HK1246167B - Depot preparation containing citric acid ester - Google Patents

Description

Depot formulations containing citrate esters

Technical Field

The present invention relates to a depot preparation containing a trialkyl citrate and/or a trialkyl acetyl citrate, wherein the alkyl group of the ester has 3 to 5 carbon atoms.

The present invention also relates to the above-mentioned depot preparation containing a drug, and particularly relates to a depot preparation containing a compound represented by formula (1) or a salt thereof as a drug.

[In formula (1),

^R1 represents a hydrogen atom, a halogen atom, a hydroxyl group, a _C1-6 alkyl group, a _C1-6 alkyl group substituted by one or more halogen atoms, a _C1-6 alkoxy group, or a _C1-6 alkoxy group substituted by one or more halogen atoms;

R ² represents a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkylcarbonyl group or a C _1-6 alkylcarbonyl group substituted by one or more hydroxyl groups].

The present invention particularly relates to a depot preparation containing isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof as the above-mentioned drug.

Background Art

For example, for invasive drugs such as intravitreal injections, formulations that slowly release the drug from the site of administration after administration, thereby exerting its efficacy over a long period of time, are desired from the perspective of the burden of drug administration on patients. As a means of achieving such formulations, reservoir formulations are known that form a reservoir at the site of drug administration and slowly release the drug from that site.

Patent Document 1 describes that a dexamethasone formulation containing a polymer such as acetyl triethyl citrate (ATEC) and polylactic acid (PLA) exhibits sustained drug release when injected into a release medium, compared to a formulation without the polymer. However, Patent Document 1 does not specifically disclose depot formulations containing trialkyl acetyl citrates other than triethyl acetyl citrate or depot formulations containing trialkyl citrates, nor does it describe sustained drug release when the formulation does not contain a polymer such as PLA.

Patent Documents 2 and 3 disclose injectable preparations containing a solvent and a polymer such as polylactic acid (PLA), but do not specifically disclose depot preparations containing trialkyl citrate and/or trialkyl acetyl citrate, nor do they describe the sustained release of drugs when these preparations do not contain a polymer such as PLA.

Prior art literature

Patent Literature

Patent Document 1: International Publication No. 2013/036309

Patent Document 2: International Publication No. 2005/048989

Patent Document 3: International Publication No. 2004/011054

Summary of the Invention

Problems to be solved by the invention

However, there is a need for a preparation having a higher sustained-release property of a drug than the above-mentioned preparation containing acetyl triethyl citrate in the related art.

In view of the above-mentioned actual situation, the present invention aims to provide a depot preparation that can easily form a depot and maintain the depot state for a long period of time as needed, and to provide a depot preparation that, when containing a drug, slowly releases the drug over a long period of time after administration into the body.

Means for solving problems

To solve the above-mentioned problems, the inventors of the present application conducted intensive research on additives, solvents, etc. used to form a reservoir. As a result, they discovered that a reservoir preparation containing a trialkyl citrate and/or a trialkyl acetyl citrate, wherein the alkyl group of the ester has 3 to 5 carbon atoms, can easily form a reservoir and can maintain the reservoir state for a long time as needed. When the reservoir preparation contains a drug, it can slowly release the drug, thereby completing the present invention.

That is, the present invention relates to the following aspects.

(1) A depot preparation comprising a trialkyl citrate and/or a trialkyl acetyl citrate, wherein the trialkyl citrate and the trialkyl acetyl citrate each have an alkyl group that is the same or different and has 3 to 5 carbon atoms.

(2) The depot preparation according to (1) above, wherein the alkyl group has 4 carbon atoms.

(3) The depot preparation according to (1) above, wherein the trialkyl citrate is tri-n-butyl citrate and the trialkyl acetyl citrate is tri-n-butyl acetyl citrate.

(4) The depot preparation according to any one of (1) to (3) above, further comprising a drug.

(5) The depot preparation according to (4) above, wherein the drug is a compound represented by formula (1) or a salt thereof,

[In formula (1),

^R1 represents a hydrogen atom, a halogen atom, a hydroxyl group, a _C1-6 alkyl group, a _C1-6 alkyl group substituted by one or more halogen atoms, a _C1-6 alkoxy group, or a _C1-6 alkoxy group substituted by one or more halogen atoms;

R ² represents a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkylcarbonyl group or a C _1-6 alkylcarbonyl group substituted by one or more hydroxyl groups].

(6) The depot preparation according to (5) above, wherein in formula (1),

R ¹ represents a C _1-6 alkoxy group or a C _1-6 alkoxy group substituted by one or more halogen atoms;

R ² represents a C _1-6 alkylcarbonyl group or a C _1-6 alkylcarbonyl group substituted by one or more hydroxyl groups.

(7) The depot preparation according to (5) above, wherein in formula (1),

R ¹ represents a C _1-6 alkoxy group substituted by one or more halogen atoms;

R ² represents a C _1-6 alkylcarbonyl group substituted by one or more hydroxyl groups.

(8) The depot preparation according to (5) above, wherein the compound represented by formula (1) is 2-[[[2-[(hydroxyacetyl)amino]-4-pyridyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide or a salt thereof.

(9) The depot preparation according to (4) above, wherein the drug is isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof.

(10) The depot preparation according to (4) above, wherein the drug is nepafenac, dexamethasone, indomethacin, diclofenac sodium, levofloxacin, INCB28050, cyclosporin A, timolol maleate, fluocinolone acetonide, triamcinolone acetonide, Acetonide, Budesonide, Olopatadine, Latanoprost, (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate isopropyl ester, (2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide, or sirolimus.

(11) The depot preparation according to any one of (4) to (10) above, wherein the depot preparation contains 0.001 to 30% (w/w) of the drug.

(12) The depot preparation according to any one of (1) to (11) above, comprising 0.1% (w/w) or more of trialkyl citrate and/or acetyl trialkyl citrate.

(13) The depot preparation according to any one of (1) to (12) above, which does not contain polylactic acid (PLA) and polylactic-co-glycolic acid (PLGA).

(14) The depot preparation according to any one of (1) to (13) above, which does not contain tocopherol.

(15) The depot preparation according to any one of claims (1) to (14), which is used for the prevention and/or treatment of eye diseases.

(16) The depot preparation according to any one of claims (1) to (15), which is used as a preventive and/or therapeutic drug for eye diseases.

(17) The depot preparation as described in (15) or (16) above, wherein the eye disease is age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, retinal artery occlusion, polypoidal choroidal vasculopathy, retinal angiomatous hyperplasia, myopic choroidal neovascularization, diabetic macular edema, ocular tumor, radiation retinopathy, iris rubeosis, neovascular glaucoma, proliferative glaucoma, Vitreoretinopathy (PVR), primary open-angle glaucoma, secondary open-angle glaucoma, normal-tension glaucoma, excessive aqueous humor glaucoma, primary angle-closure glaucoma, secondary angle-closure glaucoma, iris fold glaucoma, mixed glaucoma, developmental glaucoma, steroid-induced glaucoma, exfoliation glaucoma, amyloidosis glaucoma, neovascular glaucoma, malignant glaucoma, capsular glaucoma of the lens, iris syndrome, ocular hypertension, uveitis, intraocular infection, etc.

(18) The depot preparation according to any one of (1) to (17) above, which is for topical ocular administration.

(19) The depot preparation according to (18) above, which is used for intravitreal administration, subconjunctival administration or intracameral administration.

(20) The depot preparation according to any one of (1) to (19) above, wherein the depot preparation is administered in a volume of 1 to 5000 μL per administration.

(21) The depot preparation according to any one of (1) to (20) above, wherein the depot preparation is administered at intervals of once every three days to once every five years.

(22) The depot preparation according to any one of (1) to (21) above, which is used for sustained release of a drug.

(23) Use of a trialkyl citrate and/or a trialkyl acetyl citrate for producing a depot preparation according to any one of claims (1) to (22) for preventing and/or treating eye diseases.

(24) Use of a trialkyl citrate and/or a trialkyl acetyl citrate for forming the depot preparation according to any one of claims (1) to (22).

(25) Trialkyl citrate and/or trialkyl acetyl citrate, for use as a preventive and/or therapeutic drug for eye diseases.

(26) Use of the depot preparation according to any one of claims (1) to (22) for the prevention and/or treatment of eye diseases.

(27) A method for preventing and/or treating an eye disease, wherein the method prevents and/or treats the eye disease by administering the depot preparation according to any one of claims (1) to (22) to a subject in need of prevention and/or treatment of the eye disease.

