JP4453987B2 - Nasal aqueous suspension - Google Patents

Description

調製法
精製水９０ｇ、ロテプレドノール・エタボネート０.５ｇ、濃グリセリン２.６ｇ、１％塩化ベンザルコニウム液０.５ｍｌ、ポリソルベート８０ ０.２ｇを秤取し、ホモミキサー（６０００ｒｐｍ）で３０分間撹拌した。この液に結晶セルロース・カルメロースナトリウム（アビセル ＲＣ−Ａ５９１ＮＦ、旭化成工業（株）製）２.０ｇを加え、撹拌機（７５０ｒｐｍ）で６０分間撹拌した。得られた液にクエン酸の適量と精製水を加えてｐＨ５.５に調整し、さらに１０分間撹拌して水性懸濁液（ａ）１００ｇを得た。
得られた水性懸濁液を、ＢＬ型粘度計（回転数：３０回転、アダプターＮｏ.３、株式会社トキメック製）で粘度を測定したところ、その粘度は１,１６０センチポアズであった。
【００１０】
実施例２
処方

実施例１と同様の調製法により点鼻用水性懸濁液（ｂ）１００ｇを得た。
本点鼻用水性懸濁液の粘度は、１,３８０センチポアズであった。
【００１１】
実施例３
処方

実施例１と同様の調製法により点鼻用水性懸濁液（ｃ）１００ｇを得た。
本点鼻用水性懸濁液の粘度は、１,４４０センチポアズであった。
【００１２】
実施例４
処方

実施例１と同様の調製法により点鼻用水性懸濁液（ｄ）１００ｇを得た。
本点鼻用水性懸濁液の粘度は、１,３４０センチポアズであった。
【００１３】
実験例１
使用感テスト
実施例１〜４で調製された水性懸濁液（ａ）〜（ｄ）と、さらに（ａ）において結晶セルロース・カルメロースナトリウムを配合しない水性懸濁液（ｅ）（ｐＨ５.５）を調製して供試薬剤とした。
（ａ）〜（ｅ）のそれぞれの水性懸濁剤を８ｍｌのスプレー式点鼻容器に充填し、各５名のパネラーに水性懸濁液７０μｌを鼻腔内に噴霧して、使用感テストを実施した。その結果を〔表１〕に示す。
【表１】

【００１４】
実験例２
懸濁安定性テスト
前記のとおり調製された水性懸濁液（ａ）〜（ｅ）を点鼻用ポリエチレン容器（８ｍｌ）に入れ調製直後と、調製後７日および３か月間２５℃で保存した時点における液の懸濁状態を観察した。結果を〔表２〕に示す。
【表２】

