WO2024204749A1

WO2024204749A1 - Ophthalmic composition

Info

Publication number: WO2024204749A1
Application number: PCT/JP2024/013119
Authority: WO
Inventors: 紗衣子林; 昭太北澤; 昂平竹本; 卓登森川
Original assignee: ロート製薬株式会社
Priority date: 2023-03-31
Filing date: 2024-03-29
Publication date: 2024-10-03

Abstract

The present invention relates to an ophthalmic composition containing a Janus kinase inhibitor, the ophthalmic composition being accommodated in a container sterilized by a means other than an electron beam.

Description

Ophthalmic Composition

The present invention relates to an ophthalmic composition.

Janus kinase (JAK) is a non-receptor tyrosine kinase that plays an important role in immune activation signal transmission within cells, and drugs with Janus kinase inhibitory activity (hereinafter also referred to as "Janus kinase inhibitors") are expected to improve autoimmune diseases and allergic diseases by suppressing excessive activation of immune responses. Known compounds that have an inhibitory effect on Janus kinase include, for example, 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile (generic name: delgocitinib), 3-{(3S,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (generic name: tofacitinib), and 3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-1-yl]propanenitrile (generic name: ruxolitinib) (for example, Patent Documents 1 to 3).

International Publication No. 2017/006968 WO 02/096909 International Publication No. 2007/070514

On the other hand, when a Janus kinase inhibitor is used as a therapeutic agent for ophthalmic diseases, it is required that the impurities derived from the Janus kinase inhibitor in the ophthalmic formulation are less than a certain amount, but no findings have been reported so far regarding impurities derived from the Janus kinase inhibitor in ophthalmic formulations containing a Janus kinase inhibitor. The present invention aims to provide a novel ophthalmic composition containing a Janus kinase inhibitor in which the impurities derived from the Janus kinase inhibitor are reduced.

The present inventors have found for the first time that when an ophthalmic composition containing a Janus kinase inhibitor is placed in a container sterilized with electron beam, a certain amount of impurities derived from the Janus kinase inhibitor are generated, whereas when the composition is placed in a container sterilized by a means other than electron beam, the amount of impurities derived from the Janus kinase inhibitor is reduced. Furthermore, the present inventors have found for the first time that when an ophthalmic composition containing a Janus kinase inhibitor is filled into a plastic container at the same time as it is molded using the blow-fill-seal method, the amount of impurities derived from the Janus kinase inhibitor is reduced. The present invention is based on these findings, and provides the following inventions.

[1]
An ophthalmic composition comprising a Janus kinase inhibitor, the ophthalmic composition being contained in a container that has been sterilized by a means other than electron beam sterilization.
[2]
The ophthalmic composition according to [1], wherein the sterilization treatment by a means other than electron beam is sterilization by hydrogen peroxide gas or sterilization by ethylene oxide gas.
[3]
The ophthalmic composition according to [1] or [2], wherein the Janus kinase inhibitor is a compound having a pyrrolopyrimidine ring as a partial structure or a salt thereof.
[4]
The ophthalmic composition according to [3], wherein the Janus kinase inhibitor is at least one selected from the group consisting of delgocitinib, tofacitinib, ruxolitinib, oclacitinib, baricitinib, and salts thereof.
[5]
The ophthalmic composition according to [4], wherein the Janus kinase inhibitor is delgocitinib.
[6]
An ophthalmic composition containing a Janus kinase inhibitor, the ophthalmic composition being contained in a container in which some or all of the parts that come into contact with the ophthalmic composition are made of plastic, and the ophthalmic composition is filled into the container molded by a blow-fill-seal method.
[7]
The ophthalmic composition according to [6], wherein the plastic is at least one selected from the group consisting of polyethylene, polypropylene and cyclic olefin copolymer.
[8]
The ophthalmic composition according to [6] or [7], wherein the Janus kinase inhibitor is a compound having a pyrrolopyrimidine ring as a partial structure or a salt thereof.
[9]
The ophthalmic composition according to [8], wherein the Janus kinase inhibitor is at least one selected from the group consisting of delgocitinib, tofacitinib, ruxolitinib, oclacitinib, baricitinib, and salts thereof.
[10]
The ophthalmic composition according to [9], wherein the Janus kinase inhibitor is delgocitinib.

