JPH10316569A - Solubilization of argatroban and argatroban-containing aqueous medicine for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for solubilizing argatroban without causing its irritation, by mixing argatroban with an aqueous solution containing a surfactant having an anionic active group and non-ionic surfactant in a given ratio. SOLUTION: This method comprises mixing argatroban, a hydrate or a salt thereof with an aqueous solution containing a surfactant having an anionic active group and nonionic surfactant in a weight ratio of (1:1) to (1:10), and stirring the mixture to solubilize the argatroban extremely sparingly soluble in water, and including the argatroban thus solubilized as an active ingredient to obtain the objective argatroban-contg. aqueous medicine for external use. The compounding concentration of each of the ingredients in the aqueous medicine is 0.01-5 (w/v)% for aragatroban, 0.01-5 (w/v)% for the surfactant having anionic active group and 0.01-50(w/v)% for the nonionic surfactant. Thus, in the aqueous medicine for external use obtained, argatrogan is made to be water- soluble without practically causing irritation against the mucosa, the cornea, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for solubilizing argatroban, a drug which is extremely poorly soluble in water, without causing irritation, and an aqueous drug for external use of argatroban obtained by the method.

[0002]

2. Description of the Related Art Conventionally, fibrin formation has been observed at a considerably high frequency in intraocular surgery such as cataract surgery, vitreous surgery, and glaucoma surgery, and it is known that it causes postoperative complications. Steroids, indomethacin, and the like have been administered to prevent this. However, administration of these compounds several weeks after surgery is not as effective, and these compounds can rarely cause delayed healing or corneal injury of surgical wounds.

Argatroban or (2R, 4R)-
4-methyl-1- [N ² - ((RS) -3- methyl -
1,2,3,4-tetrahydro-8-quinolinesulfonyl) -L-arginyl] -2-piperidinecarboxylic acid is known to have a strong selective antithrombin action (Japanese Patent Publication No. 61-48829). Gazette). By this action, argatroban inhibits fibrin formation through inhibition of thrombin cleavage of the arginine-glycosidic bond of fibrinogen, so that for the purpose of inhibiting fibrin formation, as an intraocular drug during intraocular surgery or as a surgical procedure The use as eye drops to be administered later is expected.

On the other hand, in order to inhibit the production of fibrin,
It has also been reported that it is necessary to dissolve argatroban in an aqueous medium at a concentration of 1 mg / ml or more (Japanese Patent Application Laid-Open No. 7-228532). However, argatroban has extremely low solubility in water, for example, pH 7.2 to 7.8. In the optimal pH range for administration to a local site of the eye, the solubility is only about 0.9 mg / ml (25 ° C.). For this reason,
There is a need for a method for dissolving argatroban at higher concentrations.

Heretofore, as a method for dissolving argininamides such as argatroban, it has been known to add a large amount of sugar and alcohol (Japanese Patent Application Laid-Open No. 64-31).
727). However, local parts of the eye, such as the cornea and intraocular tissues, are extremely sensitive to irritation, and the method of adding sugars and alcohols causes a problem of irritation due to alcohol, causing eye drops and intraocular perfusion. It is not possible to obtain an aqueous argatroban drug that can be used as a liquid.

On the other hand, in general, in the case of eye drops, nasal drops, ear drops, and other external aqueous drugs, insoluble or hardly soluble drugs are dissolved in water. It is known to use surfactants as solubilizers (including herein emulsification and suspension aids) to assist in homogenous dispersion in suspension. For this purpose, surfactants conventionally used in eye drops and the like include polyoxyethylene sorbitan monooleate (Tween, polysorbate), polyoxyethylene hydrogenated castor oil, polyoxyethylene monostearyl and other nonionic surfactants Agent. Nonionic surfactants are known to have relatively weak irritation to mucous membranes and cornea, and are therefore widely used, but do not have a strong solubilizing effect. In addition, in order to enhance the solubilizing effect, it is theoretically sufficient to use a high concentration, but in doing so, the irritation also increases at the same time, and the drug cannot be used as a pharmaceutical. For this reason, these nonionic surfactants are actually used in ophthalmic preparations, otolaryngological preparations, etc. at concentrations below the upper limit of negligible irritation to mucous membranes, etc. For example, polyoxyethylene sorbitan monooleate 80 (polysorbate 8)
0) is 0.5 W / V%, polyoxyethylene hydrogenated castor oil 60 (HCO-60) is 0.5 W / V%, and polyoxyethylene monostearyl is 0.08 W / V%. However, the types of insoluble or hardly soluble drugs that can be dissolved or uniformly dispersed in water depending on these concentrations are limited, and most of insoluble or hardly soluble drugs are based on the fact that these nonionic surfactants are used. Even if the above upper concentration is used, it cannot be dissolved or dispersed in water to a concentration necessary for exhibiting a medicinal effect.