【００１５】
【発明の効果】
本発明の点鼻用水性懸濁液は長期に亙って安定で主薬ロテプレドノール・エタボネート微粉末の凝集・沈降、器壁への付着が起こらない。また、鼻粘膜に噴射した場合液の粘膜表面での貯留性がよく、液の垂れ下がりがない。さらに粘膜への刺激性もなく使用感がきわめてよい。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a stable aqueous nasal suspension of loteprednol etabonate having anti-inflammatory and anti-allergic effects.
[0002]
[Prior art]
Loteprednol etabonate is a kind of synthetic corticosteroid and has excellent anti-inflammatory and anti-allergic effects, and it is expected to be applied to external preparations such as ointments and liquids because of its low skin irritation and side effects. Yes.
[0003]
[Problems to be solved by the invention]
However, since this loteprednol etabonate is hardly soluble in water, it must be in the form of a suspension in order to be used as a topical solution. Conventionally, methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (CMC-Na) and polyvinylpyrrolidone (PVP) are frequently used as suspensions and stabilizers of this kind of poorly water-soluble drugs. Roteprednol etabonate does not have a sufficient suspension stabilizing effect with the usual amounts of MC, HPMC, CMC-Na and PVP. Therefore, if the suspension is allowed to stand for more than 3 months, the particles of loteprednol etabonate aggregate and settle and adhere to the bottom and wall of the vessel. Will not return. In such a case, as a matter of course, the concentration of the main component in the chemical solution changes from that immediately after the production. In addition, when the formulation becomes a nasal drop, the drug solution is usually stored in a spray-type nasal drop container, but a certain amount designed by aggregation and adhesion of fine particles on the nozzle part of the metering pump. May not be sprayed or the nozzle may become clogged.
Therefore, the problem of how to maintain an aqueous suspension of loteprednol etabonate over a long period of time has been brought up. From this viewpoint, WO95 / 11669 is disclosed as a stable aqueous suspension of loteprednol etabonate. However, since the viscosity of this aqueous suspension does not exceed 80 centipoise, when the aqueous suspension is dropped, the aqueous suspension drops out from the nostril. For this reason, even if this aqueous suspension is nasally sprayed, there are disadvantages that the retention in the nasal cavity is low, it is difficult to obtain a sufficient medicinal effect, and the usability is uncomfortable.
[0004]
[Means for Solving the Problems]
The present inventors include celluloses such as methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, synthetic polymer compounds such as polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, thickeners such as saccharides such as sorbitol, mannitol, sucrose, An aqueous suspension of loteprednol / ethabonate with cationic surfactants such as various quaternary ammonium salts, anionic surfactants such as various alkyl sulfates, nonionic surfactants such as polysorbate 80, polyoxyethylene hydrogenated castor oil, etc. We conducted extensive studies on the stabilization of the fluid and the improvement of nasal retention and usability. As a result, it has been found that crystalline cellulose / carmellose sodium not only has an excellent suspension stabilizing effect on the main drug, but also has less skin irritation, excellent usability, and enhances the mucosal retention of the main drug. Further studies have been made to complete the present invention. That is, the present invention comprises (1) loteprednol etabonate (a), crystalline cellulose carmellose sodium (b), glycerin or propylene glycol (c) and polysorbate 80 or polyoxyethylene hydrogenated castor oil (d) , 0.5 nasal aqueous suspension point viscosity of Ru 400 to 3000 centipoise der, (2) loteprednol etabonate and (a) 0.05~3w / w% and crystalline cellulose carmellose sodium (b) The aqueous nasal suspension according to the above (1) containing 10 w / w%, and (3) 0.1 to 1.5 w / w% of loteprednol etabonate (a) and crystalline cellulose carmellose sodium (b ) Containing 1 to 5 w / w% of an aqueous nasal suspension according to the above (1).
[0005]
DETAILED DESCRIPTION OF THE INVENTION
The concentration of loteprednol etabonate used in the present invention in the aqueous nasal suspension is preferably 0.05 to 3 w / w%, more preferably 0.1 to 1.5 w / w%.
On the other hand, crystalline cellulose / carmellose sodium is usually a mixture having a crystalline cellulose content of 80% by weight or more and carmellose sodium in an amount of 9 to 13% by weight, and the concentration in the aqueous suspension varies depending on other additives. However, it is preferably 0.5 to 10 w / w%, more preferably 1 to 5 w / w%.
In addition to loteprednol etabonate, the aqueous nasal suspension of the present invention contains, if necessary, non-steroidal anti-inflammatory agents such as mefenamic acid, for example, antihistamines such as clemastine fumarate, terfenadine, chlorpheniramine maleate, diphenhydramine hydrochloride, etc. Anti-allergic agents such as tranilast, sodium cromoglycate, ketotifen fumarate, etc., antibiotics such as erythromycin, tetracycline, etc., antibacterial agents such as sulfamethizole, sulfamethoxazole, sulfisoxazole, etc. Or 2 or more types can be mix | blended suitably.
