JPH0796501B2 - Transdermal absorption enhancer - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of use] The present invention relates to a percutaneous absorption enhancer which promotes permeation and absorption of a drug through the skin.

[Prior art]

Drug delivery systems (DDS) are being actively researched for the purpose of more efficiently reaching the target site and suppressing side effects. Among these, in recent years, a percutaneous absorption system in which the skin is the application site of the drug has attracted attention. The advantages of this system are that it avoids the first-pass effect in the liver, the skin permeation rate of the drug is controlled, the blood concentration can be maintained continuously and constantly, the administration is not affected by food and vomiting, the administration is not regulated. Easy,
The point is that it can be administered near the target site. But,
At present, there are drawbacks such that the dose is limited to a relatively small amount of drug, the drug that can be used is limited, the deterioration of the corneal layer and the skin allergic reaction may be promoted, and immediate effect cannot be expected. Therefore, in order to improve these points, the combined use of a percutaneous absorption enhancer is being studied.

Up to now, the use of dimethyl sulfoxide, N-dodecylpyrrolidone, N-dodecyl-ε-caprolactam, urea and the like has been proposed (supervised by Isao Kaetsu, Drug Delivery System, pages 213-237, CMC). Attempts have also been made to use high molecular compounds such as polyethylene glycol and water-soluble proteins (JP-A-60-214730).

[Problems to be solved by the invention]

However, although low molecular weight compounds among these accelerators have certain promoting effects, these compounds themselves are percutaneously absorbed and enter a large amount in blood, which is not preferable from the viewpoint of safety and hygiene. Further, when the above-mentioned polymer compound is used, the above-mentioned migration into blood can be hindered, but there is a serious problem in practical use in that the promoting effect is extremely small.

The present inventors have conducted extensive studies in order to solve the above problems, and as a result, have found that a polymer having a specific ammonium group has an extremely excellent transdermal absorption promoting action, and have completed the present invention. .

[Means for solving problems]

That is, the present invention comprises a polymer having an average molecular weight of 800 or more, 10 mol% or more in all repeating units of the polymer is represented by the general formula An agent for promoting percutaneous absorption of a drug, characterized by comprising a repeating unit represented by the formula (wherein R ¹ is a hydrogen atom or a lower alkyl group, R ² and R ³ are the same or different lower alkyl groups, R ⁴ is a hydrocarbon group having 6 or more carbon atoms, X is a counter anion,
n represents an integer of 0 to 5).

In the formula, the hydrocarbon group having 6 or more carbon atoms represented by R ⁴ is a saturated or unsaturated branched or linear hydrocarbon group, for example, normal-, iso- or secondary hexyl group, heptyl group, Octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, eicosanyl group, oleyl group, geranyl group, farnesyl group, etc. be able to. Among these, those having 8 or more carbon atoms, particularly those having 10 or more carbon atoms, are preferable because of their large promoting effect.

As the counter ion represented by X, a halogen anion,
Examples thereof include organic acid anion and 1 / 2SO ₄ ²⁻ , NO ₃ ^— H ₂ PO ₄ ^— .

The polymer in the present invention is a polymer in which 10 mol% or more of the repeating unit is composed of the repeating unit represented by the general formula (I), and a homopolymer comprising the repeating unit and the repeating unit and the general formula [In the formula, R ⁵ represents a hydrogen atom, a halogen atom or a lower alkyl group, Z is an unsubstituted or lower alkyl group, a lower haloalkyl group, a lower alkyloxy group, or a phenyl group or a pyridyl group substituted with a halogen atom. ,
Hydrogen atom, lower alkyl group, alkyloxy group, cyano group, group represented by -COOR ⁶ or (Wherein R ⁶ and R ⁷ represent a hydrogen atom, an alkyl group having 1 to 15 carbon atoms which may be substituted with a hydroxyl group, a phenyl group or a cycloalkyl group, and R ⁸ represents a hydrogen atom or a lower alkyl group). R ⁷ and R ⁸ may together form a polymethylene chain.) ] It includes any case of a copolymer with a repeating unit represented by the following.

These polymers have, for example, the general formula (In the formula, R ¹ , R ² , R ³ , R ⁴ , n, and X are the same as above.)
Homopolymerization of the monomer represented by or the monomer represented by the general formula (III) and the general formula (In the formula, R ⁵ and Z are the same as above.) And can be produced by copolymerization with one or more monomers having a vinyl group.