(28) A reservoir formation method comprising the step of contacting a liquid composition containing a trialkyl citrate and/or a trialkyl acetyl citrate with water, a phosphate buffer, a body fluid, or a simulated body fluid, wherein:

The trialkyl citrate and the trialkyl acetyl citrate may each have an alkyl group that is the same or different, and the number of carbon atoms of the alkyl group is 3 to 5.

It should be noted that for each of the above-mentioned structures (1) to (22), two or more items can be arbitrarily selected for combination. In addition, this principle also applies to each of the above-mentioned structures (23) to (28).

Effects of the Invention

The depot preparation of the present invention can easily form a depot and can maintain the depot state for a long period of time as needed. Moreover, when containing a drug, it can slowly release the drug after administration into the body and can also achieve long-term slow release as needed. It has sufficient safety as a pharmaceutical product.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photograph showing the extent of reservoir formation in Comparative Example 1 and Example 1.

[ FIG. 2 ] is a photograph showing the results of pathological evaluation of the preparation of Comparative Example 9. [ FIG.

[ Fig. 3 ] are photographs showing the results of pathological evaluation of the depot preparation according to one example of the present invention.

[ Fig. 4 ] are photographs showing the results of pathological evaluation of the depot preparation according to one example of the present invention.

DETAILED DESCRIPTION

Hereinafter, the present invention will be described in detail.

The present invention is a depot preparation containing a trialkyl citrate and/or a trialkyl acetyl citrate. In the present invention, the so-called depot preparation refers to a preparation for sustained drug release, which forms a depot (mass) after being administered into the body. The state of the depot preparation is not particularly limited and may be a dissolved state or a suspended state. The trialkyl citrate and the trialkyl acetyl citrate can be obtained by a condensation reaction of, for example, citric acid or acetyl citric acid with a compound such as an alcohol that provides an alkyl group having 3 to 5 carbon atoms. The alkyl groups having three in each molecule of the trialkyl citrate and the trialkyl acetyl citrate may be the same or different. The alkyl group is an alkyl group represented by ^Ra , ^Rb , and ^Rc in formula (2) described below and by ^Ra , ^Rb , and ^Rc in formula (3), excluding the methyl group constituting the acetyl group in the trialkyl acetyl citrate. The depot preparation of the present invention contains trialkyl citrates and/or trialkyl acetyl citrates, each having an alkyl group having 3 to 5 carbon atoms. Therefore, it is easy to form a reservoir and can maintain the reservoir state for a long period of time as needed. Furthermore, due to its suitable specific gravity, a reservoir can be formed at a desired location. Thus, the depot preparation of the present invention has excellent reservoir formation properties. Therefore, when containing a drug, the drug has excellent sustained release from the reservoir, enabling long-term, sustained release as needed. Furthermore, because the depot preparation of the present invention contains the aforementioned trialkyl citrates and/or trialkyl acetyl citrates, it also has sufficient safety as a pharmaceutical product.

The trialkyl citrate contained in the depot preparation of the present invention is a compound represented by the following formula (2). In formula (2), ^Ra , ^Rb , and ^Rc are the same or different and each represents an alkyl group having 3 to 5 carbon atoms. The alkyl group is preferably a linear or branched alkyl group, more preferably a linear or branched alkyl group having 4 carbon atoms. Specific examples include n-propyl, n-butyl, n-pentyl, isopropyl, isobutyl, sec-butyl, tert-butyl, and isopentyl, with n-butyl being most preferred.

The acetyl citrate trialkyl ester contained in the depot preparation of the present invention is a compound represented by the following formula (3), which is also known as acetyl citrate trialkyl ester or 2-acetoxypropane-1,2,3-tricarboxylic acid trialkyl ester. In formula (3), ^Ra , ^Rb , and ^Rc each represent an alkyl group having 3 to 5 carbon atoms. The alkyl group is preferably a linear or branched alkyl group, and more preferably a linear or branched alkyl group having 4 carbon atoms. Specific examples include n-propyl, n-butyl, n-pentyl, isopropyl, isobutyl, sec-butyl, tert-butyl, and isopentyl, with n-butyl being most preferred.

As the trialkyl citrate and/or trialkyl acetyl citrate, either the trialkyl citrate or the trialkyl acetyl citrate may be used alone, or both the trialkyl citrate and the trialkyl acetyl citrate may be used in combination. When used in combination, the ratio of the trialkyl citrate to the trialkyl acetyl citrate expressed as "trialkyl citrate/trialkyl acetyl citrate" is not particularly limited. For example, the volume ratio may be 0.1/99.9 to 99.9/0.1, preferably 5/95 to 50/50, more preferably 10/90 to 30/70, and even more preferably 15/85 to 25/75.

In the above trialkyl citrate, ^Ra , ^Rb , and ^Rc in formula (2) may be the same or different, but are preferably the same. In the above trialkyl acetyl citrate, ^Ra , ^Rb , and ^Rc in formula (3) may be the same or different, but are preferably the same.

In the depot preparation of the present invention, the content of the trialkyl citrate and/or acetyl trialkyl citrate is preferably 0.1% (w/w) or more, more preferably 0.1 to 99.999% (w/w), even more preferably 1 to 90% (w/w), particularly preferably 2 to 80% (w/w), and most preferably 3 to 70% (w/w). When the depot preparation of the present invention does not contain any additives other than the drug, the content of the trialkyl citrate and/or acetyl trialkyl citrate is preferably 70 to 99.999% (w/w), more preferably 75 to 99.99% (w/w), even more preferably 80 to 99.9% (w/w), particularly preferably 85 to 99.5% (w/w), and most preferably 88 to 99% (w/w).

Note that "% (w/w)" represents the mass (g) of the target component (here, trialkyl citrate and/or trialkyl acetyl citrate) contained in 100 g of the depot preparation of the present invention. Hereinafter, unless otherwise specified, the terms have the same meaning.

The depot preparation of the present invention may contain any of the above-mentioned trialkyl citrate and/or trialkyl acetyl citrate, and may further contain a drug. The drug contained in the depot preparation of the present invention is not particularly limited. Specific examples include tafetinib, SIM-817378, ACTB-1003, chiauranib, CT-53608, cinnamon, chim4G8-SDIE, CEP-5214, IMC-1C11, CEP-7055, 3-[5-[2-[N-(2-methoxyethyl)-N-methylamino]ethoxy]-1H-indol-2-yl]quinoline-2 (1H)-ketone, hF4-3C5, ZK-CDK, IMC-EB10, LS-104, CYC-116, OSI-930, PF-337210, JNJ-26483327, SSR-106462, R-1530, PRS-050, TG-02, SC-71710, SB-1578, AMG-191, AMG-820, Sulfatinib, Lucitanib hydrochloride, JN J-28312141, Ilorasertib, PLX-5622, ARRY-382, TAS-115, Tanibirumab, Henatinib, LY-2457546, PLX-7486, FPA-008, NVP-AEE-788, cgi-1842, RAF-265, MK-2461, SG-00529, Rebastinib, Golvatinib, Roniciclib, BVT -II, X-82, XV-615, KD-020, Lestaurtinib, Delphinidin, Semaxanib, Vatalanib, OSI-632, Telatinib, Alacizumabpegol, ATN-224, Tivozanib, XL-999, Icrucumab, Foretinib, Crenolanib besylate, R-406, Brivanib, Pegdinetanib, TG-100572, Olaratumab, Fostamatinib disodium), BMS-690514, AT-9283, MGCD-265, Quizartinib, ENMD-981693, Famitinib, Anlotinib, Tovetumab, PLX-3397, Fruquintinib, (-)-Epigallocatechin, Midostaurin, NSC-706456, Orantinib, Cediranib, Dovitinib, XL-647, Motesanib, Linifanib, Brivanib, Cediranib, Apatinib, Fedratinib, Pacritinib, Ramucirumab, Intedanib, Masitinib, Elemene, Dihydroartemisinin, WS-1442, Itraconazole, Leflunomide, Dihydroartemisinin, Imatinib, Sorafenib, Sunitinib, Dasatinib, Pazopanib, Vandetanib, Axitinib, Regorafenib Tyrosine kinase inhibitors such as regorafenib, cabozantinib, INCB28050, and ponatinib; steroids such as hydrocortisone, triamcinolone, fluocinolone, dexamethasone, betamethasone, and budesonide; prostaglandin derivatives such as isopropylunoprostone, latanoprost, bimatoprost, and travoprost; immunosuppressants such as cyclosporine, sirolimus, and FK506; antiallergic agents such as azelastine; indomethacin, bromfenac, and fenac. ), diclofenac, nepafenac and other nonsteroidal anti-inflammatory drugs; levofloxacin, ofloxacin, gatifloxacin and other antibacterial agents; pazopanib, SU5416, valatinib, ranibizumab, bevacizumab and other angiogenesis inhibitors; nicardipine, nitrendipine and other circulation-improving drugs; vitamin E and other antioxidants; acetazolamide, brinzolamide and other carbonic anhydrase inhibitors; timolol, carteolol and other beta-blockers; vitamin A derivatives and other visual cycle regulators. modulator); trophic factors such as ciliary body trophic factor (CNTF) and brain-derived neurotrophic factor (BDNF); growth factors such as nerve growth factor (NGF) and stem cell growth factor (HGF); aptamers such as pegaptanib; nucleic acid drugs such as various antisense nucleic acids and siRNA; antibody and peptide preparations such as ranibizumab (Lucentis) and IgG; Japanese Patent Application Laid-Open Nos. 2006-96739, 2011-37844, 2005-232149, 2006-273851, 2006-306861, and 2008-26 VEGF inhibitors described in JP-A-2007-230993, JP-A-2008-074829, JP-A-2008-143889, JP-A-2008-143890, JP-A-2008-143891, JP-A-2009-007344, JP-A-2009-084274, etc.; selective glucocorticoid receptor agonists such as RU24858; anticancer agents such as fluorouracil; JAK kinase inhibitors such as tofacitinib; protein kinase inhibitors such as ruboxistaurin mesylate, etc.

