Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-04-03
2002-08-13
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S428000, C514S169000, C514S178000, C514S179000, C514S912000, C514S914000, C514S938000, C514S939000, C514S943000
Reexamination Certificate
active
06432439
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an O/W emulsion composition in which fluorometholone or clobetasone butyrate is highly soluble in body fluids such as blood and lachrymal fluid and having excellent property of keeping the solubility and concentration of fluorometholone or clobetasone butyrate contained in the composition.
BACKGROUND ART
Fluorometholone and clobetasone butyrate are synthetic adrenocortical hormones having a strong anti-inflammatory activity. Fluorometholone is effective in the treatment of the inflammatory diseases of outer ocular area and anterior segment of the eye, and clobetasone butyrate is effective in the treatment of the inflammatory diseases of eyes and also those of the skin. It is expected that these drugs are also effective in the treatment of the local and generalized inflammatory diseases other than those described above. However, because these drugs are hardly soluble in water, it is impossible to dispense these drugs in the form of ordinary aqueous preparations such as eye drops and parenteral injections. Therefore, in the ophthalmic field, fluorometholone and clobetasone butyrate have been each used in the form of an aqueous suspension which is prepared by finely pulverizing the crystals thereof and dispersing and suspending a suitable amount of the fine crystals in an aqueous liquid for eye drops. However, because these drugs are hardly soluble in water, the degree of dissolution of these drugs in the form of crystalline particles, contained in the aqueous suspension, into the lachrymal fluid is low and, accordingly, the bioavailability is extremely low.
It is known that the bioavailability of a hardly soluble drug generally depends on the solubility of the drug in water. For example, when such a hardly soluble drug is administered in the form of an oral solid preparation, the rate of release of the drug from the preparation thereof and dissolution of the drug are the rate-controlling step for the absorption of the drug (see
“Iyakuhin no Bioavailability to Seibutsugaku-teki Dotosei Shiken”
written by. Hiroyasu Ogata and Masayoshi Samejima and published by Yakugyo Jiho, inc.). In addition, when such a hardly soluble drug in the form of its suspension is applied to the eyes, transition of the drug into the eye tissue depends on the dissolution rate of the drug from the crystalline particles diluted with the lachrymal fluid [J. Pharm. Sci., 64 (6), 931-936 (1975)]. Namely, the bioavailability can be improved if the concentration of the administered, hardly soluble drug in the body fluids could be increased.
WO 97/05882 discloses that an O/W emulsion comprising fluorometholone or clobetasone butyrate as a drug, a phospholipid, a liquid paraffin and water improves the solubility of the drug in the lachrymal fluid to improve transfer of the drug into the eye tissue. However, this publication is silent on the influence of the additives on the nature of the composition to improve the solubility of fluorometholone or clobetasone butyrate in the lachrymal fluid, and also on the additives used for improving the solubility. This publication is also silent on the stability of the dissolution concentration of these drugs in the lachrymal fluid and of the concentration of these drugs in the composition during the storage. The inventors examined the storability of the emulsion preparations to find that both fluorometholone and clobetasone butyrate were crystallized during the storage and the ability of the composition to improve the solubility of these drugs in the lachrymal fluid were lowered.
As for the techniques of improving the stability of such a kind of emulsion, various emulsions comprising a water-soluble polymer were disclosed [see WO 93/15736, WO 96/40051, Japanese Patent Unexamined Published Application (hereinafter referred to as “J. P. KOKAI”) No. Sho 53-121920, J. Soc. Cosmet. Chem., 37, 329-350 (1986), J. SCCJ, 27 (3), 206-215 (1993), and Int. J. Pharm., 140 (1), 97-109 (1996)]. However, these prior techniques are silent on the solubility of the drug in the body fluids and also on the improvement in the stability of the concentration of the drug contained in the composition (hereinafter referred to as “drug concentration”). J. P. KOKAI No. Hei 5-186333 discloses that an ophthalmic O/W emulsion composition comprising a drug, an oil, a phospholipid and an amphoteric surfactant is capable of keeping the average particle diameter and the drug concentration thereof during the storage.
DISCLOSURE OF THE INVENTION
The present invention has been developed for the purposes of improving the solubility of the conventional, hardly water-soluble drug in the body fluid and the stability of the improved solubility of the drugs in the body fluids. The object of the present invention is to provide a novel composition containing fluorometholone or clobetasone butyrate highly soluble in body fluids such as blood and lachrymal fluid and having excellent property of keeping the solubility of these drugs into body fluids and concentration of fluorometholone or clobetasone butyrate contained in the composition. After intensive investigations made for the purpose of attaining the above-described object, the inventors have found that an O/W emulsion composition containing fluorometholone or clobetasone butyrate, a phospholipid, an oil, a nonionic water-soluble cellulose derivative and water shows a high solubility of fluorometholone or clobetasone butyrate in the body fluids and such a high solubility thereof and the concentration of fluorometholone or clobetasone butyrate contained in the composition can be kept stable during the storage. The inventors have further found that when at least one member of the group consisting of chelating agents, polycarboxylic acid compounds and pharmaceutically acceptable salts thereof is incorporated into the emulsion composition, the solubility of fluorometholone or clobetasone butyrate in the body fluids and the concentration of fluorometholone or clobetasone butyrate contained in the composition can be kept stable for a far longer period of time. The present invention has been completed on the basis of these findings.
Namely, the present invention provides an O/W emulsion composition containing fluorometholone or clobetasone butyrate, a phospholipid, an oil, a non-ionic water-soluble cellulose derivative and water and, if necessary, at least one member of the group consisting of chelating agents, polycarboxylic acid compounds and pharmaceutically acceptable salts thereof. The present invention is characterized in that the solubility of fluorometholone and clobetasone butyrate in the body fluids is improved by incorporating the nonionic water-soluble cellulose derivative as an indispensable component. Other characteristic features of the present invention are that the solubility of fluorometholone and clobetasone butyrate in the body fluids is high and that the concentration of fluorometholone and clobetasone butyrate in the composition can be kept stable during the storage. By suitably changing the proportion of the constituents and amounts thereof, the O/W emulsion composition having a particularly high solubility of fluorometholone or clobetasone butyrate in the body fluids can be obtained, and the solubility and the concentration of fluorometholone or clobetasone butyrate contained in the composition can be kept stable for a longer period of time in the present invention. The O/W emulsion composition containing fluorometholone or clobetasone butyrate can be given to the patients by the systemic administration method or topical administration method in a suitable preparation form such as liquids for internal use, injections, ear drops, nasal drops, eye drops, aerosols or inhalations depending on the need. The O/W emulsion composition is usable for the treatment of diseases such as chronic hypoadrenocorticism, acute chronic hypoadrenocorticism, chronic articular rheumatism, ankylosing spondylitis, lupus erythematodes, systemic angitis, polymyositis, nephrosis and nephrotic syndrome, congesti
Naito Yoshikazu
Saito Yoshiaki
Suzuki Hidekazu
Takeuchi Masanobu
Yamazaki Satoshi
Kishore Gollamudi S.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Wakamoto Pharmaceutical Co., Ltd.
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