JP3147076B2 - Roteprednol etabonate aqueous suspension - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to loteprednol.
The present invention relates to an aqueous etabonate suspension, and more particularly, to a stable and safe aqueous solution of loteprednol etabonate which does not fluctuate in pH even during long-term storage and has no irritation to the eyes and nasal mucosa.

[0002]

2. Description of the Related Art Many steroid compounds have been used as topical treatments for ocular inflammation. While these steroid compounds exhibit potent anti-inflammatory effects, they can cause secondary disorders such as cataracts and glaucoma on the eyes. Therefore, steroid compounds that do not have these harmful side effects even when topically administered to the eye have been studied. In recent years, loteprednol etabonate (hereinafter, referred to as “prednisolone acetate”) has excellent anti-inflammatory properties and few side effects. LE "may be abbreviated) (US Patent Nos. 4,716,495 and 4,
996, 335). This LE is the prednisolone 17
does not have the 20-keto group at the β-position,
The β-position has an ester group which is hydrolyzed in the body to become an inactive carboxylic acid metabolite which does not bind to the glucocorticoid receptor. Therefore, unlike many other steroids, LE has a low incidence of side effects such as the onset of cataract and an increase in intraocular pressure, and is a very useful compound for treating ocular inflammation.

[0003]

Since LE is a crystalline substance that is hardly soluble in water, it is in the form of an aqueous suspension to prepare eye drops or nasal drops. However, when LE is formulated together with a tonicity agent such as sodium chloride or a buffering agent such as phosphoric acid which has been conventionally used for preparing an aqueous suspension,
Aggregation of the LE particles occurs within three months, and sometimes within one month. To solve this problem, together with LE, nonionic suspending agents such as polyvinylpyrrolidone (PVP) and polyvinyl alcohol (PVA), nonionic surfactants such as tyloxapol and polysorbate 80, and glycerin and mannitol. An aqueous suspension of LE containing a polyhydric alcohol tonicity agent has been proposed (PCT / US94 / 12059) and has shown considerable effects. However, in the preparation of an aqueous suspension, it is difficult to adjust the pH at the time of production of the aqueous suspension, and when stored for a long period of time, the pH value is lowered even though the appearance is not significantly changed. Irritation to the nasal mucosa.

[0004]

SUMMARY OF THE INVENTION The present inventors have further improved the above-mentioned formulation to make it easier to manufacture and more stable and safe without irritation to the eye and nasal mucosa even when stored for a long time. After extensive studies on a wide range of compounds to determine whether an aqueous suspension could be obtained, they unexpectedly found that certain types of amino acids were effective, and conducted further studies to complete the present invention. That is, the present invention provides (1) an aqueous suspension of loteprednol etabonate containing loteprednol etabonate and an aliphatic amino acid having 2 to 7 carbon atoms, (2) an amino acid having one or two amino groups and one or two The aqueous suspension according to the above (1), which has a carboxyl group of
(3) the aqueous suspension according to the above (2), wherein the amino acid is a neutral or acidic amino acid; (4) the aqueous suspension according to the above (3), wherein the amino acid is ε-aminocaproic acid;
Put loteprednol etabonate in an aqueous suspension at 0.
01 to 3 w / v% and 0.002 to 2 w /
v. The aqueous suspension according to (1), wherein the aqueous suspension further comprises a suspending agent, a nonionic surfactant and an isotonic agent. (7) In the aqueous suspension, 0.2 to 2 w / v% of a suspending agent, 0.05 to 1 w / v% of a nonionic surfactant, and 1 to 1 w / v% of an isotonic agent.
The aqueous suspension according to the above (6), comprising 6% w / v,
(8) the suspending agent is a water-soluble nonionic polymer,
The aqueous suspension according to (6), wherein the nonionic surfactant is a polyoxyalkylene monol or a polyol, and the tonicity agent is a polyhydric alcohol, (9) the aqueous suspension further comprising a preservative. The aqueous suspension according to 6), (10).
(11) loteprednol, wherein the aqueous suspension according to the above (9) comprises 0.0001 to 0.5 w / v% of a preservative;
The aqueous solution according to the above (6), comprising 0.1 to 5 mol of an amino acid, 0.01 to 20 mol of a suspending agent, and 0.05 to 1 mol of a nonionic surfactant per 1 mol of etabonate. A suspension, (12) an aqueous suspension according to the above (1), wherein loteprednol etabonate is a fine powder having a particle size of 0.1 to 30 μm, (13) a pH in the range of 4.5 to 7.0 The aqueous suspension according to the above (1), and (1)
4) The aqueous suspension according to the above (1), (6) or (9), which is an anti-inflammatory agent for ophthalmology or otolaryngology.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The particle size of LE suitable for preparation of the aqueous suspension of the present invention is usually 0.1 to 30 μm, preferably 1 to 20 μm, more preferably 2 to 10 μm. . This LE is produced aseptically and has a purity of 9%.
Those having 8% by weight or more are preferred. The concentration of LE in the aqueous suspension may be any concentration that is therapeutically effective for inflammation.
Usually 0.01 to 3 w / v%, preferably 0.05 to 2 w / v%
v%, more preferably 0.2 to 1 w / v%. In the aqueous suspension of the present invention, an aliphatic amino acid having 2 to 7, preferably 3 to 5 carbon atoms is incorporated as a buffer without counting the carbon atoms of the carboxyl group. The number of amino groups in this amino acid is preferably one or two,
One is more preferred. 1 or 2 carboxyl groups
Are preferred. Specific examples of the amino acid include neutral amino acids such as alanine, β-aminopropionic acid, γ-aminobutyric acid, and ε-aminocaproic acid, and acidic amino acids such as aspartic acid and glutamic acid. Acids and glutamic acid are preferred. It is considered that the addition of these amino acids to the aqueous suspension prevents the pH of the suspension from lowering, thereby suppressing irritation to the eyes and nasal mucosa. The concentration of this amino acid in an aqueous suspension is usually 0.002-2.0 w.
/ V%, preferably 0.01 to 0.5 w / v%, more preferably 0.04 to 0.2 w / v%.

