JP3504656B2 - Aqueous pharmaceutical composition - Google Patents

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention has a sufficiently low gelling temperature and is a liquid at the time of administration even when a new quinolone antibacterial agent such as ofloxacin is used as an active ingredient, but the gelation rate is fast and the viscosity rapidly after administration. TECHNICAL FIELD The present invention relates to an antibacterial aqueous pharmaceutical composition and an aqueous pharmaceutical composition that are highly elevated and stay at the administration site for a long time, and thus have high drug utilization efficiency.

BACKGROUND ART [0002] When a drug is administered to the eye, most of the drug flows from the eye to the nose. Therefore, studies have been conducted to increase the viscosity of the preparation and keep the drug on the ocular surface for as long as possible. In order to increase the viscosity of the preparation, it is common to add a polymer compound, but if the viscosity of the preparation increases, the dose will vary, and there is a drawback that it becomes difficult to administer a fixed amount.

Generally, the viscosity of an aqueous solution of a polymer compound decreases as the temperature rises. However, methyl cellulose (MC), hydroxypropyl methyl cellulose,
An aqueous solution of polyvinyl alcohol or the like has a property that it gelates at a certain temperature or higher and the viscosity increases.

In Japanese Patent No. 2729859, the viscosity of a 2 w / v% aqueous solution at 20 ° C. is 13 to 12000 mPa.
s is methyl cellulose 0.2 to 2.1 w / v%,
By adding 1.2 to 2.3 w / v% citric acid and 0.5 to 13 w / v% polyethylene glycol (PEG), the gelation temperature is lowered to around human body temperature (40 ° C or lower). Has been successful. The characteristics of this formulation are that it is easy to administer as a liquid before administration, and the gelation and viscosity increase after administration, which improves the retention of the drug at the administration site, and improves the bioavailability (BA) of the drug.
Has the advantage of improving.

The present inventor has tried to apply the thermogelation preparation described in Japanese Patent No. 2729859 to new quinolone antibacterial agents including ofloxacin which is a synthetic antibacterial agent. However, Japanese Patent No. 2729859
When comparing the eye drops of ofloxacin prepared according to the thermogelling composition described in No. 1 and the commercially available eye drops of ofloxacin, no difference was observed in the intraocular kinetics of ofloxacin.

SUMMARY OF THE INVENTION In the present invention, even when a new quinolone antibacterial agent such as ofloxacin is used as an active ingredient, the gelling temperature is sufficiently low and it is liquid at the time of administration, but the gelling rate is fast and the viscosity is rapidly increased after administration. It is an object of the present invention to provide an antibacterial aqueous pharmaceutical composition and an aqueous pharmaceutical composition in which the use efficiency of a drug is high by increasing the amount of the drug and staying at the administration site for a long time.

In the present invention, the viscosity of a 2 w / v% aqueous solution at 20 ° C. is 12 mPa · s or less, methyl cellulose 2.8 to 4 w / v%, and citric acid 1.5 to 2.3 w / v.
%, Polyethylene glycol 2 to 4 w / v%, and ofloxacin 0.1 to 0.5 w / v%.

The antibacterial agent contained in the antibacterial aqueous pharmaceutical composition of the present invention is not limited to ofloxacin, but may be other quinolone antibacterial agents such as levofloxacin and moxifloxacin hydrochloride.

The present invention also relates to 20% of a 2 w / v% aqueous solution.
2.3 to 8 w / v% of methyl cellulose having a viscosity of 12 mPa · s or less at 0 ° C., 0.14 to 4 w / v% of polyvalent carboxylic acid or lactic acid, and / or 0.5 to 13 w / v% of polyethylene glycol, And an aqueous pharmaceutical composition containing an effective amount of a drug.

DETAILED DISCLOSURE OF THE INVENTION The present invention is described in detail below. The antibacterial aqueous pharmaceutical composition of the present invention is a gelled preparation containing ofloxacin as an active ingredient. The antibacterial aqueous pharmaceutical composition of the present invention has a viscosity of a 2 w / v% aqueous solution at 20 ° C. of 12 mPa · s or less, methyl cellulose 2.8 to 4 w / v%, and citric acid 1.5.
~ 2.3 w / v% and polyethylene glycol 2 ~
Contains 4 w / v%.

In Japanese Patent No. 2729859, the viscosity of a 2 w / v% aqueous solution at 20 ° C. is 13 to 12000 mPa.
s is methyl cellulose 0.2 to 2.1 w / v%,
By adding 1.2 to 2.3 w / v% citric acid and 0.5 to 13 w / v% polyethylene glycol (PEG), the gelation temperature is lowered to around human body temperature (40 ° C or lower). However, when a new quinolone antibacterial agent such as ofloxacin was used as an active ingredient, a sufficient effect could not be exhibited.

As a result of the earnest study by the present inventor, 2 w /
By using methylcellulose having a viscosity of 12 mPa · s or less at 20 ° C. of a v% aqueous solution and adding citric acid and polyethylene glycol at a specific ratio thereto, there is no variation in the dose as a liquid at the time of administration, and ,
It has been found that an aqueous pharmaceutical composition having a high gelation temperature and a high gelation rate and high utilization efficiency of an active ingredient can be obtained. 2 w / v% of methyl cellulose used in the present invention
The viscosity of the aqueous solution at 20 ° C. is preferably 3 to 5 m.
Pa · s.

The antibacterial aqueous pharmaceutical composition of the present invention comprises 2 w /
It contains 2.8 to 4 w / v% of methyl cellulose whose viscosity at 20 ° C. of a v% aqueous solution is 12 mPa · s or less. If it is less than 2.8 w / v%, the gelling temperature is not sufficiently lowered, and the increase in viscosity due to the body temperature is also insufficient, which is 4 w.
When it exceeds / v%, the viscosity becomes high, and it becomes difficult to administer a fixed amount, and when used as an eye drop, for example,
Depending on the administration site, the feeling of use may be poor, and it may be difficult to prepare a large amount thereof, such as sticking around the eyes and causing an unpleasant sticky feeling. The methyl cellulose used in the present invention preferably has a methoxyl group content of 26 to 33%.

The antibacterial aqueous pharmaceutical composition of the present invention contains citric acid in an amount of 1.5 to 2.3 w / v%. If it is less than 1.5 w / v%, the gelation temperature is not sufficiently lowered to 2.3 w / v.
If it exceeds v%, irritation becomes too strong when administered to the eye, which is not preferable. The citric acid may be added in the form of its salt. In that case, the blending amount is determined in terms of acid.

The antibacterial aqueous pharmaceutical composition of the present invention contains 2 to 4 w / v% of polyethylene glycol. 2 w / v%
If it is less than 4, the gelling temperature is not sufficiently lowered and it is 4 w / v.
If it exceeds%, the viscosity will be high and it will be difficult to administer a certain amount. Also, for example, when used as an eye drop, it may adhere to the periphery of the eye and cause an unpleasant sticky feeling. Inferior feeling.

The polyethylene glycol used in the present invention is not particularly limited, and commercially available products can be appropriately used. For example, PEG-200 and -30.
0, -600, -1,000, -1,540, -2,0
00, -4,000, -6,000, -20,000,
-50,000, -500,000, -2,000,0
00, -4,000,000 (above, Wako Pure Chemical Industries, Ltd.); Macrogol -200, -300, -400,-
600, -1,500, -1,540, -4,000,
-6,000, -20,000 (above, NOF Corporation)
Etc. can be mentioned.

The weight average molecular weight of the polyethylene glycol used in the present invention is preferably 300 to 50,000. When it is less than 300, the osmotic pressure becomes high, and especially in the case of eye drops, irritation at the time of administration becomes strong, which is not preferable.
On the other hand, when it exceeds 50,000, the viscosity in a liquid state is high, and when it is used as an eye drop, for example, it is attached to the periphery of the eye and causes an unpleasant sticky feeling, which leads to a deterioration in usability, which is not preferable. . More preferably, 400-2
It is 10,000. In addition, two or more kinds of polyethylene glycols may be mixed to adjust the weight average molecular weight within the above-mentioned preferable range.

The antibacterial aqueous pharmaceutical composition of the present invention contains 0.1 to 0.5 w / v% ofloxacin as an active ingredient. When it is less than 0.1 w / v%, sufficient drug effect cannot be exhibited, and when it exceeds 0.5 w / v%, there is a problem in stability of the preparation.

The antibacterial aqueous pharmaceutical composition of the present invention contains ofloxacin as an active ingredient, but levofloxacin and moxifloxacin hydrochloride, which are the same new quinolone antibacterial agents, can also be used as an active ingredient.

The antibacterial aqueous pharmaceutical composition of the present invention having the above-mentioned constitution is characterized in that it has a low gelation temperature, reaches a sufficient viscosity at a low temperature, and has a high gelation rate. Such an antibacterial aqueous pharmaceutical composition of the present invention, for example, when used as an eye drop, because it stays on the eye surface for a long time, it is also excellent in the transferability of the drug to the eye tissue, and the effect that the drug utilization efficiency is high Play.

