Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-10-18
2001-05-08
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S315000, C530S317000, C530S328000, C930S260000, C424S422000, C514S808000, C514S807000, C514S016700
Reexamination Certificate
active
06228836
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a composition containing a compound represented by the following formula:
Pmp: &bgr;,&bgr;-(3-thiapentamethylene)-p-mercaptopropionic acid
D-Trp: D-tryptophan
Pen: L-penicillamine
Ile: L-isoleucine
Asn: L-asparagine
Arg: L-arginine
Gln: L-glutamine
Pro: L-proline
(hereunder referred to as “Antago-3”) or a physiologically acceptable salt thereof, and more specifically it relates to a permucosal preparation containing as an effective component Antago-3 or a physiologically acceptable salt thereof.
BACKGROUND ART
Antago-3 is a synthetic peptide with a molecular weight of 1172.47, which is an oxytocin analog with a powerful and specific oxytocin antagonism effect (WO94/25485-A).
Physiologically active peptides readily undergo enzymolysis by peroral or permucosal administration, while they are virtually unabsorbed by percutaneous administration due to their low membrane permeability, and hence they are generally administered in the form of injections.
For permucosal administration of physiologically active peptides, expression of their drug effects has required a method whereby an enzyme inhibitor or protective substance is added to protect the drugs from enzymes, or a method whereby an absorption enhancer is added to promote absorption of the drugs before their degradation.
As permucosal preparations of physiologically active peptides there are known preparations containing cyclodextrin (Japanese Patent Publication No. 19092 of 1990), preparations containing bile acid (Japanese Patent Publication No. 25068 of 1994, Japanese Laid-open Patent Publications No. 2932 of 1988 and No. 194260 of 1993), preparations containing surfactants (Japanese Laid-open Patent Publications No. 130820 of 1984 and No. 185030 of 1987), preparations containing absorption accelerators (Japanese Laid-open Patent Publications No. 267528 of 1986 and No. 196524 of 1988), preparations containing sucrose fatty acid esters (Japanese Laid-open Patent Publications No. 39822 of 1988, No. 214 of 1990 and No. 101020 of 1990), preparations containing saccharides (Japanese Laid-open Patent Publication No. 502920 of 1991) and preparations containing ethylenediamine tetraacetate (Japanese Laid-open Patent Publication No. 306921 of 1990), but no permucosal preparation is known that contains Antago-3 or a physiologically acceptable salt thereof as an effective component.
DISCLOSURE OF INVENTION
When an aqueous solution (10 &mgr;g/kg) of Antago-3 acetate (hereunder referred to simply as “Antago-3”) was intravenously administered to rats, the response rate on uterine motility was 30% after 30 minutes, and the response rate was 5% after one hour.
However, with pernasal administration of the Antago-3 aqueous solution, it was not possible to express a similar drug effect with intravenous administration even at a dose of 400 &mgr;g/kg.
When polyoxyethylene polyoxypropylene ether, lecithin, sodium caprylate, sodium caprate, aprotinin or bacitracin, sodium ethylenediamine tetraacetate, sodium deoxycholate, &bgr;-cyclodextrin, sodium salicylate or disodium glycyrrhizinate was added to the Antago-3 aqueous solution as an absorption enhancer, it was not possible to express the drug effect obtained by intravenous administration with any of these other than sodium deoxycholate. Incidentally, sodium deoxycholate was shown to have an irritating effect on the nasal cavity mucosa.
The absorption enhancing effect of adding polysorbate 80, polyoxyethylene sorbitan monolaureate, taurine or N,N-dimethylacetamide (hereunder, “DMA”) to the Antago-3 aqueous solution was evaluated based on the Antago-3 blood concentration and blood concentration area under the curve (hereunder, “AUC”), but no absorption enhancing effect was exhibited by any of the compounds.
For permucosal administration of an absorption enhancer-added Antago-3 liquid preparation, it is necessary that the presence of the additive cause no non-uniformity such as clouding or precipitation, or irritation at the site of administration.
The present inventors have conducted diligent research on permucosal preparations containing Antago-3 as the effective component, and as a result we have found that when a composition containing Antago-3 and a sucrose fatty acid ester (hereunder referred to a “composition of the invention”) is administered, the Antago-3 is very efficiently absorbed through the nasal mucosa and rectal mucosa, thus allowing expression of a drug effect.
However, it was not easy to maintain a transparent state for an aqueous preparation containing the composition of the invention, due to clouding or precipitation of the sucrose fatty acid ester.
Upon conducting diligent research on Antago-3-containing aqueous preparations that maintain transparency, the present inventors then found, surprisingly, that the preservative benzalkonium chloride (hereunder, “BZCL”) has a preventive a effect against clouding and precipitation of the sucrose fatty acid ester while also causing virtually no mucosal irritation so that it is highly safe for the body, and the present invention has thus been completed.
The composition for permucosal administration provided by the invention comprises a sucrose fatty acid ester in a proportion of 0.25-50 parts by weight to one part by weight of Antago-3. The fatty acid of the sucrose fatty acid ester may be stearic acid, palmitic acid, myristic acid, lauric acid, etc., and esters, diesters and triesters of these fatty acids, or mixtures thereof, may be used.
The preparation form may be a solution preparation or other type of liquid preparation, or a powder preparation.
BZCL may be used as a preservative that can be added to the aqueous preparation as a solution preparation, and it is combined at 0.03-0.5 part by weight, and preferably 0.04-0.16 part by weight of BZCL to one part by weight of the sucrose fattyacidester. Asisotonizingagentstheremaybementioned polyols such as glycerin and propylene glycol, saccharides such as mannitol, and nicotinamide, and as viscosity agents there may be mentioned hydroxypropylcellulose (hereunder, “HPC”), polyvinylpyrrolidone (hereunder, “PVP”), carboxymethylcellulose sodium (hereunder, “CMC-Na”) and polyvinyl alcohol (hereunder, “PVA”).
A powder preparation may be administered by a method whereby a mixture of the composition of the invention with lactose, sucrose, mannitol, sorbitol, crystalline cellulose, starch or a low-substituted HPC is sprayed by air power, or a method of spraying with an appropriate volatile carrier.
After adding the preservative, viscosity agent, surfactant, etc. to the composition of the invention, it may be filled into a container and used as a rectal preparation or vaginal preparation. As preservatives there may be mentioned p-hydroxybenzoic acid ester, BZCL, chlorobutanol and sodium dehydroacetate, as viscosity agents, HPC, PVP, CMC-Na, PVA and carboxyvinyl polymer, and as surfactants, hydrogenated castor oil and macrogol.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention will now be described by way of production examples. These examples, however, are not intended to be restrictive on the invention.
REFERENCES:
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Hashimoto Mitsuo
Nakanishi Seiki
Yazaki Takashi
Low Christopher S. F.
Mitsubishi-Tokyo Pharmaceuticals, Inc.
Nixon & Vanderhye
Robinson Patricia
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