JP3207212B2 - Absorption promoter and external preparation containing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a two-component absorption enhancer for promoting permeation or absorption of a drug through a transdermal or transmucosal membrane and an external preparation containing the absorption enhancer and a pharmaceutically active ingredient.

[0002]

2. Description of the Related Art Drug administration methods have conventionally been oral,
It is usually performed in injection, transrectal, transdermal, etc.,
Of these, oral and injection administration methods often require large doses in order to have sufficient drug efficacy, so that many side effects such as gastrointestinal tract disorders, anorexia, vomiting, and abdominal pain are observed. There were drawbacks.

Therefore, in recent years, transdermal and transmucosal drug absorption and treatment systems have been spotlighted, and research institutes and companies of universities around the world are actively conducting research and development. In particular, this treatment system maintains a sustained and constant effective blood concentration, avoids metabolic degradation by first pass through the intestinal tract and liver, easily regulates administration, can be administered near the target site, and controls the drug penetration rate through the skin. Attention has been paid to a method of administering a drug for the purpose of systemic action because of its advantages.

At present, drugs such as scopolamine, nitroglycerin, isosorbide dinitrate, clonidine, fentanyl, nicotine, estradiol, and nonsteroidal anti-inflammatory drugs (indomethacin, ketoprofen, flurbiprofen) are formulated as transdermal therapeutic agents. Have been.

However, the skin or each mucous membrane at the application site originally exists as a barrier to the outside world, and the permeation of each drug into the skin or mucous membrane is generally low. This has been a major barrier to the development of transdermal and transmucosal applications, so far only the aforementioned highly permeable drugs have been formulated.

[0006] Therefore, for a drug having low skin permeability, improvement of the skin permeability is an important point in developing a therapeutic system for transdermal and transmucosal. Therefore, studies on absorption enhancers have been actively conducted as one of the methods for improving this point. For example, dimethyl sulfoxide (DMSO), urea, pyrrolidone derivatives, Azone, medium-chain fatty acid esters, oleic acid, oils and fats such as lecithin, surfactants, terpenes such as d-limonene, cyclohexanone derivatives and many other absorptions Accelerators have been reported. Also, studies have been made on two-component absorption promoters and the like using these absorption promoters in combination, but they have not yet been put to practical use.

[0007] The present applicant also does not exhibit the following physical absorption enhancers, ie, does not exhibit pharmacological activity. The action is specific. The duration can be predicted immediately and the effect is reversible. Chemically ideally stable and compatible with all components in the formulation. Does not show odor, color or taste.
Not toxic, allergic or irritating. As a result of intensive research to find a substance satisfying such conditions, among the newly synthesized azacycloalkane derivative compounds, 1-
[2- (decylthio) ethyl] azacyclopentane-2
-On (hereinafter abbreviated as HPE-101) has been found to be an excellent absorption promoter (JP-A-62-238).
No. 261). In addition, cyclodextrins have been variously studied for the purpose of improving solubility or stability, increasing release, reducing toxicity, or promoting absorption. [Reference materials: Chem. Pharm. Bull 1989. 37 (4), 1059-63, Acta P
harm. Nord. 1989. 1 (4), 185-94, Pharm. Res. 1990.
7 (6), 612-615, J. Pharm.Sci. 1986.75 (6), 571-2
Int. J. Pharm. 1986. 29 (1), 73-82, DE-3,815,90.
No. 2, EP-332,346, EP-330,511, EP-332,346, DE-
3,843,059, US-4,889,634, US-4,877,778, JP-A-1-63,552, US-4,727,064, JP-A-63-218,663)
However, it cannot be said that the absorption promoting action for the purpose of promoting the absorption of cyclodextrins is still sufficiently satisfactory. At present, there is no report on the use of the above-mentioned absorption enhancer of HPE-101 in combination with cyclodextrins.

[0008]

However, these absorption enhancers have not been able to say that their absorption enhancing effect is still sufficient.
In many types of drugs, practical pharmacological effects cannot be obtained in many cases, and problems such as skin irritation due to the absorption enhancer itself remain, and a more versatile absorption enhancer is desired. This is the actual situation. Therefore, an object of the present invention is to provide a two-component absorption enhancer obtained by using HPE-101 in combination with another absorption enhancer to enhance the absorption of a drug.

Another object of the present invention is to provide an external preparation having a composition of various drugs and a two-component absorption enhancer.

[0010]

The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, have found various absorption promoting adjuvants that can be blended with the known HPE-101 as an absorption promoting agent. Upon examination, it was surprisingly found that the use of a two-component composition with cyclodextrins as an absorption-promoting adjuvant significantly accelerated the permeation and absorption of the drug to the transdermal or transmucosal, and completed the present invention. did.

The first component of the absorption promoter used in the present invention is the aforementioned HPE-101 [1- [2- (decylthio) ethyl] azacyclopentan-2-one].
Further, the cyclodextrins as the second component of the absorption promoting adjuvant used in the present invention are cyclodextrins which are utilized, applied or under development in the field of foods or pharmaceuticals and are cyclodextrins having high water solubility, that is, 2,6. -Di-O
-Methyl- (α, β or γ) -cyclodextrin,
2,3,6-tri-O-methyl- (α, β or γ)-
Cyclodextrin, 2-hydroxyethyl- (α, β
Or γ) -cyclodextrin, 2-hydroxypropyl- (α, β or γ) -cyclodextrin, 3-
Hydrophilic cyclodextrins such as hydroxypropyl- (α, β or γ) -cyclodextrin and 2,3-dihydroxypropyl- (α, β or γ) -cyclodextrin are included. Among them, particularly preferred is 2-hydroxypropyl- (α, β or γ) -cyclodextrin.

[0012]

The mixing ratio of each component in the present invention is as follows. That is, the first component-based accelerator, HPE
The compounding ratio of -101 to the auxiliary auxiliary agent, which is a cyclodextrin of the second component, is 1: 1 to 1:50, preferably 1: 2 to 1:20, and more preferably 1: 5 to 1:15. . The mixing ratio of the two-component absorption promoter in the external preparation is 0.1 to 50% by weight, preferably 1 to 30% by weight, more preferably 1 to 20% by weight based on the total amount (100% by weight). . The blending of these HPE-101 and cyclodextrins can be appropriately performed according to the type of the dosage form, and is usually adjusted according to a known method or a general method.

The drug is not particularly limited as long as it has a local or systemic effect. In the present invention, a drug intended for local action allows the drug to penetrate into the percutaneous and deep portions of the transmucosal membrane, and a drug intended for systemic action allows the drug to be rapidly transferred to the blood. For example, the drug used in the present invention is a drug whose biomembrane permeability or permeability is low enough to require an enhancer, such as an antibiotic, a chemotherapeutic agent, bacteriostatic / bactericidal /
Disinfectants, antifungals, non-steroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, anticancer drugs, psychotropic drugs, local anesthetics, anti-Parkinson's disease drugs, sex hormone drugs, antiperspirants, sunscreens, antiallergic drugs , Antiarrhythmic agents, antihypertensive agents, vasodilators, vasodilators, muscle relaxants, antiemetic agents, psoriasis treatment agents,
Over-the-counter drugs such as emollients, emollients, prostaglandins, fat-soluble vitamins, enzymes, peptide hormones, antidiabetic agents, analgesics, insect repellents, insecticides, pesticides, and drugs under investigation. No.