The present invention provides a gelling preparation containing a conventionally known new quinolone antibacterial agent such as ofloxacin as an active ingredient, which has a sufficiently low viscosity at the time of administration and no variation in dosage, and a sufficiently low gelling temperature. Although it was made in view of the fact that there is no excellent drug utilization efficiency, by further study, even if other drug is applied to such a pharmaceutical composition as an active ingredient, it is similarly excellent. It has been found that such characteristics can be exhibited. Thus, an aqueous pharmaceutical composition containing another drug as an active ingredient is also a part of the present invention.
Is one.

When another drug is used as an active ingredient, the composition of the aqueous pharmaceutical composition thereof needs to be appropriately changed according to the drug to be used, unlike the case where a new quinolone antibacterial agent such as ofloxacin is used as an active ingredient. . Further, citric acid is used in an antibacterial aqueous pharmaceutical composition containing a new quinolone antibacterial agent such as ofloxacin as an active ingredient, but other polyvalent carboxylic acid, lactic acid or gluconic acid can be used instead of citric acid. It turned out to be Furthermore,
It was also clarified that, depending on the drug used as the active ingredient, either one of the polyvalent carboxylic acid, lactic acid or gluconic acid and polyethylene glycol may exhibit the same effect without using together.

The amount of the above-mentioned methyl cellulose compounded in the aqueous pharmaceutical composition of the present invention can be appropriately set within the range of 2.3 to 8 w / v% according to the drug used. 2.
If it is less than 3 w / v%, the gelation temperature is not sufficiently lowered, and the increase in viscosity due to body temperature is also insufficient, and 8 w / v%
If it exceeds, the viscosity becomes too high and it becomes difficult to administer a certain amount.In addition, when used as an eye drop, for example, it may adhere to the surroundings of the eye and cause an unpleasant sticky feeling. It is inferior in feeling and is difficult to prepare in large quantities.

The amount of polyvalent carboxylic acid, lactic acid or gluconic acid in the aqueous pharmaceutical composition of the present invention is 0.14 to 4
It can be appropriately set within the range of w / v% according to the drug used. If it is less than 0.14 w / v%, the gelling temperature is not sufficiently lowered, and if it exceeds 4 w / v%, irritation becomes too strong when administered to the eye, which is not preferable.

Examples of the polycarboxylic acid used in the present invention include aspartic acid, glutamic acid, gluconic acid, citric acid, tartaric acid, malic acid, fumaric acid, succinic acid and maleic acid. The polycarboxylic acid may be added in the form of its salt or hydrate. In that case, the compounding amount is determined in terms of anhydrous acid.

The amount of polyethylene glycol in the aqueous pharmaceutical composition of the present invention is 0.5 to 13 w / v%. If it is less than 0.5 w / v%, the gelling temperature is not sufficiently lowered, and if it exceeds 13 w / v%, the viscosity becomes too high and it becomes difficult to administer a fixed amount, and for example, as an eye drop. When it is used, it may adhere to the surroundings of the eye and cause an unpleasant sticky feeling, etc., resulting in a poor feeling in use depending on the administration site, and further, it becomes difficult to prepare a large amount. 0.5-13w
Within the range of / v%, it can be appropriately set according to the drug used.

In the aqueous pharmaceutical composition of the present invention, a sufficiently low gelling temperature can be realized by using a polycarboxylic acid, lactic acid or gluconic acid in combination with polyethylene glycol. Depending on the type of polycarboxylic acid, lactic acid or gluconic acid, polyethylene glycol may be used alone without using any one of them.

For example, when a gelled preparation is prepared by using tranilast which is an antiallergic agent as an active ingredient, tranilast forms an insoluble complex with polyvalent carboxylic acid such as citric acid, and therefore polyaniline such as citric acid is used. It is not preferable to add a carboxylic acid. However, 2w /
By using methyl cellulose whose viscosity at 20 ° C. of a v% aqueous solution is 12 mPa · s or less, when a drug such as tranilast is used as an active ingredient, a predetermined amount of the above methyl cellulose can be obtained without using polyvalent carboxylic acid or lactic acid. It was clarified that the gelling temperature can be sufficiently lowered by using polyethylene glycol.

The drug used in the aqueous pharmaceutical composition of the present invention is not particularly limited, and examples thereof include amphotericin B,
Chemotherapeutic agents such as miconazole nitrate, idoxuridine;
Antibiotics such as chloramphenicol, sodium colistin methanesulfonate, carbenicillin sodium, gentamicin sulfate; antiallergic agents such as acitazanolast, ketotifen fumarate, sodium cromoglycate, tranilast; betamethasone sodium phosphate, dexamethasone, fluorometholone, Dipotassium glycyrrhizinate, lysozyme chloride, diclofenac sodium,
Pranoprofen, indomethacin, cortisone acetate,
Anti-inflammatory drugs such as azulene, allantoin, epsilon-aminocaproic acid, prednisolone acetate, and bromfenac sodium; miotic agents such as pilocarpine hydrochloride, carbachol; flavin adenine dinucleotide, vitamins such as pyridoxal phosphate, cyanocobalamin; naphazoline nitrate, Vasoconstrictors such as phenylephrine hydrochloride; antihistamines such as chlorpheniramine maleate and diphenhydramine hydrochloride; mydriatic agents such as tropicamide, phenylephrine hydrochloride; timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, isopropylunoprostone, nipradirol, latanoprost, Dorzolamide,
Anti-glaucoma agents such as levobunolol hydrochloride and pilocarpine hydrochloride; Cataract therapeutic agents such as glutathione and pyrenoxine; Local anesthetics such as lidocaine hydrochloride and oxybuprocaine hydrochloride; Ophthalmic diagnostic agents such as sodium fluorescein; Immunosuppressants such as acids; antimetabolites such as fluorouracil and tegafur; decongestants such as epinephrine hydrochloride;
[5- (3-thienyl) tetrazol-1-yl] acetic acid, aminoguanidine and other diabetic retinopathy therapeutic agents; amino acids such as sodium chondroitin sulfate and aminoethyl sulfonic acid; autonomic nerve agents such as methylsulfate neostigmine; bifonazole , Agents for parasitic skin diseases such as siccanin, bisdecalinium acetate, clotrimazole, salicylic acid; agents for purulent diseases such as sodium sulfamethoxazole, erythromycin, gentamicin sulfate; indomethacin, ketoprofen, benmethasone valerate, fluocinolone Anti-inflammatory analgesics such as acetonide; Antipruritic agents such as diphenhydramine; Local anesthetics such as procaine hydrochloride and lidocaine hydrochloride; Disinfectant for external skin such as iodine, povidone iodine, benzalkonium chloride, chlorhexidine gluconate; Dife hydrochloride Antihistamines such as hydramine and chlorpheniramine maleate; agents for reproductive organs such as clotrimazole, nafazolyl nitrate, ketotifen fumarate, and miconazole nitrate; otolaryngeal agents such as tetrizoline hydrochloride; bronchodilators such as aminophylline; fluorouracil etc. Antimetabolites; hypnotic analgesics such as diazepam; antipyretic and analgesic anti-inflammatory agents such as aspirin, indomethacin, sulindac, phenylbutazone, ibuprofen; adrenal hormone agents such as dexamethasone, triamcinolone, hydrocortisone; local anesthetics such as lidocaine hydrochloride; sulfi Agents for purulent diseases such as soxazole, kanamycin, tobramycin, erythromycin; enoxacin, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, ofloxacin,
Synoxacin, sparfloxacin, tosufloxacin tosylate, nalidic acid, norfloxacin, fleroxacin, grepafloxacin hydrochloride, gatifloxacin, plurifloxacin, citafloxacin, pazufloxacin tosylate, gemifloxacin, moxifloxacin hydrochloride, Examples thereof include synthetic antibacterial agents such as olamfloxacin and levofloxacin; antiviral agents such as acyclovir, ganciclovir, cidofovir, trifluorothymidine and the like.

The effective content of the above-mentioned drug varies depending on the kind of the drug, but in general, it is preferably within the range of about 0.001 to 10 w / v%.

The application site of the antibacterial aqueous pharmaceutical composition and the aqueous pharmaceutical composition of the present invention is not particularly limited as long as it is not intravenous, but, for example, eyes, skin, rectum, urethra, nasal cavity,
Examples thereof include body cavities such as vagina, ear canal, oral cavity, and oral cavity.

The antibacterial aqueous pharmaceutical composition and the aqueous pharmaceutical composition of the present invention preferably have a pH of 3.5 to 10.
When using the aqueous pharmaceutical composition of the present invention as an eye drop,
The pH is preferably 4.5 or higher. pH is 4.5
If it is less than the above range, irritation to the eyes may be too strong. The pH is more preferably 5.5 to 8.

A pharmaceutically acceptable pH adjuster may be used to adjust the pH, and examples of the pH adjuster include acids such as hydrochloric acid, sulfuric acid, boric acid, phosphoric acid and acetic acid, and water. Examples thereof include bases such as sodium oxide, monoethanolamine, diethanolamine and triethanolamine.

The antibacterial aqueous pharmaceutical composition and the aqueous pharmaceutical composition of the present invention may further contain a pharmaceutically acceptable buffering agent, salt, preservative, solubilizing agent and the like, if necessary.

