Topical antifungal non-aqueous formulations and methods of making same

Abstract

Provided are topically administered pharmaceutical compositions for the treatment of fungal infected eye and ear diseases, such as fungal keratitis, otitis externa or otitis media caused by fungal infection, and methods of making the same. The pharmaceutical composition comprises a triazole antifungal agent as an active ingredient, a non-aqueous solvent and an optional tension regulator, and can be a non-aqueous composition without preservatives. The non-aqueous composition has one or more of the following advantages: the non-aqueous composition is high in stability, free of preservatives and low in irritation, the concentration of antifungal drugs in local tissues is increased, the toxic and side effects of the whole body are reduced, the residence time of the antifungal drugs in the local tissues is prolonged, the administration frequency is reduced, and the compliance of patients is improved.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical preparations, and particularly relates to a topical pharmaceutical preparation for treating fungal infections of the eye and ear diseases and its preparation method. Background Art

[0002] Fungal keratitis (FK) is a serious blinding corneal disease directly caused by fungal infection of the cornea, and is the leading cause of blindness in infectious corneal diseases. Fungal keratitis requires long-term drug delivery to the ocular surface. Two antifungal drugs, amphotericin B and natamycin, are used to treat fungal keratitis. The currently used 0.25% amphotericin B eye drops need to be freshly prepared with an injection due to the instability of the preparation and sensitivity to both heat and light, which greatly limits its clinical application. The 5% natamycin suspension eye drops used clinically have a high preparation cost and are expensive, and need to be administered once every 1-2 hours.

[0003] In addition, after the aqueous ophthalmic preparation is instilled, the blink reflex will be activated, and most of the topical drug will be washed away within 15 to 30 seconds. At the same time, the high surface tension of the water-based droplets further hinders the diffusion of the water-based droplets on the ocular surface. Therefore, the bioavailability of traditional aqueous ophthalmic preparations is low, even as low as 3% - 4%.

[0004] Clinically, fluconazole injection is used topically for ear canal irrigation to treat otomycosis or otitis media, and there is currently no dedicated ear preparation for treating otomycosis or otitis media.

[0005] Voriconazole is a triazole broad-spectrum antifungal drug. Currently, its injection, oral suspension, and oral tablets are on the market, but there are no ophthalmic and ear preparations on the market.

[0006] Voriconazole is extremely slightly soluble in water, with a solubility of 0.61 mg / ml at pH 7 and 0.2 mg / ml at pH 3. Voriconazole undergoes a retro-aldol condensation reaction in water to produce inactive enantiomers. The hydroxyl group on voriconazole is protonated in proton solvents (such as water, alcohol, etc.), accelerating degradation, and it is also unstable in polar aprotic solvents due to an increase in the hydrogen-oxygen dipolarization of the hydroxyl group. Voriconazole is unstable under both alkaline and strong acidic conditions. The logD of voriconazole is 1.8, and its semi-polar nature poses certain difficulties in selecting appropriate solubilization means. It is reported that the cyclodextrin inclusion technology is used, adding a cross-linking agent to associate with the hydrogen bonds on hydroxypropyl beta-cyclodextrin to fix the un-included voriconazole in the complex. However, this method has complex preparation steps and the effect of improving the solution stability of voriconazole is not significant.

[0007] Therefore, there is an urgent need for a long-acting and stable topical antifungal pharmaceutical preparation clinically. Summary of the Invention

[0008] On the one hand, the present application provides a pharmaceutical composition, which comprises a triazole antifungal drug as an active ingredient, a non-aqueous solvent and an optional tensio-active agent.

[0009] On the other hand, the present application provides a method for preparing a pharmaceutical composition comprising a triazole antifungal drug as an active ingredient, a non-aqueous solvent and an optional tensio-active agent, which comprises mixing the triazole antifungal drug with the non-aqueous solvent, and then optionally adding the tensio-active agent.

[0010] On the other hand, the present application provides the use of a pharmaceutical composition comprising a triazole antifungal drug as an active ingredient, a non-aqueous solvent and an optional tensio-active agent in the preparation of a medicament for treating eye diseases and ear diseases caused by fungal infections, such as fungal keratitis, otitis externa or otitis media caused by fungal infections.