[0015] Specific examples of these drugs are as follows. 1) Antibiotics For example, penicillin G, penicillin V, methicillin, oxacillin, cloxacillin, ampicillin, hetacillin, cyclacillin, amoxicillin, carbenicillin,
Penicillin-type antibiotics such as sulbenicillin. Cephalosporin-type antibiotics such as fusarolidine, cephalotin, cefazolin, cephaloglysin, and cephalexin.
Aminoglycoside-type antibiotics such as streptomycin, kanamycin, dipekacin, gentamicin, and fradiomycin. Tetracycline-type antibiotics such as oxytetracycline, tetracycline, dimethylchlorotetracycline, doxycycline and minocycline.
Macrolide antibiotics such as erythromycin, leucomycin and josamycin. Lincomycin-type antibiotics such as lincomycin and clindamycin. Chloramphenicol, Micamycin, Gramicidin, Gramicidin S, Capreomycin, Cycloserine, Enviomycin, Rifampicin, Nystatin, Tricomycin, Amphotericin B, Griseofulvin, Variotin, Pyrrolenitrin, Siccanin, Nitrofurantoin, 5-Iodo-2 -Deoxyuridine, cefamedin, phosphonomycin, N-formimidoylchenamycin monohydrate and the like.

2) Chemotherapeutic agents Sulfa drugs for external use such as mafenide acetate, sulfadiazine, silver sulfadiazine, sodium sulfamethoxazole, sulfisomidine, sodium sulfisomidine, and naldixic acid.

3) Antifungal agent naphthiomate, clotrimazole, griseofulvin, siccanin, tricomycin, nystatin, pyrrolnitrin, exalamide, croconazole hydrochloride, isoconazole nitrate, econazole nitrate, oxyconazole nitrate, sulconazole nitrate, miconazole, thionazole, Tolcyclate, varioten, haloprosin, ferruodoundecinoate, bifonazole, naphthyfin, ketoconazole, ciclopirox, olamine, amphotericin B, flucytosine, fluconazole, itraconazole and the like.

4) Non-steroidal anti-inflammatory agents For example, salicylic acid, aspirin, acetaminophen,
Aminopyrine, antipyrine, oxyphenbutazone,
Sulpyrin, indomethacin, diclofenac sodium, ibuprofen, sulindac, naproxen, ketoprofen, etofenamate, salicylamide, triethanolamine salicylate, flufenamic acid, meclofenamic acid, colchicine, bufexamac, diflunisal, alclofenac, phenylbutazone , Mefenamic acid, fenoprofen, bendazac, piroxicam, flurbiprofen, tenoxicam, ketorolac, tolmetin, ampfenac sodium, fenbufen, planoprofen, thiaprofenic acid, fentiazac, oxaprozin, loxoprofen, lobenzarit, felbinac ethyl and the like Can be

5) Steroidal anti-inflammatory agents For example, amcinoid, prednisolone acetate valerate, diflucortron valerate, betamethasone valerate, betamethasone acetate, dexamethasone acetate, betamethasone dipropionate, dexamethasone, triamcinolone acetonide,
Hydrocortisone, flumethasone pivalate, fluocinonide, fluocinolone acetonide, fluorometholone,
Fludroxycortide, prednisolone, clobetasol propionate, beclomethasone propionate, betamethasone, methylprednisolone, methylprednisolone acetate, hydrocortisone butyrate, and the like.

6) Anticancer agent 5-fluorouracil, 6-mercaptopurine, methotrexate, pleomycin, mitomycin C, adriamycin, carbone, actinomycin C, daunorubicin, neocarzinostatin, chromomycin A, L-asparakinase, picibanil, vinblastine And vincristine.

7) Psychotropic Agents Chlorpromazine, chlordiazepoxide, reserpine, etizolam, oxazolam, mexazolam, haloxazolam and the like.

8) Local anesthetics Examples include benzocaine, procaine, propoxycaine, dibucaine, lidocaine, mepivacaine, bupivacaine, tetracaine and the like.

9) Anti-Parkinson's agent L-dopa, chlorzoxazone and the like.

10) Sex Hormones Estrogen, androgen, estradiol, testosterone, progesterone and the like.

11) Antiperspirants For example, propantheline bromide, scopolamine, quaternary acyloxymethyl ammonium salt and the like can be mentioned.

12) Sunscreen agent For example, p-aminobenzoic acid, p-dimethylaminobenzoic acid or an alkyl ester thereof can be mentioned.

13) Anti-allergic agents Examples thereof include sodium cromoglycate, tranilast, oxatomide, amlexanox, repirinast, ketotifen, azelastine, mequitazine and the like.

14) Antiarrhythmic agents Examples include acebutolol, alprenolol, indenolol, carteolol, bucmorol, bufetrol, bupranolol, propyranolol, pindolol and the like.

15) Antihypertensive agents Laurofia alkaloids such as reserpine and resinamine. Clonidine, prazosin, dihydroergotoxin mesylate, methicran, methyldopa, guanethidine, betanidine and the like.

16) Vasodilators For example, efloxate, etaphenone, oxyfedrine, carbochromene, dilazep, diltiazem, trimetazidine, pentaerythritol tetranitrate, dipyridamole, isosorbide dinitrate, trapidil, nitroglycerin, nifedipine, prenilamine, molsidomine, trolol nitrate , Inositol hexanicotinate, isoxsuprine, nylidrin, nicamethate, cyclandulate, cinnarizine, nicotinic alcohol, hepronicat and the like.

17) Vascular reinforcing agent For example, rutin and the like can be mentioned.

18) Muscle relaxants For example, eperisone hydrochloride, tizanidine and the like can be mentioned.

19) Antiemetic agents For example, chlorpromazine and the like can be mentioned.

20) A therapeutic agent for psoriasis, such as methoxalate.

21) Emollients or emollients Examples thereof include hydroquinone, urea, heparin, chondroitin sulfate and the like.

22) Prostaglandins For example, prostaglandin F ₂ , prostaglandin, prostaglandin E ₁ , prostaglandin E ₂ , 7-thiaprostaglandin E ₁ , 16,17,18,19,20- Pentanor
15-cyclohexyl-7-thia-prostaglandin E _1,
16,17,18,19,20-Pentanol-15-cyclopentyl-7
- thiaprostaglandin E _1, 16, 16 - dimethyl-7
Thiaprostaglandin E _1, 17,20 - dimethyl --7-
Thiaprostaglandin E _1, 16,17,18,19,20- Pentanoru 15-cyclohexyl - [delta ^{2-7-thia-prostaglandin} E _1, 16, 16 - dimethyl - [delta ² prostaglandins
E _1, 7- fluoro prostacyclin, 5-fluoro prostacyclin, 16, 17, 18, 19, 20 - Pentanoru -15
-Cyclohexyl prostacyclin, 16,17,18,19,20
-Pentanol-15-cyclopentylprostacyclin, sodium dl-4-[(IR, 2R, 3aS, 8b
S) -1,2,3a, 8b-Tetrahydro-2-hydroxy-1 [(8s, 4RS) -3-hydroxy-4
-Methyl-oct-6-ene- (E) -1-eryl] 5
-Cyclopenta [b] benzofuranyl] -butylate and the like.