Examples of the preservatives include reverse soaps such as benzalkonium chloride, benzethonium chloride and chlorhexidine gluconate, parabens such as methylparaben, ethylparaben, propylparaben and butylparaben, chlorobutanol and phenylethyl alcohol. Also, alcohols such as benzyl alcohol, organic acids such as sodium dehydroacetate, sorbic acid and potassium sorbate, and salts thereof can be used. Further, a surfactant or a chelating agent may be added appropriately. These components are generally used in the range of about 0.001 to 2 w / v%, preferably about 0.002 to 1 w / v%.

Examples of the buffering agent include alkali metal salts of acids such as phosphoric acid, boric acid, acetic acid, tartaric acid, lactic acid and carbonic acid, glutamic acid, epsilon aminocaproic acid,
Examples thereof include amino acids such as aspartic acid, glycine, arginine and lysine, taurine, trishydroxymethylaminomethane and the like. These buffers add to the composition the amount necessary to maintain the pH of the composition at 3.5-10.

Examples of the solubilizer include polysorbate 80, polyoxyethylene hydrogenated castor oil, and cyclodextrin, and 0 to 15 w / v%.
Used in the range of.

The method for producing the antibacterial aqueous pharmaceutical composition and the aqueous pharmaceutical composition of the present invention is not particularly limited. For example, citrate or polyethylene glycol is added to sterile purified water and dissolved, and then the pH of the solution is adjusted. Is adjusted with a pH adjuster,
After adding the drug as an active ingredient and, if necessary, a preservative, add a solution of methyl cellulose dissolved in sterile purified water in advance, adjust the pH again, stir the mixture while cooling with sterile purified water and cooling with ice. To do. If necessary, various additives such as buffers, salts and preservatives are added after this. When the drug is sparingly soluble or insoluble, it is suspended or solubilized with a solubilizer before use.

According to the antibacterial aqueous pharmaceutical composition and the aqueous pharmaceutical composition of the present invention, the gelling temperature can be sufficiently lowered even when a new quinolone antibacterial agent such as ofloxacin is used as an active ingredient to enhance the drug effect and administer the drug. It can be expected to reduce the dose and the number of drug administrations. In particular, synthetic antibacterial agents have recently become a problem with the emergence of resistant bacteria, and there is a demand for antibacterial agents that are highly effective in a short period of time. Therefore, the present invention is preferably used when the active ingredient is a synthetic antibacterial agent.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to Examples.
The invention is not limited to these examples only.

Test Example 1 [Gelling Behavior of OFLX-Containing Thermal Gelation Preparation] Methylcellulose (Metronose (registered trademark) SM-4, manufactured by Shin-Etsu Chemical Co., Ltd., 2 w / v% aqueous solution has a viscosity of 3.2 at 20 ° C.). 4.8 mPa · s) and polyethylene glycol (Macrogol 4000, manufactured by NOF CORPORATION) were mixed in a predetermined amount, and sterilized purified water heated to 85 ° C. was added thereto and dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, a predetermined amount of sodium citrate was gradually added and dissolved with stirring. In addition, a certain amount of ofloxacin (O
FLX, the final blending amount was 0.3 w / v%) was added and dispersed by stirring. To this, 1N HCl was gradually added with stirring until the whole became clear. Furthermore, 1N HCl was added to adjust the pH to 6.5, and the volume was adjusted to a predetermined volume with sterile purified water to prepare a 0.3 w / v% OFLX thermogelation preparation of the present invention.

Separately from this, methyl cellulose was added to SM-
4 to SM-15 (manufactured by Shin-Etsu Chemical Co., Ltd., Metroze (registered trademark), 2 w / v% aqueous solution has a viscosity of 1 at 20 ° C.
3-18 mPa · s), 0.3 w / v% O for comparison
The FLX heat gelled formulation was prepared in the same manner as the heat gelled formulation of the present invention described above.

The relationship between the temperature and the viscosity of the prepared thermogelling preparation was examined, and the viscosity at 20 ° C. and the gelling temperature were determined. Further, for the thermogelling preparation of the present invention, the temperature at which the viscosity of the preparation was 100 mPa · s or more was also determined. If the viscosity is 100 mPa · s or more, it can stay on the eye surface for a long time even when used as an eye drop.

The viscosity of the heat gelled preparation was measured as follows. The prepared OFLX-TG was placed in a stainless steel container for a B-type viscometer, and the container was allowed to stand in a water tank kept at a predetermined temperature for 3 minutes. Immediately after standing, the rotor of the B-type viscometer was rotated, and the viscosity was measured 2 minutes after the start of rotation of the rotor. The viscosity of the prepared OFLX-TG at each temperature was measured, and the viscosity at 20 ° C., the gelling temperature, and the temperature at which the viscosity of the preparation became 100 mPa · s or more were determined.

The formulation of the preparation prepared in Table 1, the viscosity at 20 ° C., the gelling temperature and the viscosity of the preparation were 100 mPa · s.
The above temperatures are shown. The viscosity at 20 ° C. is lower in the thermogelling preparation of the present invention using SM-4 in any of the formulations, and in comparison with the ease of handling the formulation and the less sticky feeling when the formulation is instilled, the comparative thermal gel. It was shown to be superior to the modified formulation. Further, the thermogelling preparation of the present invention using SM-4 showed a lower gelation temperature as compared with the comparative gelling preparation using SM-15, and was found to be more likely to gel at body temperature. It was

[0046]

[Table 1]

Test Example 2 [Gelling Behavior of LVFX-Containing Thermal Gelation Formulation Example] SM-4 and Macrogol 4000 were mixed in a predetermined amount, and sterilized purified water heated to 85 ° C. was added thereto and stirred. Dispersed. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, a predetermined amount of sodium citrate was gradually added and dissolved with stirring. Furthermore, a predetermined amount of levofloxacin (LVFX, the final blending amount was 0.5 w / v%) was added, and dispersed by stirring. After adding 1N NaOH to adjust the pH to 7.8,
0.5 w / v% of the present invention with sterile purified water to the specified volume
The LVFX thermogelling formulation was prepared.

For comparison, 6.0 g of SM-4 was added to 85 ° C.
The sterilized purified water heated to was added to and dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, 0.5 g of levofloxacin was added and dissolved by stirring. 1N NaOH was added to this to adjust the pH to 7.8, and the total volume was adjusted to 100 mL with sterile purified water, and 0.5 w / v% LV for comparison was used.
An FX heat gelled formulation was prepared.

The relationship between the temperature and the viscosity of the prepared thermogelling preparation was examined, and the viscosity at 20 ° C., the gelling temperature and the temperature at which the viscosity of the preparation was 100 mPa · s or more were determined. Table 2
The formulation of the preparation prepared in Example 1, the viscosity at 20 ° C., the gelling temperature, and the temperature at which the viscosity of the preparation becomes 100 mPa · s or more are shown.

The LVFX-containing thermogelling preparation of the present invention comprises 2
It was shown that the viscosity at 0 ° C. was less than 100 mPa · s, the handling was easy, and gelation occurred at 30 ° C. or lower. On the other hand, a comparative LVF consisting of only SM-4
In the X-containing heat gelled preparation, the amount of SM-4 compounded was 6.0 w /
Despite the high concentration of v%, the gelling temperature was 36 ° C, and the temperature at which the viscosity of the preparation was 100 mPa · s or higher was 4
It was shown that the thermal gelation behavior was not so good at 0 ° C or higher.

[0051]

[Table 2]

Test Example 3 [Gelling Behavior of Thermal Gelation Formulation Example Containing Moxifloxacin Hydrochloride] SM-4 and Macrogol 4000 were mixed in a predetermined amount, and sterilized purified water heated to 85 ° C. was added thereto, It was dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, a predetermined amount of sodium citrate was gradually added and dissolved with stirring. Furthermore, add a predetermined amount of moxifloxacin hydrochloride,
It was dispersed by stirring. 1N NaOH was added thereto, and the pH was adjusted to a predetermined value, and then sterilized purified water was added to a predetermined volume to prepare the moxifloxacin hydrochloride thermogelation preparation of the present invention.

The relationship between the temperature and the viscosity of the prepared thermogelling preparation was examined, and the viscosity at 20 ° C., the gelling temperature and the temperature at which the viscosity of the preparation was 100 mPa · s or more were determined. Table 3
The formulation of the preparation prepared in Example 1, the viscosity at 20 ° C., the gelling temperature, and the temperature at which the viscosity of the preparation becomes 100 mPa · s or more are shown. In all of the moxifloxacin hydrochloride thermogelling preparations of the present invention, the viscosity at 20 ° C. is 100 mPa ·
It was shown that it is less than s, it is easy to handle, and gels at a temperature below body temperature.

[0054]

[Table 3]

Test Example 4 [Thermogelling preparation containing various synthetic antibacterial agents] SM-4 and Macrogol 4000 were mixed in a predetermined amount, and sterilized purified water heated to 85 ° C was added thereto and dispersed by stirring. It was After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, a predetermined amount of citric acid was gradually added and dissolved by stirring. Furthermore,
A predetermined amount of synthetic antibacterial agent was added and dissolved by stirring. 1 here
After adding N NaOH and adjusting the pH to a predetermined value, the mixture was made to have a predetermined volume with sterile purified water to prepare a synthetic antibacterial agent-containing thermogelling preparation of the present invention.