[0011] Brief Description of the Drawings

[0012] Figure 1 Shows the content changes of voriconazole eye drops and voriconazole injection prepared according to Example 1 and Comparative Example 1 during the accelerated experiment for 0 to 2 months.

[0013] Figure 2 Shows the total impurity changes of related substances of voriconazole eye drops and voriconazole injection prepared according to Example 1 and Comparative Example 1 during the accelerated experiment for 0 to 2 months.

[0014] Figure 3 Shows the maximum single impurity changes of related substances of voriconazole eye drops and voriconazole injection prepared according to Example 1 and Comparative Example 1 during the accelerated experiment for 0 to 2 months.

[0015] Figure 4 Shows the logarithmic plot of the plasma concentration-time curve of voriconazole eye drops and voriconazole injection prepared according to Example 1 and Comparative Example 1 in rabbit plasma.

[0016] Figure 5 Shows the logarithmic plot of the drug concentration-time curve of voriconazole eye drops and voriconazole injection prepared according to Example 1 and Comparative Example 1 in rabbit aqueous humor.

[0017] Figure 6 Shows the logarithmic plot of the drug concentration-time curve of voriconazole eye drops and voriconazole injection prepared according to Example 1 and Comparative Example 1 in rabbit cornea.

[0018] Figure 7Displays the logarithmic plots of the drug concentration-time curves of voriconazole eye drops and voriconazole injection prepared according to Example 1 and Comparative Example 1 in the rabbit conjunctiva.

[0019] Detailed Description

[0020] On the one hand, the present application provides a pharmaceutical composition comprising a triazole antifungal drug as an active ingredient, a non-aqueous solvent, and an optional tonicity modifier.

[0021] In some embodiments, the pharmaceutical composition is non-aqueous. In some embodiments, the pharmaceutical composition does not contain a preservative. In some embodiments, the pharmaceutical composition is a non-aqueous composition without a preservative.

[0022] Preservatives are generally regarded as undesirable necessities that preserve the preparation but are toxic to the eyes. A common solution to the preservative problem is to package the product in unit doses. However, unit-dose packaging is significantly more expensive than multi-dose packaging, increasing the cost of the final product. The pharmaceutical composition of the present application is a non-aqueous preparation and does not require an anti-infective preservative. Therefore, the pharmaceutical composition of the present application is allowed to use multi-dose delivery from a single applicator, which is more convenient for carrying and traveling. The non-aqueous pharmaceutical composition without a preservative has been proven not to cause corneal damage. Moreover, the non-aqueous preparation can avoid hydrolysis and oxidation reactions, thereby improving the stability of the preparation and avoiding possible tip blockage.

[0023] In some embodiments, the triazole antifungal drug is a triazole-based antifungal drug, examples of which include but are not limited to fluconazole, voriconazole, and isavuconazole. In some embodiments, the triazole antifungal drug is voriconazole.

[0024] In some embodiments, the non-aqueous solvent is a glyceride of C6-C 12 fatty acids, or the non-aqueous solvent contains a glyceride of C6-C 12 fatty acids. In some embodiments, the C6-C 12 glyceride of fatty acids is a saturated glyceride of C6-C 12 fatty acids and / or an unsaturated glyceride of C6-C 12 fatty acids. In some embodiments, the glyceride of fatty acids is selected from saturated or unsaturated glycerol monoesters, glycerol diesters, glycerol triesters, and any combination thereof of C6-C 12 fatty acids.

[0025] In some embodiments, the non-aqueous solvent has an ester bond (-C(O)-O-) content of about 20.0% to about 35.0% or about 22.0% to about 28.0% by molecular weight. In some embodiments, the C6-C 12 The ester bond (-C(O)-O-) content of the glyceride of fatty acid is about 20.0% to about 35.0% or about 22.0% to about 28.0% by molecular weight. For example, the molecular weight of glyceryl trihexanoate is 386.5, and the molecular weight of three ester bonds (-C(O)-O-) is 132. That is, the ester bond content of glyceryl trihexanoate is 34.2% by molecular weight.