23) Water-soluble vitamins and fat-soluble vitamins, such as vitamin B ₁ (Vitamin B ₁ ) and vitamin B ₂ (Vitami
n B ₂ ), vitamin B ₆ (Vitamin B ₆ ), nicotinic acid (Nico
tinic acid), nicotinamide (Nicotin amide), pantothenic acid (Pantothenic acid), biotin (biotin),
Vitamin B ₁₂ (Vitamin B _12), vitamin C (Vitamin C)
Water-soluble vitamins such as lipoic acid, inositol, and vitamin A (Vitamin A), vitamin D (Vitamin D), vitamin D ₂ (Vitamin D ₂ ), vitamin D ₃ (Vitamin D ₃ ) , Vitamin E (Vitamin E), vitamin K ₁ (Vitamin K ₁ ), vitamin K ₂ (Vitamin K ₂ ), ubiquinone (Ubiquinone), vitamin F (Vitamin F) or 1α, 25-dihydroxycholecalciferol (1
and fat-soluble vitamins such as α, 25-dihydroxy cholecalciferol).

24) Enzyme preparations For example, trypsin, papain, protease, lysozyme, streptokinase, plasmin, urokinase,
Examples include hyaluronidase, α-chymotrypsin, serathiopeptidase, bromelain, semi-alkali peptidase and the like.

25) Peptide hormones For example, insulin, angiotensin, vasopressin,
Buserelin, ferripressin, protirelin, gontropin hormone, corticotropin, prolactin, somatropin, thyrotropin, luteinizing hormone, calcitonin, kallikrein, glucagon, oxytocin, gastrin, secretin, gonadotropin, growth hormone, endorphin, chitotorphin, superoxide dismutase ( SOD), erythropoietin (EPO), atrial sodium polypeptide (hAN)
P) and the like.

26) Antidiabetic agent Examples include glibenclamide, gliclazide and the like.

27) Polysaccharides Examples include heparin, chondroitin sulfate and the like.

28) Extracts of plant and animal extracts Water-soluble extracts of human placenta, for example.

29) Analgesics Morphine, fentanyl, butorphanol, eptazocine, pentazocine, buprenorphine, dihydrocodine, oxycodone, hydromorphone, levorphanol, methadone, oxycodone, pethidine and the like.

30) Others For example, inotropic agents, antitussives, diuretics, antihistamines, nicotine, contraceptives, liver growth factor (HGF), interferons (α, β or γ), interleukins (1α or 1β Leukin, 2 or 6 interleukins) and the like.

Among the above-mentioned drugs, the combination with drugs such as nonsteroidal anti-inflammatory drugs, prostaglandins, peptide hormones and analgesics is particularly preferable. These drugs are compounded in a safe and effective amount, and the ratio is prescribed depending on the type of the drug, and is preferably 20% by weight or less, more preferably 10% by weight or less.

The two-component absorption enhancer of the present invention is applied to an external preparation for transdermal or transmucosal use.
The application is to the skin, scalp, nails, rectum, oral cavity, eyes, vagina, nose and the like. The formulation dosage forms used for these application sites include plasters, poultices, ointments, gels,
Examples include creams, liniments, suppositories, nasal drops, aerosols, and oral adhesives. The bases used in these dosage forms will be described below, but these bases are merely examples, and any bases usable in the preparation are not particularly limited.

First, the plaster will be described. Bases for plasters are known polymer bases (eg, acrylic compositions which are copolymers with vinyl monomers such as methacrylates, acrylonitrile, vinyl acetate, vinyl propionate, silicone resins, Isoprene rubber, polyisobutylene rubber, natural rubber, acrylic rubber, styrene
Butadiene-styrene block copolymer, styrene-isoprene-styrene block copolymer, etc.), fats and oils or higher fatty acids (eg, almond oil, olive oil, camellia oil,
Selected from versic oil, peanut oil, oleic acid, liquid paraffin, polybutene, etc., tackifiers (eg, rosin, rosin-modified maleic acid, hydrogenated rosin ester, etc.), anti-rash agents, and other additives to the base Object (example: dl
-Camphor, l-menthol, thymol, nonylate vanillylamide, pepper tincture, peppermint oil, peppermint oil, etc.) if necessary, and then compound a medicinal ingredient, and further add an ultraviolet absorber or an antioxidant as necessary And a stretchable or non-stretchable support (eg, polypropylene, polyester, polyvinylidene chloride, polyacryl, polyurethane, rayon, cotton, ethylene-
A plaster can be obtained by spread-coating a vinyl acetate copolymer, non-woven fabric, non-woven paper, etc.) and then applying a release coating thereon.

Next, the poultice will be described. Compress base,
For example, pressure-sensitive adhesives (eg, synthetic water-soluble polymers such as sodium polyacrylate, polyacrylic acid, poval, polyvinylpyrrolidone, polyethylene oxide, and polyvinyl methacrylate), natural products such as gum arabic, starch, and gelatin, methylcellulose, and hydroxypropylcellulose , Alginic acid, sodium alginate, ammonium alginate, sodium carboxymethyl cellulose), wetting agents (eg, urea, glycerin, propylene glycol, butylene glycol, sorbitol, etc.), fillers (eg, kaolin, zinc oxide, talc, titanium, benite, Epoxy resins, organic acids (citric acid, oxalic acid, maleic acid, succinic acid, etc.), calcium, magnesium,
Aluminum, etc.), water, dissolution aids (eg, propylene carbonate, crotamiton, diisopropyl adipate, etc.), tackifiers (eg, rosin, ester gum, polybutene, polyacrylic acid esters, etc.), anti-rash agents (eg, diphenhydramine hydrochloride) , Chlorpheniramine maleate, glycyrrhizinate, dexamethasone, betamethasone, fluocinolone acetonide, etc., and other additives (eg, l-
Menthol, camphor, vanillyl amide nonylate, thymol, capsicum extract, peppermint oil, etc.), adding a medicinal ingredient to each base, and further appropriately blending an ultraviolet absorber or an antioxidant as necessary. Agent can be obtained.

First, when molded as an ointment,
The ointment base is selected from known or commonly used ones. Examples thereof include higher fatty acids and esters thereof (eg, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester,
Myristate, palmitate, diethyl sebacate, hexyl laurate, cetyl isooctanoate, etc., waxes (eg, spermaceti, beeswax, ceresin, etc.), surfactants (eg, polyoxyethylene alkyl ether phosphate) Etc.), higher alcohols (eg, cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (eg, dimethyl polycycloxane, methyl phenyl polysiloxane, glycol methyl polysiloxane, silicone glycol copolymer, etc.), hydrocarbons (eg, : Hydrophilic petrolatum, white petrolatum,
Purified lanolin, liquid paraffin, etc., water, humectants (eg:
It is preferably selected from glycerin, propylene glycol, butylene glycol, sorbitol, etc., rash preventives, and other additives (eg, l-menthol, camphor, peppermint oil, etc.). By appropriately compounding these bases, preparations for transdermal, oral mucosa and rectal mucosa can be obtained.