The present invention provides a novel ophthalmic composition containing a Janus kinase inhibitor that has reduced impurities derived from the Janus kinase inhibitor.

Below, the form for implementing the present invention will be described in detail. However, the present invention is not limited to the following embodiment.

In this specification, unless otherwise specified, the unit of content "%" means "w/v %" and is synonymous with "g/100 mL."

The ophthalmic composition of this embodiment contains a Janus kinase inhibitor.

[Janus kinase inhibitors]
The Janus kinase inhibitor can be used without any particular limitation as long as it is a drug that inhibits at least one selected from the group consisting of Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). Known Janus kinase inhibitors that are commercially available or under development include, for example, compounds having the following nitrogen-containing condensed heterocycle (e.g., a pyrrolopyrimidine ring, a pyrrolopyridine ring, an imidazopyrrolopyrazine ring, or a triazolopyridine ring) as a partial structure, or salts thereof, and these can be suitably used as Janus kinase inhibitors.

There are no particular limitations on the salts of compounds having a nitrogen-containing fused heterocycle as a partial structure, so long as they are medicamentally, pharmacologically (pharmaceutical), or physiologically acceptable. Specific examples of such salts include salts with inorganic acids (e.g., salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.), salts with organic acids (e.g., salts with acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid (mesylic acid), ethanesulfonic acid, p-toluenesulfonic acid, etc.), salts with inorganic bases (e.g., alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, ammonium salts), salts with organic bases (e.g., salts with diethylamine, diethanolamine, meglumine, N,N-dibenzylethylenediamine, etc.), salts with acidic or basic amino acids (e.g., salts with aspartic acid, glutamic acid, arginine, lysine, ornithine, etc.), etc.

(1) Delgocitinib Delgocitinib is also known as 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile and has the following formula:

It is a known compound represented by the formula: Delgocitinib or a salt thereof can be produced by, for example, the methods described in WO 2017/006968 and WO 2018/117151.

(2) Tofacitinib Tofacitinib is also known as 3-{(3S,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile and has the following formula:

Tofacitinib or a salt thereof can be produced, for example, by the method described in WO 01/42246. As tofacitinib or a salt thereof, tofacitinib citrate is preferred.

(3) Ruxolitinib Ruxolitinib is also known as (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile and has the following formula:

Ruxolitinib or a salt thereof can be produced, for example, by the method described in WO 2007/070514. Ruxolitinib or a salt thereof is preferably ruxolitinib phosphate.

(4) Oclacitinib Oclacitinib is also known as N-methyl-1-[trans-4-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclohexyl]methanesulfonamide and has the following formula:

It is a known compound represented by the following formula: As oclacitinib or a salt thereof, oclacitinib maleate is preferred.

(5) Baricitinib Baricitinib is also known as {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile and has the following formula:

It is a known compound represented by the formula:

(6) Upadacitinib Upadacitinib is also known as (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and has the following formula:

It is a known compound represented by the following formula: As upadacitinib or a salt thereof, upadacitinib tartrate is preferred.

(7) Peficitinib Peficitinib is also known as 4-{[(1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide and has the following formula:

It is a known compound represented by the following formula: As peficitinib or a salt thereof, peficitinib hydrobromide is preferred.

Among these Janus kinase inhibitors, from the viewpoint of more prominently exerting the effects of the present invention, a compound having a pyrrolopyrimidine ring as a partial structure or a salt thereof is preferred, delgocitinib, tofacitinib, ruxolitinib, oclacitinib, baricitinib, upadacitinib, peficitinib or a salt thereof is more preferred, delgocitinib, tofacitinib or a citrate salt thereof, ruxolitinib or a phosphate salt thereof, oclacitinib or a maleate salt thereof, and baricitinib are even more preferred, and delgocitinib is particularly preferred.

The ophthalmic composition according to this embodiment contains a Janus kinase inhibitor as an active ingredient, and can be used to treat, for example, corneal and conjunctival epithelial disorders caused by endogenous diseases such as dry eye (xerophthalmia), Sjögren's syndrome, and Stevens-Johnson syndrome, or corneal and conjunctival epithelial disorders caused by exogenous diseases such as postoperative, drug-induced, traumatic, contact lens wear, etc.