[0026] In some embodiments, the C6-C 12 The fatty acid moiety in the glyceride of fatty acid is selected from one or more of caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, and dodecanoic acid. In some embodiments, the C6-C 12 The glyceride of fatty acid is selected from monoglycerides, diglycerides, triglycerides of caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, or dodecanoic acid, and any combination thereof. In some embodiments, the C6-C 12 The glyceride of fatty acid is selected from triglycerides of caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, or dodecanoic acid, and any combination thereof.

[0027] In some embodiments, the non-aqueous solvent is selected from one or more of medium-chain triglycerides, glyceryl trihexanoate, glyceryl trioctanoate, glyceryl tridecanoate, and glyceryl trilaurate.

[0028] In some embodiments, the medium-chain triglycerides are selected from one or more of triglycerides of caprylic acid, pelargonic acid, capric acid, undecanoic acid, and dodecanoic acid. In some embodiments, the medium-chain triglycerides are glyceryl trioctanoate or glyceryl tridecanoate or a saturated caprylic acid-capric acid mixed triglyceride.

[0029] In some embodiments, the pharmaceutical composition further comprises a tonicity regulator. In some embodiments, the tonicity regulator is a reagent for reducing tonicity.

[0030] In some embodiments, the tension regulator is cyclomethicone. In some embodiments, cyclomethicone is a mixture of cyclic dimethylpolysiloxane compounds. It is a fully methylated cyclic siloxane with a repeating unit molecular formula of [-(CH3)2SiO-]n, where n is 4, 5 or 6, or a mixture thereof. It is a colorless, odorless, transparent, non-greasy silicone liquid with low viscosity and surface tension and a relatively high vapor pressure. The volatility of cyclomethicone can be achieved by mixing different polymers thereof, and they have slight variations in properties such as molecular weight, solubility, specific gravity, viscosity, etc.

[0031] The following table exemplarily lists the physical and chemical properties of four cyclomethicones of Dow Corning Corporation.

[0032]

[0033] Studies have shown that undiluted cyclomethicone applied to intact and damaged skin of rabbits produces little or no irritation. Ocular studies have shown that cyclomethicone produces only mild and transient conjunctival irritation in rinsed and unrinsed eyes, and the symptoms completely subside within 24 hours without corneal damage. Cyclomethicone is non-irritating and non-sensitizing to human skin. According to the existing data, the application of cyclomethicone is very safe.

[0034] In some embodiments, the pharmaceutical composition comprises about 0.2% (w / v) to about 2% (w / v) of a triazole antifungal drug, about 80% (v / v) to about 100% (v / v) of a non-aqueous solvent, and about 0% (v / v) to about 20% (v / v) of a tension regulator.

[0035] In some embodiments, the content of the triazole antifungal drug in the pharmaceutical composition is about 0.2% (w / v) to about 2% (w / v), about 0.5% (w / v) to about 2% (w / v), about 0.5% (w / v) to about 1.5% (w / v), about 0.5% (w / v) to about 1.0% (w / v), or about 1.0% (w / v) to about 1.5% (w / v).

[0036] In some embodiments, the content of the non-aqueous solvent in the pharmaceutical composition is about 80% (v / v) to about 100% (v / v), about 80% (v / v) to about 99% (v / v), about 80% (v / v) to about 98% (v / v), about 90% (v / v) to about 100% (v / v), about 90% (v / v) to about 99% (v / v), or about 90% (v / v) to about 98% (v / v).

[0037] In some embodiments, the content of the tonicity regulator in the pharmaceutical composition is about 0% (v / v) to about 20% (v / v), about 0% (v / v) to about 10% (v / v), about 2% (v / v) to about 20% (v / v), or about 2% (v / v) to about 10% (v / v).

[0038] In some embodiments, the pharmaceutical composition is in liquid form, such as eye drops or ear drops.

[0039] On the other hand, the present application provides a method for preparing a pharmaceutical composition comprising a triazole antifungal drug as an active ingredient, a non-aqueous solvent and an optional tonicity regulator, which comprises mixing the triazole antifungal drug with the non-aqueous solvent and then optionally adding the tonicity regulator.

[0040] On the other hand, the present application provides the use of a pharmaceutical composition comprising a triazole antifungal drug as an active ingredient, a non-aqueous solvent and an optional tonicity regulator in the preparation of a drug for treating eye diseases and ear diseases caused by fungal infections, such as fungal keratitis, otitis externa or otitis media caused by fungal infections.