Next, the gel agent will be described. The gel base is selected from various known or commonly used bases,
For example, lower alcohols (eg, ethanol, isopropyl alcohol, etc.), water, gelling agents (eg, carboxyvinyl polymer, hydroxyethylcellulose, ethylcellulose, carboxymethylcellulose, propylene glycol alginate), neutralizing agents (eg, triethanol) Amine, diisopropanolamine, sodium hydroxide, etc.), surfactants (eg, sorbitan sesquioleate, sorbitan trioleate, sorbitan monooleate, sorbitan monostearate, sorbitan monolaurate, polyethylene glycol monostearate,
Polyoxyethylene nonyl phenyl ether, polyoxyethylene lauryl ether, etc.), rash inhibitors, and other additives (eg, l-menthol, camphor, peppermint oil, etc.). A formulation for transdermal, oral mucosa and rectal mucosa can be prepared by appropriately blending and formulating these bases.

Next, the cream will be described. The cream base is selected from various known or commonly used bases. Examples thereof include higher fatty acid esters (eg, myristic ester, palmitic ester, diethyl sebacate, hexyl laurate, cetyl isooctanoate), Alcohols (eg, ethanol, isopropanol, etc.), carbohydrates (eg, liquid paraffin, squalane, etc.), polyhydric alcohols (eg, propylene glycol, 1,
3-butylene glycol, etc.), higher alcohols (eg: 2
Hexyldecanol, cetanol, 2-octyldodecanol, etc.), emulsifiers (eg, polyoxyethylene alkyl ethers, fatty acid esters, polyethylene glycol fatty acid esters, etc.), preservatives (eg, paraoxybenzoic acid ester), anti-rash agents, Other additives (eg:
l-menthol, camphor, peppermint oil and the like). The cream of the present invention can be obtained by adding a medicinal ingredient to each of the above bases, and further appropriately blending an ultraviolet absorber or an antioxidant as required. In addition, gelling agents (eg, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, carboxymethylcellulose, etc.) and neutralizing agents (eg, Diisopropanolamine, triethanolamine, sodium hydroxide, etc.)
A gel cream can be obtained by adjusting the pH to preferably 5 to 6.5. In addition, a formulation for transdermal, oral mucosa and rectal mucosa can be obtained by appropriately blending and formulating the base in a cream or gel cream formulation.

Next, the liniment will be described. The liniment of the present invention is an alcohol (eg, ethanol,
Monohydric alcohols such as propanol and isopropanol, polyethylene glycol, propylene glycol,
Add medicinal ingredients to polyhydric alcohols such as butylene glycol, etc., water, fatty acid esters (eg, various esters of adipic acid, sebacic acid, myristic acid, etc.) and surfactants (eg, polyoxyethylene alkyl ether). A liniment can be obtained by blending an ultraviolet absorber and, if necessary, an antioxidant. In the liniment of the present invention, if necessary, a neutralizing agent for adjusting pH, a viscosity imparting agent such as methylcellulose, carboxyvinyl polymer, hydroxypropylcellulose, a rash inhibitor, or other additives (eg, l-menthol) , Camphor, mint oil, pepper extract, vanillyl amide nonylate, thymol, crotamiton, propylene carbonate, diisopropyl adipate, etc.).

Next, suppositories will be described. Suppository bases are selected from synthetic oil bases such as cocoa butter, hydrogenated peanut oil and hydrogenated coconut oil, and water-soluble bases such as polyethylene glycols, monolen, twine and pluronic.

Next, nasal drops will be described. In the aqueous solution, the drug and the two-component absorption enhancer of the present invention may be combined with water, a buffer (for example, a Sorensen buffer [Ergeb. Physiol. 12, 393 (1912)]), Clarkrubbs
(Clark-Lubs) buffer (J. Bact. 2, (1), 109, 191 (19
17), Macl-vaine buffer [J. Biol, Ch.
em. 49, 183 (1921)), Michaelis buffer (Die Wasserstoffionen Komzentration, P. 186 (191)
4)), Kolthoff buffer (Bio-Chem.Z. 179,
410 (1926)]) and dissolved, suspended or emulsified in an aqueous solution. The oily suspension may be a drug and the two-component absorption enhancer of the present invention using an oily base (eg, sesame oil, leaven oil, corn oil, soybean oil, cottonseed oil, peanut oil, lanolin, petrolatum, paraffin,
Isopar, silicon oil, medium-chain fatty acids or their glycerin or alcohol esters)
It is formulated by suspending or emulsifying in water.

Semisolid preparations (ointments, gels, creams) are formulated by using the above-mentioned ointments, gels and cream bases. In the case of a liquid preparation, it is particularly preferable to put the liquid preparation in a nasal drop container, a spray container or the like suitable for intranasal application, and to drip or spray into the nasal cavity.

Next, the aerosol is formulated by using a base component such as liquefied natural gas, dimethyl ether, carbon dioxide, and CFC as a propellant and an excipient.

Finally, examples of the oral adhesive include hydroxypropylcellulose, acrylic acid copolymer, carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, alginic acid or a salt thereof, and maleic anhydride-methyl vinyl ether copolymer. , Chitosan, chitosan derivatives, vinyl acetate copolymer, agar, gluten, hydrophilic polymers such as gelatin, antibacterial agents, softeners, surfactants, crosslinking agents, neutralizing / buffering agents, extenders, flavors, coloring agents, An adhesive tablet or a film-shaped adhesive patch can be formed by appropriately mixing and formulating base components such as a flavoring agent and other excipients.

The external preparation containing the two-component absorption enhancer of the present invention, which comprises these preparation bases and the like, can be produced by a commonly known method. [For example,
New Formulation Development System Comprehensive Technology-Base and Additives, Publication Date: July 12, 1985, Publisher: R & D Planning,
Today's skin external preparation, published on May 15, 1981 (first edition)
Issued by: Nanzando, 11th Revised Japanese Pharmacopoeia Manual, Issued on July 18, 1986, Issued by: Hirokawa Shoten, Pharmaceuticals I and II-Dispensing and Pharmaceutical Sciences, Published: 1988 , Issuer: Japan Federation of Industrial Technology and other related documents and magazines]

[0059]

EXAMPLES The present invention will be described in detail with reference to formulation examples and experimental examples, but the present invention is not limited thereto. Example 1 An ointment is prepared according to the following formulation. (Total amount 100% by weight) Ketoprofen 3.0% by weight Propylene glycol 3.5% by weight Isopropyl myristate 2.5% by weight White petrolatum 85.0% by weight HPE-101 1.0% by weight 2-hydroxypropyl-β-cyclodextrin 5.0% by weight (hereinafter referred to as 2HP- (abbreviated as β-CyD) * The above-mentioned medicinal ingredient ketoprofen is prescribed within the range of 0.1 to 10.0% by weight.

