JPH0784393B2 - Transdermal absorption promoter - Google Patents

Description

TECHNICAL FIELD The present invention relates to a percutaneous absorption enhancer that promotes permeation / 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,
Concomitant use of transdermal absorption enhancers is under consideration.

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-60-2147).
30).

[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.

As a result of intensive studies to solve the above problems, the present inventors have found that a polymer having a pyridinium group has an extremely excellent transdermal absorption promoting action and completed the present invention.

[Means for solving problems]

That is, the present invention has the general formula In regard to a promoter for percutaneous absorption of a drug consisting of a polymer having an average molecular weight of 800% or more containing 10 mol% or more of all repeating units represented by the formula (wherein R ¹ is a hydrogen atom or a lower alkyl group, R ² is a hydrocarbon group having 6 or more carbon atoms, X
Represents a counter anion).

In the formula, the hydrocarbon group having 6 or more carbon atoms represented by R ² is a saturated or unsaturated branched or linear hydrocarbon group, for example, a normally, 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, funercyl group, etc. be able to. Of these, those having 8 or more carbon atoms, and more preferably 10 or more carbon atoms, are preferable because of their large promoting effect.

As the counter ion represented by X, a halogen anion,
Organic acid _{^{anion, 1 / 2SO ▲ 2- 4 ▼}} , NO ▲ - 3 ▼, H 2 PO ▲ - 4 ▼ like can be exemplified.

The polymer in the present invention has 10 mol% of all repeating units.
The above is composed of the repeating unit represented by the general formula (I), and a homopolymer comprising the repeating unit represented by the general formula (I), the repeating unit and the general formula [Wherein R ³ represents a hydrogen atom, a halogen atom or a lower alkyl group, Z is an unsubstituted or lower alkyl group, a perfluoroalkyl group, a lower alkyloxy group or a phenyl group substituted with a halogen atom, a pyridyl group, Hydrogen atom, lower alkyl group, alkyloxy group, cyano group, group represented by -COOR ⁴ or (Wherein R ⁴ and R ⁵ 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 ⁶ represents a hydrogen atom or a lower alkyl group). Represents a group). ] 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 is the same as above.) A homopolymer consisting of repeating units or a copolymer with a repeating unit represented by the general formula (II) containing 10 mol% or more of the repeating units. General formula R ² Y (wherein R ² is the same as above, Y
Can be produced by acting an alkylating agent represented by a halogen atom, a lower alkylsulfonyloxy group or an arylsulfonyl group).

A solvent can be used for the alkylation, and examples of the solvent include hexane, benzene, toluene, N, N-dimethylformamide (DMF), N-methylpyrrolidone and the like.

The reaction proceeds smoothly in the range of 0 ° C to 100 ° C, preferably 20 ° C to 80 ° C.

In the reaction, in order to achieve complete alkylation, an excessive amount of alkylating agent can be used and a relatively high reaction temperature can be selected. Conversely, the amount of alkylating agent and / or the reaction can be changed. The alkylation rate (quaternization rate) can be controlled by selecting the temperature.

The polymer as a raw material has, for example, a general formula (In the formula, R ¹ is the same as the above.) The homopolymerization of the monomer represented by the above, or the monomer represented by the general formula (IV) and the general formula (In the formula, R ³ and Z are the same as above), and can be produced by copolymerization with one or more monomers.

For the polymerization, either an anionic polymerization method or a radical polymerization method can be used.

The anionic polymerization method is useful in homopolymerization or copolymerization with styrene, p-methylstyrene, α-methylstyrene and the like, and butyllithium, naphthalene-sodium and the like can be used as an initiator. The reaction is carried out in a solvent, and examples of the solvent include benzene, toluene, dioxane, tetrahydrofuran, (THF) and ethylene glycol dimethyl ether. Reaction temperature is -100
C. to 50.degree. C., particularly -80.degree. C. to around room temperature is preferable.