[0007] Anionic surfactants widely used in other fields have a strong solubilizing effect and are very advantageous if they can be used for aqueous preparations for external use, but they are more irritating to mucous membranes and the like. Because it shows significant irritation even at low concentrations, it can be applied to eye drops, nasal drops, ear drops (if the eardrum has a perforation, it can move to the mucous membrane side) and other sensitive tissues such as mucous membranes It could not be used for aqueous drugs or drugs that could come into contact with such tissues.
Further, the amphoteric surfactant is a surfactant having a cation active group and an anion active group in the same molecule, but also an externally applied aqueous drug or such an aqueous drug applied to highly sensitive tissues such as mucous membrane. Not used for drugs that may come in contact with tissue.

[0008]

Under such a background, the present invention provides argatroban and its hydrate (monohydrate) without causing substantial irritation to mucous membranes, cornea and the like. And a method for solubilizing a pharmaceutically acceptable salt in water or a pharmaceutically acceptable salt to obtain a homogeneous external aqueous preparation, and an argatroban-containing external aqueous preparation obtained thereby. With the goal.

[0009]

Means for Solving the Problems The present inventors prepared a surfactant having an anionic active group (including an anionic surfactant and an amphoteric surfactant) and a nonionic surfactant in water. It was found that when mixed at a constant ratio, the irritation of these surfactants was almost completely eliminated. In addition, the present invention provides that such a combination of surfactants makes it possible to solubilize argatroban in water, and that the resulting aqueous drug is more irritating than the argatroban aqueous drug obtained by the conventional method. Was much lower.

That is, a surfactant having an anionic active group is very irritating even at a very low concentration, so that it has not been used in eye drops, nasal drops and the like. If the active agent also exceeds a certain concentration (for example, 0.5 W / V% in ophthalmic solution for polysorbate 80), the irritation may become so large that it may not be suitable for use. The process to reach the invention shows that the aqueous solution containing no significant irritation even at very high concentrations (eg 1 W / V% sodium lauryl sulfate + 5 W / V% POE (25) lauryl ether). Headlined. In addition, this phenomenon is not limited to the combination of a specific nonionic surfactant and a surfactant having a specific anionic active group, and a combination of a surfactant having an anionic active group and a nonionic surfactant may be used. It was also confirmed that the same can be seen in various combinations. In addition, a surfactant having an anionic active group and a nonionic surfactant have a weight concentration (W / V%).
The effect was recognized even at a ratio of 1: 1. The effect was more apparent at 1: 2, and the effect was more remarkable at 1: 4 to 1: 6.

This phenomenon is caused by the fact that a surfactant having an anion-active group exhibiting a high degree of irritation which cannot withstand a sensitive portion such as a mucous membrane and a high concentration of a high concentration which exhibits a strong irritation. Non-ionic surfactants are formulated into a composition having a non-irritating solubilizing action by being mixed in water at a fixed ratio, which is completely unexpected from the conventional technical knowledge. The mechanism of this phenomenon is not clear at present. The present inventors further used such a surfactant combination for solubilization of argatroban, which was difficult in the past. Can be made lower than the case of solubilization by the conventional method.

That is, the present invention relates to a method for solubilizing argatroban in the production of an external aqueous drug containing argatroban, which comprises converting argatroban, a hydrate or a pharmaceutically acceptable salt thereof into an interface having an anion-active group. Provided is a method characterized by mixing an aqueous solution containing a surfactant and a nonionic surfactant in a fixed ratio. The present invention also relates to an externally applied aqueous drug containing solubilized argatroban as an active ingredient, which contains a surfactant having an anionic active group and a nonionic surfactant in a fixed ratio. A drug characterized by the following is also provided.

In the present invention, “external aqueous drug” refers to an aqueous drug which is not administered systemically by internal administration, injection or the like and is applied to a local body for the purpose of medical treatment / treatment. Agents, intraocular preparations such as intraocular fluid, nasal drops, ear drops, dermatological agents and dentifrices.

In the aqueous preparation for external use of the present invention and the method for producing the same, the ratio of the surfactant having an anionic active group to the nonionic surfactant is preferably in a weight concentration ratio, preferably 1: 1 to 1: 1. 6, more preferably 1: 2 to 1: 6, even more preferably 1: 4 to 1: 6.

In the present invention, even if the concentration of each of the surfactant having an anionic active group and the nonionic surfactant for solubilizing argatroban is a high concentration which cannot be considered from the conventional technical knowledge, Aqueous drugs containing them in a certain ratio have substantially no irritation to sensitive tissues such as mucous membrane and cornea. For example, a surfactant having an anionic active group (conventionally practically unusable due to irritation) was contained at a concentration as high as 1%, and a nonionic surfactant was added at a much higher 5W than before. / V%, it does not substantially show irritation, and further contains 2 W / V% of a surfactant having an anionic active group and 10 W / V% of a nonionic surfactant. Even when contained in a concentration, it is not substantially irritating. In addition, when argatroban is solubilized, irritation does not occur.