The content of the Janus kinase inhibitor in the ophthalmic composition according to this embodiment is not particularly limited, and is appropriately set according to the type and content of other blended ingredients, the purpose of the ophthalmic composition, the formulation form, etc. From the viewpoint of more prominently exhibiting the effects of the present invention and appropriately exhibiting the efficacy of the Janus kinase inhibitor, for example, based on the total amount of the ophthalmic composition according to this embodiment, the total content of the Janus kinase inhibitor is preferably 0.001 w/v% to 5 w/v%, more preferably 0.003 w/v% to 3 w/v%, even more preferably 0.005 w/v% to 1 w/v%, even more preferably 0.01 w/v% to 0.5 w/v%, particularly preferably 0.015 w/v% to 0.4 w/v%, and particularly more preferably 0.02 w/v% to 0.3 w/v%. The total content of the Janus kinase inhibitor may be 0.3 w/v%.

[Buffer]
The ophthalmic composition according to the present embodiment may further contain a buffering agent. When the ophthalmic composition further contains a buffering agent, the effect of the present invention is more pronounced. The buffering agent is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable.

Examples of buffers include inorganic buffers, which are buffers derived from inorganic acids, and organic buffers, which are buffers derived from organic acids or organic bases.

Examples of inorganic buffers include borate buffers, phosphate buffers, carbonate buffers, etc. Examples of borate buffers include boric acid or its salts (alkali metal borates, alkaline earth metal borates, etc.). Examples of phosphate buffers include phosphoric acid or its salts (alkali metal phosphates, alkaline earth metal phosphates, etc.). Examples of carbonate buffers include carbonic acid or its salts (alkali metal carbonates, alkaline earth metal carbonates, etc.). Furthermore, hydrates of borates, phosphates, or carbonates may be used as borate buffers, phosphate buffers, or carbonate buffers. More specific examples of borate buffers include boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); phosphate buffers include phosphoric acid or a salt thereof (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); and carbonate buffers include carbonic acid or a salt thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.).

Examples of organic buffers include citrate buffers, acetate buffers, lactate buffers, succinate buffers, tris buffers, AMPD buffers, etc. Examples of citrate buffers include citric acid or its salts (alkali metal citrate, alkaline earth metal citrate, etc.). Examples of acetate buffers include acetic acid or its salts (alkali metal acetate, alkaline earth metal acetate, etc.). Examples of lactate buffers include lactic acid or its salts (alkali metal lactate, alkaline earth metal lactate, etc.). Examples of succinate buffers include succinic acid or its salts (alkali metal succinate, etc.). In addition, hydrates of citrate, acetate, lactate, or succinate may be used as citrate buffers, acetate buffers, lactate buffers, or succinate buffers. More specific examples of the citrate buffer include citric acid or a salt thereof (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.); the acetate buffer includes acetic acid or a salt thereof (ammonium acetate, sodium acetate, potassium acetate, calcium acetate, etc.); the lactate buffer includes lactic acid or a salt thereof (sodium lactate, potassium lactate, calcium lactate, etc.); the succinate buffer includes succinic acid or a salt thereof (monosodium succinate, disodium succinate, etc.). An example of a tris buffer is trometamol or a salt thereof (trometamol hydrochloride, etc.). An example of an AMPD buffer is 2-amino-2-methyl-1,3-propanediol or a salt thereof.

As the buffer, boric acid buffers (e.g., a combination of boric acid and borax), phosphate buffers (e.g., a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate), and Tris buffers (e.g., trometamol) are preferred, with boric acid buffers being more preferred, boric acid and its salts being even more preferred, and a combination of boric acid and borax being even more preferred.

Commercially available buffers may be used. One type of buffer may be used alone, or two or more types may be used in combination.

The content of the buffering agent in the ophthalmic composition according to this embodiment is not particularly limited, and is set appropriately depending on the type of buffering agent, the type and content of other blended ingredients, the intended use of the ophthalmic composition, the formulation form, etc. From the viewpoint of more significantly achieving the effects of the present invention, the content of the buffering agent is, for example, preferably 0.01 w/v% to 10 w/v%, more preferably 0.05 w/v% to 5 w/v%, and even more preferably 0.1 w/v% to 3 w/v%, based on the total amount of the ophthalmic composition.