A preferred specific example of the drug contained in the depot preparation of the present invention is the compound represented by the above formula (1) or a salt thereof.

The "halogen atom" refers to fluorine, chlorine, bromine or iodine.

The term "C _1-6 alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a linear or branched alkyl group having 1 to 4 carbon atoms. Specific examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, and isopentyl.

The term "C _1-6 alkoxy" refers to a group in which the hydrogen atom of a hydroxy group is substituted with a C _1-6 alkyl group as described above. Specific examples include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexoxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, and isopentoxy.

The term "C _1-6 alkylcarbonyl" refers to a group in which the hydrogen atom of a formyl group is substituted with the aforementioned C _1-6 alkyl group. Specific examples include methylcarbonyl (acetyl), ethylcarbonyl, n-propylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, isopropylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, and isopentylcarbonyl.

The term "substituted with one or more halogen atoms" in the present invention means that the C _1-6 alkyl group (including the C _1-6 alkyl group constituting the C _1-6 alkoxy group) is substituted with one or more halogen atoms and up to the number of halogen atoms that can be substituted. The halogen atoms may be the same or different, and the number of halogen atoms is preferably 2 or 3, and particularly preferably 3.

In the present invention, "one or more hydroxyl groups are substituted" means that the C _1-6 alkyl group is substituted with one or more hydroxyl groups and no more than the number of substitutable groups. The number of hydroxyl groups is preferably one or two, and particularly preferably one.

In addition, the drugs of the present invention also include derivatives such as esters, amides, and acetone compounds of pharmacologically active compounds. The derivatives can also be prodrugs of the pharmacologically active compounds. As specific examples of esters, esters obtained by condensing a hydroxyl group in the drug with a carboxylic acid such as acetic acid, propionic acid, isopropionic acid, butyric acid, isobutyric acid, and pivalic acid can be exemplified. As specific examples of amides, amides obtained by condensing an amino group in the drug with a carboxylic acid such as acetic acid, propionic acid, isopropionic acid, butyric acid, isobutyric acid, and pivalic acid can be exemplified. As specific examples of acetone compounds, acetone compounds (acetals) obtained by reacting two hydroxyl groups (1,2-diol, 1,3-diol) in the drug with acetone or its equivalent (2,2-dimethoxypropane, etc.) can be exemplified.

Furthermore, the contained drug may be in the form of a hydrate or a solvate.

When the contained drug exists in geometric isomers, tautomers or optical isomers, these isomers are also included in the scope of the present invention.

Furthermore, when the contained drug exists in polymorphic forms, the polymorphic forms are also encompassed within the scope of the present invention.

(a) Preferred examples of the compound represented by formula (1) include compounds wherein each group in formula (1) is a group shown below, or salts thereof.

(a1) R ¹ represents a C _1-6 alkoxy group or a C _1-6 alkoxy group substituted by one or more halogen atoms; and/or

(a2) R ² represents a C _1-6 alkylcarbonyl group or a C _1-6 alkylcarbonyl group substituted by one or more hydroxyl groups.

That is, among the compounds represented by formula (1), preferred examples include compounds composed of one or a combination of two or more selected from the above-mentioned (a1) and (a2), or salts thereof.

(b) More preferred examples of the compound represented by formula (1) include compounds in which each group is represented by the following groups or salts thereof.

(b1) R ¹ represents a C _1-6 alkoxy group substituted by one or more halogen atoms; and/or

(b2) R ² represents a C _1-6 alkylcarbonyl group substituted by one or more hydroxyl groups.

That is, among the compounds represented by formula (1), preferred examples include compounds composed of one or a combination of two or more selected from the above-mentioned (b1) and (b2), or salts thereof. Furthermore, the selection conditions may be combined with the conditions of (a).

(c) The most preferred example of the compound represented by formula (1) is a compound represented by formula (4) (2-[[[2-[(hydroxyacetyl)amino]-4-pyridyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide) or a salt thereof.

The compound represented by formula (1) or a salt thereof contained in the depot preparation of the present invention can be produced by a conventional method in the art, such as the method described in US Patent Application Publication No. 2007/0149574.

Another preferred specific example of the drug contained in the depot preparation of the present invention is (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetic acid isopropyl ester represented by formula (5) or a salt thereof.

The compound represented by formula (5) or a salt thereof contained in the depot preparation of the present invention can be produced by conventional methods in the art, such as those described in U.S. Patent Application Publication No. 2011/0054172 and U.S. Patent Application Publication No. 2012/0190852.

The drug contained in the depot preparation of the present invention may be a salt, and there are no particular limitations as long as it is a salt permitted for use as a drug. Examples of the salt include salts formed with inorganic acids, salts formed with organic acids, quaternary ammonium salts, salts formed with halogen ions, salts formed with alkali metals, salts formed with alkaline earth metals, metal salts, and salts formed with organic amines. Examples of the salt formed with inorganic acids include salts formed with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Examples of salts with organic acids include salts with acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, dimethyl sulfate, naphthalenesulfonic acid, and sulfosalicylic acid. Examples of quaternary ammonium salts include salts with methyl bromide, methyl iodide, and the like. Examples of salts with halogen ions include salts with chloride ions, bromide ions, and iodide ions; examples of salts with alkali metals include salts with lithium, sodium, potassium, and the like; examples of salts with alkaline earth metals include salts with calcium, magnesium, and the like; and examples of metal salts include salts with iron, zinc, and the like. Examples of salts with organic amines include salts with triethylenediamine, 2-aminoethanol, 2,2-iminobis(ethanol), 1-deoxy-1-(methylamino)-2-D-sorbitol, 2-amino-2-(hydroxymethyl)-1,3-propanediol, procaine, and N,N-bis(phenylmethyl)-1,2-ethylenediamine.

The content of the drug contained in the depot preparation of the present invention is not particularly limited as long as it is an amount sufficient to achieve the desired pharmaceutical effect, but is preferably 0.001 to 30% (w/v), more preferably 0.01 to 25% (w/v), even more preferably 0.1 to 20% (w/v), even more preferably 0.5 to 15% (w/v), particularly preferably 1 to 12% (w/v), and most preferably 1% (w/v), 1.5% (w/v), 2% (w/v), 2.5% (w/v), 3% (w/v), 3.5% (w/v), 4% (w/v), 5% (w/v), 6% (w/v), 7% (w/v), 8% (w/v), 9% (w/v), 10% (w/v), 11% (w/v) or 12% (w/v).

Note that "% (w/v)" represents the mass (g) of the target component (drug in this case) contained in 100 mL of the depot preparation of the present invention. Hereinafter, unless otherwise specified, the terms have the same meaning.

The depot preparation of the present invention may contain additives as needed. Examples of the additives include surfactants, buffers, isotonicity agents, stabilizers, preservatives, antioxidants, high molecular weight polymers, excipients, and solvents.

In the depot preparation of the present invention, a surfactant that can be used as a pharmaceutical additive, such as a cationic surfactant, an anionic surfactant, or a nonionic surfactant can be added. Examples of anionic surfactants include phospholipids, and examples of phospholipids include lecithin. Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyldiethylamine salts, fatty acid polyamine condensates, alkyltrimethylammonium salts, dialkyldimethylammonium salts, alkyldimethylbenzylammonium salts, alkylpyridinium salts, acylaminoalkyl ammonium salts, acylaminoalkylpyridinium salts, diacyloxyethylammonium salts, alkylimidazolines, 1-acylaminoethyl-2-alkylimidazolines, and 1-hydroxyethyl-2-alkylimidazolines. Examples of alkyldimethylbenzylammonium salts include benzalkonium chloride and cetyldimethylbenzylammonium chloride. Examples of the nonionic surfactant include polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid esters, and vitamin E TPGS.