[0006] In order to prepare the stable aqueous suspension of the present invention, a suspending agent, a nonionic surfactant, an isotonic agent, and if necessary, a preservative and other additives are added. The suspending agent is not particularly limited as long as it is a water-soluble polymer. For example, polyvinylpyrrolidone (PVP),
Polyvinyl alcohol (PVA), sodium carboxymethylcellulose (CMC · Na), dextrin,
Examples thereof include cyclodextrin, and a nonionic polymer such as PVP is preferable. The mixing ratio of this suspending agent in the aqueous suspension is usually 0.2 to 2 w / v%, preferably 0.2%.
4-1 w / v%. The nonionic surfactant, together with the suspending agent, has a function of maintaining a good suspension state of the main drug loteprednol etabonate over a long period of time. As the nonionic surfactant, for example, a polyoxyalkylene monomer obtained by addition-polymerizing one or more alkylene oxides such as ethylene oxide and propylene oxide to an organic compound having one or more hydroxyl groups can be used. All or polyol,
Examples thereof include esters or mixtures thereof.
Specific examples of useful nonionic surfactants include, for example, polysorbate 80, tyloxapol, poloxamer, and the like. Of these, tyloxapol and polysorbate 80 are preferred. The mixing ratio of the nonionic surfactant in the aqueous suspension is usually 0.05 to 1 w / v%,
Preferably it is 0.1 to 0.6 w / v%.

As the tonicity agent, aliphatic polyhydric alcohols are preferable, and in particular, aliphatic polyhydric alcohols having 2 to 6 carbon atoms, such as glycerol and mannitol are preferable. The mixing ratio of the tonicity agent to the aqueous suspension is usually 1
-6 w / v%, preferably 1.5-4 w / v%.
Further, a preservative can be blended if necessary. Specific examples of preservatives include, for example, benzalkonium chloride,
And sodium edetate and mixtures thereof. The mixing ratio of the preservative to the aqueous suspension is usually 0.0.
001 to 0.5 w / v%, preferably 0.001 to 0.2
w / v%. The aqueous suspension of the present invention can be appropriately mixed with a therapeutically effective amount of a glaucoma therapeutic agent, a steroidal or non-steroidal anti-inflammatory agent, an antiallergic agent, an antibacterial substance, a vasoconstrictor, and the like. Examples of the therapeutic agent for glaucoma include betaxolol, atenolol, ribovanol, epinephrine, dipivefrin hydrochloride, pilocarpine hydrochloride, physostigmine salicylate, distigmine bromide, ecothiopart iodide, carteolol hydrochloride, metazolamide and the like. Steroidal anti-inflammatory agents include, for example, beclomethasone, dexamethasone, betamethasone, fluocinolone, fluorometholone and the like, and non-steroidal anti-inflammatory agents include, for example, piroxicam, indomethacin, naproxen, phenylbutazone, ibuprofen, sodium diclofenacate and the like. Can be Antiallergic agents include, for example, sodium cromoglycate, tranilast, ketotifen fumarate, diphenhydramine hydrochloride, and antimicrobial agents such as idoxuridine, erythromycin, sulfisoxazole, tobramycin, gentamicin, and the like as vasoconstrictors. Include naphazoline hydrochloride and the like.