The relationship between the temperature and the viscosity of the prepared thermogelling preparation was examined, and the viscosity at 20 ° C., the gelling temperature and the temperature at which the viscosity of the preparation was 100 mPa · s or more were determined. Table 4
The formulation of the preparation prepared in Example 1, the viscosity at 20 ° C., the gelling temperature, and the temperature at which the viscosity of the preparation becomes 100 mPa · s or more are shown. It was shown that all of the synthetic antibacterial drug-containing thermogelling preparations of the present invention have a viscosity at 20 ° C. of less than 100 mPa · s, are easy to handle, and gel at a temperature below body temperature.

[0057]

[Table 4]

Test Example 5 [Example of Thermal Gelation Formulation Containing Various Anti-Glaucoma Remedies] SM-4 and Macrogol 4000 were mixed in a predetermined amount, and sterilized purified water heated to 85 ° C. was added thereto and dispersed by stirring. Let After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, a predetermined amount of citric acid or sodium citrate was gradually added, and dissolved by stirring. Further, a predetermined amount of a drug for treating glaucoma (drugs shown in Table 5 excluding isopropyl unoprostone and nipradilol) was added and dissolved with stirring. 1N here
After adding aOH or 1N HCl to adjust the pH to a predetermined value, sterile purified water was added to a predetermined volume to prepare a thermogelling preparation containing a therapeutic agent for glaucoma of the present invention.

Further, 2.8 g of SM-4 and 2.0 g of Macrogol 4000 were mixed, and 70 mL of sterilized purified water heated to 85 ° C. was added thereto and dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, 3.53 g of sodium citrate was gradually added and dissolved with stirring. After adding 1N HCl to adjust the pH to 6.5,
The volume was adjusted to 100 mL with sterile purified water to prepare a heat gelling base. Separately, 50 mL of Rescula (registered trademark) eye drop (manufactured by Ueno Pharmaceutical Co., Ltd.) was freeze-dried. 50 mL of the above-mentioned thermogelling base was added to this, and the mixture was stirred and dissolved under ice cooling to prepare an isopropylunoprostone-containing thermogelation preparation.

Further, 4.0 g of SM-4 and 4.0 g of Macrogol 4000 were mixed, and 70 mL of sterilized purified water heated to 85 ° C. was added thereto and dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, 3.53 g of sodium citrate was gradually added and dissolved with stirring. After adding 1N HCl to adjust the pH to 7.0,
The volume was adjusted to 100 mL with sterile purified water to prepare a heat gelling base. Separately, 50 mL of Hypazile Kowa eye drop (manufactured by Kowa Co., Ltd.) was freeze-dried. 50 mL of the above-mentioned thermogelling base was added thereto, and the mixture was stirred and dissolved under ice cooling to prepare a nipradilol-containing thermogelling preparation.

The relationship between the temperature and the viscosity of the prepared thermogelling preparation was examined, and the viscosity at 20 ° C., the gelling temperature and the temperature at which the viscosity of the preparation was 100 mPa · s or more were determined. Table 5
The formulation of the preparation prepared in Example 1, the viscosity at 20 ° C., the gelling temperature, and the temperature at which the viscosity of the preparation becomes 100 mPa · s or more are shown. It was shown that all of the thermal gelation preparations containing a therapeutic agent for glaucoma of the present invention have a viscosity at 20 ° C. of less than 100 mPa · s, are easy to handle, and gel at a temperature below body temperature.

[0062]

[Table 5]

Test Example 6 [Gelling Behavior of Thermogelling Preparations Containing Various Nonsteroidal Anti-inflammatory Drugs] SM-4 and Macrogol 4000 were mixed in predetermined amounts, and sterile purified water heated to 85 ° C. was added thereto. , And was dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, a predetermined amount of sodium citrate was gradually added and dissolved with stirring. A predetermined amount of anti-inflammatory drug was added thereto, dissolved and then mixed well. Furthermore, 1N NaOH or 1N HCl was added, and the pH was adjusted to a predetermined level, and then the volume was adjusted to a predetermined volume with sterile purified water to prepare a non-steroidal anti-inflammatory therapeutic drug-containing thermogelling preparation of the present invention.

The relationship between the temperature and the viscosity of the prepared thermogelling preparation was examined, and the viscosity at 20 ° C., the gelling temperature and the temperature at which the viscosity of the preparation was 100 mPa · s or more were determined. Table 6
The formulation of the preparation prepared in Example 1, the viscosity at 20 ° C., the gelling temperature, and the temperature at which the viscosity of the preparation becomes 100 mPa · s or more are shown. All of the non-steroidal anti-inflammatory therapeutic agent-containing thermogelling preparations of the present invention have a viscosity at 20 ° C. of 100.
Since it is less than mPa · s, it is easy to handle, and
It was shown to gel at temperatures below body temperature.

[0065]

[Table 6]

Test Example 7 [Gelling behavior of thermogelling preparations containing various antiallergic agents] SM-4 and Macrogol 4000 were mixed in predetermined amounts, and sterilized purified water heated to 85 ° C was added thereto and stirred. It was dispersed. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, a predetermined amount of sodium citrate was gradually added and dissolved with stirring. Further, a predetermined amount of antiallergic drug was added and dissolved by stirring. To this, 1N NaOH or 1N HCl was added, adjusted to a predetermined pH, and made to have a predetermined volume with sterile purified water to prepare the anti-allergic drug-containing thermogelling preparation of the present invention.

The relationship between the temperature and the viscosity of the prepared thermogelling preparation was examined, and the viscosity at 20 ° C., the gelling temperature and the temperature at which the viscosity of the preparation was 100 mPa · s or more were determined. Table 7
The formulation of the preparation prepared in Example 1, the viscosity at 20 ° C., the gelling temperature, and the temperature at which the viscosity of the preparation becomes 100 mPa · s or more are shown. It was shown that all of the anti-allergic drug-containing thermogelling preparations of the present invention have a viscosity at 20 ° C. of less than 100 mPa · s, are easy to handle, and gel at a temperature below body temperature.

[0068]

[Table 7]

Test Example 8 [Gelling Behavior of Thermogelling Preparations Containing Various Steroidal Anti-inflammatory Drugs] SM-4 and Macrogol 4000 were mixed in a predetermined amount, and sterilized purified water heated to 85 ° C. was added thereto, It was dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, a predetermined amount of sodium citrate was gradually added and dissolved with stirring. Furthermore, a predetermined amount of betamethasone sodium phosphate was added and dissolved by stirring. Where 1N NaOH or 1N
HCl was added to adjust the pH to 8.0 and the volume was adjusted to a predetermined volume with sterile purified water to prepare the betamethasone sodium phosphate-containing thermogelling preparation of the present invention.

Also, SM-4 and Macrogol 4000
Was mixed in a predetermined amount, sterilized purified water heated to 85 ° C. was added thereto, and the mixture was dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, a predetermined amount of sodium citrate was gradually added and dissolved with stirring. Where 1N NaOH or 1
After adding N HCl and adjusting the pH to a predetermined level, the volume was adjusted to a predetermined volume with sterile purified water to prepare a thermogelation base. here,
A predetermined amount of fluorometholone or prednisolone acetate was added and uniformly dispersed to prepare a steroidal anti-inflammatory therapeutic drug-containing thermogelling preparation of the present invention.

The relationship between the temperature and the viscosity of the prepared thermogelling preparation was examined, and the viscosity at 20 ° C., the gelling temperature and the temperature at which the viscosity of the preparation was 100 mPa · s or more were determined. Table 8
The formulation of the preparation prepared in Example 1, the viscosity at 20 ° C., the gelling temperature, and the temperature at which the viscosity of the preparation becomes 100 mPa · s or more are shown. In all of the thermogelling preparations containing the steroidal anti-inflammatory therapeutic agent of the present invention, the viscosity at 20 ° C. is 100 m
It was shown that it was less than Pa · s, was easy to handle, and gelled at a temperature below the body temperature.

[0072]

[Table 8]

Test Example 9 [Gelling Behavior of Thermal Gelation Preparations Containing Various Drugs] SM-4 and Macrogol 4000 were mixed in a predetermined amount, and sterilized purified water heated to 85 ° C. was added thereto and stirred. Dispersed. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, a predetermined amount of sodium citrate or citric acid was gradually added and dissolved with stirring. Further, a predetermined amount of sodium fluorescein, gentamicin sulfate or pyrenoxine was added and dissolved with stirring. Here, 1N or 5N NaO
H or 1N HCl was added to adjust the pH to a predetermined value, and the volume was adjusted to a predetermined volume with sterile purified water to prepare the drug-containing thermogelling preparation of the present invention.