Example 2 A solution is prepared according to the following formulation. (Total amount 100% by weight) Ketoprofen 1.0% by weight Ethanol 33.0% by weight 2-hydroxy-4-methoxybenzophenone 0.5% by weight Propylene glycol 12.0% by weight Methylcellulose 0.8% by weight Ethyl sebacate 2.0% by weight Purified water Appropriate amount 0.07% by weight of sodium hydroxide HPE-101 1.0% by weight 3-hydroxypropyl-β-cyclodextrin 10.0% by weight * The above-mentioned medicinal component ketoprofen is prescribed within the range of 0.1 to 10.0% by weight.

Example 3 A spray agent is prepared according to the following formulation. (Total amount 100% by weight) Ketoprofen 1.0% by weight Isopropyl myristate 1.0% by weight Ethanol 15.0% by weight Propellant gas HPE-101 1.0% by weight 2HP-β-CyD 5.0% by weight * The above-mentioned medicinal component ketoprofen is 0.1 to 10.0. It is formulated in the range of weight%.

Example 4 An ointment was prepared according to the following formulation. (Total amount 100% by weight) Indomethacin 1.0% by weight White petrolatum 65.0% by weight Isopropyl myristate 10.0% by weight Whale wax 4.0% by weight Polyoxyethylene lauryl ether sodium phosphate 2.0% by weight HPE-101 3.0% by weight 2HP-β-CyD 15.0 % By weight * The above-mentioned medicinal ingredient indomethacin is prescribed in the range of 0.1 to 10.0% by weight.

Example 5 A gel was prepared according to the following formulation. (Total amount 100% by weight) Piroxicam 3.0% by weight Diisopropyl adipate 2.0% by weight Ethanol 36.5% by weight Carboxyvinyl polymer 2.0% by weight Purified water Proper amount Hydroxypropyl cellulose 2.0% by weight Propylene glycol 15.0% by weight Diisopropanolamine 2.5% by weight HPE-101 1.0 % By weight 2HP-β-CyD 5.0% by weight * The above-mentioned medicinal ingredient piroxicam is prescribed within the range of 0.1 to 10.0% by weight.

Example 6 A gel cream was prepared according to the following formulation. (Total amount 100% by weight) Loxoprofen sodium 1.0% by weight Isopropyl myristate 10.0% by weight Ethanol 5.0% by weight Carboxyvinyl polymer 1.5% by weight Purified water Appropriate amount Polyoxyethylene (55) monostearate 1.0% by weight Coconut oil fatty acid diethanolamide 3.0% by weight % HPE-101 1.0% by weight 2HP-β-CyD 5.0% by weight * The above-mentioned medicinal ingredient loxoprofen sodium is
It is formulated in the range of 0.1 to 10.0% by weight.

Example 7 A suppository is prepared according to the following formulation. (Total amount 100% by weight) Diclofenac sodium 3.0% by weight Polyethylene glycol 5.0% by weight Bleached beeswax 8.0% by weight Sorbitan sesquioleate 3.49% by weight Medium-chain fatty acid triglyceride 74.5% by weight Dibutylhydroxytoluene 0 0.01% by weight HPE-101 1.0% by weight 2,6-di-O-methyl-β-cyclodextrin 5.0% by weight * The above-mentioned medicinal component diclofenac sodium is 0.1 to 10.0% by weight. Is prescribed within the range.

Example 8 A poultice is prepared according to the following formulation. (Total amount 100% by weight) Ketoprofen 3.0% by weight Gelatin 8.0% by weight Aluminum silicate 10.0% by weight Polyvinyl alcohol 3.5% by weight Purified water suitable amount Glycerin 25.0% by weight Carboxymethylcellulose 3.0% by weight HPE-101 1.0% by weight 2HP-β-CyD 5.0 % By weight * The above-mentioned medicinal ingredient ketoprofen is prescribed in the range of 0.1 to 10.0% by weight.

Example 9 A plaster was prepared according to the following formulation. (Total amount 100% by weight) Ketoprofen 3.0% by weight Styrene-isoprene-styrene block copolymer 22.5% by weight (Califlex TR 1107, manufactured by Shell Chemical Company) Liquid paraffin 40.5% by weight Hydrogenated rosin ester 28.0% by weight HPE-101 1.0 % By weight 2HP-β-CyD 5.0% by weight * The above-mentioned medicinal ingredient ketoprofen is prescribed within the range of 0.1 to 10.0% by weight.

Example 10 A liquid preparation is prepared according to the following formulation. (Total volume about 100ml) Salmon calcitonin (5000 IU / mg) 8 mg Hydroxypropylcellulose 1000 mg Isotonic phosphate buffer suitable amount HPE-101 1.0 g 2HP-β-CyD 10.0 g * 0.1-100
It is prescribed in the range of mg.

Example 11 A nasal spray was prepared according to the following formulation. (Total amount 100% by weight) Calcitonin 0.20% by weight HPE-101 1.0% by weight 2HP-β-CyD 10.0% by weight Sodium citrate 1.20% by weight Citric acid 0.60% by weight Purified water Appropriate amount * The above-mentioned medicinal ingredient calcitonin is 0.01 to 10% by weight
Is prescribed within the range.

Reference Example A nasal spray was prepared according to the following formulation. (Total amount 100% by weight) Calcitonin 0.5% by weight HPE-101 1.0% by weight β-cyclodextrin 10.0% by weight Sodium citrate 2.30% by weight Citric acid 0.40% by weight Purified water Appropriate amount ※ In addition, the above active ingredient calcitonin is 0.01 to 10 weight%
Is prescribed within the range.

Example 13 A nasal spray was prepared according to the following formulation. (Total volume: approx. 100 ml) Human insulin 5000 U 2 IU Isotonic phosphate buffer (pH 7.4) 8 ml HPE-101 1.0 g 2HP-β-CyD 10.0 g Chlorobutanol 18 mg Physiological saline Appropriate amount ※ The above active ingredients Human insulin is 0.1 IU to 50
It is prescribed within the range of 0 IU.

Example 14 A cream is prepared according to the following formulation. (Total amount 100% by weight) Fluocinolone acetonide 0.1% by weight Cetyl alcohol 9.2% by weight Stearyl alcohol 1.5% by weight Glycerol monostearate 4.0% by weight 1,3-butylene glycol 10.0% by weight HPE-101 2.5% by weight 2HP-β -CyD 12.5% by weight Purified water qs * The above-mentioned medicinal ingredient fluocinolone acetonide is
It is formulated in the range of 0.001 to 5.0% by weight.

Example 15 A solution is prepared according to the following formulation. (Total amount 100% by weight) 5-Fluorouracil (5-FU) 1.0% by weight Carboxymethylcellulose 0.1% by weight pH adjuster (pH 5.0 to 7.5) Suitable amount Polyethylene glycol 5.0% by weight HPE-101 1.0% by weight 2HP-β-CyD 6.0 % By weight Purified water qs * The above-mentioned medicinal ingredient 5-FU is prescribed within the range of 0.1 to 10% by weight.