The concentration of argatroban in the external aqueous preparation of the present invention is preferably (a) 0.01 to 5 W / V.
%, (B) more preferably 0.05 to 2.5 W / V%, (c)
More preferably, it is 0.1 to 2 W / V%. To solubilize argatroban in each of these concentration ranges, the preferred concentrations of the surfactant having an anionic active group and the non-ionic surfactant used are the surfactant having an anionic active group and the non-ionic surfactant. Weight ratio of a surfactant to 1:
In the case of the above (a), for example, 0.01 to 5 W / V% and 5 to 50 W / V, provided that they are in the range of 1 to 1:10.
%, In the case of (b), for example, 0.05 to 2.5 W / V% and 0.3 to
15 W / V%, in the case of (c), for example, 0.1 to 2 W / V% and
0.6 to 12 W / V%.

Among the surfactants having an anionic active group, examples of the anionic surfactant which can be used in the present invention include carboxylate such as sodium lauryl sulfate belonging to the category of sulfonate and sulfate. Lauroyl sarcosine sodium (Sarcosinate L
N: NIKKOL, etc.), and phosphate ester salt, phosphene HLP-N, etc., but are not limited thereto.

Among the surfactants having an anionic active group, examples of the zwitterionic surfactant which can be used in the present invention include, but are not limited to, lauryldimethylaminoacetate betaine.

Examples of nonionic surfactants include polyoxyethylene type surfactants such as polyoxyethylene hydrogenated castor oil such as HCO-60, polyoxyethylene sorbitan monooleate such as Tween 80, polyoxyethylene lauryl ether ( For example POE (25)
Lauryl ether, etc.), polyoxyethylene monostearate (eg, POE (40) monostearate, etc.), polyhydric alcohol ester decaglyceryl monolaurate (Decaglyn 1-L: NIKKOL), ethylene oxide propylene oxide block copolymer Polyoxyethylene polyoxypropylene glycol (eg, Pronone 1)
02, etc .: NIKKOL) and the like, but are not limited thereto.

In producing an aqueous drug according to the present invention, one or more of a surfactant having an anionic active group and a nonionic surfactant may be used.

Furthermore, the aqueous drug for external use containing solubilized argatroban of the present invention may contain other components depending on the use, for example, other medicinal components, pH regulators, buffers, osmotic pressure regulators, suspensions, etc. It may contain agents, antioxidants, preservatives and the like. The pH of the externally applied aqueous drug of the present invention can be appropriately set depending on the application, but generally, preferably 3 to 10,
It is more preferably 4 to 9, and further preferably 5 to 8.

Next, some examples of animal tests will be presented below in order to first clarify the combination of the surfactants used in the present invention and the point that the combination removes irritation.

[Anterior eye irritation test on rabbit combination with surfactant-1] (Animal and ophthalmic operation) Japanese white male rabbits of 8 to 9 weeks of age were used for the compositions of the following formulations 1 to 3 ( First to third
Group, 3 birds / group), and the presence or absence and degree of irritation of the anterior segment were tested. Instillation of Formulations 1 and 2 was carried out twice on one eye (eye to be examined) once and eight times at 1 hour intervals, and at the same time, physiological saline was instilled on the other eye (control eye). Prescription 3
Instillation of (comparative prescription) was performed only once for one eye (eye to be examined), and physiological saline was instilled simultaneously for the other eye.

(Observation / Evaluation Method) For the first and second groups, macroscopic observation of the anterior segment was performed immediately before the start of instillation, first, second, third,
Thirty minutes after the fourth, sixth, and eighth instillation and on the next day (24 hours later), corneal staining with fluorescein was observed with a slit lamp microscope immediately before the start of instillation and 30 minutes after the last instillation. For the third group, macroscopic observation of the anterior segment was performed immediately before the start of instillation, 0.5, 1, 1.5, 2, 2.5, 3, 5, and 24 hours after instillation, and a slit lamp of corneal staining by fluorescein was used. Microscopic observation was performed immediately before the start of instillation and 5 hours after instillation. For macroscopic observation, scoring was evaluated by the improved Draize method.

[0025]

[0026]

[0027]

(Results) (1) Visual observation of the anterior segment: The results are shown in Tables 1 to 6. Since the scores for the cornea and the iris were all 0, the description is omitted.