The content ratio of the buffering agent to the Janus kinase inhibitor in the ophthalmic composition according to this embodiment is not particularly limited, and is appropriately set depending on the types of Janus kinase inhibitor and buffering agent, the types and contents of other blended components, the purpose and formulation form of the ophthalmic composition, etc. From the viewpoint of further enhancing the effect of the present invention, for example, the content ratio of the buffering agent to the Janus kinase inhibitor is preferably 0.03 parts by mass to 500 parts by mass, more preferably 0.1 parts by mass to 250 parts by mass, even more preferably 0.3 parts by mass to 200 parts by mass, even more preferably 0.1 parts by mass to 180 parts by mass, particularly preferably 0.2 parts by mass to 150 parts by mass, and particularly more preferably 0.3 parts by mass to 100 parts by mass.

[Inorganic salts]
The ophthalmic composition according to the present embodiment may further contain an inorganic salt. When the ophthalmic composition further contains an inorganic salt, the effect of the present invention is more remarkable. The inorganic salt is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable.

Inorganic salts include chloride salts such as sodium chloride, potassium chloride, calcium chloride, and magnesium chloride. Commercially available inorganic salts may be used. One type of inorganic salt may be used alone, or two or more types may be used in combination. Sodium chloride and potassium chloride are preferred inorganic salts.

The content of inorganic salts in the ophthalmic composition according to this embodiment is not particularly limited, and is set appropriately depending on the type of inorganic salt, the type and content of other blended ingredients, the purpose and formulation form of the ophthalmic composition, etc. From the viewpoint of more significantly achieving the effects of the present invention, the content of inorganic salts is, for example, preferably 0.00001% by mass to 3% by mass, more preferably 0.0001% by mass to 2% by mass, even more preferably 0.001% by mass to 1.5% by mass, even more preferably 0.01% by mass to 1.0% by mass, and even more preferably 0.1% by mass to 1.0% by mass, based on the total amount of the ophthalmic composition.

The pH of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a medicamentously, pharmacologically (pharmaceutical), or physiologically acceptable range. The pH of the ophthalmic composition according to this embodiment may be, for example, 4.0 to 6.5, preferably 4.5 to 6.0, and more preferably 4.5 to 5.5. The pH of the ophthalmic composition according to this embodiment may be, for example, 4.0 to 6.0, or 4.0 to 5.5.

The ophthalmic composition according to this embodiment can be adjusted to an osmotic pressure ratio within a range acceptable to the living body, if necessary. The appropriate osmotic pressure ratio can be set appropriately depending on the application, formulation form, method of use, etc. of the ophthalmic composition, and can be, for example, 0.4 to 5.0, preferably 0.6 to 3.0, more preferably 0.8 to 2.2, and even more preferably 0.8 to 2.0. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (the osmotic pressure of a 0.9 w/v% sodium chloride aqueous solution) based on the 17th Revised Japanese Pharmacopoeia, and the osmotic pressure is measured with reference to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia. The standard solution for measuring osmolality ratios (0.9 w/v% sodium chloride aqueous solution) can be prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650°C for 40-50 minutes, allowing it to cool in a desiccator (silica gel), and then accurately weighing out 0.900 g of it and dissolving it in purified water to make exactly 100 mL, or a commercially available standard solution for measuring osmolality ratios (0.9 w/v% sodium chloride aqueous solution) can be used.

The viscosity of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a range that is medicamentally, pharmacologically (pharmaceutical), or physiologically acceptable. For example, the viscosity of the ophthalmic composition according to this embodiment is preferably 0.5 to 10 mPa·s, more preferably 1 to 5 mPa·s, and even more preferably 1 to 3 mPa·s, at 20°C, measured with a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34' x R24).

The ophthalmic composition according to this embodiment can be prepared, for example, by adding and mixing a Janus kinase inhibitor and, if necessary, other ingredients to obtain a desired content. Specifically, for example, the ophthalmic composition can be prepared by dissolving or suspending the above ingredients in purified water, adjusting the pH and osmotic pressure to a predetermined level, and sterilizing the composition by filtration sterilization or the like.

The ophthalmic composition according to this embodiment can be in various dosage forms depending on the purpose, such as a liquid, gel, semi-solid (ointment, etc.), etc.

The ophthalmic composition according to this embodiment can be used for ophthalmic purposes. The ophthalmic composition according to this embodiment can be used, for example, as eye drops (also called eye drops or eye drops. Eye drops include artificial tears and eye drops that can be applied while wearing contact lenses).