Example 16 A suppository is prepared according to the following formulation. (Total amount 100% by weight) Morphine hydrochloride 0.5% by weight Polyethylene glycol 400 10.0% by weight Polyethylene glycol 1,000 28.0% by weight Polyethylene glycol 6,000 42.0% by weight HPE-101 1.0% by weight 2HP-β-CyD 5.0% by weight Propylene glycol Appropriate amount * The above active ingredient morphine hydrochloride is prescribed in the range of 0.001 to 5.0% by weight.

Example 17 A plaster was prepared according to the following formulation. (Total amount 100% by weight) Estradiol 3.0% by weight Styrene-isoprene-styrene block copolymer 30.0% by weight (trade name: Califrex TR-1107) Butyl hydroxytoluene 2.0% by weight Water-absorbing polymer (SAN) Wet IM-300MPS) 5.0% by weight Liquid paraffin Appropriate amount HPE-101 3.0% by weight 2HP-β-CyD 10.0% by weight * The above-mentioned medicinal component estradiol is 0.1 to 1
It is formulated in the range of 0% by weight.

Example 18 A spray gel was prepared according to the following formulation. (Total amount 100% by weight) Loxoprofen sodium 2.0% by weight Condensed glycerin 1.0% by weight Carboxyvinyl polymer (4% aqueous solution) 17.5% by weight Sodium hydroxide (2% aqueous solution) 14.0% by weight Disodium edetate (1% aqueous solution) 10.0% by weight % Sodium chloride (10% aqueous solution) 2.0% by weight HPE-101 1.0 to 10.0% by weight Cyclodextrins (eg, 2HP-β-CyD) 1.0 to 30.0% by weight Purified water suitable amount The compounding ratio in dextrins is prescribed in the range of 1: 1 to 1:50.

Example 19 A spray gel was prepared according to the following formulation. (Total amount 100% by weight) Sodium cromoglycate 2.0% by weight Polysorbate 80 1.0% by weight Carboxyvinyl polymer (4% aqueous solution) 18.0% by weight Sodium hydroxide (2% aqueous solution) 14.0% by weight Disodium edetate (1% aqueous solution) 10.0 % By weight Sodium chloride (10% aqueous solution) 1.5% by weight HPE-101 0.1 to 10.0% by weight Cyclodextrins (eg: 2HP-β-CyD) 0.1 to 40.0% by weight Purified water suitable amount The compounding ratio in cyclodextrins is prescribed in the range of 1: 1 to 1:50.

Example 20 A spray gel was prepared according to the following formulation. (Total amount 100% by weight) Insulin 0.19% by weight (including human, bovine, porcine or semi-synthetic insulin) Carboxyvinyl polymer (4% aqueous solution) 5.0% by weight L-arginine (4% aqueous solution) 10.0% by weight Sodium chloride (10%) % Aqueous solution) 0.6% by weight HPE-101 0.8% by weight Cyclodextrins (Example: 2HP-β-CyD) 10.0% by weight Purified water suitable amount * In addition, the blending ratio of HPE-101 and cyclodextrins in the above formulation is (total amount) (With respect to 100% by weight) may be within the range of 0.1 to 50% by weight, and it is preferable that the mixing ratio thereof is 1: 1 to 1:50. Thus, HPE-101 is 0.05-25% by weight,
The cyclodextrins are appropriately formulated in the range of 0.05 to 49% by weight in accordance with the above-mentioned blending ratio, and other bases are naturally formulated in the same manner. Insulin as a medicinal component includes human, bovine, porcine and semi-synthetic insulins, which are appropriately selected and used.

The details of the formulations in Examples 1 to 20 are prepared according to well-known or known ordinary methods. It should be noted that various formulations can be prescribed according to each symptom by changing the medicinal component, and the formulation or blending ratio of each base can also be dealt with by the formulation according to the situation. It is not limited. In addition, all of the preparations of these examples show a remarkable absorption effect, and are preferable in terms of drug efficacy or irritation (especially stabilization of erythrocyte membrane).

Experimental Example 1 H for Intranasal Absorption of Inulin
Combination test of PE-101 and 2-hydroxypropyl-β-cyclodextrin (hereinafter abbreviated as 2HP-β-CyD) (Purpose) In a formulation containing an absorption enhancer, its absorption is enhanced by selecting a solvent or a base. It is known that it exerts a great influence on the onset of action. Therefore, in this experiment, the usefulness of a water-soluble cyclodextrin as an absorption-promoting aid was examined for the purpose of increasing the thermodynamic activity in the formulation of the fat-soluble absorption promoter HPE-101.

Experiment A Intranasal Mucosal Absorption Test of Inulin in Rats (Effect of 2HP-β-CyD Concentration) In order to confirm the efficacy of the system of the present invention, inulin, a poorly-absorbable peptide polysaccharide, was selected as a drug model. It was formulated in the system and administered intranasally to rats, and the change in serum inulin concentration over time was measured. Test Examples 1, 2,
The compositions obtained in 3,4,5 and Comparative Examples 1,2,3,4,5,6 were prepared according to Hussain et al. [Journal of Pharmaceutical
According to the method of Sciences, Vol. 69, No. 12, p. 1411 (1980)], 25 μl (81.25 μg as inulin) was administered intranasally to Wistar rats in which the nasal cavity was obstructed and the airway was secured. Blood was collected over time up to 3 hours after administration, and radioactivity was measured with a liquid scintillation counter to measure the serum inulin concentration. The obtained serum inulin concentration was subjected to moment analysis to determine each pharmacokinetic parameter.

Test Example 1 50 mg (1 W / V%) of 2HP-β-CyD and HPE-101
50 mg (1 W / V%) is weighed, and isotonic phosphate buffer (pH 7.
4) After adding 4 ml and shaking sufficiently, inulin 16.25 mg
And adjust the volume to 5 ml with an isotonic phosphate buffer, and shake gently.

Test Example 2 250 mg (5 W / V%) of 2HP-β-CyD and HPE-101
50 mg (1 W / V%) is weighed, and isotonic phosphate buffer (pH 7.
4) After adding 4 ml and shaking sufficiently, inulin 16.25 mg
And adjust the volume to 5 ml with an isotonic phosphate buffer, and shake gently.

Test Example 3 500 mg (10 W / V%) of 2HP-β-CyD and HPE-10
Weigh 150 mg (1 W / V%) and add isotonic phosphate buffer (pH
7.4) After adding 4 ml and shaking well, inulin 16.25 mg
And adjust the volume to 5 ml with an isotonic phosphate buffer, and shake gently.

Test Example 4 1000 mg (20 W / V%) of 2HP-β-CyD and HPE-10
Weigh 150 mg (1 W / V%) and add isotonic phosphate buffer (pH 7.
4) After adding 4 ml and shaking sufficiently, inulin 16.25 mg
And adjust the volume to 5 ml with an isotonic phosphate buffer, and shake gently.

Test Example 5 1500 mg (30 W / V%) of 2HP-β-CyD and HPE-10
Weigh 150 mg (1 W / V%) and add isotonic phosphate buffer (pH 7.
4) After adding 4 ml and shaking sufficiently, inulin 16.25 mg
And adjust the volume to 5 ml with an isotonic phosphate buffer, and shake gently.

