Aqueous composition

Abstract

To provide an aqueous composition that contains a Janus kinase inhibitor and exhibits superior preservation effect.SOLUTION: An aqueous composition containing a Janus kinase inhibitor and a biguanide-based preservative.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an aqueous composition. [Background technology]

[0002] Janus kinase (JAK) is a non-receptor tyrosine kinase that plays an important role in intracellular immune activation signal transduction. Drugs with Janus kinase inhibitory activity (hereinafter referred to as "Janus kinase inhibitors") are expected to improve autoimmune and allergic diseases by suppressing excessive activation of immune responses. Known compounds that have inhibitory activity against 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) and 3-{(3S,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (generic name: tofacitinib) (e.g., Patent Documents 1 and 2). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2017 / 006968 [Patent Document 2] International Publication No. 02 / 096909 Summary of the Invention [Problem to be solved by the invention]

[0004] A certain level of preservative effectiveness is required for aqueous preparations such as eye drops, but until now, nothing was known about the preservative effectiveness of aqueous preparations containing Janus kinase inhibitors as active ingredients.

[0005] An object of the present invention is to provide an aqueous composition containing a Janus kinase inhibitor, which has excellent preservative effectiveness. [Means for solving the problem]

[0006] As a result of intensive research aimed at solving the above problems, the present inventors have found that the preservative effect of an aqueous composition containing a Janus kinase inhibitor is significantly enhanced when a biguanide preservative is added. The present invention is based on this finding and provides the following inventions.

[0007] [1] An aqueous composition comprising a Janus kinase inhibitor and a biguanide preservative. [2] The aqueous composition according to [1], wherein the content of the Janus kinase inhibitor is 0.001% by mass to 5% by mass based on the total amount of the aqueous composition. [3] The aqueous composition according to [1] or [2], wherein the Janus kinase inhibitor is delgocitinib. [4] The aqueous composition according to any one of [1] to [3], wherein the biguanide antiseptic is chlorhexidine or a salt thereof. [5] The aqueous composition according to any one of [1] to [4], which has a pH of 4.0 to 6.5. [6] The aqueous composition according to any one of [1] to [5], which is for ophthalmic use. [Effects of the Invention]

[0008] According to the present invention, an aqueous composition containing a Janus kinase inhibitor, which has excellent preservative effectiveness, can be provided. DETAILED DESCRIPTION OF THE INVENTION

[0009] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments.

[0010] The aqueous composition according to this embodiment contains a Janus kinase inhibitor and a biguanide preservative.

[0011] [Janus kinase inhibitors] The Janus kinase inhibitor can be any 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), without any particular limitation. Known Janus kinase inhibitors that are commercially available or under development include, for example, compounds or salts thereof having the following nitrogen-containing fused heterocycle (preferably a pyrrolopyrimidine ring, a pyrrolopyridine ring, an imidazopyrrolopyrazine ring, or a triazolopyridine ring) as a partial structure, and these can be suitably used as Janus kinase inhibitors.

[0012] The salt of the compound having a nitrogen-containing fused heterocycle as a partial structure is not particularly limited, so long as it is medicamentarily, 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 salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, ammonium salt), 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.), and the like.

[0013] (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: [ka] Delgocitinib or a salt thereof can be produced by, for example, the methods described in WO 2017 / 006968 and WO 2018 / 117151.

[0014] (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: [ka] Tofacitinib or a salt thereof can be produced, for example, by the method described in WO 01 / 42246. Tofacitinib or a salt thereof is preferably tofacitinib citrate.

[0015] (3) Upadacitinib Upadacitinib, 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, has the following formula: [ka] It is a known compound represented by the following formula: As upadacitinib or a salt thereof, upadacitinib tartrate is preferred.

[0016] (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: [ka] It is a known compound represented by the following formula: As oclacitinib or a salt thereof, oclacitinib maleate is preferred.

[0017] (5) 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: [ka] It is a known compound represented by the following formula: Peficitinib or a salt thereof is preferably peficitinib hydrobromide.

