The present invention relates to a method for improving adsorption on the gastrointestinal mucous layers of one or more selected from polyethylene glycol, polyethylene oxide, and polyoxyethylene polypropylene copolymer wherein the average number of repeating oxyethylene units of one ethylene oxide chain length is 17 or greater. It is possible to enhance pharmacological effects by using the present invention with drugs that have anti-H. pylori activity.

FIELD OF THE INVENTION

The present invention relates to a method for improving adsorption of a drug on the gastrointestinal mucous layers characterized in administration of a specific ethylene oxide derivative as the active ingredient for improving adsorption of a drug. Specifically, it relates to a method for improving adsorption of a drug on the gastrointestinal mucous layers characterized in administration as the active ingredient for improving adsorption of a drug one or more selected from polyethylene glycol, polyethylene oxide, and polyoxyethylene polypropylene copolymer where the average number of repeating oxyethylene units of one ethylene oxide chain length is 17 or greater.

PRIOR ART

The existence of H. pylori was ascertained from the stomach tissues of gastritis patients and since that time, H. pylori has been shown to participate in the morbid state of stomach and duodenal disorders, including gastritis and peptic ulcer. There have been reports of the prevention of recurrence of ulcer associated with H. pylori, and the importance of the eradication of H. pylori is now recognized. It has further been suggested that there is a cause-effect correlation between the occurrence of stomach cancer and H. pylori infection, even in the absence of carcinogens ([non-patent reference 1]).

Triple eradication therapy with antibiotics (amoxicillin and clarithromycin) and a proton pump inhibitor (lansoprazole) is currently the H. pylori eradication method of first choice. This is because acid stability of the drug is poor with singular use or concomitant use of two antibiotics due to the fact that the active optimum pH of antibiotics is generally near neutrality, and because the highest eradication rate has thus far been obtained by concomitant use of three drugs. Nevertheless, the eradication rate when 750 mg amoxicillin, 400 mg clarithromycin, and 30 mg lansoprazole are administered twice/day for one week is only 85 to 90%. Furthermore, a novel H. pylori eradication therapy is needed because of problems including diarrhea, development of resistant bacteria, varied doses, and reduced compliance that is attributed to the complexity of long-term treatment.

The use of 2-(2-trans-nonenyl)-3-methyl-4(1H)-quinolone derivatives (hereafter 1-hydroxy-2-(2-trans-nonenyl)-3-methyl-4(1H)-quinolone is referred to as compound A) alone or in combination with other antibiotics, and the like, and a reduction in the number of live bacteria in vivo when this compound was used alone on H. pylori infected animal models (Mongolian gerbils) are recited in [patent reference 1]. Nevertheless, when the use of this compound alone is considered, further augmentation of anti-H. pylori activity is necessary and a drug delivery technology with which compound A is made to effectively act against H. pylori is needed to accomplish this purpose.

H. pylori lives in the gastric mucus and surface layer of the gastric mucous membrane epithelial cells and in the spaces in between ([non-patent reference 2]) and therefore, it is necessary to break through the barrier effect of the mucous layers by some type of means, such as promoting adsorption of the drug on the mucous layers or improving retention, so that the drug will act directly against the H. pylori.

On the other hand, the ethylene oxide derivatives that are used as a base for formulation, such as polyethylene glycol, polyethylene oxide, and polyoxyethylene polypropylene copolymer, are employed as solubilizing agents, plasticizers, dispersants, and stabilizers. Polyethylene glycol is used, for instance, as a stabilizer of polypeptides, a plasticizer of sucralfate-containing compositions, and a base for retention [of a drug] in the blood. For instance, polyethylene oxide is used as a base for controlling dissolution and polyoxyethylene polypropylene copolymer, for example, Pluronic, is used as a surfactant, solubilizer, emulsifier, dispersant, and the like.

As described above, various ethylene oxide derivatives are used as bases for formulation. However, no attempts have thus far been made in connection with technology for augmenting drug activity to use ethylene oxide derivatives in order to augment adsorption of a drug on the gastrointestinal mucous layers where H. pylori live in order to improve adsorption of a drug on the gastrointenstinal mucous layers, and in particular, in order to augment anti-H. pylori activity.

Consequently, the purpose of the present invention is to provide a method of improving adsorption of a drug on the gastrointestinal mucous layers from a specific ethylene oxide derivative.