[0029]

[Table 1]

[0030]

[Table 2]

[0031]

[Table 3]

[0032]

[Table 4]

[0033]

[Table 5]

[0034]

[Table 6]

As is evident from the table, the anterior segment findings by eye drops of Formulations 1 and 2 were almost the same as those of the control saline-administered eyes. On the other hand, prescription 3 (comparison prescription)
, Redness and secretion of the eyelid conjunctiva, bulbar conjunctiva, and nictitating membrane were observed, and edema of the conjunctiva was observed in two of three eyes. Eyes with marked edema of the eyelid conjunctiva are hidden by edema and the bulbar conjunctiva cannot be seen, and the degree of redness of the bulbar conjunctiva cannot be confirmed. It was conducted. For this reason, the numerical value relating to redness of the bulbar conjunctiva in Table 5 is estimated to be lower than the actually generated redness. These changes were maximized 1 hour after the instillation of Formulation 3 and continued to be observed until 3 hours. Eye drops 5
After a time, it showed a tendency to recover, and the next day, it was observed that it had recovered.

(2) Findings of corneal staining due to fluorescein: No abnormality was observed in any of the groups.

Discussion: As is apparent from the results, the comparative formulation containing only anionic surfactant sodium lauryl sulfate (formulation 3) has a high level of conjunctiva with only one instillation. While showing irritation,
Sodium lauryl sulfate at the same concentration (formulation 2) or higher concentration (formulation 1) and 5 times the amount of a nonionic surfactant (polysorbate 80 or polyoxyethylene (40))
Monostearate) (formulations 1 and 2) show little irritation. This indicates that the strong irritancy of the anionic surfactant sodium lauryl sulfate was masked by the incorporation of these nonionic surfactants. At the same time, the fact that these non-ionic surfactants, which should of course show obvious irritation at such a high concentration, did not show any irritation, as shown in the above results (Formulations 1 and 2), means that the anionic It shows that the incorporation of a non-ionic surfactant also masked the irritation of non-ionic surfactants. Thus, it is quite unexpected to those skilled in the art that high concentrations of two surfactants, which are clearly highly irritating to the conjunctiva, have mutually blocked their irritation by blending.

[Rabbit Anterior Eye Irritation Test on Surfactant Combination-2] The same test as the above test was conducted by further increasing the surfactant concentration and changing the combination of surfactants. (Animal and ophthalmic operation) An aqueous solution of the surfactant shown in Formulations 4 and 5 below was instilled into 8-9 week old Japanese white rabbits (groups 4 and 5 and group 3 / group, respectively). The presence and degree of irritation of the anterior segment were tested. In each formulation, one eye (examined eye) was instilled 2 drops at a time, 3 times at 1 hour intervals, and at the same time, the opposite eye (control eye) was compared with the following anionic surfactant alone, a comparative formulation 4C. And 5C were instilled.

(Formulation 4) Sodium lauryl sulfate 1.0 W / V% POE (25) lauryl ether 5.0 W / V% (Formulation 4C) Sodium lauryl sulfate 1.0 W / V%

(Formulation 5) Sarcosinate LN ... 1.0 W / V% decaglyceryl monolaurate ... 5.0 W / V% (Formulation 5C) Sarcosinate LN ... 1.0 W / V%

(Observation / Evaluation Method) In each group, macroscopic observation of the anterior segment was performed immediately before the start of instillation, 30 minutes after each instillation, and 24 and 48 hours after the last instillation, and scored by the improved Draize method. . The observation of corneal staining by fluorescein was performed immediately before the start of instillation and 30 minutes and 24 hours after the last instillation.

(Results) (1) Visual observation of the anterior eye part: Tables 7 to 10 show the results. Since the scores for the cornea and the iris were all 0, the description is omitted.

[0043]

[Table 7]

[0044]

[Table 8] *: Not observed due to conjunctival edema in one of three eyes.

[0045]

[Table 9]

[0046]

[Table 10] * 1: One of three eyes could not be observed due to conjunctival edema. * 2: Two of three eyes could not be observed due to conjunctival edema. -: Not observed due to conjunctival edema in all three eyes.

As is clear from the table, the comparative formulas 4C (1% sodium lauryl sulfate alone) and 5C
In the case of (1% sarcosinate LN alone), a high degree of irritation was observed in all the items shown in the table, and edema of the eyelid conjunctiva was remarkable. Eyes with marked edema of the eyelid conjunctiva are hidden by edema and the bulbar conjunctiva cannot be seen, and the degree of redness of the bulbar conjunctiva cannot be confirmed. It was conducted. For this reason,
The values for redness of bulbar conjunctiva in Tables 8 and 10 are estimated to be lower than the actual redness. In contrast to these comparative prescriptions, the eye drops of prescription 4 had only a slight degree of eyelid conjunctival redness that could be seen in normal cases,
No irritation was observed. In Formula 5, although there was a little more redness and the like, the irritation was very slight, if any, and it was recognized that the irritation was almost eliminated compared to the remarkable irritation of Comparative Formulation 5C. Was.