[0018] (6) 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: [ka] It is a known compound represented by the formula:

[0019] (7) Filgotinib Filgotinib, also known as N-(5-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide, has the following formula: [ka] It is a known compound represented by the formula:

[0020] Among these Janus kinase inhibitors, delgocitinib, tofacitinib or citrate salts thereof are preferred, with delgocitinib being more preferred, from the viewpoint of more significantly exhibiting the effects of the present invention.

[0021] The aqueous composition of this embodiment contains a Janus kinase inhibitor as an active ingredient, and can be used to treat 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, or contact lens wear disorders.

[0022] The content of the Janus kinase inhibitor in the aqueous composition according to this embodiment is not particularly limited, and is set appropriately depending on the types and contents of other blended ingredients, the intended use of the aqueous composition, the formulation, etc. From the viewpoint of more significantly achieving the effects of the present invention and appropriately exhibiting the efficacy of the Janus kinase inhibitor, the content of the Janus kinase inhibitor is, for example, preferably 0.001% by mass to 5% by mass, more preferably 0.003% by mass to 3% by mass, even more preferably 0.005% by mass to 1% by mass, even more preferably 0.01% by mass to 0.5% by mass, particularly preferably 0.015% by mass to 0.4% by mass, and particularly more preferably 0.02% by mass to 0.3% by mass, based on the total amount of the aqueous composition according to this embodiment.

[0023] [Biguanide preservatives] Biguanide preservatives include the following biguanides: [ka] In the molecule, the biguanide antiseptic agent refers to a compound having an antiseptic effect. Examples of biguanide antiseptic agents include chlorhexidine or a salt thereof, alexidine or a salt thereof, and polyhexanide or a salt thereof.

[0024] Chlorhexidine is a known compound also known as 1,1'-hexamethylene-bis-[5-(4-chlorophenyl)biguanide], and alexidine is a known compound also known as 1,1'-hexamethylene-bis-[5-(2-ethylhexyl)biguanide].

[0025] Examples of chlorhexidine salts, alexidine salts, polyhexanide or their salts include inorganic acid salts, organic acid salts, and sulfonic acid salts. Examples of inorganic acid salts include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, boric acid, phosphoric acid, and nitric acid. Examples of organic acid salts include salts with acetic acid, gluconic acid, maleic acid, ascorbic acid, stearic acid, tartaric acid, and citric acid. Examples of sulfonic acid salts include salts with methanesulfonic acid, isethionic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0026] As the biguanide antiseptic, from the viewpoint of exhibiting the effects of the present invention more significantly, chlorhexidine or a salt thereof is preferred, and chlorhexidine gluconate is more preferred.

[0027] The content of the biguanide preservative in the aqueous composition according to this embodiment is not particularly limited and is set appropriately depending on the type and content of other ingredients, the intended use of the aqueous composition, and the formulation form. To more significantly achieve the effects of the present invention, the content of the biguanide preservative is preferably 0.00001% to 2% by mass, more preferably 0.00005% to 1% by mass, and particularly preferably 0.00008% to 0.5% by mass, based on the total amount of the aqueous composition according to this embodiment. Other preferred contents include 0.00005% to 0.1% by mass and 0.0001% to 0.01% by mass.

[0028] The ratio of the biguanide preservative to the Janus kinase inhibitor in the aqueous composition according to this embodiment is not particularly limited and is set appropriately depending on the types of Janus kinase inhibitor and biguanide preservative, the types and amounts of other ingredients, the intended use of the aqueous composition, and the dosage form. From the perspective of further enhancing the effects of the present invention, the ratio of the biguanide preservative to the Janus kinase inhibitor is preferably 0.00003 to 100 parts by mass, and more preferably 0.0001 to 50 parts by mass, of the total biguanide preservative contained in the ophthalmic solution according to this embodiment per part by mass of the Janus kinase inhibitor. Other preferred ratios include 0.0001 to 5 parts by mass and 0.0003 to 0.5 parts by mass.

[0029] [Buffer] The aqueous composition according to this embodiment may further contain a buffering agent. When the aqueous composition further contains a buffering agent, the effects of the present invention are more pronounced. The buffering agent is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable.