Examples of the polyoxyethylene fatty acid ester include polyoxyl (40) stearate.

Examples of the polyoxyethylene sorbitan fatty acid esters include polysorbate 80, polysorbate 60, polysorbate 40, polysorbate 20, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, and polysorbate 65.

As the polyoxyethylene hydrogenated castor oil, various polyoxyethylene hydrogenated castor oils having different polymerization numbers of ethylene oxide can be used. The polymerization number of ethylene oxide is preferably 10 to 100, more preferably 20 to 80, particularly preferably 40 to 70, and most preferably 60. Specific examples of the polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60.

As the polyoxyethylene castor oil, various polyoxyethylene castor oils having different polymerization numbers of ethylene oxide can be used. The polymerization number of ethylene oxide is preferably 5 to 100, more preferably 20 to 50, particularly preferably 30 to 40, and most preferably 35. Specific examples of the polyoxyethylene castor oil include polyoxyethylene (5) castor oil, polyoxyethylene (9) castor oil, polyoxyethylene (15) castor oil, polyoxyethylene (35) castor oil, and polyoxyethylene (40) castor oil.

Examples of the polyoxyethylene polyoxypropylene diol include polyoxyethylene (160) polyoxypropylene (30) diol, polyoxyethylene (42) polyoxypropylene (67) diol, polyoxyethylene (54) polyoxypropylene (39) diol, polyoxyethylene (196) polyoxypropylene (67) diol, and polyoxyethylene (20) polyoxypropylene (20) diol.

Examples of the sucrose fatty acid ester include sucrose stearate and the like.

Vitamin E TPGS is also known as tocopheryl polyethylene glycol 1000 succinate.

The depot preparation of the present invention may be formulated with a buffering agent that can be used as a pharmaceutical additive. Examples of buffering agents include phosphoric acid or its salts, boric acid or its salts, citric acid or its salts, acetic acid or its salts, carbonic acid or its salts, tartaric acid or its salts, histidine or its salts, ε-aminocaproic acid, and tromethamine. Examples of phosphates include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate. Examples of borates include borax, sodium borate, and potassium borate. Examples of citrates include sodium citrate, disodium citrate, and sodium citrate. Examples of acetates include sodium acetate and potassium acetate. Examples of carbonates include sodium carbonate and sodium bicarbonate. Examples of tartrates include sodium tartrate and potassium tartrate. Examples of histidine salts include histidine hydrochloride.

The depot preparation of the present invention may be appropriately formulated with an isotonic agent that can be used as a pharmaceutical additive. Examples of isotonic agents include ionic isotonic agents and nonionic isotonic agents. Examples of ionic isotonic agents include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride, while examples of nonionic isotonic agents include glycerol, propylene glycol, sorbitol, mannitol, trehalose, sucrose, and glucose.

The depot preparation of the present invention may be appropriately formulated with a stabilizer that can be used as a pharmaceutical additive. Examples of stabilizers include ethylenediaminetetraacetic acid, sodium edetate, and sodium citrate.

The depot preparation of the present invention may be appropriately formulated with a preservative that can be used as a pharmaceutical additive. Examples of preservatives include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methylparaben, propylparaben, and chlorobutanol.

The depot preparation of the present invention may be appropriately formulated with an antioxidant that can be used as a pharmaceutical additive. Examples of antioxidants include ascorbic acid, tocopherol, butylated hydroxytoluene, butylated hydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite, or derivatives thereof. Examples of tocopherol or its derivatives include vitamin E, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, and their acetates, succinates, and their d-isomers, l-isomers, and dl-isomers.

The depot preparation of the present invention may be appropriately formulated with a high molecular weight polymer that can be used as a pharmaceutical additive. Examples of high molecular weight polymers include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, and carboxyvinyl polymers.

The depot preparation of the present invention may also contain at least one additive selected from the group consisting of polylactic acid (PLA) and polylactic-co-glycolic acid (PLGA). However, by containing the above-mentioned trialkyl citrate and/or trialkyl acetyl citrate, a sustained-release depot can be easily formed. Therefore, it is not necessary to contain at least one additive selected from the group consisting of PLA and PLGA. For the depot preparation of the present invention, by not containing at least one additive selected from the group consisting of tocopherol acetate, PLA and PLGA, suitable viscosity adjustment can be easily performed. From this point of view, it is preferably not contained. In the past, depot preparations containing such additives have easily increased viscosity due to the concentration of such additives, resulting in deterioration in operability. In addition, for the depot preparation of the present invention, especially when containing a drug, it is preferably not contained from the viewpoint of suitable elimination after administration.

When additives are added to the depot preparation of the present invention, the content of the additives can be appropriately adjusted depending on the type of additive, etc., and the total amount is preferably 0.0001 to 30% (w/v), more preferably 0.001 to 25% (w/v), further preferably 0.01 to 20% (w/v), particularly preferably 0.1 to 15% (w/v), and most preferably 1 to 10% (w/v).

In the depot preparation of the present invention, a solvent or excipient that can be used as a pharmaceutical additive can be appropriately combined. Examples of solvents or excipients include polyethylene glycol (PEG), glycofurol, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylacetamide, ethanol, benzyl benzoate, sucrose octaacetate, medium-chain fatty acid triglycerides, vegetable oils such as castor oil, mineral oils such as liquid paraffin, silicone oils, etc., with polyethylene glycol and benzyl benzoate being preferred. As solvents or excipients, only one type can be used, or two or more types can be used in combination. For example, when polyethylene glycol and benzyl benzoate are used together, the content ratio of polyethylene glycol to benzyl benzoate expressed as "polyethylene glycol/benzyl benzoate" is not particularly limited. For example, the volume ratio can be 0.1/99.9 to 99.9/0.1, preferably 5/95 to 70/30, and more preferably 10/90 to 50/50.

When polyethylene glycol is added to the depot preparation of the present invention, the average molecular weight of the polyethylene glycol is preferably 100 to 2000, more preferably 150 to 1500, even more preferably 200 to 1300, particularly preferably 300 to 1200, and most preferably 400 to 1000. Specific examples of polyethylene glycol include PEG100, PEG200, PEG300, PEG400, PEG600, PEG800, and PEG1000.

When a solvent or excipient is added to the depot preparation of the present invention, the content of the solvent or excipient is preferably 5 to 99% (w/w), more preferably 10 to 98% (w/w), further preferably 30 to 97% (w/w), and most preferably 40 to 95% (w/w).

The depot preparation of the present invention may contain the above-mentioned trialkyl citrate having an alkyl group having 3 to 5 carbon atoms and/or trialkyl acetyl citrate. Alternatively, the depot preparation may contain at least one citric acid derivative selected from the group consisting of trialkyl citrate in which at least one of ^Ra , ^Rb , and ^Rc in formula (2) is an alkyl group having 6 or more carbon atoms (e.g., trihexyl citrate) and trialkyl acetyl citrate in which at least one of ^Ra , ^Rb , and ^Rc in formula (3) is an alkyl group having 6 or more carbon atoms (e.g., trihexyl acetyl citrate). When these additional citric acid derivatives are added to the depot preparation of the present invention, the content is preferably 5 to 99% (w/w), more preferably 10 to 98% (w/w), even more preferably 30 to 97% (w/w), and most preferably 40 to 95% (w/w).

One specific embodiment of the depot preparation of the present invention is a depot preparation containing substantially only the compound represented by formula (4) or a salt thereof, and tri-n-butyl citrate.

Another specific embodiment of the depot preparation of the present invention is a depot preparation containing substantially only the compound represented by formula (4) or a salt thereof, tri-n-butyl citrate, and PEG400.

Another specific embodiment of the depot preparation of the present invention is a depot preparation containing substantially only the compound represented by formula (4) or a salt thereof, and acetyl tri-n-butyl citrate.

Another specific embodiment of the depot preparation of the present invention is a depot preparation containing substantially only the compound represented by formula (4) or a salt thereof, acetyl tri-n-butyl citrate, and PEG400.

Another specific embodiment of the depot preparation of the present invention is a depot preparation containing substantially only the compound represented by formula (4) or a salt thereof, tri-n-butyl citrate, acetyl tri-n-butyl citrate, and PEG400.