When the ophthalmic composition according to this embodiment is an eye drop, the method of use and dosage are not particularly limited as long as they are effective and have few side effects. For example, for adults (15 years or older) and children 7 years or older, one drop or one to two drops can be instilled into the eyes four times a day, and one drop or one to two drops can be instilled into the eyes five to six times a day.

〔container〕
The ophthalmic composition according to the present embodiment is provided with a part or the whole of the part in contact with the ophthalmic composition contained in a container. The container for containing the ophthalmic composition according to the present embodiment is not particularly limited, and may be made of glass or plastic, for example. It is preferably made of plastic. Examples of plastic include polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polyethylene naphthalate, polyarylate, polycarbonate, polyethylene (PE; high density polyethylene (HDPE), low density polyethylene (LDPE), linear low density polyethylene (LLDPE)), polypropylene (PP), polystyrene (PS), acrylonitrile butadiene styrene (ABS), polymethylpentene (PMP), polyimide (PI), cyclic olefin polymer (COP), cyclic olefin copolymer (COC), and copolymers of monomers constituting these, as well as mixtures of two or more of these. Examples of polymers constituting plastic include polyolefins such as polyethylene (PE) and polypropylene (PP), and cyclic olefin copolymer (COC), and more preferably polyethylene (PE). In addition, the plastic may contain an elastomer.

The plastic may contain additives such as stabilizers. The plastic may also be reinforced by including reinforcing agents such as glass fiber.

Any commercially available plastic can be used without any restrictions.

The container for storing the ophthalmic composition may be a container commonly used in the ophthalmic field, specifically, for example, an eye drop container or an eyewash container. The type of container is preferably an eye drop container.

When the container according to this embodiment is made of plastic and has a perforated plug (nozzle), only the perforated plug portion may be made of plastic, or the storage portion other than the perforated plug may be made of plastic, or the entire container may be made of plastic.

When the container according to this embodiment is made of plastic, it is preferable that the entire portion that comes into contact with the ophthalmic composition is made of plastic, from the viewpoint of achieving a more pronounced effect of the present invention. Furthermore, the container may be made of a single type of plastic, or may be made of two or more types of plastic.

The shape and capacity of the container are not particularly limited and may be set appropriately depending on the application. The container may be a container that contains an amount of ophthalmic composition for multiple uses (multi-dose type container), or a container that contains an amount of ophthalmic composition for a single use (unit dose type container).

If the container is a multi-dose container, the capacity may be, for example, 1.5 to 7.5 mL, 2.0 to 6.0 mL, or 2.5 to 5.0 mL. If the container is a unit-dose container, the capacity may be, for example, 0.01 to 1.0 mL, 0.05 to 0.9 mL, or 0.1 to 0.8 mL.

[Sterilization]
The container that holds the ophthalmic composition according to this embodiment is sterilized by a means other than electron beam sterilization, which has the effect of reducing impurities derived from the Janus kinase inhibitor in the ophthalmic composition.

Sterilization treatments by means other than electron beams include, for example, sterilization treatments by gamma rays, sterilization treatments by hydrogen peroxide gas (VHP), and sterilization treatments by ethylene oxide gas (EOG). Among these, sterilization treatments by hydrogen peroxide gas (VHP) and ethylene oxide gas (EOG) are preferred. Sterilization treatments by means other than electron beams, for example, sterilization treatments by gamma rays, sterilization treatments by hydrogen peroxide gas (VHP), and sterilization treatments by ethylene oxide gas (EOG), can be carried out by methods known to those skilled in the art. They can also be carried out by a method in which container molding and formulation filling are carried out simultaneously in an aseptic manner. For example, the plastic container containing the ophthalmic composition according to this embodiment can be manufactured by the blow-fill-seal (BFS) method (see, for example, International Publication No. WO 2004/093775). First, a parison is produced by extrusion molding plastic. Next, the obtained parison is sandwiched between a split mold, and each part of the container body is molded by either injecting air into the inside or sucking the parison through a vacuum hole installed on the mold surface (blowing process), and the ophthalmic composition is filled into the storage part (filling process). Finally, the container can be manufactured by sandwiching the parison between a split mold to form a lid and sealing the opening of the spout (sealing process). The blowing process and filling process may be performed sequentially or simultaneously.