COMPARATIVE EXAMPLE 1 16.25 mg of inulin was weighed out and mixed with an isotonic phosphate buffer (pH 7.
4) Add 4 ml, shake well, adjust to 5 ml with isotonic phosphate buffer, and shake gently.

Comparative Example 2 50 mg (1 W / V%) of 2HP-β-CyD was weighed, 4 ml of isotonic phosphate buffer (pH 7.4) was added, and the mixture was shaken sufficiently.
Add 16.25 mg of inulin, adjust to 5 ml with isotonic phosphate buffer, and shake gently.

Comparative Example 3 250 mg (5 W / V%) of 2HP-β-CyD was weighed, 4 ml of an isotonic phosphate buffer (pH 7.4) was added, the mixture was shaken sufficiently, and 16.25 mg of inulin was added. Adjust to 5 ml with isotonic phosphate buffer and shake gently.

Comparative Example 4 500 mg (10 W / V%) of 2HP-β-CyD was weighed, 4 ml of isotonic phosphate buffer solution (pH 7.4) was added, and the mixture was shaken sufficiently. 5m with phosphate buffer
Adjust to 1 and shake gently.

Comparative Example 5 1000 mg (20 W / V%) of 2HP-β-CyD was weighed, 4 ml of an isotonic phosphate buffer solution (pH 7.4) was added, and the mixture was shaken sufficiently. 5m with phosphate buffer
Adjust to 1 and shake gently.

Comparative Example 6 50 mg of HPE-101 was weighed, and the solution was adjusted to an isotonic phosphate buffer (pH
7.4) After adding 4 ml and shaking well, inulin 16.25
Add mg, adjust to 5 ml with isotonic phosphate buffer, and shake gently. The test results are shown in Table 1 below.

[0093]

[Table 1]

Experiment B Nasal mucosal absorption test of inulin in rats (effect of HPE-101 concentration) HPE-10 against 2HP-β-CyD (10 W / V%)
In order to examine the optimal concentration of No. 1, the serum inulin concentration was measured in an experiment using rats (same as the experimental method).
In addition, moment analysis of the obtained serum inulin concentration,
Each pharmacokinetic parameter was determined. The test drugs of Test Examples A to F and Comparative Examples were adjusted according to the prescription of Experiment A. The test results are shown in Table 2 below.

[0095]

[Table 2]

Experimental Example 2 Insulin and Glucose Concentration Test in Rat Serum In order to confirm the efficacy of the system of the present invention, insulin, which is a poorly absorbable peptide, was selected as a drug model, blended into the system, and administered intranasally to rats. The changes in serum concentrations of insulin and glucose over time were measured. The compositions obtained in Example 1 and Comparative Examples 1, 2, 3, and 4 shown below were prepared using Hussain et al. [Journal of Pharmaceutical Scienc
es, Vol 69, No. 12, p. 1411 (1980)).
25 μl (2 U as insulin) was administered. Blood was collected over time up to 2 hours after administration, and the serum insulin concentration was measured by enzyme immunoassay (Glazyme Insulin-EIA TEST), and the serum glucose concentration was measured by mutarose-GOD method (Glucose C Test Wako). The serum insulin concentration changes over time, and the serum glucose concentration is the ratio (% of i) of the concentration before and after administration of each composition.
nitial). The results are shown in FIG. 1 and FIG.

Test Example 1 500 mg of 2HP-β-CyD and 50 mg of HPE-101 were weighed, 4 ml of isotonic phosphate buffer (pH 7.4) was added, and the mixture was shaken sufficiently. Then, bovine insulin (25.7 U / mg) was added to 15.56. After adding 1.0 mg of hydrochloric acid to make the mixture acidic and dissolving the insulin, adjust the pH to 7.4 with a 1.0N NaOH aqueous solution, adjust to 5 ml with an isotonic phosphate buffer, and shake gently.

Comparative Example 1 5 ml of an isotonic phosphate buffer (pH 7.4) was prepared.

COMPARATIVE EXAMPLE 2 15.56 mg of bovine insulin (25.7 U / mg) was weighed, 4 ml of isotonic phosphate buffer was added, acidified with 1.0 N hydrochloric acid to dissolve the insulin, and then dissolved in a 1.0 N NaOH aqueous solution. PH 7.4
Adjust to 5 ml with an isotonic phosphate buffer and shake gently.

Comparative Example 3 500 mg of 2HP-β-CyD was weighed, and 4 ml of an isotonic phosphate buffer (pH 7.4) was added.
(25.7 U / mg) was added, and the mixture was acidified with 1.0N hydrochloric acid to dissolve insulin, and then dissolved in 1.0N NaOH aqueous solution.
Adjust the pH to 7.4, adjust to 5 ml with isotonic phosphate buffer, and shake gently.

Comparative Example 4 HPE-101 (50 mg) was weighed, and an isotonic phosphate buffer solution (pH
7.4) After adding 4 ml and shaking well, beef insulin (2
5.7 U / mg), add 1.0N hydrochloric acid to make it acidic and dissolve the insulin, and then add 1.0N NaOH aqueous solution to pH.
Adjust to 7.4, adjust to 5 ml with isotonic phosphate buffer, and shake gently.

Experimental Example 3 Human Red Blood Cell Hemolysis Test In order to examine the safety of a mixture of cyclodextrin and HPE-101, membrane stability was measured using human red blood cells. (Experimental method) Human fresh blood (citrate 3 as anticoagulant
Na was used) was washed three times with an isotonic phosphate buffer (pH 7.4) to remove leukocytes and platelets, and then resuspended in an isotonic buffer for the experiment. β-CyD, 2HP-α-Cy
D, 2HP-β-CyD was dissolved at a concentration of 1 mM, HPE-101 was prepared at a concentration of 5-500 μM with an isotonic phosphate buffer, and HPE-101 was prepared at a concentration of 5-500 μM. 0.4 ml of the above red blood cell suspension was added to 4 ml of isotonic phosphate buffer, incubated at 37 ° C. for 5 minutes, and after centrifugation, the amount of oxyhemoglobin in the supernatant was measured by absorbance at 543 nm. The test results are shown in FIG.

Experimental Example 4 Insulin Aggregation Test The effect of a mixture of cyclodextrin and HPE-101 on the aggregation of insulin was examined. (Experimental Method) The samples of Test Example 1 and Comparative Examples 2 and 4 obtained from Experimental Example 2 were sealed in a polypropylene tube and stored at 5 ° C. in a dark place for 15 days. Before the start of the test and
The sample stored for 15 days is filtered (DISMIC13CP045AN) and HP
Insulin was measured by LC. The ratio of the measured values before and after the test of the sample was determined. Table 3 shows the results.

