the present prostaglandin derivative does not require any special technique or operation, and can be prepared by a widely used method. The pH of the ophthalmic solution is 3 to 8, particularly 4 to 4. 7 is preferable.

  As will be described in detail in the section of the storage stability test described later, if the aqueous liquid preparation of the present invention is stored in a resin container formed using a polymer alloy of polyethylene terephthalate and polyarylate, a polyethylene container, a polypropylene container and The decrease in the content of the present prostaglandin derivative in the aqueous liquid can be significantly suppressed as compared with the case where it is stored in any of the polyethylene terephthalate containers.

In the following, a storage stability test (60 ° C., one week) is carried out to explain the present invention in detail, but this is for better understanding of the present invention and limits the scope of the present invention. is not.

[Storage stability test]
(1) Preparation of ophthalmic solution As a representative example of the present prostaglandin derivative, 0.0015% of 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranor prostaglandin F2α Isopropyl ester (hereinafter referred to as the present compound) was used. This compound is dissolved in purified water using a nonionic surfactant (polysorbate 80), and then an osmotic pressure adjusting agent or the like usually used in ophthalmic solutions is blended, so that the osmotic pressure is about 1, and the pH is About 6 eye drops were obtained.

(2) Production of Resin Container The resin container of the present invention is made of polyethylene terephthalate and polyarylate polymer alloy [U-8000 (manufactured by Unitika): polyethylene terephthalate about 45%, polyarylate about 55%] for injection blow. Obtained by molding. In addition, resin containers for comparison are polyethylene [Petrocene 175K (manufactured by Tosoh Corporation), low density polyethylene], polypropylene [J-225W (manufactured by Mitsui Chemicals)] and polyethylene terephthalate [PIFG5H (manufactured by Kanebo Gosei Co., Ltd.)]. Each was obtained by molding with an injection blow. All of the containers are ophthalmic containers of the same shape.

(3) Test method Each resin container obtained in “(2) Production of resin container” was sterilized, and then the ophthalmic solution obtained in “(1) Preparation of ophthalmic solution” was added. Then, these samples were put in an aluminum moisture-proof bag and stored at 60 ° C. for one week, and then the content of the present compound in each resin container was measured by a high performance liquid chromatography method. These results are shown in Table 1. In addition, the Example and comparative example in a table | surface show the average value of each 3 examples. The content of the present compound is based on the content of the present compound after the ophthalmic solution obtained in “(1) Preparation of ophthalmic solution” is added to a glass container and sealed at 5 ° C. for one week (100 %).

* 1: U-8000 (Made by Unitika)
* 2: Petrocene 175K (manufactured by Tosoh Corporation)
* 3: J-225W (Mitsui Chemicals)
* 4: PIFG5H (manufactured by Kanebo Gosei Co., Ltd.)

(4) Discussion As is apparent from Table 1, if this compound is stored in a resin container molded using a polymer alloy of polyethylene terephthalate and polyarylate, it is stored in a polyethylene container, a polypropylene container, or a polyethylene terephthalate container. The content of the present compound is higher than that of the case, and the storage stability is excellent.

Claims (6)

An aqueous liquid containing a prostaglandin F2α derivative having a fluorine atom in the molecule, a polymer of polyethylene terephthalate and polyarylate in which the component ratio of polyethylene terephthalate and polyarylate is polyethylene terephthalate / polyarylate = 1/2 to 2/1 A prostaglandin-containing product that suppresses a decrease in the content of the prostaglandin F2α derivative in an aqueous liquid by storing it in a resin container molded using an alloy. The prostaglandin-containing product according to claim 1, wherein the prostaglandin F2α derivative having a fluorine atom in the molecule is a difluoroprostaglandin F2α derivative. Prostaglandin F2α derivatives having a fluorine atom in the molecule are 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin F2α, 16- (3-chlorophenoxy ) -15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin F2α, 16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18 The prostaglandin-containing product according to claim 1, which is, 19,20-tetranorprostaglandin F2α, or an alkyl ester thereof, or a salt thereof. An aqueous liquid containing a prostaglandin F2α derivative having a fluorine atom in the molecule, a polymer of polyethylene terephthalate and polyarylate in which the component ratio of polyethylene terephthalate and polyarylate is polyethylene terephthalate / polyarylate = 1/2 to 2/1 The method of suppressing the fall of the content rate of this prostaglandin F2 (alpha) derivative in an aqueous liquid agent by preserve | saving in the resin-made containers shape | molded using the alloy. The method according to claim 4, wherein the prostaglandin F2α derivative having a fluorine atom in the molecule is a difluoroprostaglandin F2α derivative. Prostaglandin F2α derivatives having a fluorine atom in the molecule are 16-phenoxy-15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin F2α, 16- (3-chlorophenoxy ) -15-deoxy-15,15-difluoro-17,18,19,20-tetranorprostaglandin F2α, 16-phenoxy-15-deoxy-15,15-difluoro-13,14-dihydro-17,18 , 19,20-tetranorprostaglandin F2α, or an alkyl ester thereof, or a salt thereof.