(2) Findings of corneal staining due to fluorescein: The number of diffuse staining spots was significantly increased in Comparative Formulations 4C and 5C, and in particular, large map-like staining spots were observed in Comparative Formulation 5C. However, no abnormalities were observed for Formulations 4 and 5 in contrast.

Consideration: As is apparent from the results, Comparative Formulation 4C containing only 1% of sodium lauryl sulfate, which is an anionic surfactant, and 1% of sarcosinate LN, which is also an anionic surfactant. Comparative Formulation 5C contained a high concentration of irritation, while Formulations 4 and 5 each contained 5% POE (25) lauryl ether and 5% decaglyceryl monolaurate, respectively. 5 shows little irritation, especially Formulation 4 shows no irritation. This indicates that the combination of an anionic surfactant and a non-ionic surfactant, as well as the result of the above-mentioned test-1, seals off the strong irritancy of the anionic surfactant and increases the concentration of the non-ionic surfactant. It again reveals that it also blocks the irritancy that would come from surfactants.

[Rabbit anterior eye irritation test on combination of surfactants-3] (Animal and ophthalmic operation) As a surfactant having an anion active group, lauryl dimethylamino acetate betaine (amphoteric surfactant) was used. For the compositions of the following Formulations 6 and 6c containing a 35% aqueous solution under the trade name of AM-301), Formulation 6 was applied to one eye (examined eye) of a Japanese white male rabbit, and to the other eye. 2 drops (approximately 100 μL) of Formulation 6c (Comparative Formulation) were instilled three times at one-hour intervals.

Immediately before the start of instillation, 30 minutes after the first, second, and third instillations, and on the next day, the anterior eye was visually observed, and 30 minutes before the start of instillation, 30 minutes after the last instillation, and the next day. Slit lamp microscopy of corneal staining with fluorescein was performed. For macroscopic observation, scoring was evaluated by the improved Draize method.

(Formulation 6) (PH 6.2, osmotic pressure 46mOsm)

(Prescription 6c) (PH 6.7, osmotic pressure 39 mOsm)

(Results) (1) Visual observation of the anterior segment: The results are shown in Tables 11 and 12.

[0055]

[Table 11]

[0056]

[Table 12] -: Cannot be observed due to edema.

As is clear from the table, the eye drops of Formulation 6c (amphoteric surfactant lauryl dimethylaminoacetate betaine alone) showed redness in the eyelid conjunctiva and nictitating membrane, and showed very conjunctival edema and secretions, and further corneal opacity. Strong irritation was observed. Eyes with marked edema of the eyelid conjunctiva are hidden by edema and the bulbar conjunctiva cannot be seen, and the degree of redness of the bulbar conjunctiva cannot be confirmed. It was conducted. For this reason, the numerical value relating to redness of the bulbar conjunctiva in Table 12 is estimated to be lower than the actually generated redness. In contrast, administration of a mixed solution of betaine lauryl dimethylaminoacetate and polysorbate showed only slight redness and secretion in the eyelid conjunctiva, bulbar conjunctiva and nictitating membrane.

(2) Observation of corneal staining due to fluorescein: In the case of formulation 6c, which is a solution of betaine lauryldimethylaminoacetate alone, diffuse punctate staining was observed, whereas a mixed solution with polysorbate was used. In Formulation 6, no abnormality was observed.

Discussion: As is clear from the results, Formulation 6c containing only the amphoteric surfactant lauryl dimethylaminoacetate betaine as the surfactant having an anionic active group.
Showed a high degree of irritation while Formulation 6 containing 5 times the amount of the nonionic surfactant polysorbate 80 at the same time.
Then only mild irritation was observed. This indicates that the strong irritation of the amphoteric surfactant lauryl dimethylaminoacetate betaine was masked by the incorporation of the nonionic surfactant polysorbate 80. At the same time, the lack of irritation of polysorbate 80 despite such a high concentration means that the incorporation of amphoteric surfactants also masked the irritation of nonionic surfactants. Is shown.

[Rabbit Anterior Eye Irritation Test for Surfactant Combination-4] (Animal and Eye Drop Manipulation) The following formulations 7A and 7B containing sodium lauryl sulfate as a surfactant having an anionic active group, For 7C, 8, 8C, 9 and 9C, and distilled water, use Japanese white male rabbits twice at a time (about 10 drops).
(0 μL), eye drops were observed three times at one hour intervals, and observations were made.

Immediately before the start of instillation, 30 minutes after the first, second and third instillations, and the next day, respectively, the anterior eye was visually observed. 30 minutes before the start of instillation, 30 minutes after the last instillation, and the next day, Slit lamp microscopic observation of corneal staining by fluorescein was performed. For macroscopic observation, scoring was evaluated by the improved Draize method.