Also, SM-4 and Macrogol 4000
Was mixed in a predetermined amount, sterilized purified water heated to 85 ° C. was added thereto, and the mixture was dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, a predetermined amount of sodium citrate or citric acid was gradually added and dissolved with stirring. 1N N here
After adding aOH or 1N HCl to adjust to a predetermined pH, sterile purified water was added to a predetermined volume to prepare a thermogelling base. A drug-containing thermogelling preparation of the present invention was prepared by adding a predetermined amount of cyclosporin A or acyclovir to the mixture and uniformly dispersing it.

The relationship between the temperature and viscosity of the prepared thermogelling preparation was examined, and the viscosity at 20 ° C., the gelling temperature, and the temperature at which the viscosity of the preparation was 100 mPa · s or more were determined. Table 9
The formulation of the preparation prepared in Example 1, the viscosity at 20 ° C., the gelling temperature, and the temperature at which the viscosity of the preparation becomes 100 mPa · s or more are shown. It was shown that all of the drug-containing thermogelling preparations of the present invention have a viscosity at 20 ° C. of less than 100 mPa · s, are easy to handle, and gel at a temperature below body temperature.

[0076]

[Table 9]

Test Example 10 [Gelling Behavior of Thermal Gelation Preparation Containing Two or More Drugs] SM-4 and Macrogol 4000 were mixed in a predetermined amount, and sterile purified water heated to 85 ° C. was added thereto. , And was dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, a predetermined amount of sodium citrate or citric acid was gradually added and dissolved with stirring. Further, a predetermined amount of drug was added and dissolved by stirring. To this, 1N NaOH or 1N HCl was added, adjusted to a predetermined pH, and then made to have a predetermined volume with sterile purified water to prepare a thermogelling preparation containing two or more drugs of the present invention.

The relationship between the temperature and the viscosity of the prepared thermogelling preparation was examined, and the viscosity at 20 ° C., the gelling temperature and the temperature at which the viscosity of the preparation was 100 mPa · s or more were determined. Table 1
The formulation of the formulation prepared to 0, the viscosity at 20 ° C., the gelling temperature, and the temperature at which the viscosity of the formulation becomes 100 mPa · s or more are shown. It was shown that all of the drug-containing thermogelling preparations of the present invention have a viscosity at 20 ° C. of less than 100 mPa · s, are easy to handle, and gel at a temperature below body temperature.

[0079]

[Table 10]

Test Example 11 [Viscosity increase rate (thermal gelation rate) test] A predetermined amount of SM-4 and 2.0 g of Macrogol 4000
Was mixed, sterilized purified water heated to 85 ° C. was added thereto, and dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, a predetermined amount of sodium citrate was gradually added and dissolved. Furthermore, 0.3 g of OFLX was added and uniformly dispersed. 1N HCl in OFLX
Was slowly added with stirring until dissolved. After confirming that it became clear, adjust the pH to 6.5 with 1N HCl,
Bring the total volume to 100 mL with sterile purified water, and use the OFLX of the present invention.
A heat-gelled preparation (OFLX-TG) was prepared.

For comparison, a predetermined amount of SM-15 and 4.0 g of Macrogol 4000 were mixed and prepared in the same manner as in the above OFLX-TG of the present invention to obtain a comparison OF.
LX-TG was prepared. The prepared OFLX-TG was held at a constant temperature, and the relationship between the holding time and the viscosity was examined. OF
The thermal gelation rate of LX-TG was measured as follows.

The prepared OFLX-TG was placed in a stainless steel container for a B type viscometer, and the container was inserted into a water tank kept at 30 ° C or 34 ° C. Immediately, the rotor of the B-type viscometer was rotated, and the viscosity was measured every 30 seconds from the start of rotation of the rotor. The time when the viscosity became the minimum was taken as the gelation start time, and the viscosity was measured 5 minutes after the gelation started. From this, the viscosity increased 5 minutes after the start of gelation was calculated, and the viscosity increased per minute was calculated, and this was taken as the thermal gelation rate.

Table 11 shows OFLX-TG formulations and thermal gelation rates at 30 ° C or 34 ° C. As a result, it was shown that the thermogelation preparations of the present invention using SM-4 in any of the formulations had a faster thermogelation rate than the comparative preparations. For example, in the case of eye drops, the applied drug solution is quickly discharged from the eye surface. Therefore, an ophthalmic solution that gels as quickly as possible on the ocular surface is a more preferable thermal gelation formulation because the drug solution discharge rate is delayed. The thermal gelation preparation of the present invention using SM-4 has a faster thermal gelation rate as compared with the comparative thermal gelation preparation, and is shown to be a more preferable preparation.

[0084]

[Table 11]

Reference Example [Gelling Behavior of Thermogelling Base Material Containing Acid Other than Citric Acid] SM-4 and Macrogol 4000 were mixed in a predetermined amount, and sterilized purified water heated to 85 ° C. was added thereto. , And was dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, various acids shown in Table 12 were gradually added in predetermined amounts, and stirred to dissolve. Furthermore, pH is adjusted with 1N NaOH or 1N HCl.
Was adjusted to 7.5 and the volume was adjusted to a predetermined volume with sterile purified water to prepare a thermogelling base containing various acids of the present invention.

Separately from this, an acid-free comparative thermogelling base was prepared in the same manner as the above-mentioned various acid-containing thermogelling bases. The relationship between the temperature and the viscosity of the prepared thermogelling preparation was examined, and the viscosity at 20 ° C., the gelling temperature, and the temperature at which the viscosity of the preparation was 100 mPa · s or more were determined. Table 12 shows the formulation of the prepared preparation, the viscosity at 20 ° C, the gelling temperature, and the temperature at which the preparation has a viscosity of 100 mPa · s or more.

Compared to the comparative thermogelling preparation containing no acid, the thermogelling base containing acids shown in Table 12 has a lower gelling temperature and a temperature at which the viscosity of the preparation is 100 mPa · s or more. It was shown that the preparation was more likely to gel at body temperature. From this, it was suggested that higher bioavailability was obtained when the thermogelling preparation using the thermogelling base containing the acids shown in Table 12 was administered.

[0088]

[Table 12]

Test Example 12 <Preparation of formulation> 4.0 g of SM-4 and 4.0 g of Macrogol 400
0 was mixed, sterilized purified water heated to 85 ° C. was added thereto, and the mixture was dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, 3.53 g of sodium citrate was gradually added and dissolved with stirring. Furthermore, 0.5 g of levofloxacin (LVFX) was added and dissolved by stirring. Here 1
After adding N NaOH and adjusting the pH to 7.8, the total volume was adjusted to 100 mL with sterile purified water to prepare the LVFX thermogelling preparation (LVFX-TG) of the present invention.

For comparison, 1.5 g of SM-15,
0.4 g of Metroze (registered trademark) SM-400 (methyl cellulose, manufactured by Shin-Etsu Chemical Co., Ltd., 2 w / v% aqueous solution has a viscosity of 350 to 550 mPa · s at 20 ° C.) and 4.0 g of Macrogol 4000 are mixed, Prepared in the same manner as the LVFX-TG of the present invention described above, and used for comparison LVFX-TG.
It was TG.

The relationship between temperature and viscosity of the prepared LVFX-TG was examined. The viscosity of LVFX-TG of the present invention at 20 ° C is 19.3 mPa · s, the gelling temperature is 22 ° C, and the temperature at which the viscosity of the preparation is 100 mPa · s or more is 26 ° C.
Met. On the other hand, the viscosity of the comparative LVFX-TG at 20 ° C. is 38.1 mPa · s, the gelling temperature is 30 ° C., and the temperature at which the viscosity of the preparation is 100 mPa · s or more is 34 ° C.
Met.

<Transferability test of LVFX-TG or Cravit ophthalmic solution to rabbit conjunctiva and aqueous humor> Japanese white rabbits (male, body weight 2.3 to 2.8 kg) were
50 μL each of the prepared LVFX-TG or Cravit eye drop (manufactured by Santen Pharmaceutical Co., Ltd., containing LVFX 0.5%) was instilled,
LVFX in the conjunctiva and aqueous humor after 1, 2 and 4 hours after instillation
The concentration was measured.

The LVFX concentration in the conjunctiva was determined as follows. The collected conjunctiva was transferred to a Spitz tube containing physiological saline and washed by inversion stirring. After homogenizing the washed conjunctiva, LV is washed with an organic solvent.
FX was extracted and measured by HPLC. The LVFX concentration in the aqueous humor was determined by filtering the aqueous humor and then analyzing the filtrate by HPLC.

The LVFX concentrations in the obtained conjunctiva and aqueous humor are shown in Tables 13 and 14, respectively. LVFX of the present invention
With regard to -TG, the LVFX concentration in the conjunctiva after 1, 2 and 4 hours after instillation was significantly higher than that of comparative LVFX-TG and Cravit ophthalmic solution at any time. Further, the LVFX-TG of the present invention is L in the aqueous humor after 1, 2 and 4 hours after instillation.
The VFX concentration was significantly higher than that of the Cravit ophthalmic solution, and was also significantly higher than that of the comparative LVFX-TG one hour after the instillation. From this, the LFVX- of the present invention
TG is LVFX-T prepared in Japanese Patent No. 2729859.
It was shown that the drug has a much higher ocular tissue transfer property than G or commercially available eye drops, and is preferable as an eye drop.