The ophthalmic composition according to this embodiment may also be provided as a containerized ophthalmic composition. The present invention may also be considered as an ophthalmic product (such as eye drops) in which the ophthalmic composition of the present invention is contained in a container.

The present invention will be specifically explained below based on test examples, but the present invention is not limited to these. Furthermore, unless otherwise specified, the units of each component in the table are w/v %. Furthermore, containers that were not sterilized after molding were classified as "non-sterile."

[Example 1] Heat Stress Test Ophthalmic compositions were prepared at pH 5.0 according to the conventional method with the compositions shown in Table 1 or 2. Each prepared ophthalmic composition was filtered and sterilized with a 0.2 μm membrane filter. Thereafter, the ophthalmic composition was filled into an eye dropper bottle (material: polyethylene (PE), capacity: 5 mL) previously treated with each sterilization method, and stored under light-shielded conditions at 50 ° C. for 1 month (Table 1) or 2 months (Table 2). The content of two types of delgocitinib-derived impurities (substances A and B) contained in the ophthalmic composition after storage was measured by HPLC, and the production rates (%) of substances A and B were calculated by dividing the peak area by the peak area of the delgocitinib standard solution. In addition, the reduction rates (%) of substances A and B were calculated from the calculated production rates of substances A and B according to the following formula. The results are shown in Tables 1 and 2.
(Formula 1-1)
Reduction rate (%) of substance A in Test Examples 2 to 4=100×{(production rate of substance A in Test Example 1−production rate of substance A in each Test Example)/production rate of substance A in Test Example 1}
(Formula 1-2)
Reduction rate (%) of substance B in Test Examples 2 to 4=100×{(production rate of substance B in Test Example 1−production rate of substance B in each Test Example)/production rate of substance B in Test Example 1}
(Formula 2-1)
Reduction rate (%) of substance A in Test Examples 6 to 8=100×{(production rate of substance A in Test Example 5−production rate of substance A in each Test Example)/production rate of substance A in Test Example 5}
(Equation 2-2)
Reduction rate (%) of substance B in Test Examples 6 to 8=100×{(production rate of substance B in Test Example 5−production rate of substance B in each Test Example)/production rate of substance B in Test Example 5}

Compared to containers sterilized with electron beams, containers sterilized by methods other than electron beams significantly suppressed the production of delgocitinib-derived impurities, confirming that delgocitinib was present stably.

[Example 2] Wettability test Ophthalmic compositions were prepared at pH 5.0 according to the usual method with the composition shown in Table 3. Each prepared ophthalmic composition was filtered and sterilized with a 0.2 μm membrane filter. On the other hand, a polyethylene (PE) container treated with each sterilization method was cut in half lengthwise, the neck and bottom were cut off, and double-sided tape was attached to the outside of the container (the side of the container that does not contact the filling), and the long side of the container slice was set on the table of the measuring device so that it was in front of the photograph. The short side of the container slice was fixed on the entire surface so that it would not float, and the container slice was pressed and attached to the table. The droplet was adjusted so that it was dripped onto the edge of the container slice so that the container slice and the grounded part of the droplet were reflected by the camera. 1.0 μL of the ophthalmic composition prepared above was discharged from the syringe and dripped onto the container slice, and the left and right contact angles of the obtained image were manually adjusted to calculate the contact angle. The contact angle was measured three times, and the average value was calculated to be the contact angle of each ophthalmic composition.
According to the following formula 3, the contact angle increase rate of each ophthalmic composition was calculated with respect to Test Example 9. The results are shown in Table 3.
[Formula 3] Contact angle increase rate (%)={(contact angle of each ophthalmic composition−contact angle of Test Example 9)/contact angle of Test Example 9}×100

Compared to containers sterilized with electron beam, containers sterilized by methods other than electron beam had a larger contact angle and were less likely to become wet, which meant that the ophthalmic composition tended to be easier to expel down to the last drop. It is suggested that electron beam sterilization has some effect on the container surface, which acts with the Janus kinase inhibitor to lower the contact angle. Therefore, when containers other than PE are used and sterilized by methods other than electron beam, a similar increase in the contact angle is expected even when the ophthalmic composition is filled into the container using the blow-fill-seal (BFS) method.