One specific embodiment of the depot preparation of the present invention is a depot preparation containing substantially only the compound represented by formula (5) or a salt thereof, and tri-n-butyl citrate.

Another specific embodiment of the depot preparation of the present invention is a depot preparation containing substantially only the compound represented by formula (5) or a salt thereof, tri-n-butyl citrate, and PEG400.

Another specific embodiment of the depot preparation of the present invention is a depot preparation containing substantially only the compound represented by formula (5) or a salt thereof, and acetyl tri-n-butyl citrate.

Another specific embodiment of the depot preparation of the present invention is a depot preparation containing substantially only the compound represented by formula (5) or a salt thereof, acetyl tri-n-butyl citrate, and PEG400.

Another specific embodiment of the depot preparation of the present invention is a depot preparation containing substantially only the compound represented by formula (5) or a salt thereof, acetyl tri-n-butyl citrate, PEG400, and benzyl benzoate.

The depot preparation of the present invention can be administered orally or parenterally. The dosage form of the depot preparation of the present invention is not particularly limited as long as it can be used as a pharmaceutical. As dosage forms, for example, liquids and suspensions can be mentioned for oral dosage forms, and injections, infusions, nasal drops, ear drops, eye drops, etc. can be mentioned for parenteral dosage forms. Ophthalmic injections and eye drops can be preferably mentioned, and ophthalmic injections can be more preferably mentioned. The best choice can be an injection for intravitreal administration, intracameral administration, or subconjunctival administration. These dosage forms can be manufactured according to conventional methods in the art.

The depot preparation of the present invention can be appropriately administered according to its dosage form. For example, in the case of an ophthalmic injection, it can be administered into the vitreous body, near the posterior sclera, around the eye socket, between the sclera and the conjunctiva. For example, when an ophthalmic injection is administered into the vitreous body, as long as it is a sufficient amount for achieving the desired drug effect, there is no particular limitation on the amount administered, preferably 1 to 5000 μL per time, more preferably 5 to 1000 μL, further preferably 10 to 100 μL, particularly preferably 20 to 50 μL, and most preferably 20 μL, 30 μL, 40 μL or 50 μL. When an ophthalmic injection is administered into the anterior chamber, as long as it is a sufficient amount for achieving the desired drug effect, there is no particular limitation on the amount administered, preferably 0.1 to 300 μL per time, more preferably 1 to 100 μL, further preferably 2 to 50 μL, particularly preferably 5 to 20 μL, and most preferably 5 μL, 10 μL, 15 μL or 20 μL. When administering an ophthalmic injection under the conjunctiva, the dosage is not particularly limited as long as it is a sufficient amount to achieve the desired drug effect. However, it is preferably 10 to 5000 μL per dose, more preferably 20 to 1000 μL, even more preferably 30 to 500 μL, particularly preferably 50 to 200 μL, and most preferably 50 μL, 100 μL, 150 μL, or 200 μL. The dosage of the drug is preferably 0.001 to 30 mg/eye, more preferably 0.01 to 10 mg/eye, even more preferably 0.1 to 5 mg/eye, particularly preferably 0.2 to 1.6 mg/eye, and most preferably 0.2 mg/eye, 0.3 mg/eye, 0.4 mg/eye, 0.5 mg/eye, 0.6 mg/eye, 0.7 mg/eye, 0.8 mg/eye, 1 mg/eye, 1.2 mg/eye, 1.4 mg/eye, or 1.6 mg/eye.

When the depot preparation of the present invention is continuously administered into the vitreous body or the anterior chamber, the administration interval is not particularly limited as long as it is sufficient to achieve the desired pharmaceutical effect. Preferably, it is administered at an interval of once every 3 days to once every 5 years, more preferably once every 3 days, once every 5 days, once every week, once every 2 weeks, once every 1 month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, once every 6 months, once every 1 year, once every 2 years, once every 3 years, once every 4 years, or once every 5 years, and most preferably once every 2 months, once every 3 months, once every 4 months, once every 5 months, once every 6 months, or once every 1 year. In addition, the administration interval can be appropriately changed.

The depot preparation of the present invention is useful as a pharmaceutical and can be used as a preventive or therapeutic agent for the following eye diseases: for example, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, retinal artery occlusion, polypoidal choroidal vasculopathy, retinal angiomatous proliferation, myopic choroidal neovascularization, diabetic macular edema, ocular tumors, radiation retinopathy, iris rubeosis, neovascular glaucoma The present invention relates to a pharmaceutical composition comprising the following: 1) a pharmaceutical composition comprising: ...

The depot preparation of the present invention, when not containing a drug, can be used, for example, for testing the reservoir-forming properties of the entire preparation during preparation design, administration training, and the like.

Furthermore, the depot preparation of the present invention, when containing a drug, can be used as an injection for the prevention and/or treatment of ophthalmic diseases, for example. Such a depot preparation, when administered into the vitreous body, can form a reservoir near the administration site, thereby enabling efficient and continuous delivery of the drug to the affected area of the eye (e.g., the choroid and retina).

The detailed description of the depot preparation of the present invention described above also applies to the trialkyl citrate and/or trialkyl acetyl citrate for use as a preventive and/or therapeutic agent for ocular diseases, and the depot formation method of the present invention.

The present invention also includes a method for forming a reservoir comprising contacting a liquid composition containing a trialkyl citrate and/or an acetyl trialkyl citrate with water, a phosphate buffer, a body fluid, or a simulated body fluid, wherein the trialkyl citrate and the acetyl trialkyl citrate each have the same or different alkyl groups and have 3 to 5 carbon atoms. The trialkyl citrate and/or acetyl trialkyl citrate are the same as the trialkyl citrate and/or acetyl trialkyl citrate essential components of the depot preparation of the present invention. Examples of body fluids include tears, aqueous humor, and vitreous humor.

Preparation examples and test results are shown below. However, these preparation examples and test results are for better understanding of the present invention and do not limit the scope of the present invention.

Example

Preparation Examples

Representative formulation examples of the present invention are shown below.

Preparation Example 1

It should be noted that the types and amounts of the drug, trialkyl citrate, trialkyl acetyl citrate, additives, and solvent in the above-mentioned Preparation Examples 1 to 6 can be appropriately adjusted to obtain a desired depot preparation.

1. Depot elimination test

The elimination of acetyl triethyl citrate (ATEC) and acetyl tri-n-butyl citrate (ATBC) in solvents was evaluated.

1-1. Preparation of release solvent

Add 800 mL of water for injection, 1 g of polysorbate 80, 3 g of sodium dihydrogen phosphate, and 29 g of sodium hydrogen phosphate hydrate to a beaker and stir to dissolve. Dilute to 1 L with water for injection.

1-2. Elimination test

5 mL of release solvent warmed to 37°C was added to a 5 mL standard bottle. 0.05 mL of the test preparation was injected into the release solvent using a Hamilton syringe equipped with a 30G needle. Visual observation was performed immediately after administration and 1 day and 37 days after administration.

1-3. Test results and discussion

The test results are shown in Table 1. A photograph of the test results is shown in FIG1 .

[Table 1]

As shown in Table 1, compared to the preparation of Comparative Example 1, the preparation of Example 1 was able to maintain the formed depot for a longer period of time, with the depot still being observed 37 days after administration. Based on the above, it can be confirmed that the depot preparation of the present invention can maintain the depot state for a long period of time after administration. This also indicates that the depot preparation, when containing a drug, is capable of long-term, slow release of the drug.

2. Formulation studies using depot preparations of each drug

The depot formulations of the respective drugs were studied using acetyl tri-n-butyl citrate (ATBC).

2-1. Formulation Study 1

30 mg of nepafenac, dexamethasone, indomethacin, diclofenac sodium, levofloxacin, timolol maleate, fluocinolone acetonide, triamcinolone acetonide, and budesonide were weighed into standard bottles, 0.3 mL of dimethyl sulfoxide was added for dissolution, and 2.7 mL of acetyl tri-n-butyl citrate or tri-n-butyl citrate was added and mixed to prepare the preparations of Examples 2 to 8 and Examples 13 to 19.

30 mg of INCB28050 was weighed in a standard bottle, 1.5 mL of dimethyl sulfoxide was added to dissolve the mixture, and 1.5 mL of acetyl tri-n-butyl citrate or tri-n-butyl citrate was added and mixed to prepare the formulations of Examples 9 and 10.

30 mg of cyclosporin A was weighed in a standard bottle, and 3 mL of acetyl tri-n-butyl citrate or tri-n-butyl citrate was added, dissolved, and mixed to prepare the preparations of Examples 11 and 12.