[0030] Examples of buffering agents include boric acid buffering agents (e.g., boric acid, a combination of boric acid and borax, etc.). Commercially available buffering agents may be used. One type of buffering agent may be used alone, or two or more types may be used in combination. Boric acid is preferred as the buffering agent.

[0031] The content of the buffering agent in the aqueous composition according to this embodiment is not particularly limited and is set appropriately depending on the type of buffering agent, the types and contents of other blended ingredients, the intended use and formulation of the aqueous composition, etc. From the viewpoint of more significantly exhibiting the effects of the present invention, the content of the buffering agent is, for example, preferably 0.01% by mass to 10% by mass, more preferably 0.05% by mass to 5% by mass, and even more preferably 0.1% by mass to 3% by mass, based on the total amount of the aqueous composition.

[0032] The content ratio of the buffering agent relative to the Janus kinase inhibitor in the aqueous composition according to this embodiment is not particularly limited, and is set appropriately depending on the types of Janus kinase inhibitor and buffering agent, the types and contents of other blended ingredients, the intended use and formulation of the aqueous composition, etc. From the viewpoint of further enhancing the effects of the present invention, the content ratio of the buffering agent relative to the Janus kinase inhibitor is, for example, preferably 0.03 parts by mass to 500 parts by mass, more preferably 0.1 parts by mass to 250 parts by mass, and even more preferably 0.3 parts by mass to 150 parts by mass, of the total content of the Janus kinase inhibitor contained in the aqueous composition according to this embodiment.

[0033] [Inorganic salts] The aqueous composition according to this embodiment may further contain an inorganic salt. When the aqueous composition further contains an inorganic salt, the effects of the present invention are more pronounced. The inorganic salt is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable.

[0034] Examples of 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. Preferred inorganic salts are sodium chloride and potassium chloride.

[0035] The content of inorganic salts in the aqueous composition according to this embodiment is not particularly limited and is set appropriately depending on the type of inorganic salts, the types and contents of other blended ingredients, the intended use and formulation of the aqueous composition, etc. From the viewpoint of more significantly exhibiting 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, and even more preferably 0.001% by mass to 1.5% by mass, based on the total amount of the aqueous composition.

[0036] The pH of the aqueous composition according to this embodiment is not particularly limited as long as it is within a medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable range. The pH of the aqueous composition according to this embodiment may be, for example, 5.0 to 6.5, and preferably 5.0 to 6.0. The pH of the aqueous composition according to this embodiment may also be, for example, 4.0 to 6.5, 4.0 to 6.0, or 4.5 to 6.0.

[0037] The aqueous composition according to the present embodiment can be adjusted to have an osmotic pressure ratio within a biologically acceptable range, as needed. The appropriate osmotic pressure ratio can be determined as appropriate depending on the intended use, formulation, and method of use of the aqueous composition, but 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 defined as 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) in accordance with the Japanese Pharmacopoeia, 17th Edition, and is measured using 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), accurately weighing 0.900 g of the solution, and dissolving it in purified water to make exactly 100 mL; alternatively, a commercially available standard solution for measuring osmolality ratios (0.9 w / v% sodium chloride aqueous solution) can be used.

[0038] The viscosity of the aqueous composition according to this embodiment is not particularly limited as long as it is within a medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable range. The viscosity of the aqueous composition according to this embodiment, as measured at 20°C using a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34' x R24), is preferably 0.5 to 10 mPa s, more preferably 1 to 5 mPa s, and even more preferably 1 to 3 mPa s.

[0039] The aqueous composition according to the present embodiment can be prepared by, for example, adding and mixing a Janus kinase inhibitor, a biguanide preservative, and, if necessary, other ingredients to a desired content. Specifically, the aqueous composition can be prepared by, for example, dissolving or suspending the above ingredients in purified water, adjusting the pH and osmotic pressure to a predetermined value, and sterilizing the resulting mixture by filtration or the like.

[0040] The aqueous composition according to this embodiment can be in various dosage forms depending on the purpose, and examples thereof include liquids, gels, semi-solids (ointments, etc.), and the like.