The polymerization can be carried out by a radical polymerization method, and as the method used at that time, known methods such as bulk polymerization, solution polymerization and emulsion polymerization can be used. The radical polymerization reaction is rapidly initiated simply by irradiation with heat, ultraviolet rays or addition of a radical initiator. Radical initiators suitably used in the reaction include dilauroyl peroxide,
Examples thereof include organic peroxides such as benzoyl peroxide and azo compounds such as α, α′-azobisisobutyronitrile. Examples of the organic solvent that can be used in the polymerization reaction include benzene, toluene, chlorobenzene, tetrahydrofuran, carbon tetrachloride, chloroform, methyl ethyl ketone, fluorobenzene, hexafluorobenzene, benzotrifluoride, 1,4-bis (trifluoromethyl) benzene, Examples thereof include N, N-dimethylformamide and N, N-dimethylacetamide, but are not limited thereto. The reaction normally proceeds smoothly in the range of 40 ° C to 100 ° C.

As the vinyl group-containing monomer used in the copolymerization, styrene derivatives such as styrene, p-methylstyrene, p-chlorostyrene, p-chloromethylstyrene, pentafluorostyrene, p-aminostyrene, ethylene, propylene, etc. , Alkenes such as butene, ethyl vinyl ether, propyl vinyl ether, butyl vinyl ether, hexyl vinyl ether, vinyl ethers such as octyl vinyl ether, methyl acrylate, ethyl acrylate, 2-hydroxyethyl acrylate, butyl acrylate, 2,3-dihydroxypropyl acrylate, poly Acrylic esters such as fluoroalkyl acrylate, p-fluorophenyl acrylate and m-trifluoromethylphenyl acrylate, methylmethacrylate Over DOO, ethyl methacrylate, propyl methacrylate, 2-hydroxyethyl methacrylate, glycidyl methacrylate, butyl methacrylate, cyclohexyl methacrylate, benzyl methacrylate, methacrylic acid esters of perfluoroalkyl methacrylate, acrylonitrile, acrylamide, p- methoxy acrylic anilide,
N-hydroxymethylacrylamide, N- (1,1-dimethyl-3-oxobutyl) acrylamide, N, N-dimethylacrylamide, methacrylamide, N-hydroxyethylmethacrylamide, acrolein, acrylic acid, methacrylic acid, vinylpyridine, etc. Can be used. Further, the repeating unit represented by the general formula (I) constituting the polymer is at least 10 mol% of all the repeating units, and is 30 mol% or more for exhibiting an excellent effect of promoting percutaneous absorption per unit weight. Is desirable.

Further, the average molecular weight of the polymer needs to be 800 or more from the viewpoint of skin permeability, and it is preferably 50,000 or less, particularly 20,000 or less in order to exhibit an excellent promoting effect.

The molecular weight can be easily controlled by using a chain transfer agent. Examples of the chain transfer agent include thiols such as ethanethiol, butanethiol and dodecanethiol, P-benzoquinone, chloranil, carbon tetrachloride and carbon tetrabromide.

The styrene derivative having an ammonium group represented by the general formula (III) is, for example, a compound represented by the general formula (Wherein R ¹ and n are the same as above, and Y represents a halogen atom, a lower alkylsulfonyloxy group, or an arylsulfonyloxy group) and the general formula (In the formula, R ² , R ³ and R ⁴ are the same as above.) A compound which can be easily produced by reacting with a tertiary amine.

The transdermal absorption enhancer of the present invention, together with the drug to be administered,
A tincture dissolved in a solvent such as water or alcohol, or an ointment or cream mixed with an ointment or cream base,
Furthermore, it can be used in any form such as a tape preparation mixed in a polymer film or an adhesive.

The content of the absorption enhancer of the present invention varies depending on its use form, but is generally 0.1% by weight to 50% by weight, preferably 1% by weight to 20% by weight. In many cases, side effects such as skin irritation become significant and the release of the drug may be suppressed.