The molar ratio of the specific amino acid, the suspending agent and the nonionic surfactant to LE in the aqueous suspension of the present invention is usually 1: 0.1: 0.01: 0.05 to 1: 5. :
20: 1. The viscosity of the aqueous suspension according to the invention is 100 c
Those which do not exceed p are preferred. The pH is usually 4.5 to 7.0, preferably 5.0 to 6.5. The aqueous suspension of the present invention is prepared according to a known aqueous suspension preparation method. For example, a suspending agent is dissolved in water, a surfactant, a buffer, an isotonic agent, a preservative, and other additives are sequentially added, and the mixture is sterilized by filtration or an autoclave. Then, pre-sterilized LE is added, and the mixture is stirred with a stirrer. By doing so, an LE aqueous suspension can be produced. The aqueous LE suspension prepared in this manner is used in the ophthalmic and otolaryngology fields.
E aqueous suspension can be used for prevention and treatment of various inflammations in eyes, ears, nose and throat. For example, the aqueous ophthalmic suspension of the present invention containing 0.5% w / v LE contains 0.05 to 0.1 ml 3 to 10 times daily for allergic conjunctivitis, trachoma and other inflammations in the eye. It is good to instill about.

[0009]

The present invention will be described more specifically with reference to examples and test examples, but the present invention is not limited to these examples. Example 1 An eye drop A having the formulation shown in the following [Table 1] was prepared according to a conventional method for preparing eye drops.

[Table 1]

Stability test The ophthalmic solution A obtained in Example 1 and the ophthalmic solution B prepared by removing the ε-aminocaproic acid from the formulation of Example 1 were each filled in a colorless polypropylene container, and were charged at 40 ° C., 75 ° C.
After storage at 6% RH for 6 months, properties, pH and average particle size of loteprednol etabonate were measured. The results are listed in [Table 2]. Eye irritation test [Method] Eye drops A stored at 40 ° C. and 75% RH for 6 months
And B were instilled once in 0.05 to 0.1 ml test subjects, and an irritation test was performed. [Results] The results of the irritation test are shown in [Table 2].

[0011]

[Table 2] In eye drops in which ε-aminocaproic acid is prescribed, 4
Even after storage at 0 ° C. and 75% RH for 6 months, it was found that there was no eye irritation and safe use.

[0012]

According to the present invention, the aqueous suspension of loteprednol etabonate containing an aliphatic amino acid having 2 to 7 carbon atoms can be easily adjusted in pH at the time of production.
Since it is stable and does not lower the pH even when stored for a long period of more than one month, there is no irritation to the eyes and nasal mucosa at the time of eye drops or nasal drops, and it can be safely administered as eye drops or nasal drops.

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁷ identification symbol FI A61P 27/12 A61P 27/12 29/00 29/00 (58) Field surveyed (Int.Cl. ⁷ , DB name) A61K 31 / 56 A61K 9/107 A61K 47/18 A61P 27/02 A61P 27/06 A61P 27/12 A61P 29/00 CAPLUS (STN) MEDLINE (STN) REGISTRY (STN) BIOSIS (STN) EMBASE (STN)

Claims (14)

(57) [Claims] An aqueous suspension of loteprednol etabonate comprising loteprednol etabonate and an aliphatic amino acid having 2 to 7 carbon atoms. 2. The amino acid having one or two amino groups and one or two carboxyl groups.
Aqueous suspension as described. 3. The aqueous suspension according to claim 2, wherein the amino acid is a neutral or acidic amino acid. 4. The aqueous suspension according to claim 3, wherein the amino acid is ε-aminocaproic acid. 5. An aqueous suspension containing 0.01 to 3% w / v of loteprednol etabonate and 0.00% amino acid.
2. The aqueous suspension according to claim 1, comprising 2 to 2% w / v. 6. The aqueous suspension according to claim 1, further comprising a suspending agent, a nonionic surfactant and an isotonic agent. 7. The aqueous suspension contains 0.2 to 2 w / suspension agent.
The aqueous suspension according to claim 6, comprising 0.5% to 1% w / v of a nonionic surfactant and 1% to 6% w / v of a tonicity agent. 8. The suspending agent is a water-soluble nonionic polymer, the nonionic surfactant is a polyoxyalkylene monool or a polyol, and the isotonic agent is a polyhydric alcohol. The aqueous suspension according to claim 6. 9. The aqueous suspension according to claim 6, further comprising a preservative. 10. The aqueous suspension according to claim 9, which comprises 0.0001 to 0.5 w / v% of a preservative. 11. A mole of loteprednol etabonate is used in an amount of 0.1 to 5 moles of an amino acid and 0.0 mole of a suspending agent.
The aqueous suspension according to claim 6, comprising 1 to 20 mol, and 0.05 to 1 mol of the nonionic surfactant. 12. The aqueous suspension according to claim 1, wherein loteprednol etabonate is a fine powder having a particle size of 0.1 to 30 μm. 13. The aqueous suspension according to claim 1, wherein the pH is in the range of 4.5 to 7.0. 14. The aqueous suspension according to claim 1, 6 or 9, which is an anti-inflammatory agent for ophthalmology or otolaryngology.