[0041] The aqueous composition according to this embodiment can be used for ophthalmic purposes. The aqueous composition according to this embodiment can also be used, for example, as eye drops (also called eye drops or eye drops, and eye drops include artificial tears and eye drops that can be applied while wearing contact lenses).

[0042] When the aqueous composition according to the present embodiment is an eye drop, the dosage and administration method are not particularly limited as long as they are effective and have few side effects. For example, for adults (15 years of age or older) and children aged 7 years of age or older, one drop or one to two drops may be instilled into the eyes four times a day, or one drop or one to two drops may be instilled into the eyes five to six times a day.

[0043] The aqueous composition according to this embodiment is preferably provided in a container in which a part or all of the parts that come into contact with the aqueous composition are formed of a polyolefin resin (also simply referred to as a "polyolefin resin container"). The polyolefin resin container may be any packaging having a part that comes into contact with the aqueous composition, and may be composed of, for example, a container body that contains the aqueous composition, a part including the container discharge part (e.g., a nozzle, an inner plug), a suction tube, a cap, etc.

[0044] The polyolefin resin may be either a polymer obtained by polymerizing one type of olefin alone or a polymer obtained by copolymerizing two or more types of olefins. These polymers may contain other polymerizable monomers as constituent components. Specific examples of polyolefin resins include polyethylene (including low-density polyethylene, medium-density polyethylene, high-density polyethylene, etc.), polypropylene (including isotactic polypropylene, syndiotactic polypropylene, and atactic polypropylene), ethylene-propylene copolymer, polymethylpentene, etc. Among these, polyethylene and polypropylene are preferred, and polyethylene is more preferred. [Example]

[0045] The present invention will be specifically explained below based on test examples, but the present invention is not limited to these. Unless otherwise specified, the unit of each component in the tables is w / v %.

[0046] [Test Example 1: Preservative Effectiveness Test (1)] Aqueous compositions were prepared according to standard methods with the compositions shown in Table 1. Each aqueous composition was sterilized by filtering through a 0.2 μm membrane filter. The aqueous compositions were then filled into eye dropper bottles (material: polyethylene, capacity: 5 mL) and stored at 50°C for two months under light-shielded conditions. The preservative effectiveness of each aqueous composition after two months of storage at 50°C was evaluated according to the preservative effectiveness test method specified in the 17th Edition of the Japanese Pharmacopoeia. Specifically, Pseudomonas aeruginosa was inoculated onto the surface of soybean-casein-digest agar medium and cultured at 30-35°C for 24 hours. The cultured cells were aseptically collected using a platinum loop and suspended in an appropriate amount of sterile physiological saline to obtain a concentration of approximately 1 × 10 7 A bacterial suspension containing viable bacteria at CFU / mL was prepared. This bacterial suspension was added to each formulation at approximately 1 × 10 5After adding the aqueous composition so that the concentration of CFU / mL was reached, the mixture was allowed to stand at 20-25°C for 7 days. The bacteria were then collected using the membrane filtration method and placed on the surface of soybean-casein-digest agar medium. After allowing the mixture to stand at 30-35°C for 2-3 days, the viable cell count per mL of each aqueous composition was measured, and the log reduction was calculated based on this value. The results are shown in Table 1.

[0047] Test Example 2: Evaluation of the stability of chlorhexidine gluconate Each aqueous composition prepared in Test Example 1 was sterilized by filtration through a 0.2 μm membrane filter. The aqueous compositions were then filled into eye dropper bottles (material: polyethylene, capacity: 5 mL) and stored at 50°C for 2 months under light-shielded conditions. The chlorhexidine gluconate content in each aqueous composition immediately after preparation and after 2 months of storage at 50°C was quantified by HPLC (measurement conditions are described below), and calculated as the improvement rate of the decrease in chlorhexidine gluconate concentration according to the following (Equation 1) and (Equation 2). The results are shown in Table 1. (Equation 1) Chlorhexidine gluconate concentration decrease (mg / 100 mL) = Chlorhexidine gluconate concentration immediately after manufacture - Chlorhexidine gluconate concentration after 2 months of storage at 50°C (Equation 2) Chlorhexidine gluconate concentration reduction improvement rate (%) = {(reduced concentration in Comparative Example 2 - reduced concentration in each Example) / reduced concentration in Comparative Example 2} × 100 (HPLC measurement conditions) Detector: ultraviolet absorption photometer (measurement wavelength: 254 nm) Column: Inertsil ODS-2 (inner diameter 4.6 mm, length 150 mm, particle diameter 5 μm) Column temperature: constant temperature around 40°C Mobile phase: 1.50 g of sodium lauryl sulfate dissolved in 1000 mL of acetonitrile / diluted acetic acid (100) (1 → 60) mixture (7:3) Flow rate: 0.9mL / min