[0006]
Moreover, you may add appropriate amounts, such as a vasoconstrictor and a surface anesthetic, to the aqueous nasal suspension of the present invention. Examples of the vasoconstrictor include naphazoline nitrate and phenylephrine hydrochloride. Examples of the surface anesthetic include lidocaine, lidocaine hydrochloride, mepivacaine hydrochloride and the like. These pharmacologically active substances are usually blended in an amount of 0.01 to 10 w / w%, preferably 0.05 to 5 w / w%.
The aqueous nasal suspension of the present invention may contain additives commonly used for known nasal drops. Examples of such additives include preservatives, isotonic agents, buffers, stabilizers, pH adjusters, suspending aids, and the like. Preservatives include parabens (methyl paraoxybenzoate, propyl paraoxybenzoate, etc.), reverse soaps (benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, cetylpyridinium chloride, etc.), alcohol derivatives (chlorobutanol, Phenethyl alcohol, etc.), organic acids (dehydroacetic acid, sorbic acid, etc.), phenols (parachloromethoxyphenol, parachlorometacresol, etc.) and organic mercury agents (thimerosal, phenylmercuric nitrate, nitromesol, etc.).
[0007]
Examples of the isotonic agent include glycerin, propylene glycol, sorbitol, mannitol and the like. Examples of the buffer include boric acid, phosphoric acid, acetic acid and amino acids. Examples of the stabilizer include antioxidants (dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), propyl gallate, etc.) and chelating agents (edetic acid, citric acid, etc.). Examples of the pH adjuster include hydrochloric acid, acetic acid, sodium hydroxide, phosphoric acid, citric acid and the like. Surfactant as a suspending aid (polysorbate 80, polyoxyethylene hydrogenated castor oil, nonionic surfactant such as tyloxapol, cationic surfactant such as quaternary ammonium salt, anionic interface such as alkyl sulfate, etc. An active agent and a zwitterionic surfactant such as lecithin) may be used.
The amount of these additives used varies depending on the active ingredient and the amount used, but it is usually desirable to approximate the physiological state of the nose (isotonic with nasal discharge). For example, the osmotic pressure is 0.2 to 4 w / w%. Is a range corresponding to a salt solution of 0.5 to 2 w / w%, more preferably a range corresponding to a salt solution of 0.9 to 1.5 w / w%.
[0008]
The aqueous nasal suspension of the present invention is advantageously adjusted to be used within the pH range usually used for nasal drops, and is preferably adjusted to pH 5-7.
The aqueous nasal suspension of the present invention is advantageously prepared and used within the osmotic pressure range normally used for nasal drops, and is usually 140 to 1140 mOsm, preferably 200 to 870 mOsm, more preferably 280. It is used by adjusting to ˜310 mOsm.
The aqueous nasal suspension of the present invention is advantageously prepared and used within a viscosity range that is sufficiently retained in the nasal cavity and does not flow out from the nostril after nasal drop, and is usually 400 to 3,000 centipoise. , Preferably 1,000 to 1,600 centipoise, more preferably 1,200 to 1,450 centipoise.
The aqueous nasal suspension of the present invention can be produced according to a method known per se. For example, it is manufactured by the method described in the 9th revised dispensing guidelines (edited by the Japanese Pharmacists Association, pages 128-129, published by Yakuji Nippo).
The aqueous nasal suspension of the present invention can be used according to a method generally used for known nasal drops, and can be performed, for example, by a spraying method or a dropping method. In the case of the spraying method, for example, depending on age, weight, symptoms, etc., the aqueous nasal suspension of the present invention is used once daily to treat allergic rhinitis and vasomotor rhinitis in adults. It is better to inhale by inhalation using a nebulizer into the nasal cavity once or twice, once or twice. In the case of the dropping method, for example, depending on age, weight, symptoms, etc., the aqueous nasal suspension of the present invention is used for the treatment of allergic rhinitis in adults, and the concentration of loteprednol etabonate is set. 0.05 to 3.0 w / w%, preferably 0.1 to 1.5 w / w%, and this is kept in a standing or sitting position once or twice a day, 2-3 drops at a time. Bend the neck backwards and drop from the nostril.
[0009]
【Example】
The present invention will be described in more detail below with reference to examples and test examples, and the effects of the present invention will be clarified. However, these are merely examples, and the scope of the present invention is not limited thereby. .
Example 1
Prescription