[Example 3] Heat Stress Test Ophthalmic compositions were prepared at pH 5.0 according to a conventional method with the compositions shown in Tables 4 to 7. Each prepared ophthalmic composition was filtered through a 0.2 μm membrane filter and sterilized. For Test Examples 3-1 to 3-4, 3-7 to 3-10, 3-13 to 3-14, 4-1 to 4-4, 4-7 to 4-10, and 4-13 to 4-14, the ophthalmic compositions were filled into eye dropper bottles (material: polyethylene (PE), capacity: 5 mL) that had been previously treated by each sterilization method, and stored under conditions of light-shielding and at 50° C. for 1 month (Tables 4 and 5) or 2 months (Tables 6 and 7). For Test Examples 3-5 to 3-6, 3-11 to 3-12, 4-5 to 4-6, and 4-11 to 4-12, eye drop bottles filled with ophthalmic compositions by the blow-fill-seal (BFS) method (material: polyethylene or cyclic olefin copolymer (COC), capacity: 0.5 mL) were stored under conditions of light shielding and 50 ° C. for 1 month (Tables 4 and 5) or 2 months (Tables 6 and 7). The contents of two types of delgocitinib-derived impurities (substances A and B) contained in the ophthalmic composition after storage were measured by HPLC, and the production rates (%) of substances A and B were calculated by dividing the peak areas by the peak areas of the delgocitinib standard solution. In addition, the reduction rates (%) of substances A and B were calculated from the calculated production rates of substances A and B according to the following formula. The results are shown in Tables 4 to 7.
(Formula 3-1)
Reduction rate (%) of substance A in Test Examples 3-2 to 3-6=100×{(production rate of substance A in Test Example 3-1−production rate of substance A in each Test Example)/production rate of substance A in Test Example 3-1}
(Equation 3-2)
Reduction rate (%) of substance B in Test Examples 3-8 to 3-12=100×{(production rate of substance B in Test Example 3-7−production rate of substance B in each Test Example)/production rate of substance B in Test Example 3-7}
(Equation 3-3)
Reduction rate (%) of substance B in Test Example 3-14=100×{(production rate of substance B in Test Example 3-13−production rate of substance B in Test Example 3-14)/production rate of substance B in Test Example 3-13}
(Formula 4-1)
Reduction rate (%) of substance A in Test Examples 4-2 to 4-6=100×{(production rate of substance A in Test Example 4-1−production rate of substance A in each Test Example)/production rate of substance A in Test Example 4-1}
(Equation 4-2)
Reduction rate (%) of substance B in Test Examples 4-8 to 4-12=100×{(production rate of substance B in Test Example 4-7−production rate of substance B in each Test Example)/production rate of substance B in Test Example 4-7}
(Equation 4-3)
Reduction rate (%) of substance B in Test Example 4-14=100×{(production rate of substance B in Test Example 4-13−production rate of substance B in Test Example 4-14)/production rate of substance B in Test Example 4-13}

Compared to containers sterilized with electron beams, containers sterilized by methods other than electron beams significantly suppressed the generation of delgocitinib-derived impurities, confirming that delgocitinib remained stable. In addition, when filled into plastic containers using the blow-fill-seal method, the generation of delgocitinib-derived impurities was significantly reduced, confirming that delgocitinib remained stable.

[Example 4] Heat Stress Test Ophthalmic compositions were prepared at pH 5.0 according to the usual method with the compositions shown in Tables 8 and 9. Each prepared ophthalmic composition was filtered through a 0.2 μm membrane filter and sterilized. For Test Examples 5-1 to 5-4 and 6-1 to 6-4, the ophthalmic compositions were filled into eye drop bottles (material: polyethylene (PE), capacity: 5 mL) that had been previously treated with each sterilization method, and stored under light-shielded conditions at 50° C. for 1 month (Table 8) or 2 months (Table 9). For Test Examples 5-5 to 5-6 and 6-5 to 6-6, eye drop bottles (material: polyethylene or cyclic olefin copolymer (COC), capacity: 0.5 mL) filled with the ophthalmic compositions by the blow-fill-seal (BFS) method were stored under light-shielded conditions at 50° C. for 1 month (Table 8) or 2 months (Table 9). The content of impurities (substance C) derived from tofacitinib contained in the ophthalmic composition after storage was measured by HPLC, and the peak area was divided by the peak area of the standard solution of tofacitinib to calculate the production rate (%) of substance C. In addition, the reduction rate (%) of substance C was calculated from the calculated production rate of substance C according to the following formula. The results are shown in Tables 8 and 9.
(Equation 5)
Reduction rate (%) of substance C in Test Examples 5-2 to 5-6=100×{(production rate of substance C in Test Example 5-1−production rate of substance C in each Test Example)/production rate of substance C in Test Example 5-1}
(Equation 6)
Reduction rate (%) of substance C in Test Examples 6-2 to 6-6=100×{(production rate of substance C in Test Example 6-1−production rate of substance C in each Test Example)/production rate of substance C in Test Example 6-1}