[0048] [Table 1]

[0049] In Comparative Example 1, in which chlorhexidine gluconate was not blended into the aqueous composition containing delgocitinib, the preservative effect was extremely weak. On the other hand, in Examples 1 and 2, in which chlorhexidine gluconate was blended into the aqueous composition containing delgocitinib, it was confirmed that the preservative effect was significantly enhanced compared to Comparative Example 1 and Comparative Example 2, in which only chlorhexidine gluconate was blended. Furthermore, the decrease in chlorhexidine gluconate was improved in a delgocitinib concentration-dependent manner (Examples 1 and 2), confirming that delgocitinib increases the stability of chlorhexidine gluconate.

[0050] [Test Example 3: Preservative Effectiveness Test (2)] Aqueous compositions were prepared according to standard methods with the compositions shown in Table 2. Each aqueous composition was filtered through a 0.2 μm membrane filter for sterilization, and the preservative effectiveness of each aqueous composition was evaluated according to the preservative effectiveness test method specified in the 17th edition of the Japanese Pharmacopoeia. Specifically, Pseudomonas aeruginosa was inoculated onto the surface of soybean-casein-digest agar medium and cultured at 30-35°C for 24 hours. The cultured cells were aseptically collected with a platinum loop and suspended in an appropriate amount of sterile physiological saline to obtain a concentration of approximately 3 × 10 7 A bacterial suspension containing viable bacteria at CFU / mL was prepared. This bacterial suspension was added to each formulation at approximately 3 × 10 5 After adding the aqueous composition so that the concentration of CFU / mL was reached, the mixture was allowed to stand at 20-25°C for 7 days. The bacteria were then collected using the membrane filtration method and placed on the surface of soybean-casein-digest agar medium. After allowing the mixture to stand at 30-35°C for 1 day, the viable cell count per mL of each aqueous composition was measured, and the log reduction was calculated based on this value. The results are shown in Table 2.

[0051] [Table 2]

[0052] [Test Example 4: Preservative Effectiveness Test (3)] Aqueous compositions were prepared according to standard methods with the compositions shown in Table 3. Each aqueous composition was sterilized by filtering through a 0.2 μm membrane filter. The aqueous compositions were then filled into eye dropper bottles (material: polyethylene, capacity: 5 mL) and stored at 60°C for 3 weeks under light-shielded conditions. The preservative effectiveness of each aqueous composition was evaluated according to the preservative effectiveness test method specified in the 17th Edition of the Japanese Pharmacopoeia. Specifically, Pseudomonas aeruginosa was inoculated onto the surface of soybean-casein-digest agar medium and cultured at 30-35°C for 24 hours. The cultured cells were aseptically collected with a platinum loop and suspended in an appropriate amount of sterile physiological saline to obtain a concentration of approximately 3 × 10 7 A bacterial suspension containing viable bacteria at CFU / mL was prepared. This bacterial suspension was added to each formulation at approximately 3 × 10 5 After adding the aqueous composition so that the concentration of CFU / mL was reached, the mixture was allowed to stand at 20-25°C for 14 days. The bacteria were then collected using the membrane filtration method and placed on the surface of soybean-casein-digest agar medium. After allowing the mixture to stand at 30-35°C for one day, the viable cell count per mL of each aqueous composition was measured, and the log reduction was calculated based on this value. The results are shown in Table 3.

[0053] [Table 3]

Claims

[Claim 1] The invention described in the specification.

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