[0104]

[Table 3] Aggregation rate of insulin ────────────────── Aggregation rate (%) ────────────────── Test Example 1 0 Comparative Example 2 76.69 Comparative Example 4 20.58 ──────────────────

[0105]

In the test results shown in Tables 1 and 2 above, nasal absorption of inulin, which is a poorly-absorbable peptide polysaccharide, showed almost no absorption promoting effect with inulin and 2HP-β-CyD alone. HPE-101 (1
(W / V%) alone exhibits an approximately three-fold absorption-enhancing effect, but the two-component absorption enhancer in combination with HPE-101 and 2HP-β-CyD of the present invention has a maximum blood concentration of about 90% relative to inulin alone. It has a 3- to 9-fold effect, and an approximately 2- to 3-fold effect at the highest blood concentration with respect to HPE101 alone. In addition, the maximum blood concentration reached the maximum blood concentration in a very short time, which proved to be excellent in rapid efficacy. Also, the absorption rate within 3 hours was markedly enhanced, and it was proved that the absorption promoting action was remarkable. Also, 2HP-
These effects on β-CyD (10 W / V%) were found to be particularly significant. In addition, 2HP-β-CyD (10
(W / V%), the optimal concentration of HPE-101 is 0.6 W / V
% To 1.5 W / V% is most preferable, and shows a remarkable maximum blood concentration, a time to reach the maximum concentration and an absorption rate which are more remarkable than inulin alone and HPE-101 alone. Was found to have.

From the test results shown in FIGS. 1 and 2, it can be seen that the insulin-containing HPE-101 and 2HP containing the insulin of the present invention were used.
In Test Example 1 of the two-component absorption enhancer of -β-CyD, the serum insulin concentration was clearly higher than in each of the comparative examples, and the absorption was quicker. In addition, a remarkable lowering effect on serum glucose concentration, which is a pharmacological effect of insulin, and a sustained effect of the effect are observed. This clearly indicates a significant absorption of insulin from the nasal mucosa. In addition, from the test results shown in FIG. 3, a significant improvement in erythrocyte membrane stability was observed by mixing cyclodextrins with HPE-101,
It was also found that the hemolysis of red blood cells was significantly suppressed. Further, from the test results shown in Table 3, it was found that the two-component absorption enhancer also suppressed the aggregation action of insulin. In addition, no damage or irritation to the nasal mucosa in rats was observed. This was due to 2HP-β-CyD against lipid components on the surface of stratum corneum or mucosal surface or inside.
It seems to be due to the protective action of In addition, the two-component absorption enhancer has a remarkably increased solubility in drugs and is excellent in dissolution.

As described above, it was found that the composition obtained by using the combination of HPE-101 and 2HP-β-CyD, which is a cyclodextrin, has a remarkable absorption-promoting action, a relieving action against irritation, a drug-dissolving action, and the like. These are new findings discovered for the first time by the present inventors as a result of earnest studies. In addition, this two-component absorption enhancer was confirmed to have a remarkable absorption-enhancing effect even when used in combination with other drugs, and was found to be widely applicable.

[0108]

The present invention comprises a novel composition obtained by using the absorption enhancer HPE-101 in combination with a cyclodextrin as an absorption enhancer, and these two-component compositions are prepared by the present inventors. It has been found that the compound has a remarkable absorption promoting effect in an experiment using this drug. This two-component absorption enhancer has a remarkable absorption-promoting effect on a poorly-absorbable drug model compound, and also in combination with other drugs, remarkably promotes absorption into the transdermal or transmucosal,
In addition, it has a relaxing effect on stimulation. Therefore, the present invention provides a variety of external preparations by adding a drug that can be used as a medicament, thereby replacing conventional oral preparations or injections, and quickly and continuously absorbing the drug in the blood. It is possible to administer with an external preparation with a small amount.

[0109]

[Brief description of the drawings]

FIG. 1 shows an insulin concentration test in rat serum. The horizontal axis indicates the elapsed time after intranasal administration. The vertical axis shows the serum insulin concentration.

[Explanation of symbols]

*: Control (Comparative Example 1) ●: Insulin (Comparative Example 2) □: 2HP-β-CyD (Comparative Example 3) Δ: HPE-101 (Comparative Example 4) ○: of 2HP-β-CyD and HPE-101 Two-component system (Test Example 1)

FIG. 2 shows a glucose concentration test in rat serum. The horizontal axis indicates the elapsed time after intranasal administration. The vertical axis shows the ratio of the serum glucose concentration before administration and after administration.

[Explanation of symbols]

*: Control (Comparative Example 1) ●: Insulin (Comparative Example 2) □: 2HP-β-CyD (Comparative Example 3) Δ: HPE-101 (Comparative Example 4) ○: of 2HP-β-CyD and HPE-101 Two-component system (Test Example 1)

FIG. 3 shows the effect of a mixture of HPE-101 and cyclodextrins on the hemolytic action of human erythrocytes. The horizontal axis represents the logarithm of the HPE-101 concentration (μM), and the vertical axis represents the hemolysis rate (%).

[Explanation of symbols]

 ●: HPE-101 alone without CyD △: β-CyD (1 mM) and HPE-101 □: 2HP-α-CyD (1 mM) and HPE-101 ○: 2HP-β-CyD (1 mM) and HPE-101 101

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI A61K 47/40 A61K 47/40 (56) References JP-A-62-238261 (JP, A) JP-A-62-39572 (JP) , A) JP-A-61-109738 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 9/00-9/72 A61K 47/00-47/48 CA (STN) REGISTRY (STN) MEDLINE (STN)

Claims (6)

(57) [Claims] (1) 2,6-di-O-methyl- (α, β or γ) -cyclodextrin, 2,3,6-tri-O-methyl- (α, β or γ) -cyclodextrin, −
Hydroxyethyl- (α, β or γ) -cyclodextrin, 2-hydroxypropyl- (α, β or γ)
-Cyclodextrin, 3-hydroxypropyl- (α,
β- or γ) -cyclodextrin, and one or more water-soluble cyclodextrins selected from the group consisting of 2,3-dihydroxypropyl- (α, β or γ) -cyclodextrin and 1- [2- ( Decylthio) ethyl]
An absorption enhancer comprising a composition containing azacyclopentan-2-one. 2. The absorption enhancer according to claim 1, wherein the water-soluble cyclodextrin is 2-hydroxypropyl- (α, β or γ) -cyclodextrin. 3. The absorption enhancer according to claim 1, wherein the water-soluble cyclodextrin is 2-hydroxypropyl-β-cyclodextrin. 4. A 2,6-di-O-methyl- (α, β or γ) -cyclodextrin, 2,3,6-tri-O-methyl- (α, β or γ) -cyclodextrin, −
Hydroxyethyl- (α, β or γ) -cyclodextrin, 2-hydroxypropyl- (α, β or γ)
-Cyclodextrin, 3-hydroxypropyl- (α,
β- or γ) -cyclodextrin, and one or more water-soluble cyclodextrins selected from the group consisting of 2,3-dihydroxypropyl- (α, β or γ) -cyclodextrin and 1- [2- ( Decylthio) ethyl]
An external preparation containing azacyclopentan-2-one and a pharmaceutically active ingredient. 5. The method according to claim 1, wherein the cyclodextrin having high water solubility is 2-
The external preparation according to claim 4, which is hydroxypropyl- (α, β or γ) -cyclodextrin. 6. A cyclodextrin having a high water solubility is 2-
The external preparation according to claim 4, which is hydroxypropyl-β-cyclodextrin.