[0041] The inventors of the present application have found that the extraordinary spreading properties of the oily matrix, especially specific fatty acid glycerides, support the distribution of triazole antifungal drugs on the corneal surface, and compared with the aqueous matrix, the low viscosity and low surface tension of the oily matrix produce much smaller droplet sizes, thereby avoiding liquid overflow and immediate loss of most of the dose, thus improving the bioavailability of the drug.

[0042] The non-aqueous pharmaceutical preparation of the present application has one or more of the following advantages: high stability, no preservatives, low irritation, increased concentration of the antifungal drug in local tissues, reduced systemic toxic side effects, at the same time, increased residence time of the antifungal drug in local tissues, reduced dosing frequency, and improved patient compliance. Examples

[0043] The present application will be further described in detail below with reference to specific examples. These examples can be modified to obtain other embodiments without departing from the scope or spirit of the present application. Therefore, the following examples are non-limiting.

[0044] Unless otherwise specified, all numbers expressing feature sizes, amounts and physical and chemical characteristics used in this specification and the claims should be understood to be modified in all cases by the term "about". Therefore, unless otherwise indicated, the numerical parameters set forth in the foregoing specification and the appended claims are approximate values, and those skilled in the art can, using the teachings disclosed herein, seek to obtain the desired characteristics and appropriately change these approximate values. The use of numerical ranges expressed with endpoints includes all numbers within that range and any range within that range. For example, 1 to 5 includes 1, 1.1, 1.3, 1.5, 2, 2.75, 3, 3.80, 4, and 5, and so on.

[0045] The drugs or reagents used in this application are all conventional commercially available products unless otherwise specified.

[0046] Comparative Example 1 (Patent CN 110812323 A)

[0047] Component Sample weight Voriconazole 1g Hydroxypropyl-β-cyclodextrin (HP-β-CD) 20g Polyvinyl alcohol PVA 0.6g Glycine 0.1g Hydrochloric acid Appropriate amount Sodium chloride 0.1g Add up to the total volume 100ml

[0048] Preparation process: 1. Add HP-β-CD to 40 ml of water and dissolve until clear. Adjust the pH to 5.0 with HCl, and then add the prescribed amount of NaCl to dissolve it.

[0049] 2. Add voriconazole to the above solution and stir for 3 h until dissolved and clear.

[0050] 3. Add PVA and stir to dissolve for 30 min to obtain a transparent solution, and then add glycine to dissolve and stir for 30 min for stabilization.

[0051] 4. Transfer to a 100 ml volumetric flask, make up the volume with water, and filter through a 0.22 μm aqueous filter head.

[0052] 5. Divide the filtrate into 5 portions and adjust the pH to 5.5, 6, 6.5, 7, and 7.35 in sequence with HCl.

[0053] Comparative Example 2 (Glycerol triacetate)

[0054] Component Sample weight Voriconazole 1g Triacetin 49ml Total volume 50ml

[0055] Preparation process: 1. Add voriconazole to glycerol triacetate, seal and fill with nitrogen, and heat to dissolve at a temperature of 60 - 65 °C.

[0056] 2. Wait for the oil solution of voriconazole to cool to room temperature and filter through a 0.22 μm nylon filter head to obtain the preparation.

[0057] Drop the oil solution into the eyes of rabbits, and it is found that it causes strong irritation to the eye surface of rabbits, and the hair of rabbits is messy.

[0058] Comparative Example 3 (Glycerol tributyrate)

[0059] Component Sample weight Voriconazole 1g Tributyrin 49ml Cyclomethicone 1ml Total volume 50ml

[0060] Preparation process: 1. Add voriconazole to glycerol tributyrate, seal and fill with nitrogen, and heat and dissolve at a temperature of 60 - 65°C.

[0061] 2. Wait for the oil solution of voriconazole to cool to room temperature, add cyclomethicone and stir evenly, and filter through a 0.22 μm nylon filter head to obtain the preparation.

[0062] Drop the oil solution on the surface of human skin, and it is found that it produces an irritating odor and is not suitable as an eye drop or ear drop.