[0095]

[Table 13]

[0096]

[Table 14]

Test Example 13 [Rabbit drug eye tissue transfer test of LVFX-containing thermogelling preparations having different gelling temperatures] <Preparation of preparation> 4.0 g of SM-4 and 4.0 g of Macrogol 400
0 was mixed, 70 mL of sterile purified water heated to 85 ° C. was added thereto, and dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, 3.53 g of sodium citrate was gradually added and dissolved with stirring. Furthermore, 0.5 g of levofloxacin (LVFX) was added and dissolved by stirring.
To this, 1N NaOH was added to adjust the pH to 7.8, and the volume was adjusted to 100 mL with sterilized purified water.
v% LVFX thermogelation formulation (LVFX-TG, formulation A)
Was prepared.

The viscosity of the prepared preparation A at 20 ° C. is 2
The gelation temperature was 0.1 mPa · s, the gelation temperature was 20 ° C., and the temperature at which the viscosity of the preparation was 100 mPa · s or more was 26 ° C.
Separately from this, 2.8 g of SM-4 and 4.0 g of Macrogol 4000 were mixed, and then 0.5 w / v% LVFX-TG of the present invention (Preparation B) prepared in the same manner as the above Preparation A. Was prepared. The viscosity of the prepared preparation B at 20 ° C was 12.1 mPa · s, the gelling temperature was 24 ° C, and the temperature at which the viscosity of the preparation was 100 mPa · s or higher was 32 ° C.

<Levofloxacin (LVFX) heat-responsive gel ophthalmic solution or clavit ophthalmic solution transfer test to rabbit conjunctival surface, conjunctiva and aqueous humor> Japanese White Rabbit (male, body weight 2.1-2.6 kg) To
50 μL each of the prepared LVFX-TG2 formulation (formulation A, formulation B) or Cravit ophthalmic solution (manufactured by Santen Pharmaceutical Co., Ltd., containing LVFX 0.5%) was instilled into the conjunctiva 1 and 2 hours after the instillation, the conjunctival surface and the aqueous humor. The LVFX concentration of was measured.

The LVFX concentration in the conjunctiva was determined in the same manner as in Test Example 12. The LVFX concentration on the surface of the conjunctiva was determined as follows. LVFX dissolved in physiological saline after washing the conjunctiva was extracted with an organic solvent and measured by HPLC. Then, the amount of LVFX dissolved in the conjunctival washing solution (physiological saline) was calculated, and 1 g of the collected conjunctiva
The value obtained by converting into per hit was used as the LVFX concentration on the surface of the conjunctiva. The LVFX concentration in the aqueous humor was determined in the same manner as in Test Example 12. The LVFX concentrations in the obtained conjunctiva, the conjunctival surface and the aqueous humor are shown in Tables 15, 16 and 17, respectively.

[0101]

[Table 15]

From the results shown in Table 15, the LVFX concentration in the conjunctiva 1 and 2 hours after the prescription of the preparations A and B was significantly higher than that of Cravit ophthalmic solution at any time.

[0103]

[Table 16]

From the results shown in Table 16, the LVFX concentrations on the conjunctival surface 1 hour after the instillation of formulation A and formulation B were 10.6 and 9.2 times higher than those of Cravit ophthalmic solution, which were obviously higher values. Further, even after 2 hours from the instillation, the values were 4.9 and 7.6 times, respectively, which were clearly higher than those of Cravit ophthalmic solution.

[0105]

[Table 17]

From the results in Table 17, the LVFX concentration in the aqueous humor after 1 and 2 hours from the prescription of the preparations A and B was significantly higher than that of Cravit ophthalmic solution at any time. From the above results, in the conjunctival surface, conjunctiva and aqueous humor, the case of administering the formulation A and the formulation B is more than the case of administering the commercial eye drops, Cravit ophthalmic solution,
It was shown that a high concentration of LVFX remained over a long period of 2 hours or more. Moreover, it was shown that formulation A and formulation B had a much higher antibacterial effect than Cravit eye drops, which is a commercially available eye drop.

Test Example 14 [Rabbit drug ocular tissue transfer test of OFLX-containing heat-gelated preparations having different gelation temperatures] <Preparation of OFLX-containing heat-gelled preparation> 4.0 g of SM-4 and 4.0 g Macrogol 400
0 was mixed, 70 mL of sterile purified water heated to 85 ° C. was added thereto, and dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, 3.53 g of sodium citrate was gradually added and dissolved with stirring. Further, 0.3 g of ofloxacin (OFLX) was added and dispersed by stirring. To this, 1N HCl was gradually added with stirring until the whole became clear. Further, add 1N HCl to adjust the pH.
Was adjusted to 6.5, and the volume was adjusted to 100 mL with sterile purified water.
A 3 w / v% OFLX thermogelling formulation (OFLX-TG, formulation C) was prepared. The viscosity of the prepared preparation C at 20 ° C. was 19.3 mPa · s, the gelling temperature was 22 ° C., and the temperature at which the preparation viscosity was 100 mPa · s or higher was 26 ° C.

Separately from this, 2.8 g of SM-4 and 4.0 g of Macrogol 4000 were mixed, and then 0.3 w / v% OFLX-TG prepared in the same manner as in the above preparation C was prepared.
(Formulation D) was prepared. The viscosity of the prepared preparation D at 20 ° C is 11.0 mPa · s, the gelling temperature is 24 ° C, and the temperature at which the viscosity of the preparation is 100 mPa · s or more is 30 ° C.
Met.

For comparison, 0.4 g of SM-40
0.3 w / v% OFLX-TG for comparison (comparative formulation E) prepared by mixing 0, 1.5 g of SM-15 and 4.0 g of Macrogol 4000, and then preparing the same as the above formulation C.
Was prepared. The prepared comparative preparation E had a viscosity at 20 ° C. of 45.0 mPa · s, a gelation temperature of 28 ° C., and a temperature at which the viscosity of the preparation became 100 mPa · s or more was 34 ° C.

<Transferability test of ofloxacin (OFLX) thermoresponsive gel ophthalmic solution or talibid ophthalmic solution to rabbit conjunctival surface, conjunctiva and aqueous humor> Japanese White Rabbit (male, body weight 2.0 to 2.6 kg) To
50 μL each of 3 formulations of OFLX thermoresponsive gel ophthalmic solution (formulation C, formulation D and comparative formulation E) or Tarivid ophthalmic solution (manufactured by Santen Pharmaceutical Co., Ltd., containing 0.3% OFLX) prepared in the examples.
After instillation, and 15 minutes after instillation, 1 and 2 hours later, the OFX concentration in the conjunctiva, on the surface of the conjunctiva and in the aqueous humor was measured. The OFLX concentrations in the conjunctiva, the conjunctival surface and the aqueous humor were determined in the same manner as in Test Example 13. The concentrations of OFLX in the obtained conjunctiva, the conjunctival surface and the aqueous humor are shown in Tables 18, 19 and 20, respectively.

[0111]

[Table 18]

From the results of Table 18, formulation C prescription eye drops 15
Minutes, 1 and 2 hours later, the concentration of OFLX in the conjunctiva was significantly higher than that of Tarivid ophthalmic solution at any time,
The values for the comparative formulation E were also significantly higher after 15 minutes and 2 hours after instillation. Further, the concentration of OFLX in the conjunctiva after 15 minutes and 2 hours after instillation of the formulation D formulation was significantly higher than that of the formulation E of the comparative formulation and the eye drop of Tarivid.

[0113]

[Table 19]

From the results shown in Table 19, the concentrations of OFLX on the conjunctival surface 1 hour after the instillation of formulation C and formulation D were 14.4 and 11.3 times higher than those of Tarivid ophthalmic solution, respectively. Further, even after 2 hours from the instillation, the values were 2.3 and 5.3 times higher than that of the Tarivid ophthalmic solution, respectively.

[0115]

[Table 20]

From the results shown in Table 20, the OFLX concentration in the aqueous humor at 1 and 2 hours after the instillation of the formulation C and the formulation D was significantly higher than that of Tarivid ophthalmic solution. From the above results, in the conjunctival surface, conjunctiva and aqueous humor, the case of administering the formulation C and the formulation D is longer than the case of administering the commercially available eye drops, Tarivid ophthalmic solution, for a longer period of 2 hours or more. It was shown that a high concentration of OFLX remained throughout. From this, it was shown that the formulations C and D prescriptions have a far higher antibacterial effect than the commercially available eye drops Talibid ophthalmic solution. Further, the formulations C and D also showed high concentrations of ofloxacin on the surface of the conjunctiva, the conjunctiva, and the aqueous humor, as compared to the comparative formulation E.

Test Example 15 [LVF Using Rabbit Experimental Pseudomonas aeruginosa Corneal Infection Model
Pharmacological and Pharmacological Test of X-Containing Thermogelation Preparation] <Preparation of LVFX-Containing Thermogelation Preparation> 4.0 g of SM-4 and 4.0 g of Macrogol 400
0 was mixed, 70 mL of sterile purified water heated to 85 ° C. was added thereto, and dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, 3.53 g of sodium citrate was gradually added and dissolved with stirring. Furthermore, 0.5 g of levofloxacin (LVFX) was added and dissolved by stirring.
To this, 1N NaOH was added to adjust the pH to 7.8, and the volume was adjusted to 100 mL with sterilized purified water.
A v% LVFX thermogelling formulation (LVFX-TG) was prepared. The viscosity of the prepared LVFX-TG at 20 ° C. is 1
The gelation temperature was 20 ° C., and the temperature at which the viscosity of the preparation was 100 mPa · s or higher was 26 ° C.