The drug used in the present invention may be any drug for humans or animals. For example, as an anti-inflammatory analgesic, acetaminophenone, aspirin, methyl salicylate, choline salicylate, glycol salicylate, l
-Menthol, camphor, mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, ibuprofen, ketoprofen, naproxen, pranoprofen, fenoprofen, fenbufen, flurbiprofen, indoprofen, fentiazac, tolmetin, Suprofenic acid, Penzadac, Bufexamac, Piroxicam, Phenylbutazone, Oxyphenbutazone, Clofezone, Pentazocine, Mepyrizole, etc .; Steroid anti-inflammatory agents include hydrocortisone, prednisolone, dexamethasone,
Triamcinolone acetonide, fluocinolone acetonide, fludrocortisone acetate, etc .; Antihistamines or antiallergic agents include chlorpheniramine, glycyrrhizic acid, diphenhydramine,
Periactin, etc .; local anesthetics, benzocaine, procaine, dibucaine, lidocaine, etc .; antibacterial agents, etc., tetracyclines such as chlortetracycline, penicillins such as ampicillin, cephalosporins such as cephalothin, aminoglycosides such as kanamycin, Macrolides such as erythromycin, chloramphenicol, iodo compounds, nitrofurantoin, nystatin, amphotericin, fradiomycin, sulfonamides, pyrrolenitrin,
Clotrimazole, nitrofurazone, etc .; antihypertensive agents clonidine, α-methyldopa, reserpine, syrosingopine, resinamine, cinnarizine, hydralazine, brazosin, etc .; antihypertensive agents, theophylline, trichloromethiazide, furosemide,
Trypamide, methiclothiazide, penfluzide, hydrothiazide, spironolactone, metrazone, etc .; as cardiotonics digitalis, ubidecarenone, dopamine, etc .; as coronary vasodilators, nitroglycerin, isosorbitol dinitrate, erythritol tetranitrate, pentaerythritol tetranite Rate, dipyridamole, dilazep, trapidil, trimetazidine, etc .; vasoconstrictors such as dihydroergotamine, dihydroergotoxin, etc .; β-blocker or antiarrhythmic agents such as pindolol, propranolol hydrochloride, etc .; calcium antagonists diltiazem, nifedipine, nicardipine , Verapamil, bencyclane, dilacept, etc .; Antiepileptic agents nitrazepam, meprovame Door,
Phenytoin, etc .; anti-vertigo, isoprenaline, betahistine, scopolamine, etc .; tranquilizers, diazepam, lorazepam, flunitrazepam, fluphenazine, etc .; hypnotics, phenobarbital, amobarbital, cyclobarbital; muscle relaxants, etc. Triperizone, baclofen, dantrolene sodium, cyclobenzaprine, etc .; autotrophic agents, atropine, levodova, etc .; respiratory agents, codeine, ephedrine, isoproterenol, dextromethorphan, orciprenaline, ipratropium bromide, cromoglycic acid, etc .; Hormonal or antihormonal agents include corticotropin, oxytocin, vasopressin, testosterone, progesterone, estradiol , Salivary gland hormone, thyroid hormone, adrenal hormone, kallikrein, insulin, oxendron, etc .; as vitamins, vitamins A, B, C, D, E, K and their derivatives, calciferols, mecobalamin, etc .; as antitumor agents Is 5-fluorouracil and its derivatives, adriamycin, krestin, picibanil, ancitabine, cytarabine, etc .; Enzymes are urokinase, etc .; Herbal medicines or herbal extracts are licorice, aloe, purple root, etc .; Antiulcer agents are allantoin, aldioxa, etc .; Others Examples include prostaglandins and antidiabetic agents.

If necessary, two or more of these drugs may be used in combination.

The drug preparation containing the percutaneous absorption enhancer of the present invention can be applied by applying a necessary amount to the skin and mucous membranes (oral cavity, nasal cavity, rectum, vagina) of various parts of the human body according to the purpose. For example, for local treatment of trauma, skin ulcer, myalgia, arthritis, etc., directly to the affected area or its vicinity, and for systemic treatment of internal organs, etc. (Example: Area where keratin is not developed)
It is preferable to apply to When used as a cosmetic, the above formulation as it is or one selected from the above drugs or a mixture of known cosmetic ingredients is used for purposes such as skin washing, packs, measures against sunburn and rough skin, and moisturizing. Can be used in.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Production Examples, Examples, and Comparative Examples.

Reference Examples 1 to 3 Chloromethylstyrene and the amines shown in Table 1 were mixed in the amounts shown in Table 1 and reacted overnight at room temperature to obtain a white solid. This was washed with a large amount of diethyl ether or recrystallized from acetone to obtain a corresponding monomer having a quaternary ammonium group as a white powder.

Production Examples 1 to 6 Glass ampoule tubes for polymerization in the proportions shown in Table 2 of the monomers of Reference Examples 1 to 3, azobisisobutyronitrile (AIBN) as a polymerization initiator, and dimethylformamide (DMF) as a solvent After degassing according to a conventional method, the tube was sealed under vacuum. By shaking this for 60 hours at 60 ℃,
A polymerization reaction was carried out.

The polymer was obtained by throwing the reaction mixture into a large amount of acetone. The molecular weight of the obtained polymer was determined by GPC measurement in terms of polyethylene glycol.

Production Examples 7 and 8 Monomers and acrylamide of Reference Examples 2 and 3, azobisisobutyronitrile (AIBN) as a polymerization initiator, and dimethylformamide (DMF) as a solvent at the ratios shown in Table 3 for glass polymerization. An ampoule tube was charged, deaerated according to a conventional method, and then the tube was sealed under vacuum. The mixture was shaken at 60 ° C. for a predetermined time to carry out a polymerization reaction.

The copolymer was obtained by throwing the reaction mixture into a large amount of acetone. The molecular weight of the obtained polymer was determined by GPC measurement in terms of polyethylene glycol. The composition of the obtained copolymer was determined by elemental analysis.