[0063] Comparative Example 4 (Castor oil)

[0064] Component Sample weight Voriconazole 0.5g Castor oil 49ml Cyclomethicone 1ml Total volume 50ml

[0065] Preparation process: 1. Add voriconazole to castor oil, seal and fill with nitrogen, and heat and dissolve at a temperature of 60 - 65°C.

[0066] 2. Wait for the oil solution of voriconazole to cool to room temperature, add cyclomethicone and stir evenly, and filter through a 0.22 μm nylon filter head to obtain the preparations of 3 prescriptions.

[0067] Test results: After standing for 24 hours, it was observed that the solution showed a turbid state with solute precipitation.

[0068] Comparative Example 5 (Soybean oil)

[0069]

[0070]

[0071] Preparation process: 1. Add voriconazole to soybean oil, seal and fill with nitrogen, and heat and dissolve at a temperature of 60 - 65°C.

[0072] 2. Wait for the oil solution of voriconazole to cool to room temperature, add cyclomethicone and stir evenly, and filter through a 0.22 μm nylon filter head to obtain the preparations of 3 prescriptions.

[0073] Test results: After standing for 24 hours, it was observed that the solution showed a turbid state with solute precipitation.

[0074] Comparative Example 6 (Sesame oil)

[0075] Component Sample weight Voriconazole 0.5g Sesame oil 49ml Cyclomethicone 1ml Total volume 50ml

[0076] Preparation process: 1. Add voriconazole to sesame oil, seal and fill with nitrogen, and heat and dissolve at a temperature of 60 - 65°C.

[0077] 2. After the oily solution of voriconazole is cooled to room temperature, cyclomethicone is added and stirred evenly, and then filtered through a 0.22 μm nylon filter head to obtain the preparations of 3 prescriptions.

[0078] Test results: After standing for 24 hours, the solution was observed to be turbid with solute precipitation.

[0079] Example 1

[0080] Component Sample weight Voriconazole 0.5g Medium-chain triglyceride MCT 50ml Total volume 50ml

[0081] Preparation process: 1. Voriconazole is added to the medium-chain triglyceride (Liaoning Xinxing Pharmaceutical Co., Ltd., batch number: 210502-2-01) solvent, sealed with nitrogen, and heated to dissolve at a temperature of 60-65 °C.

[0082] 2. After the oily solution of voriconazole is cooled to room temperature, it is filtered through a 0.22 μm nylon filter head to obtain Preparation 1.

[0083] Example 2

[0084] Component Sample weight Voriconazole 0.75g Trihexanoin 49ml Cyclomethicone 1ml Total volume 50ml

[0085] Preparation process: 1. Voriconazole is added to glyceryl trihexanoate, sealed with nitrogen, and heated to dissolve at a temperature of 60-65 °C.

[0086] 2. After the oily solution of voriconazole is cooled to room temperature, cyclomethicone is added and stirred evenly, and then filtered through a 0.22 μm nylon filter head to obtain Preparation 2.

[0087] Example 3

[0088] Component Sample weight Voriconazole 0.5g Tricaprin 49ml Cyclomethicone 1ml Total volume 50ml

[0089] Preparation process: 1. Voriconazole is added to glyceryl tridecanoate, sealed with nitrogen, and heated to dissolve at a temperature of 60-65 °C.

[0090] 2. After the oily solution of voriconazole is cooled to room temperature, cyclomethicone is added and stirred evenly, and then filtered through a 0.22 μm nylon filter head to obtain Preparation 3.

[0091] Example 4

[0092] Component Sample weight Voriconazole 1g Trioctanoin 45ml Cyclomethicone 5ml Total volume 50ml

[0093] Preparation process: 1. Voriconazole is added to the glyceryl trioctanoate solvent, sealed with nitrogen, and heated to dissolve at a temperature of 60-65 °C.

[0094] 2. After cooling the oily solution of voriconazole to room temperature, add cyclomethicone and stir evenly. Filter through a 0.22 μm nylon filter head to obtain Preparation 4.