(Formulation 7A) Sodium lauryl sulfate 0.5 g Polysorbate 80 0.5 g distilled water Appropriate amount (pH 6.5) Total amount 100 mL

(Formulation 7B) Sodium lauryl sulfate 0.5 g polysorbate 80 1.0 g distilled water Appropriate amount (pH 6.6) Total amount 100 mL

(Formulation 7C) Sodium lauryl sulfate 0.5 g Distilled water Appropriate amount (pH 6.0) Total amount 100 mL

(Formulation 8) Sodium lauryl sulfate 0.1 g Polysorbate 80 0.5 g distilled water Appropriate amount (pH 6.7) Total amount 100 mL

(Formulation 8C) Sodium lauryl sulfate 0.1 g distilled water Appropriate amount (pH 5.9) Total amount 100 mL

(Formulation 9) Sodium lauryl sulfate 2.0 g Polysorbate 80 10.0 g distilled water Appropriate amount (pH 6.8) Total amount 100 mL

(Formulation 9C) Sodium lauryl sulfate 2.0 g Distilled water Appropriate amount (pH 6.0) Total amount 100 mL

(Results) (1) The results are shown in Tables 13 to 20. "SL" in the table title
"S" represents sodium lauryl sulfate and "PS" represents polysorbate 80.

[0070]

[Table 13]

[0071]

[Table 14]

[0072]

[Table 15]

[0073]

[Table 16]

[0074]

[Table 17]

[0075]

[Table 18]

[0076]

[Table 19]

[0077]

[Table 20] −: Unobservable due to edema

As shown in Table 15, in the case of the 0.5% sodium lauryl sulfate solution (Formulation 7C), strong irritation was generally observed, and conjunctival edema particularly occurred, reaching a total score of 7.0 after the third instillation. I have. Eyes with marked edema of the eyelid conjunctiva are hidden by edema and the bulbar conjunctiva cannot be seen, and the degree of redness of the bulbar conjunctiva cannot be confirmed. It was conducted. For this reason, the numerical value relating to redness of the bulbar conjunctiva in Table 20 is estimated to be lower than the actual redness. On the other hand, Table 14 obtained by adding 1.0% polysorbate 80 thereto.
Formulation 7B (anionic surfactant: nonionic surfactant = 1: 2) is generally less irritating,
In particular, no conjunctival edema occurred, and the total score after three instillations was remarkably suppressed to 1.75. Furthermore, even with a solution of 0.5% sodium lauryl sulfate + 0.5% polysorbate 80 (Formulation 7B: anionic surfactant: nonionic surfactant = 1: 1), the irritation is generally higher than that of Formulation 7C. In addition, conjunctival edema was not observed, and the total score after the third instillation was 4.00, which was clearly suppressed as compared to 7.0 of the prescription 7C. No irritation is observed in distilled water drops (Table 16). From these results, it can be seen that even when the ratio of sodium lauryl sulfate (anionic surfactant) to polysorbate 80 (nonionic surfactant) is 1: 1, the effect of suppressing irritation exists, and that the ratio is 1: 2, it can be seen that the suppression effect is more remarkable.

Also, for the lower concentration range of surfactants, the total score for the 0.1% strength sodium lauryl sulfate solution (Formulation 8C) shown in Table 18 and Table 17
Compared to the total score with 0.1% sodium lauryl sulfate + 0.5% polysorbate 80 (Formulation 8: anionic surfactant: nonionic surfactant = 1: 5), some irritation seen in the former was observed. It turns out that the latter is not seen at all. This indicates that sodium lauryl sulfate, an anionic surfactant, shows some irritation even at such a low concentration, but even in such a concentration range, the nonionic surfactant polysorbate 80 This shows that suppression of irritation can be obtained by combining with.

Further, for the range of higher surfactant concentrations, the score at 2.0% concentration of sodium lauryl sulfate (Formulation 9C) shown in Table 20 and the 2.0% concentration in Table 19
Sodium lauryl sulfate + 10% polysorbate 80 (Formulation 9: anionic surfactant: nonionic surfactant =
Comparison of the total scores at 1: 5) shows that the prominent irritation in the former is substantially completely suppressed in the latter.

(2) Observation of corneal staining by fluorescein: Formulation 7C containing only 0.5% sodium lauryl sulfate
In Table 15, diffuse punctate spots were observed covering the entire cornea, while formulations 7A and 7B containing polysorbate at a concentration ratio of 1: 1 and 1: 2, respectively (Table 1).
In 3 and 14), punctate spots were only observed locally, and the corneal irritation was suppressed. No abnormalities were found in any of the low-concentration formulations 8 (Table 17) and 8C (Table 18). Formulation 9C containing only 2.0% sodium lauryl sulfate (Table 20) showed a widespread corneal epithelial defect that stained more densely than fluorescein, whereas Formulation 9 containing polysorbate 80 at a concentration ratio of 1: 5. In Table 19, no corneal abnormality was observed, and corneal irritation was completely suppressed.