[Table 2]

[Table 3]

formula Example 9 Example 10 Example 11 Example 12 Example 13 INCB28050 30mg 30mg — — — Cyclosporine A — — 30mg 30mg — Timolol Maleate — — — — 30mg Acetyl tri-n-butyl citrate 1.5mL — 3mL — 2.7mL Tri-n-butyl citrate — 1.5mL — 3mL — dimethyl sulfoxide 1.5mL 1.5mL — — 0.3mL

[Table 4]

formula Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Fluocinolone 30mg 30mg — — — — Triamcinolone acetonide — — 30mg 30mg — — budesonide — — — — 30mg 30mg Acetyl tri-n-butyl citrate 2.7mL — 2.7mL — 2.7mL — Tri-n-butyl citrate — 2.7mL — 2.7mL — 2.7mL dimethyl sulfoxide 0.3mL 0.3mL 0.3mL 0.3mL 0.3mL 0.3mL

2-2. Formulation Study 2

5 mg of olopatadine was weighed into a standard bottle, 0.5 g of dimethyl sulfoxide was added to dissolve it, and then acetyl tri-n-butyl citrate was added to make the total volume of the preparation 5 mL, and the mixture was mixed to prepare the preparation of Example 20.

[Table 5]

formula Example 20 Olopatadine 5mg Acetyl tri-n-butyl citrate appropriate amount dimethyl sulfoxide 0.5g Total 5mL

Each of the preparations shown in Tables 2 to 5 can dissolve drugs, indicating that the depot preparation of the present invention can be formulated for various drugs.

3. Sustained release evaluation test (1)

The drug sustained-release properties of the depot preparation of the present invention were evaluated.

3-1. Preparation of test preparation

10 mg of latanoprost was weighed into a standard bottle and dissolved in 1 mL of acetyl triethyl citrate to prepare the preparation of Comparative Example 2. Separately, 50 mg of latanoprost was weighed into a standard bottle and dissolved in 5 mL of tri-n-butyl citrate or acetyl tri-n-butyl citrate, respectively, to prepare the preparations of Examples 21 and 22.

3-2. Preparation of release solvent

Add 800 mL of water for injection, 1 g of polysorbate 80, 3 g of sodium dihydrogen phosphate, and 29 g of sodium hydrogen phosphate hydrate to a beaker and stir to dissolve. Dilute to 1 L with water for injection.

3-3. Release test

Add 5 mL of release solvent heated to 37°C to a 5 mL standard bottle. Use a Hamilton syringe equipped with a 30G injection needle to administer 0.025 mL of the test preparation and stir at 86 rpm at 37°C. Collect 0.75 mL of release solvent 1, 4, 7, 11, 14, 18, 21, 25, and 28 days after the test preparation is administered and dilute it with 0.75 mL of acetonitrile/water (1:1 by volume). Add 0.75 mL of new release solvent to the standard bottle. Determine the content of latanoprost in the collected release solvent by HPLC, and calculate the cumulative release rate after administration.

3-4. Test results and investigation

The test results are shown in Table 2.

[Table 6]

As shown in Table 6, the preparation of Comparative Example 2 released 107.7% of latanoprost 11 days after administration, while the preparations of Examples 21-22 released only 54.4-80.3% of latanoprost 11 days after administration. Furthermore, the preparations of Examples 21-22 showed sustained release until 28 days after administration. This confirms that the depot preparations of the present invention can slowly release the drug. Furthermore, the preparation of Example 21, which uses tri-n-butyl citrate as a base, exhibited higher sustained release than the preparation of Example 22, which uses acetyl tri-n-butyl citrate as a base. This result confirms that sustained release can be controlled by selecting, for example, the type of base according to the desired degree of sustained release.

4. Sustained-release evaluation test (2)

The drug sustained-release properties of the depot preparation of the present invention were evaluated.

4-1. Preparation of test preparation

6 mg of isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate (hereinafter also referred to as Compound A) was weighed into a volumetric flask, dissolved in tri-n-butyl citrate or acetyl tri-n-butyl citrate, and the volume was adjusted to 3 mL to prepare the preparations of Examples 23 and 24.

6 mg of Compound A was weighed in a volumetric flask, 0.3 mL of PEG400 was added, and the mixture was dissolved in tri-n-butyl citrate and the volume was adjusted to 3 mL to prepare the preparation of Example 25.

6 mg of Compound A was weighed in a volumetric flask, 1 mL of a solution prepared by dissolving 500 mg of sucrose octaacetate in 5 mL of tri-n-butyl citrate was added, and the volume was adjusted to 3 mL with tri-n-butyl citrate to prepare the preparation of Example 26.

10 mg of compound A was weighed into a standard bottle and dissolved in 5 mL of a mixture of acetyl tri-n-butyl citrate, benzyl benzoate, and PEG400 to prepare the preparations of Examples 27 to 30.

Separately, 10 mg of Compound A was weighed into a standard bottle and dissolved in 5 mL of a mixture of acetyl tri-n-butyl citrate, benzyl benzoate, PEG400, and vitamin E to prepare the preparation of Example 31.

4-2. Preparation of release solvent

Add 800 mL of water for injection, 1 g of polysorbate 80, 3 g of sodium dihydrogen phosphate, and 29 g of sodium hydrogen phosphate hydrate to a beaker and stir to dissolve. Dilute to 1 L with water for injection.

4-3. Release test

Add 5 mL of release solvent heated to 37°C to a 5 mL standard bottle. Use a Hamilton syringe equipped with a 30G needle to administer 0.025 mL of the test preparation and stir at 86 rpm at 37°C. Collect 0.75 mL of release solvent 1, 3, 4, 7, 14, 21, and 28 days after administration of the test preparation and dilute it with 0.75 mL of acetonitrile/water (1:1 by volume). Add 0.75 mL of new release solvent to the standard bottle. Determine the content of compound A and tri-n-butyl citrate or acetyl tri-n-butyl citrate in the collected release solvent by HPLC, and calculate the cumulative release rate after administration.

4-4. Test results and discussion

The test results are shown in Tables 7 and 8.

[Table 7]

[Table 8]

As shown in Table 7, the preparations of Examples 23 to 26 released only 7.3% to 13.0% of Compound A 7 days after administration. Furthermore, tri-n-butyl citrate or acetyl tri-n-butyl citrate, used as the base, released only 5.5% to 7.5% 7 days after administration. The above results confirm that the depot preparations of the present invention can provide sustained release of the drug. Furthermore, as shown in Table 8, the preparations of Examples 27 to 31, prepared with acetyl tri-n-butyl citrate at a ratio of 10% (v/v) to 40% (v/v) relative to the total amount of ingredients other than the drug, showed a cumulative release rate of Compound A of 42.4% to 69.0% 28 days after administration, confirming that sustained drug release is possible at any of the formulation ratios.

5. Sustained-release evaluation test (3)

The drug sustained-release properties of the depot preparation of the present invention were evaluated.

5-1. Preparation of test preparation

To 32 mg of (2-[[[2-[(hydroxyacetyl)amino]-4-pyridyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide (hereinafter also referred to as Compound B) was added 1 mL of PEG400, and the mixture was stirred and dissolved to prepare a preparation of Comparative Example 3.

To 32 mg of compound B were added 0.5 mL of PEG400 and 0.5 mL of tri-n-butyl citrate, and the mixture was stirred and dissolved to prepare the preparation of Example 32.

To 32 mg of compound B were added 0.5 mL of PEG400, 0.1 mL of tri-n-butyl citrate, and 0.4 mL of acetyl tri-n-butyl citrate, and the mixture was stirred and dissolved to prepare the preparation of Example 33.

To 32 mg of Compound B were added 0.5 mL of dimethyl sulfoxide and 0.5 mL of tri-n-butyl citrate, and the mixture was stirred and dissolved to prepare the preparation of Example 34.

To 32 mg of Compound B were added 0.5 mL of polyoxyethylene glycol ether and 0.5 mL of tri-n-butyl citrate, and the mixture was stirred and dissolved to prepare the preparation of Example 35.

5-2. Preparation of release solvent

76.8 g of Dulbecco's PBS(-) powder "Nissui" was weighed into a 10 L container and dissolved in 8 L of distilled water. 8 g of polyethylene glycol monostearate (MYS40) was then added and stirred to dissolve.

5-3. Release test

Add 25 mL of release solvent heated to 37°C to a 30 mL standard bottle. Use a Hamilton syringe equipped with a 30G needle to administer 0.025 mL of the test preparation and stir at 86 rpm at 37°C. Collect 0.75 mL of release solvent 1, 5, and 7 days after administration of the test preparation and dilute with 0.75 mL of acetonitrile/water (1:1 by volume). Add 0.75 mL of new release solvent to the standard bottle. Determine the content of compound B in the collected release solvent by HPLC and calculate the cumulative release rate after administration.