[0095] Example 5

[0096] Component Sample weight Voriconazole 0.25g Medium-chain triglyceride MCT 40ml Cyclomethicone 10ml Total volume 50ml

[0097] Preparation process: 1. Add voriconazole to the medium-chain triglyceride (Liaoning Xinxing Pharmaceutical Co., Ltd., batch number: 210502-2-01) solvent, seal and fill with nitrogen, and heat and dissolve at a temperature of 60-65 °C.

[0098] 2. After cooling the oily solution of voriconazole to room temperature, add cyclomethicone and stir evenly. Filter through a 0.22 μm nylon filter head to obtain Preparation 5.

[0099] Performance test

[0100] Unless otherwise specified, the following high-performance liquid chromatography conditions are used to detect the amount of voriconazole:

[0101] Chromatographic conditions for content determination and related substance inspection: Determined according to the high-performance liquid chromatography method (General Rule 0512) in Part IV of the Chinese Pharmacopoeia 2020 Edition. Use octadecylsilane chemically bonded silica gel as the filler (4.6 mm × 250 mm, 5 μm or a chromatographic column of equivalent efficiency); use 0.02 mol / L ammonium acetate buffer solution (adjust the pH value to 4.0 ± 0.3 with acetic acid)-methanol-acetonitrile (55:15:30) as the mobile phase; the column temperature is 35 °C, and the detection wavelength is 256 nm.

[0102] Chromatographic conditions for pharmacokinetic determination

[0103] Detection system: HPLC-UV (Shimadzu SPD-10AVP, LC-20AD)

[0104] Liquid chromatography column: Luna Omega C18 50×2.1mm 1.6μm S / N: H19-309764

[0105] Column temperature: 40 °C

[0106] Cleaning solution: isopropanol: methanol: water = 1:1:1

[0107] Flow rate: 0.5 mL / min

[0108] Autosampler temperature: 4 °C

[0109] Injection volume: 10 μL

[0110] Mobile phase A: aqueous solution of 0.1% formic acid

[0111] Mobile phase B: methanol

[0112] Gradient elution:

[0113] Time (min) Unit Command Value 0.00 Column oven CTO.RVL 1 0.40 Column oven CTO.RVL 0 1.50 Pump B.Conc 100 1.50 Pump B.Conc 100 2.00 Pump B.Conc 50 2.01 Pump Stop - 3.00 Column oven CTO.RVL

[0114] Mass spectrometry conditions:

[0115] Mass spectrometry system: LC-MS / MS

[0116] Ionization mode: (-)ESI

[0117] Scanning mode: MRM

[0118] Parent ion, fragment ion and collision energy (CE)

[0119]

[0120] Test and compare Example 1 with Examples 1 to 5

[0121] Determine the accelerated stability of the preparation of Comparative Example 1 and the preparations of Examples 1 to 5.

[0122] Experimental method: Place the preparations prepared according to Comparative Example 1 and Examples 1 to 5 at 40°C and 75% RH for 2 months, and determine the contents of the active ingredient and related substances of each preparation at 0, 1, and 2 months respectively.

[0123]

[0124]

[0125] The experimental results show that the contents of the active ingredient, related substances, solution color and clarity of the preparations of Examples 1 to 5 have no significant changes within 2 months under the accelerated test conditions, and the stability is good. The content of the active ingredient in the preparation of Comparative Example 1 decreased significantly (about 10%) within 2 months under the accelerated test conditions, the content of the largest single impurity of related substances increased significantly (about 10%), and the content of total impurities of related substances increased significantly, and the stability was poor.

[0126] Test Example 1: Plasma and ocular tissue pharmacokinetic studies after ocular administration of the preparations of Comparative Example 1 (pH 6.5) and Example 1 to rabbits

[0127] Experimental method: 42 male rabbits were divided into 3 groups. Group 1 consisted of 16 rabbits, and 20 μL of the preparation of Example 1 was instilled into both eyes of each rabbit. Group 2 consisted of 16 rabbits, and 20 μL of the preparation of Comparative Example 1 was instilled into both eyes of each rabbit. Group 3 consisted of 10 rabbits, and 5 mg / kg of the preparation of Comparative Example 1 was injected into the marginal ear vein of each rabbit. Blood was collected from the middle ear artery at 0.25, 1, 2, 3, 4, 6, 8, 10 h after administration in Group 1, at 0.25, 1, 1.5, 2, 2.5, 3, 4, 5 h after administration in Group 2, and at 0.5, 1, 2, 3, 4 h after administration in Group 3. After that, the rabbits were euthanized by carbon dioxide, the eyes were dissected, and the corresponding eye tissues were collected. The concentration of voriconazole in whole blood and eye tissue samples was determined by LC-MS / MS method.