Compared to containers sterilized with electron beams, the production of impurities derived from tofacitinib was significantly suppressed in containers sterilized by methods other than electron beams, and it was confirmed that tofacitinib remained stable. Furthermore, when filled into plastic containers using the blow-fill-seal method, the production of impurities derived from tofacitinib was significantly reduced, and it was confirmed that tofacitinib remained stable.

[Example 5] Antifoam test

Ophthalmic compositions were prepared at pH 5.0 according to conventional methods with the compositions shown in Tables 10 to 12. Each prepared ophthalmic composition was filtered through a 0.2 μm membrane filter and sterilized. For Test Examples 7-1 to 7-4, 8-1 to 8-4, and 9-1 to 9-4, the ophthalmic compositions were filled into eye dropper bottles (material: polyethylene (PE), capacity: 5 mL) that had been previously treated with each sterilization method. Next, 1 mL of air was poured into each filled ophthalmic composition using a micropipette (Gilson, P1000) to create air bubbles. After that, the time until the bubbles completely disappeared (defoaming) was set to a maximum of 30 seconds and measured.

Among ophthalmic compositions, foreign body inspection is essential in the manufacturing process for pharmaceuticals such as eye drops, eyewashes, etc. However, in general, when bubbles are generated in the ophthalmic composition during filling, if the bubbles disappear slowly, it is difficult to distinguish between foreign bodies and bubbles, and therefore the foreign body inspection process takes time, resulting in an inefficient manufacturing process.
As shown in Tables 10 to 12, whether delgocitinib or tofacitinib citrate is contained, the time until defoaming was significantly shortened in the container sterilized by a method other than electron beam compared to the container sterilized by electron beam. It is suggested that electron beam sterilization has some effect on the inner surface of the container, which acts with the Janus kinase inhibitor to affect the defoaming effect. Therefore, when a container other than PE is used and sterilized by a method other than electron beam, the time until defoaming is similarly shortened even when the ophthalmic composition is filled into the container by the blow-fill-seal (BFS) method.

Claims

An ophthalmic composition containing a Janus kinase inhibitor, the ophthalmic composition being contained in a container that has been sterilized by a means other than electron beam sterilization.
The ophthalmic composition according to claim 1, wherein the sterilization treatment by a means other than electron beam is sterilization by hydrogen peroxide gas or sterilization by ethylene oxide gas.
The ophthalmic composition according to claim 1 or 2, wherein the Janus kinase inhibitor is a compound having a pyrrolopyrimidine ring as a partial structure or a salt thereof.
The ophthalmic composition according to claim 3, wherein the Janus kinase inhibitor is at least one selected from the group consisting of delgocitinib, tofacitinib, ruxolitinib, oclacitinib, baricitinib, and salts thereof.
The ophthalmic composition according to claim 4, wherein the Janus kinase inhibitor is delgocitinib.
An ophthalmic composition containing a Janus kinase inhibitor, the ophthalmic composition being contained in a container in which a part or all of the part that comes into contact with the ophthalmic composition is made of plastic, and the ophthalmic composition is filled in the container molded by the blow-fill-seal method.
The ophthalmic composition according to claim 6, wherein the plastic is at least one selected from the group consisting of polyethylene, polypropylene, and cyclic olefin copolymer.
The ophthalmic composition according to claim 6 or 7, wherein the Janus kinase inhibitor is a compound having a pyrrolopyrimidine ring as a partial structure or a salt thereof.
The ophthalmic composition according to claim 8, wherein the Janus kinase inhibitor is at least one selected from the group consisting of delgocitinib, tofacitinib, ruxolitinib, oclacitinib, baricitinib, and salts thereof.
The ophthalmic composition according to claim 9, wherein the Janus kinase inhibitor is delgocitinib.