[Patent reference] U.S. Pat. No. 6,184,230

[Non-patent reference 1] T. Watanabe et al., Gastroenterol., 115; 642 648 (1998)

[Non-patent reference 2] Y. Akiyama et al., Drug Delivery System, 15-3; 185 192 (2000)

DISCLOSURE OF THE INVENTION

As a result of performing intense studies under these circumstances, the inventors found that adsorption of a drug of compound A on the gastrointestinal mucous layers is high in the presence of an ethylene oxide derivative. As a result of further studies, the inventors successfully completed the present invention upon discovering that anti-H. pylori activity in particular is augmented when the average number of repeating oxyethylene units in the ethylene oxide derivatives is greater than 17.

That is, the present invention relates to

1. a method for improving adsorption of a drug on the gastrointestinal mucous layers, characterized in that one or more selected from polyethylene glycol, polyethylene oxide, and polyoxyethylene polypropylene copolymer where the average number of repeating oxyethylene units of one ethylene oxide chain length is 17 or greater is administered as the active ingredient for improving adsorption of a drug;

2. the method for improving adsorption of a drug on the gastrointestinal mucous layers according to above-mentioned 1, wherein the drug is an antibiotic;

3. the method for improving adsorption of a drug on the gastrointestinal mucous layers according to above-mentioned 2, whereby the drug has anti-H. pylori activity;

4. a pharmaceutical composition for improving adsorption of a drug on the gastrointestinal mucous layers, which contains at least a drug and one or more selected from polyethylene glycol, polyethylene oxide, and polyoxyethylene polypropylene copolymer where the average number of repeating oxyethylene units of one ethylene oxide chain length is 17 or greater;

5. the pharmaceutical composition for improving adsorption of a drug on the gastrointestinal mucous layers according to above-mentioned 4, where the drug is an antibiotic;

6. the pharmaceutical composition according to above-mentioned 5, wherein the drug has anti-H. pylori activity;

7. the pharmaceutical composition according to above-mentioned 4, wherein the ratio of the components of the composition when the administration form is a liquid is 0.00005% to 50% of drug and 0.1% to 37.5% of ethylene oxide derivative per total composition and/or 0.1 mg to 1 g of drug and 2 mg to 1 g of ethylene oxide derivative; and

8. the pharmaceutical composition according to above-mentioned 4, wherein the ratio of the components of the composition when the administration form is a solid is 0.01% to 95% of drug and 5% to 99.99% of ethylene oxide derivative per total composition and/or 0.1 mg to 1 g of drug and 50 mg to 1 g of ethylene oxide derivative.

As cited in the present invention, "gastrointestinal mucus" means the adhesive secretion that is secreted from the gastrointestinal mucous membrane, for instance, the mucus at the stomach walls. "Gastrointestinal mucous layers" refers to the layers of the above-mentioned gastrointestinal mucus that are formed on the surface of the gastrointestinal epithelial cells. As also cited in the present invention, "adsorption of a drug on the gastrointestinal mucous layers" means in vitro adsorption of a drug on the gastrointestinal mucus components, reflecting in vivo adsorption of the drug. For instance, it is possible to bring a lipid (oil phase) that is a component of gastrointestinal mucus and a drug suspension (aqueous phase) into contact with one another and then evaluate adsorption by determining the rate of adsorption of the drug on the lipid (refer to W. L. Agneta et al., Pharm. Res., 15; 66 71 (1998) on mucous layer composition). It appears that when adsorption is improved, "retention" in the gastrointestinal mucous layer is also improved, and there are cases in the present invention where "retention" is synonymous with adsorption. It is assumed that the ability of a drug to move to the mucous layers also improves with improvement of adsorption of a drug on the mucous layers. For convenience, "improvement of adsorption on the mucous layers" means that, for instance, the rate of adsorption of a drug on the oil phase when ethylene oxide derivative has been added to the aqueous phase is significantly increased in comparison to when ethylene oxide derivative is not added.

As cited in the present invention, "ethylene oxide derivatives" are substances containing ethylene oxide chains in the molecules thereof, and examples are polyethylene glycol, polyethylene oxides, and polyoxyethylene polypropylene copolymer. Of these, polyethylene glycol 6000 (brand name Macrogol 6000, average relative molecular weight (hereafter average molecular weight) of 8000) or polyethylene glycol 20000 (brand name Macrogol 20000, average molecular weight of 20000), polyethylene oxides (average molecular weight of 900,000 or 7,000,000), and polyoxyethylene polypropylene copolymer (brand name, Pluronic F68, Asahi Denka) are examples.