<Pharmaceutical Pharmacological Test Using Rabbit Experimental Pseudomonas aeruginosa Corneal Infection Model> In the test, 11 to 13-week-old white rabbits were used, and the test was carried out with 4 eyes per group. The group composition is a physiological saline 3 times a day eye drop group, a Cravit (registered trademark) eye drop (manufactured by Santen Pharmaceutical Co., Ltd.) 3 times a day eye drop group, a once a day eye drop group, and an LVFX-TG once a day eye drop group. . Rabbit experimental Pseudomonas aeruginosa corneal infection model is described by Hadano et al. (Ophthalmology Clinic Bulletin 79 (7) (1985) 32-3.
It was prepared according to the report of 9). The eye drop test is performed on the day of inoculation (0
From the first day), instillation (50 μL) was performed once a day or three times a day every 4 hours for a total of 4 consecutive days. The observation of infectious symptoms was conducted by Kuriyama et al. (Okiki 44 (4) (1993) 434.
-44), and after inoculation of each bacterium 8, 22, 3
It was carried out after 1, 46, 55, 70, 79 and 96 hours.
Infectious symptoms are scored for each eye tissue, the total is calculated,
It was used as an indicator of the severity of infectious diseases.

<Results> The scores of infection symptoms of each drug are shown in FIG. In the saline-administered group, the score increased immediately after the bacterial inoculation (infection was established)
However, the infection symptoms became the most severe at 46 hours, and thereafter, the symptoms tended to heal spontaneously, though gradually. After the infection was established, the commercially available LVFX eye drop administration group did not show any worsening of the symptoms as in the physiological saline administration group, and showed a tendency to be cured for a while, although gradually. In addition, infection symptoms were lower in the group administered three times a day than in the group administered once a day. In contrast to these groups, in the LVFX-TG administration group of the present invention, the infection symptoms were rapidly reduced after the infection was established, and it was shown that at 96 hours, the condition was almost restored to that before the bacterial inoculation. This indicates that the LVFX-TG administration group of the present invention, despite the once-daily administration, has a stronger drug effect than the commercially available LVFX eyedrops three times daily administration group. As described above, it is shown that the thermal gelation preparation of the commercially available eye drops can reduce the number of administrations (improve QOL) and have a stronger effect.

Test Example 16 [OFL Using Rabbit Experimental Pseudomonas aeruginosa Corneal Infection Model
Pharmacological Efficacy Test of X-Containing Thermal Gelation Preparation] <Preparation of OFLX-Containing Thermal Gelation Preparation> 4.0 g of SM-4 and 4.0 g of Macrogol 400
0 was mixed, 70 mL of sterile purified water heated to 85 ° C. was added thereto, and dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, 3.53 g of sodium citrate was gradually added and dissolved with stirring. Further, 0.3 g of ofloxacin (OFLX) was added and dispersed by stirring. To this, 1N HCl was added to dissolve OFLX, and then the pH was adjusted to 6.5 with 1N HCl. And
Bring the total volume to 100 mL with sterile purified water, and add 0.3 w of the present invention.
/ V% OFLX thermogelling preparation (OFLX-TG) was prepared. The viscosity of the prepared OFLX-TG at 20 ° C. was 19.7 mPa · s, the gelling temperature was 22 ° C., and the temperature at which the viscosity of the preparation was 100 mPa · s or more was 26 ° C.

<Pharmaceutical Efficacy Pharmacological Test Using Rabbit Experimental Pseudomonas aeruginosa Corneal Infection Model> The test method was the same as in Test Example 15. The group composition is a physiological saline 3 times a day instillation group, Cravit (registered trademark) eye drop (manufactured by Santen Pharmaceutical Co., Ltd.) 3 times a day instillation group, and OFLX-TG once a day instillation group. In the eye drop test, the eye drop (50 μL) was performed once a day from the day of inoculation (day 0) or four times every four hours for a total of 4 consecutive days. Observation of infection symptoms
Kuriyama et al. (Eki 44 (4) (1993) 434-44
According to the report in 4), 8, 22, 31, 4 after inoculation of each bacterium
It was carried out after 6, 55, 70, 79 and 96 hours. Infection symptoms were scored for each eye tissue, and the sum was calculated to be used as an index of the severity of infection.

<Results> The scores of infection symptoms of each drug are shown in FIG. In the saline-administered group, the score increased immediately after the bacterial inoculation (infection was established)
However, the infection symptoms became the most severe at 32 hours, and thereafter, the symptoms gradually tended to spontaneously recover. Commercially available LVFX eye drop administration group and OFLX-TG of the present invention
After the infection was established, the administration group did not show any worsening of symptoms unlike the physiological saline administration group, and tended to be cured for a while.

LVFX, which is an optical separator of OFLX,
It is said that the antibacterial activity is twice as strong as that of OFLX. The concentration of the preparation used in this test was 0.3 w / v% OFLX for OFLX-TG, while the concentration of the commercially available LVF was
The X eye drop is 0.5 w / v% LVFX. The results of this test indicate that the commercial efficacy of the commercially available LVFX eyedrops three times daily administration group and OFLX-TG once daily administration group, which have strong antibacterial activity and high concentration, are almost equal. As described above, by using a commercially available eye drop (OFLX is marketed as TARIVID (registered trademark) eye drop) as a heat-gelled preparation, it is possible to reduce the number of administrations (improve QOL) and obtain a stronger effect. Is shown.

Test Example 17 [Rabbit Experimental Pseudomonas aeruginosa corneal infection severe model O
Pharmacological and Pharmacological Test of FLX-Containing Thermal Gelation Preparation] <Pharmacological and Pharmacological Test with Rabbit Experimental Pseudomonas aeruginosa Corneal Infection Model> The test was conducted with 11 rabbits of 13 to 13 weeks of age using 4 eyes per group. It was The group composition is a physiological saline 3 times a day eye drop group, a Cravit (registered trademark) eye drop (manufactured by Santen Pharmaceutical Co., Ltd.) 3 times a day eye drop group, and an OFLX-TG once a day eye drop group prepared in Test Example 16. A rabbit experimental Pseudomonas aeruginosa corneal infection model was prepared in the same manner as in Test Example 15. In the eye drop test, 24 hours after the inoculation, the eye drop (50 μL) was performed once a day or three times a day every 4 hours for a total of 4 consecutive days. The instillation was not performed on the 0th day after inoculation of the bacterium, but after 24 hours, to make a serious Pseudomonas aeruginosa infection model. Observation of infection symptoms was carried out in the same manner as in Test Example 15, and 24, 32 after inoculation of each bacterium,
It was carried out after 46, 55, 70, 79, 96, 103 and 120 hours. Infection symptoms were scored for each eye tissue, and the sum was calculated to be used as an index of the severity of infection.

<Results> The scores of infection symptoms of each drug are shown in FIG. In the saline-administered group, the score increased immediately after the bacterial inoculation (infection was established)
However, the symptoms of infection became most severe at 55 hours, and thereafter, although slightly, the symptoms tended to heal spontaneously.
Similar to the physiological saline administration group, the commercially available LVFX eyedrop administration group exhibited the most severe infection symptoms at 55 hours, and showed a transition similar to that of physiological saline. However, after 55 hours, the symptoms rapidly recovered, showing a healing effect as compared with the physiological saline-administered group.

On the other hand, in the OFLX-TG-administered group of the present invention, the symptoms became most severe 32 hours after the infection was established.
Time scores were comparable to the other treatment groups. After that, unlike the other administration groups, it became clear that the symptoms did not worsen and the healing was rapid. LVFX, which is an optical separator of OFLX, is said to have twice the antibacterial activity as OFLX. The concentration of the drug product used in this test is
OFLX-TG is 0.3 w / v% OFLX, while commercially available LVFX eye drops are 0.5 w / v% LVFX.

The results of this test show that OFLX eye drops, which have a high antibacterial activity and a high concentration, are more than OFLX in the group administered three times a day.
-TG shows that the once-daily administration group is more effective. As described above, by using a commercially available eye drop (OFLX is marketed as TARIVID (registered trademark) eye drop) as a heat-gelled preparation, it is possible to reduce the number of administrations (improve QOL) and obtain a stronger effect. Is shown.

Test Example 18 [Rabbit Drug Ocular Tissue Transfer Test of Moxifloxacin Hydrochloride-Containing Thermal Gelation Formulation] <Preparation of Formulation> 4.0 g of SM-4 and 4.0 g of Macrogol 400
0 was mixed, sterilized purified water heated to 85 ° C. was added thereto, and the mixture was dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, 3.53 g of sodium citrate was gradually added and dissolved. To this, 0.32 g of moxifloxacin hydrochloride was added and stirred until it was uniformly dissolved.
Furthermore, the pH was adjusted to 7.2 with 1N NaOH, and the total amount was adjusted to 100 mL with sterile purified water to prepare the moxifloxacin hydrochloride-containing thermogelling preparation (hereinafter, MOLX-TG) of the present invention.