Production Examples 9-11 Monomers of Reference Example 3 and N, N-dimethylacrylamide (DMA
A), azobisisobutyronitrile (A
IBN), dodecanethiol as a chain transfer agent, and chloroform as a solvent were charged into a glass-made ampoule tube for polymerization at a ratio shown in Table 4, deaerated according to a conventional method, and then sealed under vacuum. By shaking this at 60 ℃ for a predetermined time,
A polymerization reaction was carried out.

The copolymer was obtained by throwing the reaction mixture into a large amount of acetonitrile. The molecular weight of the obtained copolymer is GPC
It was determined by measurement in terms of polyethylene glycol. The composition of the obtained polymer was determined by elemental analysis.

Production Examples 12 to 14 Table 5 shows monomers of Reference Example 3 and 2-hydroxyethyl methacrylate (HEMA), azobisisobutyronitrile (AIBN) as a polymerization initiator, dodecanethiol as a chain transfer agent, and chloroform as a solvent. A glass ampoule tube for polymerization was charged at the indicated ratio, deaerated according to a conventional method, and then sealed under vacuum. The mixture was shaken at 60 ° C. for a predetermined time to carry out a polymerization reaction.

A polymer was obtained by throwing the reaction mixture into a large amount of a mixed solution of ethyl acetate and 2-propanol. The molecular weight of the obtained polymer was determined by GPC measurement in terms of polyethylene glycol. The composition of the obtained polymer was determined by elemental analysis.

Examples 1 to 6 Two-chamber diffusion cells (effective area 0.95 cm ² ) were used to sandwich rabbit abdominal peel skin, and the donor site was treated with the antitumor agent 5-fluorouracil (5-FU) (1%). 2 ml of a solution of a skin absorption promoter (polymer or copolymer, 5%) in ethyl alcohol was placed, 2 ml of a phosphate buffer solution was placed in the receptor part, and the entire cell was immersed in a constant temperature bath at 37 ° C. Both chambers were sampled from the receptor part 12 hours after stirring,
The quantity of permeated 5-FU was quantified by high performance liquid chromatography. The transmission measurement results are shown in Table 6. Further, Comparative Example 1 shows the case where no transdermal absorption enhancer was added.

Examples 7 to 11 Rabbit abdominal exfoliated skin was sandwiched between two-chamber diffusion cells (effective area 0.95 cm ² ), and an antitumor agent 5-fluorouracil (5-FU) (1%) was added to the donor site. 2 ml of a solution of a skin absorption promoter (copolymer, 5%) in ethyl alcohol was placed, 2 ml of a phosphate buffer solution was placed in the receptor portion, and the entire cell was immersed in a constant temperature bath at 37 ° C. Both chambers were sampled from the receptor part 12 hours after stirring, and the amount of 5-FU permeated was measured by high performance liquid chromatography.
The transmission measurement results are shown in Table 7. Further, Comparative Example 1 shows the case where no transdermal absorption enhancer was added.

Example 12 Rabbit abdominal exfoliated skin (0.95 cm) in a two-chamber diffusion cell
² ) is sandwiched, and 300 mg of a commercially available ointment of the antitumor agent 5-fluorouracil (5-FU) containing 5% of the percutaneous absorption enhancer (Production Example 6) of the present invention is placed on the skin surface, and tetrafluoro is added thereto. It was fixed with an ethylene membrane filter.
Put 2 ml of phosphate buffer on the receptor side and
It was immersed in a constant temperature bath at 7 ° C.

The receptor side chamber was agitated and sampled from the receptor portion 12 hours later, and the amount of permeated 5-FU was quantified by high performance liquid chromatography. The transmission measurement results are shown in Table 8. Further, Comparative Example 2 shows the case where only the ointment was used without adding the transdermal absorption enhancer.

Example 13 A two-chamber diffusion cell (effective area 0.95 cm ² ) was pinched with rabbit abdominal peel skin, and a β-blocker was placed at the donor site.
2 ml of an ethyl alcohol solution of propranolol hydrochloride (5%) and the percutaneous absorption enhancer of the present invention (Production Example 6) (2%)
Put the phosphate buffer in the receptor, and put the whole cell
It was immersed in a constant temperature bath at 37 ° C. Both chambers were stirred and sampled from the receptor 12 hours later, and the amount of propranol permeated was measured by high performance liquid chromatography. Table 9 shows the transmission measurement results. Further, Comparative Example 3 shows the case where no transdermal absorption enhancer was added.

Claims (1)

[Claims] 1. A polymer having an average molecular weight of 800 or more,
At least 10 mol% of all repeating units of the polymer have the general formula An agent for promoting percutaneous absorption of a drug, characterized by comprising a repeating unit represented by the formula (wherein R ¹ is a hydrogen atom or a lower alkyl group, R ² and R ³ are the same or different lower alkyl groups, R ⁴ is a hydrocarbon group having 6 or more carbon atoms, X is a counter anion,
n represents an integer of 0 to 5).