Moreover, as cited in the present invention, the "average number of repeating oxyethylene units of one ethylene oxide chain length" means the number of repeating oxyethylene units per one ethylene oxide chain within a molecule as conveniently calculated. Specifically, this is found by calculating the value obtained by dividing the number of repeating oxyethylene units of all ethylene oxide chains contained in one molecule by the structural number of ethylene oxide chains. The "structural number of ethylene oxide chains" means the number of ethylene oxide chains anywhere in the structure. For example, "the average number of repeating oxyethylene units of one ethylene oxide chain length" can be calculated as follows:

It is clear from the schematic drawing in Table 4 that there is one ethylene oxide chain in the chemical structure of Macrogol 6000. Consequently, the total number of repeating oxyethylene units (n) of ethylene oxide chains per molecule shown in Table 3 itself becomes "the average number of repeating oxyethylene units of one ethylene oxide chain length (m)." That is, the "average number of repeating oxyethylene units of one ethylene oxide chain length" of Macrogol 400, Macrogol 4000, Macrogol 6000, and Macrogol 20,000 is 8, 72, 188, and 455, respectively. Moreover, Pluronic has two ethylene oxide chains in its structure (Table 4) and therefore, the value obtained by dividing the total number of repeating oxyethylene units of ethylene oxide chains per molecule (n, Table 3) by two is "the average number of repeating oxyethylene units of one ethylene oxide chain length." That is, the total number of repeating oxyethylene units of ethylene oxide chains molecules of L31, L44, L64, P103, P85, and F68 is 3, 20, 27, 29, 54, and 160, respectively; therefore, the "average number of repeating oxyethylene units of one ethylene oxide chain length" becomes 1.5, 10, 13.5, 14.5, 27, and 80, respectively.

Adsorption of a drug on the gastrointestinal mucous layers is improved when the "average number of repeating oxyethylene units of one ethylene oxide chain length" is 17 or greater, preferably 27 or greater.

By means of the present invention, adsorptivity of compound A and 2-(2-trans-nonenyl)-3-methyl-4(1H)quinolone derivatives on the gastrointestinal mucous layers is improved. Examples of these other drugs are pharmaceutically acceptable antibiotics, including nitroimidazole antibiotics, specifically tinidazole and metronidazole; tetracyclines, specifically tetracycline, minocycline, and doxycycline; penicillins, specifically amoxicillin, ampicillin, talampicillin, bacampicillin, lenampicillin, mezlocillin, and sultamicillin; cephalosporins, specifically cefaclor, cefadroxil, cephalexin, cefpodoxime proxetil, cefixime, cefdinir, ceftibuten, cefotiam hexetil, cefetamet pivoxil, and cefuroxime axetel; penems, specifically, faropenem and ritipenem acoxil; macrolides, specifically erythromycin, oleandomycin, josamycin, midecamycin, rokitamycin, clarithromycin, roxithromycin, and azithromycin; lincomycins (for instance, lincomycin and clindamycin); aminoglycosides, specifically, paromomycin; and quinolones, specifically ofloxacin, levofloxacin, norfloxacin, enoxacin, ciprofloxacin, lomefloxacin, tosufloxacin, fleroxacin, sparfloxacin, temafloxacin, nadifloxacin, grepafloxacin, and pazfloxacin, as well as nitrofurantoin, and the like. Other examples are pharmaceutical compounds that are used to treat disease associated with stomach acid secretion, and the like, such as acid pump inhibitors, specifically omeprazole and lansoprazole; and H2 antagonists, specifically, ranitidine, cimetidine, and famotidine. Further examples include drugs used to treat hyponatremia, specifically 4'-[2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl]carbonyl]- -2-phenylbenzanilide hydrochloride; and antigastrin drugs, specifically (R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiaze- pin-3-yl]-3-(3-methylphenyl)urea, pirenzepine hydrochloride, secretin, and proglumide. One of these drugs or a combination of two or more of these drugs can be used.

There are no special restrictions to the amount of drug used in the present invention as long as it is the amount that is effective in terms of treating disease.