[0128] Group Name of test substance Route of administration Dose (mg / animal) Number of animals 1 Example 1 (Voriconazole eye drops) Instillation 20 μL / eye 16 2 Comparative Example 1 (Voriconazole injection) Instillation 20 μL / eye 16 3 Comparative Example 1 (Voriconazole injection) Injection 5 mg / kg 10

[0129] The experimental results showed that compared with intravenous administration, local intraocular administration could increase the concentration of the drug in ocular tissues and achieve the purpose of enriching the active drug in the eye. At the same time, after local intraocular administration, the exposure of the drug in plasma was lower, and the adverse reactions caused by systemic administration could be avoided.

[0130] In Group 1 and Group 2, the animals were respectively administered 20 μL / eye of the preparation of Example 1 and the preparation of Comparative Example 1 by local intraocular administration, and the plasma exposure was relatively low. For the exposure and half-life of the conjunctiva, cornea, and target tissue (aqueous humor), Group 1 was higher than Group 2. After Group 3 was injected with 5 mg / kg of the preparation of Comparative Example 1 through the marginal ear vein, the plasma exposure was relatively high, the conjunctival exposure was comparable to that of Group 2, and the exposure of the remaining eye tissues was lower than that of Group 1 and Group 2.

[0131] The main pharmacokinetic parameters are shown in the following table:

[0132]

[0133]

Claims

1. A pharmaceutical composition comprising a triazole antifungal agent as an active ingredient, a non-aqueous solvent and optionally a tonicity regulator, preferably, the pharmaceutical composition is a non-aqueous composition without preservatives.

2. The pharmaceutical composition according to claim 1, wherein the triazole antifungal agent is selected from fluconazole, voriconazole and isavuconazole.

3. The pharmaceutical composition according to any one of claims 1-2, wherein the non-aqueous solvent is a glyceride of C6-C 12 fatty acid, or the non-aqueous solvent contains C6-C 12 fatty acid glyceride.

4. The pharmaceutical composition according to any one of claims 1 - 3, wherein the non-aqueous solvent has an ester bond (-C(O)-O-) content of about 20.0% to about 35.0% or about 22.0% to about 28.0% by molecular weight.

5. The pharmaceutical composition according to claim 3 or 4, wherein the fatty acid moiety of the glyceride of C6-C 12 fatty acid is one or more selected from caproic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, and dodecanoic acid; or the glyceride of C6-C 12 fatty acid is one or more selected from medium-chain triglycerides, glyceryl trihexanoate, glyceryl trioctanoate, glyceryl tridecanoate, and glyceryl trilaurate.

6. The pharmaceutical composition according to any one of claims 1 - 5, wherein the pharmaceutical composition further comprises a tonicity regulator, for example, the tonicity regulator is cyclomethicone.

7. The pharmaceutical composition according to claim 6, wherein the cyclomethicone is a fully methylated cyclosiloxane with a repeating unit molecular formula of [-(CH3)2SiO-]n, where n is 4, 5 or 6, or a mixture thereof.

8. The pharmaceutical composition according to any one of claims 1 - 7, wherein the pharmaceutical composition comprises about 0.2% (w / v) to about 2% (w / v) of the triazole antifungal agent, about 80% (v / v) to about 100% (v / v) of the non-aqueous solvent and about 0% (v / v) to about 20% (v / v) of the tonicity regulator.

9. A method for preparing the pharmaceutical composition according to any one of claims 1 - 8, which comprises mixing the triazole antifungal agent with the non-aqueous solvent and then optionally adding the tonicity regulator.

10. Use of the pharmaceutical composition according to any one of claims 1 - 8 in the preparation of a medicament for treating eye and ear diseases caused by fungal infections, such as fungal keratitis, otitis externa or otitis media caused by fungal infections.

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