As the method used in the radical polymerization method, known methods such as bulk polymerization, solution polymerization and emulsion polymerization can be used. The radical polymerization reaction is initiated simply by heat, irradiation with ultraviolet rays or addition of a radical initiator. Examples of the radical initiator preferably used in the reaction include organic peroxides such as dilauroyl peroxide and benzoyl peroxide, and azo compounds such as α, α′-azobisisobutyronitrile. Organic solvents that can be used in the polymerization reaction include, for example, benzene, toluene, chlorobenzene, tetrahydrofuran, carbon tetrachloride, chloroform, methyl ethyl ketone, fluorobenzene, hexafluorobenzene, benzotrifluoride, 1,4-bis (trifluoromethyl) benzene, N. , N-
Dimethylformamide and the like can be used, but the invention is not limited thereto. Reaction is usually 40 ℃ ~ 100 ℃
Smoothly progresses within the range. The vinyl group-containing monomer used in the copolymerization includes styrene derivatives such as styrene, p-methylstyrene, p-chlorostyrene and pentafluorostyrene, alkenes such as ethylene, propylene and butene, ethyl vinyl ether and propyl. Vinyl ethers such as vinyl ether, hexyl vinyl ether, octyl vinyl ether, methyl acrylate, ethyl acrylate, 2-hydroxyethyl acrylate, butyl acrylate, 2,3-dihydroxypropyl acrylate, polyfluoroalkyl acrylate, p-fluorophenyl acrylate, m-trifluoro Acrylic esters such as methyl phenyl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, 2-hydroxy Chill methacrylate, glycidyl methacrylate, butyl methacrylate, cyclohexyl methacrylate, benzyl methacrylate, methacrylic acid esters of perfluoroalkyl methacrylate, acrylonitrile, acrylamide, p- methoxy acrylic anilide,
N-hydroxymethyl acrylamide, N- (1,1-dimethyl-3-oxobutyl) acrylamide, methacrylamide, N-hydroxyethyl methacrylamide, acrolein, acrylic acid, methacrylic acid, vinyl pyridine and the like can be used.

By the way, the repeating unit represented by the general formula (I) constituting the polymer in the present invention is at least 10 mol% or more, and 30 mol% or more per unit weight for exhibiting an excellent transdermal absorption enhancer effect. 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 10,000 or less in order to exert the promoting effect.

The percutaneous absorption promoter 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 drug release may be suppressed.

The drug used in the present invention may be any drug for humans and animals, for example, as an anti-inflammatory analgesic, acetaminophen, aspirin, methyl salicylate,
Choline salicylate, glycol salicylate, l-menthol, camphor, mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, ibuprofen, ketoprofen, naproxen,
Planoprofen, Fenoprofen, Fenbufen, Flurbiprofen, Indoprofen, Fenthiazak, Tolmethine, Suprofenic acid, Penzadac, Bufexamac, Piroxicam, Phenylbutazone, Oxyphenbutazone, Clofezone, Pentazocine, Mepyrizole As a steroidal anti-inflammatory agent, hydroco-thizone, prednisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, fludrocortisone acetate, and the like, chlorpheniramine as an antihistamine or antiallergic agent,
Glycyrrhizic acid, diphenhydramine, periactin, etc. as local anesthetics such as benzocaine, procaine, dibucaine, lidocaine, etc., as antibacterial agents etc. as tetracyclines such as chlortetracycline, penicillins such as ampicillin, cephalosporins such as cephalothin, kanamycin Aminoglycosides such as, macrolides such as erythromycin, chloramphenicol, iodo compounds, nitrofurantoin, nice titanium, amphotericin, fradiomycin, sulfonamides, pyrrolenitrin, clotrimazole,
Clonidine as an antihypertensive agent such as nitrofurazone,
α-Methyldopa, reserpine, syrosingopine, resinamine, cinnarizine, hydralazine, brazosin, etc., antihypertensive diuretics such as theophylline, triclomethiazide, furosemide, tripamide, meticlotiazide, penfluzide, hydrothiazide, spironolactone, metorazone, etc. Ubidecalenone, dopamine and other coronary vasodilators such as nitroglycerin, isosorbitol dinitrate, erythritol tetranitrate, pentaerythritol tetranitrate, dipyridamole, dilazep, trapidil, trimetazidine, and vasoconstrictors such as dihydroergotamine and dihydroergo. Pindolol as a β-blocker or antiarrhythmic therapeutic agent such as toxin,
Calcium antagonists such as hydrochloric acid and propranolol are diltiazem, nifedipine, nicardipine, verapamil bencyclane, dilazep and other antiepileptic agents such as nitrazepam, meprobamate, and phenytoin.Anti-dizziness agents include isoprenaline, betahistine, scopolamine, and tranquilizers. Is diazepam, lorazepam, flunitrazepam, fluphenazine, etc. as a hypnotic sedative such as phenobarbital, amobarbital, cyclobarbital, etc., as a muscle relaxant such as triperizone, baclofen, dantrolene sodium, cyclobenzaprine, etc., as an autonomic nerve agent, atropine, As agents for respiratory organs such as levodova, codeine, ephedrine, isoproterenol, dextromethorphan,
Hormone or antihormonal agents such as orciprenaline, ipratropium bromide, cromoglic acid, etc., as corticotropin, oxytocin, vasopressin, testosterone, progesterone, estradiol, water hormone, thyroid hormone, adrenal hormone, kallikrein, insulin, oxendron, etc. as vitamins Is vitamins A, B, C, D, E, K and their derivatives,
5-fluorouracil and its derivatives as antitumor agents, such as calciferphers and mecobalamin, adriamycin, krestin, picibanil, ancitabine, cytarabine, etc. as enzymes, urokinase, herbal medicines, herbal medicines, aloe, purple root, etc. Examples of the anti-ulcer agent include allantoin, aldioxa and the like, other prostaglandins, antidiabetic agents and the like.