Discussion: The above results show that the irritation of the anionic surfactant was reduced even when the ratio of the anionic surfactant to the nonionic surfactant was 1: 1. This shows that the higher the ratio of the nonionic surfactant is, the more the effect of suppressing irritation becomes significant. Also, in terms of surfactant concentration, some of the irritation seen with anionic surfactants as low as 0.1% can be suppressed by the addition of nonionic surfactants, and
It shows that even the high irritation of anionic surfactants as high as 2.0% can be substantially completely suppressed by nonionic surfactants. Furthermore, it is shown that the combination of both surfactants also suppresses the irritancy that would be seen with a high concentration of nonionic surfactant alone.

[0083]

DETAILED DESCRIPTION OF THE INVENTION To solubilize argatroban, its hydrates or their pharmaceutically acceptable salts in water according to the present invention in order to obtain a topical aqueous drug, the usual procedure is used. The drug may be mixed with an aqueous solution obtained by combining a surfactant having an ionic active group and a nonionic surfactant with stirring. The concentration of the surfactant combination to be used may be appropriately set according to the concentration of argatroban to be solubilized and according to the use of the obtained external aqueous drug. Even in the case of a drug applied directly to the ocular mucosa, up to 2 W / V% of a surfactant having an anionic active group and 10 W / V% of a nonionic surfactant, unless the drug is frequently administered. The combination described above can be used without causing substantial irritation. Also, other components commonly used in the preparation of aqueous medicaments and known to those skilled in the art, such as pH adjusting agents, buffers, osmotic agents, suspending agents, antioxidants, preservatives, etc. It may be used depending on the use of the aqueous drug.

Next, an example of an irritation test for the argatroban-containing external aqueous preparation of the present invention will be described. [Ocular irritation test of argatroban-containing topical aqueous drug-
1) (Animal and ophthalmic operation) Following test formulation A containing solubilized argatroban according to the description in Examples
RG-1.0 and a control formulation ARG-0 (base) were prepared and administered to three Japanese white male rabbits weighing about 2.5 kg by eye drops to test the presence and degree of irritation of the anterior segment. Formula A
RG- and eye drops were performed four times at an interval of 2 hours and 20 minutes, two drops at a time on one eye (eye to be examined), and the other eye (control eye)
Was similarly treated with the control formulation ARG-0.

(Test prescription: ARG-1.0)

(Control formulation: ARG-0)

(Observation / Evaluation Method) Macroscopic observation of the anterior segment was performed immediately before the start of instillation, 30 minutes after each instillation, and the next day (24 hours later), and corneal staining by fluorescein was observed with a slit lamp microscope. Was performed immediately before the start of instillation and 30 minutes after the last instillation.
For macroscopic observation, scoring was evaluated by the improved Draize method.

(Results) (1) Macroscopic observation of the anterior segment: Tables 21 and 22 show the results of macroscopic observation of the anterior segment.

[0089]

[Table 21]

[0090]

[Table 22]

(2) Findings of corneal staining due to fluorescein: No abnormality was observed on any side.

Consideration: As is clear from the table and the above-mentioned corneal staining spots with fluorescein, the test formulation ARG
At -1.0, no irritation was observed, as in the control formulation (base).

[Ocular irritation test of argatroban-containing external topical aqueous drug-2] (Animal and ophthalmic operation) Following test formulation A containing argatroban solubilized and contained as described in the Examples
RG-0.75 and a physiological saline solution as a control were prepared, and administered repeatedly to two Japanese white male rabbits weighing about 2.5 kg for 2 weeks to test the presence and degree of irritation of the anterior segment. The test prescription and physiological saline were instilled in one eye, two drops at a time, four times a day at 2.5 hour intervals.

(Test prescription: ARG-0.75)

(Observation / Evaluation Method) Visual observation of the anterior segment, observation of corneal staining by fluorescein, and the last day of the day before the start of instillation and on days 0, 3, 7, and 13 after the start of instillation Performed 30 minutes after instillation. In addition, observation of the presence or absence of eye behavior suggesting irritation, such as blinking and eyelid closure, was performed at the time of each eye drop on days 0, 3, 7, and 13 after the start of eye drop. For macroscopic observation, scoring was evaluated by the improved Draize method.

(Results) (1) Visual observation of the anterior eye part: Tables 23 and 24 show the results of the visual observation of the anterior eye part.

[0097]

[Table 23]

[0098]

[Table 24]

(2) Findings of corneal staining due to fluorescein: The test prescription ophthalmic solution, like the physiological saline ophthalmic solution, only occasionally showed normal range staining.

(3) Eye behavior: A sporadic blink was observed on the side of the prescribed eye drops to be examined, but this was only normal and was not enough to suspect an abnormality.