5-4. Test results and discussion

The test results are shown in Table 9.

[Table 9]

As shown in Table 9, the preparation of Comparative Example 3 released more than 50% of Compound B 7 days after administration, whereas the preparations of Examples 32 to 35 released only 10.6 to 18.9% of Compound B 7 days after administration. The above results confirm that the depot preparation of the present invention can provide sustained release of the drug.

6. Sustained-release evaluation test (4)

The drug sustained-release properties of the depot preparation of the present invention were evaluated.

6-1. Preparation of test preparation

30 mg of INCB28050 was weighed into a standard bottle, dissolved in 1.5 mL of dimethyl sulfoxide, and further mixed with 1.5 mL of acetyl triethyl citrate to prepare the preparation of Comparative Example 4. Separately, the preparation prepared in Example 10 was used.

6-2. Preparation of release solvent

Add 800 mL of water for injection, 1 g of polysorbate 80, 3 g of sodium dihydrogen phosphate, and 29 g of sodium hydrogen phosphate hydrate to a beaker and stir to dissolve. Dilute to 1 L with water for injection.

6-3. Release test

To a 5 mL standard vial, add 5 mL of release solvent warmed to 37°C. Using a Hamilton syringe equipped with a 30G needle, administer 0.025 mL of the test formulation, stirring at 86 rpm at 37°C. One, three, and seven days after administration of the test formulation, collect 0.75 mL of the release solvent and dilute it with 0.75 mL of acetonitrile/water (1:1 volume ratio). Add 0.75 mL of fresh release solvent to the standard vial. Determine the INCB28050 content in the collected release solvent by HPLC, and calculate the cumulative release rate after administration.

6-4. Test results and discussion

The test results are shown in Table 10.

[Table 10]

As shown in Table 10, the preparation of Comparative Example 4 released 91.5% of the administered amount of INCB28050 by 3 days after administration. In contrast, the preparation of Example 10 released only 89.6% of the administered amount of INCB28050 even after 7 days of administration. This confirms that the depot preparation has improved sustained-release properties.

7. Sustained-release evaluation test (5)

The drug sustained-release properties of the depot preparation of the present invention were evaluated.

7-1. Preparation of test preparation

30 mg of cyclosporin A was weighed into a standard bottle, and 3 mL of acetyl triethyl citrate was added for dissolution and mixing to prepare the preparation of Comparative Example 5. In addition, the preparations prepared in Examples 11 and 12 were used.

7-2. Preparation of release solvent

Add 800 mL of water for injection, 1 g of polysorbate 80, 3 g of sodium dihydrogen phosphate, and 29 g of sodium hydrogen phosphate hydrate to a beaker and stir to dissolve. Dilute to 1 L with water for injection.

7-3. Release test

To a 5 mL standard vial, add 5 mL of release solvent warmed to 37°C. Using a Hamilton syringe equipped with a 30G needle, administer 0.025 mL of the test preparation, stirring at 86 rpm at 37°C. One, three, and seven days after administration of the test preparation, collect 0.75 mL of the release solvent and dilute it with 0.75 mL of acetonitrile/water (1:1 volume ratio). Add 0.75 mL of fresh release solvent to the standard vial. Determine the cyclosporine A content in the collected release solvent by HPLC, and calculate the cumulative release rate after administration.

7-4. Test results and investigation

The test results are shown in Table 11.

[Table 11]

As shown in Table 11, the preparation of Comparative Example 5 released 66.3% of the administered amount of cyclosporin A 28 days after administration. In contrast, the preparations of Examples 11 and 12 released only 46.2% and 45.6% of the administered amount of cyclosporin A, respectively, 28 days after administration. This confirms that the depot preparations have improved sustained-release properties.

8. Sustained-release evaluation test (6)

The drug sustained-release properties of the depot preparation of the present invention were evaluated in animals.

8-1. Preparation of test preparation

240 mg of sirolimus was weighed into a standard bottle, 0.8 mL of dimethyl sulfoxide was added to dissolve it, and 7.2 mL of acetyl triethyl citrate and acetyl tri-n-butyl citrate were added and mixed. The mixture was then sterilized by filtration using a filter with a pore size of 0.20 μm to prepare the preparations of Comparative Example 6 and Example 36.

240 mg of sirolimus was weighed into a standard bottle, 3.6 mL of premixed benzyl benzoate/ethanol (40:5 by volume) or 3.68 mL of vitamin E/benzyl benzoate/ethanol (1:40:5 by volume) was added to dissolve the mixture, and then 4.4 mL or 4.32 mL of acetyl tri-n-butyl citrate was added and mixed. The mixture was then sterilized by filtration using a filter with a pore size of 0.20 μm to prepare the preparations of Examples 37 and 38.

8-2. Pharmacokinetic evaluation in rabbits

Using a Hamilton syringe equipped with a 30G needle, 0.03 mL of the depot formulations of Comparative Example 6 and Examples 36-38 were administered intravitreally to each eye of a rabbit. Four and 12 weeks after administration, the rabbits were euthanized by intravenous anesthesia with an overdose of sodium pentobarbital, and the eyeballs were enucleated. The enucleated eyeballs were immediately frozen, and the vitreous was collected while still containing the depot formulation. Sirolimus concentrations in the vitreous at each collection time point were measured by LC-MS/MS to assess the amount of drug remaining after administration.

8-3. Test results and investigation

The test results are shown in Table 12.

[Table 12]

As shown in Table 12, only 10.0% of the administered dose of sirolimus remained in the preparation of Comparative Example 6 four weeks after administration. In contrast, 67.3% of the administered dose remained in the preparation of Example 36, 71.1% remained in Example 37, and 83.7% remained in Example 38. These results confirm that the depot preparations improve sustained-release properties.

9. Sustained-release evaluation test (7)

The drug sustained-release properties of the depot preparation of the present invention were evaluated in animals.

9-1. Preparation of test preparation

15 mg of latanoprost was weighed into a standard bottle, 3 mL of acetyl triethyl citrate and acetyl tri-n-butyl citrate were added, dissolved and mixed, and then filtered and sterilized using a filter with a pore size of 0.20 μm to prepare the preparations of Comparative Example 7 and Example 39.

9-2. Pharmacokinetic evaluation in rabbits

Using a Hamilton syringe equipped with a 30G injection needle, the depot preparations of Comparative Example 7 and Example 39 were administered into the vitreous body in an amount of 0.02 mL per eye of a white rabbit. Two weeks and four weeks after administration, the rabbits were euthanized by intravenous administration of sodium pentobarbital for overdose anesthesia and the eyeballs were removed. The removed eyeballs were immediately frozen and the vitreous was collected while containing the depot preparation. The concentration of latanoprost in the vitreous at each collection time point was measured by LC-MS/MS to evaluate the drug residue after administration. In addition, the concentration of latanoprost carboxylate in the iris and ciliary body was also measured by LC-MS/MS.

9-3. Test results and investigation

The test results are shown in Table 13.

[Table 13]

As shown in Table 13, the residual rate of latanoprost was less than 0.3% for the formulation of Comparative Example 7 two weeks after administration, whereas the residual rate for the formulation of Example 39 was as high as 13.0%. Furthermore, the concentration of the carboxylate form of latanoprost, the active ingredient, in the irido-ciliary body, the target tissue, was less than 10.3 ng/g two weeks after administration for Comparative Example 7, whereas it was 57.1 ng/g for the formulation of Example 39, indicating sufficient drug concentrations even four weeks after administration. These results confirm that the depot formulation improves sustained-release properties.

10. Sustained-release evaluation test (8)

The drug sustained-release properties of the depot preparation of the present invention were evaluated in animals.

10-1. Preparation of test preparations

15 mg of Compound A was weighed in a standard bottle, 3 mL of acetyl triethyl citrate and acetyl tri-n-butyl citrate were added for dissolution and mixing, and then filtered and sterilized using a filter with a pore size of 0.20 μm to prepare the preparations of Comparative Example 8 and Example 40.

15 mg of compound A was weighed into a standard bottle, and 3 mL of a mixture of acetyl tri-n-butyl citrate, benzyl benzoate, and PEG400 was added and dissolved and mixed. The mixture was then sterilized by filtration using a filter with a pore size of 0.20 μm to prepare the preparations of Examples 41 and 42.