The viscosity of MOLX-TG of the present invention at 20 ° C. was 20.6 mPa · s, the gelling temperature was 22 ° C., and the temperature at which the viscosity of the preparation was 100 mPa · s or more was 26 ° C. For comparison, 0.32 g of moxifloxacin hydrochloride was dissolved in physiological saline, adjusted to pH 7.2 with 5N NaOH, and then adjusted to 100 mL with physiological saline.
An aqueous solution containing moxifloxacin hydrochloride for comparison (hereinafter referred to as a comparative aqueous solution) was prepared.

<MOLX-TG or Comparative Aqueous Solution Transferability Test to Rabbit Conjunctival Surface, Conjunctiva and Aqueous Water> Japanese white rabbits (male, body weight 1.7 to 2.1 kg) were
The prepared MOLX thermal gelation formulation (MOLX-TG) formulation or MOLX aqueous ophthalmic solution (comparative aqueous solution) was instilled at 50 μL each, and the MOLX concentration in the conjunctival surface, in the conjunctival surface and in the aqueous humor after 15 minutes, 1 and 2 hours after instillation. It was measured. The MOLX concentrations in the conjunctiva, the conjunctival surface and the aqueous humor were determined in the same manner as in Test Example 13. The MOLX concentrations in the obtained conjunctiva, conjunctival surface and aqueous humor are shown in Tables 21, 22 and 23, respectively.

[0131]

[Table 21]

From the results shown in Table 21, the MOLX concentration in the conjunctiva after 15 minutes, 1 and 2 hours after instillation of MOLX-TG was significantly higher than that of the comparative aqueous solution at any time.

[0133]

[Table 22]

From the results of Table 22, MOLX-TG prescription 15 minutes, 1 and 2 hours after, MOLX on the conjunctival surface
The concentration was significantly higher than that of the comparative aqueous solution at any time.

[0135]

[Table 23]

From the results in Table 23, the MOLX concentration in the aqueous humor after 15 minutes, 1 and 2 hours after instillation of MOLX-TG was significantly higher than that of the comparative aqueous solution at any time. From the above results, in the conjunctival surface, conjunctiva, and aqueous humor, the direction when the MOLX-TG formulation was administered was higher than that when the comparative aqueous solution was administered, and high concentration of MOLX remained for a longer period of 2 hours or more. It was shown to be doing. This indicates that the MOLX-TG formulation has a much higher antibacterial activity than the comparative aqueous solution.

Test Example 19 [Intraocular pressure lowering action of isopropyl unoprostone-containing heat gelled preparation] <Preparation of preparation> 2.3 g of SM-4 and 2.0 g of Macrogol 400
0 and mixed with sterilized purified water heated to 85 ° C.
mL was added and dispersed by stirring. After confirming uniform dispersion, the mixture was ice-cooled with stirring. After confirming that the whole became clear, 3.53 g of sodium citrate was gradually added and dissolved with stirring. Here, 1N HCl
Was added to adjust the pH to 6.5, and then 100 with sterile purified water.
The heat-gelling base was prepared by making up to mL. Separately, 50 m of Rescula (registered trademark) eye drop (manufactured by Ueno Pharmaceutical Co., Ltd.)
L freeze-dried. 50 mL of the above-mentioned thermogelling base was added to this, and the mixture was stirred and dissolved under ice cooling to prepare an isopropylunoprostone-containing thermogelation preparation. The viscosity of the prepared isopropyl unoprostone-containing thermogelling preparation of the present invention at 20 ° C. is 6.3 mPa · s, the gelling temperature is 28 ° C., and the temperature at which the viscosity of the preparation is 100 mPa · s or more is 36.
It was ℃.

<Intraocular pressure drop test using a white rabbit> For the test, a white rabbit weighing 2.6 to 3.5 kg was used.
The test was performed with 6 eyes in a group. The group composition includes a saline eye drop group, a Rescula (registered trademark) eye drop eye drop group which is a commercially available aqueous solution preparation, and an isopropyl unoprostone-containing thermogelation preparation eye drop group of the present invention. In the eye drop test, the left eye is instilled once,
Intraocular pressure was measured 6, 8, 10 and 12 hours after instillation. The right eye was untreated. The average intraocular pressure of the physiological saline administration group was compared with the average intraocular pressure of the commercially available aqueous solution eye drop group or the eye drop group of the thermal gelation preparation of the present invention. Then, the intraocular pressure value of the commercial aqueous solution eye drop group was subtracted from the intraocular pressure value of the physiological saline administration group, and this was taken as the intraocular pressure value lowered by the commercial aqueous solution eye drop. Similarly,
The lowered intraocular pressure value was obtained by instillation of the thermogelation preparation of the present invention. Further, the ratio of the intraocular pressure value lowered by the instillation of the thermal gelation preparation of the present invention to the eye pressure value lowered by the commercial aqueous solution eyedrop was determined as the intraocular pressure lowering rate. The results are shown in Table 24.

[0139]

[Table 24]

It was shown that, even 12 hours after the instillation, the thermogelling preparation of the present invention had a higher decrease rate of the intraocular pressure as compared with the commercially available aqueous solution preparation. This indicates that a stronger drug effect can be continuously obtained by using the thermogelling preparation of the present invention.

Industrial Applicability Since the present invention has the above-mentioned constitution, even when a new quinolone antibacterial agent such as ofloxacin is used as an active ingredient,
Although the gelling temperature is sufficiently low and it is a liquid at the time of administration, the antibacterial aqueous pharmaceutical composition and the aqueous pharmaceutical composition have a high drug utilization efficiency by rapidly increasing the viscosity after administration and staying at the administration site for a long time. Can be provided. According to the present invention as described above, it is possible to supply an antibacterial gelled eye drop having a high drug concentration on the conjunctival surface, conjunctiva and aqueous humor. Furthermore, according to the present invention, the number of administrations of eye drops can be reduced, and therefore improvement of compliance is expected.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI A61K 47/38 A61K 47/38 A61P 31/04 A61P 31/04 (72) Inventor Masafumi Takeuchi 1 Nihonbashi Muromachi, Chuo-ku, Tokyo, Japan 5-5 No. 3 Wakamoto Pharmaceutical Co., Ltd. (56) Reference Japanese Patent Laid-Open No. 1-153639 (JP, A) International Publication 98/030221 (WO, A1) International Publication 94/023750 (WO, A1) (58) Survey Fields (Int.Cl. ⁷ , DB name) A61K 31/538 A61K 9/08 A61K 31/437 A61K 47/12 A61K 47/34 A61K 47/38 A61P 31/04 BIOSIS (STN) CAPLUS (STN) MEDLINE ( STN) EMBASE (STN)

Claims (5)

(57) [Claims] 1. Methylcellulose 2.8 to which the viscosity of a 2 w / v% aqueous solution at 20 ° C. is 12 mPa · s or less.
It is characterized by containing 4 w / v%, citric acid 1.5 to 2.3 w / v%, polyethylene glycol 2 to 4 w / v%, and ofloxacin 0.1 to 0.5 w / v%. A thermogelling antibacterial aqueous pharmaceutical composition which gels at body temperature. 2. Methyl cellulose 2.8 to which the viscosity of a 2 w / v% aqueous solution at 20 ° C. is 12 mPa · s or less.
4 w / v%, citric acid 1.5 to 2.3 w / v%, polyethylene glycol 2 to 4 w / v%, and at least one selected from the group consisting of ofloxacin, levofloxacin, and moxifloxacin hydrochloride. A thermogelling antibacterial aqueous pharmaceutical composition that gels at body temperature, characterized in that it contains 0.1 to 0.5 w / v% of a new quinolone antibacterial agent. 3. Methyl cellulose 2.3 to which the viscosity of a 2 w / v% aqueous solution at 20 ° C. is 12 mPa · s or less.
8 w / v%, at least one acid selected from the group consisting of polycarboxylic acids, lactic acid, and gluconic acid 0.14 to
A thermogelling aqueous pharmaceutical composition which gels at body temperature, characterized by containing 4 w / v% and an effective amount of a drug. 4. Methyl cellulose 2.3 to which the viscosity of a 2 w / v% aqueous solution at 20 ° C. is 12 mPa · s or less.
8 w / v%, polyethylene glycol 0.5 to 13 w /
A thermogelling aqueous pharmaceutical composition which gels at body temperature, characterized by containing v% and an effective amount of a drug. 5. Methyl cellulose 2.3 to which the viscosity of a 2 w / v% aqueous solution at 20 ° C. is 12 mPa · s or less.
8 w / v%, at least one acid selected from the group consisting of polycarboxylic acids, lactic acid, and gluconic acid 0.14 to
4w / v%, polyethylene glycol 0.5-13w /
A thermogelling aqueous pharmaceutical composition which gels at body temperature, characterized by containing v% and an effective amount of a drug.