Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-06-12
2001-03-06
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06197829
ABSTRACT:
TECHNICAL FIELD
This invention relates to an external preparation for topical administration, in more detail to an external preparation for topical administration which contains as the active ingredient 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol or pharmaceutically acceptable acid-addition salts thereof.
1. Background Art
WO94/08943 discloses 2-aminopropane-1,3-diol compounds which are useful as immunosuppressive agents. Among those compounds, 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol hydrochloride (hereunder sometimes referred to as Compound (I)) is under research and development for the transplantation of organs and autoimmune diseases. In order to inhibit rejection reaction at organs or bone marrow and treat autoimmune diseases and allergic diseases, drugs are usually applied topically to the affected parts in addition to the oral administration. Then, it has been desirable to develop the pharmaceutical preparations of Compound (I) which can be administered through the skin, eye, lung, bronchus, nose or rectum.
2. Disclosure of the Invention
From the point of view as above, the present inventors have made intensive investigations for the development of a pharmaceutical preparation of Compound (I) which can be administered through the skin, eye, lung, bronchus, nose or rectum, and have succeeded in formulating such pharmaceutical preparation and thereby completed the present invention.
Namely, the present invention relates to an external preparation for topical administration which contains as the active ingredient 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol or pharmaceutically acceptable acid-addition salts thereof (hereunder sometimes referred to as the compound of the present invention).
The compound of the present invention may be prepared in accordance with the methods described in WO94/08943.
The pharmaceutically acceptable acid-addition salts are inclusive of a salt with an inorganic acid such as hydrochloride, hydrobromide or sulfate, or a salt with an organic acid such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate or benzenesulfonate, preferably hydrochloride. The present invention embraces the hydrate or solvate of the compound of the present invention.
The external preparation for topical administration which is applicable to the compound of the present invention includes an ointment, a paste, a liniment, a lotion, a plaster, a cataplasm, an eye drop, an eye ointment, a suppository, a fomentation, an inhalant, a spray, an aerosol, a paint, a nasal drop, a cream, a tape, a patch and the like.
The external preparation for topical administration of the present invention contains the compound of the present invention in a form of a mixture with an organic or inorganic carrier or excipient, and, for example, can be used in a form a solid, semi-solid or solution pharmaceutical preparation.
The compound of the present invention can be mixed with, for example, a non-toxic and pharmaceutically acceptable carrier which is usually employed for obtaining an external preparation for topical administration.
A carrier which can be used includes water, glucose, lactose, arabic gum, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloid silica, potato starch, urea and other carriers which are suitable for preparing a solid, semi-solid or solution composition. Further, an adjuvant, a stabilizer, a thickener, a coloring matter or a flavoring agent can be added.
The compound of the present invention as an active ingredient of the external preparation for topical administration of the present invention can be contained in an amount enough to exhibit the desired activity depending on the symptom or severity of the diseases. In the case of the treatment of the symptom and diseases induced from immune disorder as mentioned below, the compound of the present invention can be administered by way of a topical administration, an aerosol or a rectal administration in a form of a dosage unit composition which contains pharmaceutically acceptable and non-toxic carrier, adjuvant and excipient. In the treatment of reversible obstructive airways disease, the compound of the present invention is preferably administered to lung by an aerosol in a form of, particularly a powder or a solution.
The amount of the compound of the present invention which can be mixed with a carrier can vary depending on the host to be treated and a specified dosage form. The specified dose of the specified patient should be determined depending on the various factors such as age, body weight, the whole condition of health, sex, meal, time for administration, administration route, rate of excretion, combination of drug and the severity of the specified diseases under treatment.
The external preparation for topical administration containing the compound of the present invention will be explained in more detail as follows:
When the compound of the present invention is used in the form of an ointment, it is contained in an amount of 0.01 to 10 w/w % in the ointment.
The ointment base which can be used includes oleaginous base (a natural wax such as white beeswax or carnauba wax, a petroleum wax such as solid paraffin or microcrystalline wax, a hydrocarbon wax such as liquid paraffin, white soft paraffin or yellow petrolatum, plastibase, zelen 50W, silicone, a vegetable oil, pork tallow, beef tallow, a simple ointment or lead oleate plaster), an emulsion type ointment base (an O/W type base such as a hydrophilic ointment or a vanishing cream or a W/O type base such as a hydrophilic petrolatum, a purified lanolin, aquahole, eucelin, neocelin, an absorptive ointment, a hydrated lanolin, cold cream, a hydrophilic plastibase), a water-soluble base (a macrogol ointment or solbase) or a suspension type ointment base (a lyogel base, i.e. a hydrogel base such as a non-fat ointment, a gelbase or lotion; or an FAPG base (a suspension of a microparticle of an aliphatic alcohol such as stearyl alcohol or cetyl alcohol in propylene glycol), and these ointment base can be used alone or in a combination of not less than two bases.
Further, when to be used as an ointment, the compound of the present invention is dissolved in a solubilizing and absoptive accelerating agent and added to the above-mentioned ointment base.
The solubilizing and absoptive accelerating agent to be used means the agent in which the compound of the present invention is soluble at a concentration of at least not less than 0.01 w/w % and which can accelerate the absorption of the compound of the present invention from skin when formulated as an ointment, and includes a lower alkanediol (e.g. ethylene glycol, propylene glycol or butylene glycol), an alkylene carbonate (e.g. propylene carbonate or ethylene carbonate), an alkanedicarboxylic acid ester (e.g. dimethyl adipate, diethyl adipate, diisopropyl adipate, diethyl pimerate, diethyl sebacate or dipropyl sebacate), a higher alkanoic acid glycerin ester (e.g. monolaurin, dilaurin or trilaurin), a higher alkenoic acid glycerin ester (e.g. monoolein, diolein or triolein), a higher alkanoic acid alkyl ester (e.g. isopropyl myristate or ethyl myristate), a higher unsaturated alcohol (e.g. geraniol or oleyl alcohol) or an azacycloalkane (e.g. 1-dodecylazacycloheptan-2-one). These solubilizing and absoptive accelerating agent can be used alone or in a mixture of not less than two agents, and can be added at a sufficient amount to dissolve the compound of the present invention. The amount generally ranges from 2 parts by weight to 200 parts by weight per one part by weight of the compound of the present invention. The upper amount is limited not to deteriorate the physicochemical properties of the ointment.
The ointment which contains the compound of the present invention may contain, in addition to the above-mentioned ointment base, other additives such as an emulsifier (e.g. polyoxyethylene hardened caster oil, glycerol monostearate, sorbitan sesquioleate or lauromacrogol); a suspending agent (e.g. polyoxyethylene glycol, polyvinylpyrr
Fujii Tsuneo
Imayoshi Tomonori
Mishina Tadashi
Teshima Koji
Birch & Stewart Kolasch & Birch, LLP
Channavajjala Lakshmi
Page Thurman K.
Welfide Corporation
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