Preparation Method 90 g of purified water, 0.5 g of loteprednol etabonate, 2.6 g of concentrated glycerin, 0.5 ml of 1% benzalkonium chloride solution and 0.2 g of polysorbate 80 were weighed and stirred for 30 minutes with a homomixer (6000 rpm). . To this liquid, 2.0 g of crystalline cellulose / carmellose sodium (Avicel RC-A591NF, manufactured by Asahi Kasei Kogyo Co., Ltd.) was added and stirred for 60 minutes with a stirrer (750 rpm). An appropriate amount of citric acid and purified water were added to the resulting liquid to adjust the pH to 5.5, and the mixture was further stirred for 10 minutes to obtain 100 g of an aqueous suspension (a).
When the viscosity of the obtained aqueous suspension was measured with a BL type viscometer (rotation number: 30 rotations, adapter No. 3, manufactured by Tokimec Co., Ltd.), the viscosity was 1,160 centipoise.
[0010]
Example 2
Prescription

100 g of an aqueous nasal suspension (b) was obtained by the same preparation method as in Example 1.
The viscosity of the aqueous nasal suspension was 1,380 centipoise.
[0011]
Example 3
Prescription

100 g of an aqueous nasal suspension (c) was obtained by the same preparation method as in Example 1.
The viscosity of the aqueous nasal suspension was 1,440 centipoise.
[0012]
Example 4
Prescription

100 g of an aqueous nasal suspension (d) was obtained by the same preparation method as in Example 1.
The viscosity of the aqueous nasal suspension was 1,340 centipoise.
[0013]
Experimental example 1
Usability Tests Aqueous suspensions (a) to (d) prepared in Examples 1 to 4 and an aqueous suspension (e) (pH 5.5) containing no crystalline cellulose / carmellose sodium in (a). ) Was prepared as a reagent reagent.
Each of the aqueous suspensions (a) to (e) was filled into an 8 ml spray nasal container, and 70 μl of the aqueous suspension was sprayed into the nasal cavity of each of the five panelists to conduct a usability test. did. The results are shown in [Table 1].
[Table 1]

[0014]
Experimental example 2
Suspension stability test The aqueous suspensions (a) to (e) prepared as described above were placed in a nasal polyethylene container (8 ml) and stored at 25 ° C. immediately after preparation and 7 days and 3 months after preparation. The suspension state of the liquid at the time point was observed. The results are shown in [Table 2].
[Table 2]

[0015]
【The invention's effect】
The aqueous nasal suspension of the present invention is stable over a long period of time, and does not cause aggregation / sedimentation of the main drug loteprednol / ethabonate fine powder and adhesion to the vessel wall. In addition, when sprayed on the nasal mucosa, the liquid retains well on the mucosal surface and does not sag. Furthermore, there is no irritation to the mucous membrane and the feeling of use is very good.

Claims (3)

Loteprednol etabonate (a), crystalline cellulose carmellose sodium (b), it contains glycerin or propylene glycol (c) and polysorbate 80 or polyoxyethylene hydrogenated castor oil (d), viscosity of Ru 400 to 3000 centipoise der Nasal aqueous suspension. The aqueous nasal suspension according to claim 1, comprising 0.05 to 3 w / w% of loteprednol etabonate (a) and 0.5 to 10 w / w% of crystalline cellulose carmellose sodium (b) . Loteprednol etabonate (a) a 0.1~1.5w / w% and nasal aqueous suspension point according to claim 1, wherein the crystalline cellulose carmellose sodium that the (b) containing 1~5w / w%.