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

The drug preparation containing the percutaneous absorption promoter of the present invention can be applied to the skin and mucous membranes (oral cavity, nasal cavity, rectum, vagina) of various parts of the human body in a required amount 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-mentioned preparations as they are or those containing known cosmetic ingredients selected from the above-mentioned drugs are used for the purposes of skin washing, packs, measures against sunburn rough skin, moisturizing, etc. Can be used.

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

Reference Examples 1,2 Table 1 shows purified 4-vinylpyridine and dehydrated toluene.
The mixture was placed in a three-necked flask at the ratio shown in, and the whole was immersed in a constant temperature bath at -78 ° C. After sufficiently cooling, n-
A 20% hexane solution of butyllithium was rapidly added in the amount shown in Table 1 to carry out a polymerization reaction. 1 hour later methanol
2 ml was added to stop the polymerization. The polymer was obtained by throwing the reaction mixture into a large amount of diethyl ether. The obtained polymer was dissolved in methanol and poured into a large amount of diethyl ether to repeat purification. The molecular weight of the obtained polymer was determined in terms of polystyrene by GPC measurement.

Production Examples 1 to 3 The polymers of Reference Example 2, the alkylating agent shown in Table 2 and N, N-dimethylformamide (DMF) as a solvent were mixed in the amounts shown in Table 2 and reacted at 60 ° C for 6 hours. Let The reaction mixture was poured into a large amount of diethyl ether to obtain an alkyl compound (quaternary compound). This was dissolved in methanol or ethanol and then poured into a large amount of diethyl ether to repeat purification. For the alkylated product (quaternized product), the alkylation ratio (quaternized product) was determined by elemental analysis.

Examples 1-2 The rabbit abdominal peeling skin was sandwiched between two-chamber diffusion cells (effective area 0.95 cm ² ), and the antitumor agent 5-fluorouracil (5-FU) (1%) and the transdermal absorption of the present invention were placed in the donor part. 2 ml of an ethyl alcohol solution containing a promoter (5%) was added, 2 ml of phosphate buffer was added to the receptor portion, and the entire cell was immersed in a constant temperature bath at 37 ° C. Both chambers were stirred and sampled from the receptor portion 12 hours later, and the permeation of 5-FU was determined by high performance liquid chromatography. The transmission measurement results are shown in Table 3. In addition, Comparative Example 1 shows the case where no transdermal absorption accelerator was added, and Comparative Example 2 shows the case where the 4-vinylpyridine polymer obtained in Reference Example 2 was added.

Example 3 Commercially available 5-fluorouracil in which a rabbit abdominal peeling skin is sandwiched between two-chamber diffusion cells (effective area 0.95 cm ² ) and 5% of the percutaneous absorption enhancer of the present invention (Production Example 3) is mixed therewith 300 mg of (5-FU) ointment was placed and fixed on it with a membrane filter made of tetrafluoroethylene. Also, put phosphate buffer in the receptor part and
It was immersed in a constant temperature bath at ℃. The receptor-side chamber was agitated and sampled from the receptor portion 12 hours later, and the amount of permeated 5-FU was determined by high performance chromatography. The transmission measurement results are shown in Table 4. Further, Comparative Example 3 shows the case in which the transdermal absorption accelerator is not added.

Example 4 Rabbit abdominal peeling skin was sandwiched between two-chamber diffusion cells (effective area 0.95 cm ² ), β-blocker propranol (5%) and a promoter for percutaneous absorption of the present invention in the donor part (Production Example 3). ) 2 ml of a 2% ethyl alcohol solution was added, a phosphate buffer was added to the receptor portion, and the whole cell was immersed in a constant temperature bath at 37 ° C. Both chambers were stirred and sampled from the receptor portion 12 hours later, and the permeated propranol was quantified by high performance chromatography. The result of the transmission measurement is shown in the fifth.

Further, Comparative Example 4 shows the case in which a transdermal absorption accelerator is not 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 A promoter for 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 is a hydrocarbon group having 6 or more carbon atoms, and X is Represents a counter anion).