Discussion: As is clear from the table, the macroscopic observation of the upper anterior eye showed no abnormality on the test prescription eyedrop side, similar to the physiological saline eyedrop side. No abnormalities were observed in the observation of corneal staining by fluorescein. In addition, no abnormalities were observed in eye behavior such as blinking and eyelid closure.

[0102]

EXAMPLES Examples of the aqueous drug for external use containing argatroban solubilized according to the present invention will be described below.

Example 1 Eye Drops The following components were mixed and stirred at room temperature to dissolve the hardly soluble argatroban. This was filtered and sterilized by a conventional method, and filled in an eye dropper to obtain an eye drop.

Example 2 Eye Drops The following components were mixed and stirred at room temperature to dissolve the hardly soluble argatroban. This was filtered and sterilized by a conventional method, and filled in an eye dropper to obtain an eye drop. (Test prescription: ARG-0.75)

Example 3 Eye Drops The following components were mixed and stirred at room temperature to dissolve the hardly soluble argatroban. This was filtered and sterilized by a conventional method, and filled in an eye dropper to obtain an eye drop.

Example 4 Ophthalmic Solution The following components were mixed and stirred at room temperature to dissolve the hardly soluble argatroban. This was filtered and sterilized by a conventional method, and filled in an eye dropper to obtain an eye drop.

Example 5 Eye Drops The following components were mixed and stirred at room temperature to dissolve the hardly soluble argatroban. This was filtered and sterilized by a conventional method, and filled in an eye dropper to obtain an eye drop.

Example 6 Eye Drops The following components were mixed and stirred at room temperature to dissolve the hardly soluble argatroban. This was filtered and sterilized by a conventional method, and filled in an eye dropper to obtain an eye drop.

Example 7 Eye Drops The following components were mixed and stirred at room temperature to dissolve the hardly soluble argatroban. This was filtered and sterilized by a conventional method, and filled in an eye dropper to obtain an eye drop.

Example 8 Eye Drops The following components were mixed and stirred at room temperature to dissolve the hardly soluble argatroban. This was filtered and sterilized by a conventional method, and filled in an eye dropper to obtain an eye drop.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Hideyuki Sakaki 3-17-3-1 Kita Beppu, Nishi-ku, Kobe-shi, Hyogo Prefecture (72) Inventor Miyoko Isaka 2-9-1, Otsuwa, Nishi-ku, Kobe-shi, Hyogo No. 403 (72) Inventor Seiko Kimura 527-3 Kitano, Noguchi-cho, Kakogawa-shi, Hyogo

Claims (14)

[Claims] 1. A method for solubilizing argatroban in the production of an external argatroban-containing aqueous drug, which comprises argatroban, a hydrate or a pharmaceutically acceptable salt thereof, and a surfactant having an anion-active group. A method comprising mixing an aqueous solution containing a nonionic surfactant in a fixed ratio. 2. The method according to claim 1, wherein the weight ratio of the surfactant having an anionic active group to the nonionic surfactant is 1: 1:
2. The method of claim 1, wherein the ratio is from 1 to 1:10. 3. In the aqueous drug, the concentration of argatroban is 0.01 to 5 W / V%, the concentration of the surfactant having an anionic active group is 0.01 to 5 W / V%, and the nonionic 3. The method according to claim 1, wherein the concentration of the surfactant is 0.01 to 50 W / V%. 4. The method according to claim 1, wherein the surfactant having an anionic active group is an anionic surfactant. 5. The method according to claim 1, wherein the surfactant having an anionic active group is an amphoteric surfactant. 6. The method according to claim 1, wherein the pH is 3-10. 7. An aqueous drug for external use containing solubilized argatroban as an active ingredient, which contains a surfactant having an anionic active group and a nonionic surfactant in a fixed ratio. Aqueous external preparation characterized by the following. 8. The weight ratio of the surfactant having an anionic active group to the nonionic surfactant is 1: 1:
The aqueous pharmaceutical composition for external use according to claim 7, wherein the ratio is 1 to 1:10. 9. In the aqueous drug, the concentration of argatroban is 0.01 to 5 W / V%, the concentration of the surfactant having an anionic active group is 0.01 to 5 W / V%, and the nonionic The topical aqueous drug according to claim 7 or 8, wherein the concentration of the surfactant is 0.01 to 50 W / V%. 10. The method of claim 7 for mucosal or intraocular application.
Any one of the aqueous agents for external use according to any one of items 1 to 9. 11. The external aqueous preparation according to claim 7, which is an eye drop, an intraocular preparation, a nasal drop, an ear drop, a skin preparation, or a dentifrice. 12. The topical aqueous drug according to claim 7, wherein the surfactant having an anionic active group is an anionic surfactant. 13. The external aqueous preparation according to claim 7, wherein the surfactant having an anionic active group is an amphoteric surfactant. 14. The method according to claim 7, wherein the pH is 3 to 10.
Any of the external aqueous agents of the above.