It is difficult to unconditionally specify the ratio of each component when they are made into a composition. For instance, when the administration form is a liquid, such as a suspension, there is 0.00005% to 50%, preferably 0.00015% to 0.25%, particularly 0.0003% to 0.15%, of drug per entire composition. Moreover, there is 0.1% to 37.5%, preferably 0.1% to 25%, of ethylene oxide derivative per entire composition. When the administration form is a solid, such as a powder, it is possible to bring the amount of drug per entire composition to 0.01% to 95%, preferably 0.1% to 90%, of drug per entire composition, and to bring the amount of ethylene oxide derivative per entire composition to 5% to 99.99%, preferably 10% to 99.9%.

When the administration form is a liquid, it is possible to bring the amount of drug per entire composition to 0.00005% to 50%, preferably 0.0001% to 30%, and to bring the amount of ethylene oxide derivative per entire composition to 0.1% to 37.5%, preferably 1% to 25%.

There is a chance that sufficient adsorption of a drug will not be obtained if the ethylene oxide composition ratio is lower than that cited here.

With regard to the amount of each component that is used, when the administration form is a liquid, for instance, the amount of drug is brought to 1 mg to 1 g, preferably 0.5 mg to 750 mg, and the amount of ethylene oxide derivative is brought to 2 mg to 1 g, preferably 5 mg to 750 mg.

When the administration form is a solid, for instance, the amount of drug is brought to 0.1 mg to 1 g, preferably 0.5 mg to 750 mg, and the amount of ethylene oxide derivative is brought to 50 mg to 1 g, preferably 50 mg to 750 mg.

As with the composition ratio, there is a chance that sufficient adsorption of a drug will not be realized if the amount used is less than that cited here.

The ethylene oxide derivative of the present invention can be made into a pharmaceutical composition for oral use together with a drug and an appropriate filler and the like that are generally accepted pharmaceutically. There are no special restrictions to the form of the pharmaceutical preparation that this pharmaceutical composition for oral use can take, and a form that can be orally administered, including powders, tablets, capsules, liquids, suspensions, and emulsions, can be cited as an example. Formulation can be manufactured by a conventional production method.

Excipients, such as fillers, disintegrators, binders, lubricants, fluidizing agents, dispersants, suspending agents, emulsifiers, preservatives, and stabilizers, can be included in the "filler and the like that are generally accepted pharmaceutically" as cited in the present invention.

Examples of fillers are lactose, mannitol, potato starch, wheat starch, rice starch, corn starch, and crystalline cellulose; examples of disintegrators are sodium bicarbonate and sodium lauryl sulfate; examples of dispersants are crystalline cellulose, dextrin, and citric acid; examples of solubilizing agents are hydroxypropyl methylcellulose, polyoxyethylene-hydrogenated castor oil, cyclodextrins, and polysorbate 80; examples of inflating agents are carboxymethyl cellulose, carboxymethyl cellulose calcium, and croscarmellose sodium; and examples of surfactants are sodium lauryl sulfate and sucrose fatty acid ester. One or two or more can be mixed in appropriate amounts as needed.

The manufacturing method when these are made into a pharmaceutical composition for oral use involves, for instance, introducing Macrogol 6000 (polyethylene glycol 6000), drug (compound A), and filler and the like as needed to a pharmaceutically acceptable medium and thoroughly mixing these until they are dissolved or suspended. Ion-exchanged water, buffer solution or physiological saline, and the like can be selected as the pharmaceutically acceptable medium. Furthermore, this solution and/or suspension can be filled into capsules, such as gelatin capsules, to obtain a capsule form. The method whereby Macrogol 6000, compound A, and pharmaceutical filler and the like as needed are granulated by a conventional method, such as pulverizing, spray drying, freeze drying, wet granulation, or dry granulation, can be cited as a method of making a powder. Moreover, it is also possible to further add pharmaceutical filler and the like as appropriate and tablet the mixture to obtain the tablet form.

Claim 1 of 6 Claims

1. A method for improving adsorption of a drug on the gastrointestinal mucous layers, characterized in that one or more selected from polyethylene glycol, polyethylene oxide, and polyoxyethylene polypropylene copolymer where the average number of repeating oxyethylene units of one ethylene oxide chain length is 17 or greater is administered as the active ingredient for improving adsorption of a drug.

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