10-2. Pharmacokinetic evaluation in rabbits

Using a Hamilton syringe equipped with a 30G injection needle, the depot preparations of Comparative Example 8, Example 40, Example 41, and Example 42 were administered intravitreally to the rabbits at a volume of 0.02 mL per eye. Four weeks and 12 weeks after administration for Comparative Example 8 and Example 40, and four weeks after administration for Examples 41 and 42, the rabbits were euthanized by intravenous administration of sodium pentobarbital for overdose anesthesia, and the eyeballs were removed. The removed eyeballs were immediately frozen, and the vitreous was collected while still containing the depot preparation. The concentration of Compound A in the vitreous at each collection time point was measured by LC-MS/MS to evaluate the drug residue after administration. In addition, the concentration of the carboxylate of Compound A in the iris and ciliary body was also measured by LC-MS/MS.

10-3. Test results and investigation

The test results are shown in Table 14.

[Table 14]

As shown in Table 14, the residual rate of Compound A in the formulation of Comparative Example 8 was less than 17.0% four weeks after administration, while the formulations of Examples 40-42 showed a high residual rate of 74.8% to 79.1%. Furthermore, in the target tissue, the irido-ciliary body, the concentration of the carboxylate form of Compound A, the active ingredient, was 20.0 ng/g in the formulation of Comparative Example 8 four weeks after administration, while the formulations of Examples 40-42 showed concentrations of 68.3 to 114 ng/g. Furthermore, even 12 weeks after administration, Example 40 demonstrated sustained-release properties compared to Comparative Example 8. Furthermore, it was confirmed that the same degree of sustained-release properties were exhibited when the formulation ratio of acetyl tri-n-butyl citrate to the total amount of non-drug components was 30% (v/v) to 100% (v/v), allowing for the design of the formulation ratio according to the intended purpose. These results confirm that this depot formulation improves sustained-release properties.

11. Safety evaluation test

The safety of the depot preparation of the present invention was evaluated.

11-1. Preparation of test preparation

Acetyl triethyl citrate and acetyl tri-n-butyl citrate were sterilized by filtration using a filter with a pore size of 0.20 μm to prepare preparations of Comparative Example 9 and Example 43.

The preparation of Example 44 was prepared by filtration sterilization of tri-n-butyl p-acetyl citrate using a filter with a pore size of 0.20 μm.

11-2. Pathological evaluation

Use Hamilton syringe equipped with 30G injection needle, the amount of 0.05mL is respectively applied to the vitreous body of comparative example 9 and embodiment 43 with every 1 eye of white rabbit.After 2 months after applying, deep anesthesia is implemented in the vein of sodium pentobarbital, and it is killed by bleeding in this state, and the eyeball is extracted. The eyeball is immersed in F-G fixative (10% neutral buffered formaldehyde/2.5% glutaraldehyde) for about 24 hours and fixed, then it is cut out, and then fixed again in 10% neutral buffered formaldehyde. According to conventional method, paraffin embedding is implemented, after cutting out the section (face out), from the nose side towards the ear side, thin section is carried out with sagittal plane, and the discontinuous continuous section at intervals of 1mm is made. After utilizing conventional method to make paraffin section, HE staining is implemented, then microscopic examination is carried out.

For the preparation of Example 44, except that the animals were bled out 1 month after administration instead of 2 months, sections were prepared and examined under a microscope in the same manner as above.

11-3. Test results and investigation

The test results are shown in Figures 2, 3, and 4 and Table 15.

[Table 15]

＊: Grading (P = Phenomenon, ± = Very mild change, + = Mild change, ++ = Moderate change, +++ = Severe change)

**: Number of cases found

Figures 2 and 3 show microscopic photographs of the retina near the preparations of Comparative Example 9 and Example 43, respectively (Figure 2 at 2.5x objective, Figure 3 at 10x objective). Figure 2A shows the retina on the underside of the eyeball, where thinning is confirmed at the location indicated by the arrow. Figure 2B is an enlarged view of Figure 2A, showing necrosis throughout the retinal layer and calcification in a portion.

Table 15 shows the results of macroscopic and histological observations. In the macroscopic observation results, a transparent reservoir was observed in Example 43, whereas no reservoir was confirmed in Comparative Example 9. In addition, in the histological observation results, toxic phenomena in ocular tissues most susceptible to the test preparation (granulomas and inflammatory cell infiltration in the vitreous, localized necrosis in the retina, etc.) were not confirmed in Example 43, whereas localized necrosis in the retina was confirmed in Comparative Example 9.

Based on the above results, it was confirmed that the depot preparation is a base that can be used safely.

Figure 4 shows a microscopic photograph of the retina near the preparation of Example 44 (objective lens 10x). No toxicity was confirmed in the ocular tissues most susceptible to the test preparation (granulation formation and inflammatory cell infiltration in the vitreous containing the administered substance, atrophy/disappearance and dysplasia in the retina, etc.). In addition, no toxicity was confirmed in other ocular tissues (inflammatory cell infiltration around the corner of the eye and edema/inflammatory cell infiltration in the corneal parenchyma, etc.). Based on the above results, it was confirmed that the depot preparation is a base that can be used safely.

Claims (13)

1. A storage preparation, which is an ophthalmic injectable preparation, containing: Medicine; and Tributyl citrate and/or acetylated tributyl citrate, The storage formulation does not contain high molecular weight polymers. 2. A storage preparation, which is an ophthalmic injectable preparation, composed of the following components: Medicine; and Tributyl citrate and/or acetylated tributyl citrate; and Additional additives, The additive is one or more additives selected from the group consisting of surfactants, buffers, isotonic agents, stabilizers, preservatives, antioxidants and solvents. 3. A storage preparation, which is an ophthalmic injectable preparation, composed of the following components: Medicine; and Tributyl citrate and/or acetylated tributyl citrate; and Additional solvent. 4. The reservoir formulation according to any one of claims 1 to 3, wherein the drug is a compound represented by formula (1) or a salt thereof. In equation (1), R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group, a _C1-6 alkyl group, a _C1-6 alkyl group substituted with one or more halogen atoms, a _C1-6 alkoxy group, or a _C1-6 alkoxy group substituted with one or more halogen atoms; ^R2 represents a hydrogen atom, a _C1-6 alkyl group, a _C1-6 alkyl carbonyl group, or a _C1-6 alkyl carbonyl group substituted with one or more hydroxyl groups. 5. The reservoir formulation according to claim 4, wherein the compound represented by formula (1) is 2-[[[2-[(hydroxyacetyl)amino]-4-pyridyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide or a salt thereof. 6. The reservoir formulation according to any one of claims 1 to 3, wherein the drug is (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl acetate or a salt thereof. 7. The reservoir formulation according to any one of claims 1 to 3, wherein the drug is naprafenamide, dexamethasone, indomethacin, diclofenac sodium, levofloxacin, INCB28050, cyclosporine A, timolol maleate, fluocinolone acetonide, triamcinolone acetonide, budesonide, olopatadine, latanoprost, (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetic acid isopropyl ester, (2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide, or sirolimus. 8. The reservoir formulation according to any one of claims 1 to 3, wherein the reservoir formulation contains 0.001 to 30 w/w% of the drug. 9. The reservoir formulation according to any one of claims 1 to 3, wherein the reservoir formulation contains 0.1 w/w% or more of the tributyl citrate and/or acetylated tributyl citrate. 10. Use of the storage formulation according to any one of claims 1 to 9 for the manufacture of a preventive and/or therapeutic agent for eye diseases. 11. Use of the reservoir formulation as claimed in claim 10, wherein the prophylactic and/or therapeutic agent is administered intravitreally, subconjunctivally, or intraanterior chamber. 12. Use of the reservoir preparation as described in claim 10, wherein the eye disease is age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, retinal artery occlusion, polypoid choroidal vascular disease, retinal angiomatous hyperplasia, myopic choroidal neovascularization, diabetic macular edema, ocular tumors, radiation-induced retinopathy, iris redness, neovascular glaucoma, proliferative vitreoretinopathy, primary open-angle glaucoma, secondary open-angle glaucoma, normal-tension glaucoma, hydrophobic glaucoma, primary angle-closure glaucoma, secondary angle-closure glaucoma, iris high-fold glaucoma, mixed glaucoma, developmental glaucoma, steroid glaucoma, ablative glaucoma, amyloidosis glaucoma, malignant glaucoma, capsule glaucoma of the lens, iris syndrome, ocular hypertension, uveitis, or intraocular infection. 13. Use of a liquid composition containing a drug, and tributyl citrate and/or acetylthiol tributyl citrate, for the manufacture of a reservoir formulation for intravitreal, subconjunctival, or intraanterior chamber administration, wherein, The liquid composition does not contain high molecular weight polymers.